MYEL NCCN Guidelines

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Multiple Myeloma
Version 1.2023 — September 14, 2022
NCCN.org
NCCN Guidelines for Patients® available at www.nccn.org/patients
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Version 1.2023, 09/14/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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NCCN Guidelines Version 1.2023 NCCN Guidelines Index

Table of Contents
Multiple Myeloma Discussion
*Shaji K. Kumar, MD/Chair ‡ ξ Noura Elsedawy, MD † Hans C. Lee, MD † ‡

Mayo Clinic Cancer Center St. Jude Children's Research Hospital/ The University of Texas
*Natalie S. Callander, MD/Vice Chair ‡ ξ The University of Tennessee MD Anderson Cancer Center
University of Wisconsin Health Science Center Michaela Liedtke, MD ‡
Carbone Cancer Center Alfred Garfall, MD ‡ Stanford Cancer Institute
Kehinde Adekola, MD, MSCI ‡ † Abramson Cancer Center Thomas Martin, MD ‡
Robert H. Lurie Comprehensive at the University of Pennsylvania UCSF Helen Diller Family
Cancer Center of Northwestern University Kelly Godby, MD † Comprehensive Cancer Center
Larry D. Anderson, Jr., MD, PhD ‡ † O'Neal Comprehensive James Omel, MD ¥
UT Southwestern Simmons Cancer Center at UAB Patient Advocate
Comprehensive Cancer Center Jens Hillengass, MD, PhD ‡ Aaron Rosenberg, MD † ‡ ξ
Muhamed Baljevic, MD † ‡ Þ ξ Roswell Park Comprehensive Cancer Center UC Davis Comprehensive Cancer Center
Vanderbilt-Ingram Cancer Center Leona Holmberg, MD, PhD ξ ‡ Douglas Sborov, MD, MSc † ‡ Þ ξ
Erica Campagnaro, MD ‡ Fred Hutchinson Cancer Center Huntsman Cancer Institute
University of Michigan Rogel Cancer Center Myo Htut, MD ‡ Þ at the University of Utah
*Jorge J. Castillo, MD ‡ City of Hope National Medical Center Jason Valent, MD † ‡
Dana-Farber/Brigham and Women’s Carol Ann Huff, MD † ‡ Case Comprehensive Cancer Center/
Cancer Center | Massachusetts General The Sidney Kimmel Comprehensive University Hospitals Seidman Cancer Center
Hospital Cancer Center Cancer Center at Johns Hopkins and Cleveland Clinic Taussig Cancer Institute
Caitlin Costello, MD † ‡ ξ Malin Hultcrantz, MD, PhD ‡ †
UC San Diego Moores Cancer Center Memorial Sloan Kettering Cancer Center NCCN
Christopher D'Angelo, MD † ‡ Yubin Kang, MD ‡ † ξ Ryan Berardi, MSc
Fred & Pamela Buffett Cancer Center Duke Cancer Institute Rashmi Kumar, PhD
Srinivas Devarakonda, MD ‡ † Sarah Larson, MD †
The Ohio State University Comprehensive UCLA Jonsson Comprehensive Cancer Center
Cancer Center - James Cancer Hospital
and Solove Research Institute
ξ Bone marrow transplantation † Medical oncology

‡ Hematology ¥ Patient advocacy
NCCN Guidelines Panel Disclosures Continue Þ Internal medicine * Discussion
section writing
committee

Table of Contents
NCCN Multiple Myeloma Panel Members

Summary of Guidelines Updates Clinical Trials: NCCN believes
that the best management for
any patient with cancer is in a
Initial Diagnostic Workup and Clinical Findings (MYEL-1) clinical trial.
Solitary Plasmacytoma or Solitary Plasmacytoma with Minimal Marrow Involvement: Participation in clinical trials is
Primary Treatment and Follow-up/Surveillance (MYEL-2) especially encouraged.
Smoldering Myeloma (Asymptomatic): Primary Treatment and Follow-Up/Surveillance (MYEL-3)
Multiple Myeloma (Symptomatic): Primary Treatment and Follow-Up/Surveillance (MYEL-4) Find an NCCN Member
Multiple Myeloma (Symptomatic): Response After Primary Therapy and Follow-Up Surveillance (MYEL-5) Institution: https://www.nccn.org/
Multiple Myeloma (Symptomatic): Additional Treatment for Relapse or Progressive Disease (MYEL-6) home/member-institutions
Disease Staging and Risk Stratification Systems for Multiple Myeloma (MYEL-A)
Principles of Imaging (MYEL-B) NCCN Categories of
Definitions of Smoldering and Multiple Myeloma (MYEL-C) Evidence and Consensus: All
Principles of Radiation Therapy (MYEL-D) recommendations are category
Response Criteria for Multiple Myeloma (MYEL-E) 2A unless otherwise indicated.
General Considerations for Myeloma Therapy (MYEL-F)
Myeloma Therapy (MYEL-G) See NCCN Categories of
Supportive Care for Multiple Myeloma (MYEL-H) Evidence and Consensus.
Management of Venous Thromboembolism (VTE) in Multiple Myeloma (MYEL-I) NCCN Categories of
Management of Renal Disease in Multiple Myeloma (MYEL-J) Preference:
All recommendations are
Monoclonal Gammopathy of Clinical Significance
considered appropriate.
• Monoclonal Gammopathy of Renal Significance (MGRS-1)
• Monoclonal Gammopathy of Neurological Significance (MGNS-1) See NCCN Categories of
Preference.
POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Protein, Skin Changes) (POEMS-1)
Abbreviations (ABBR-1)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2022.

Table of Contents
Updates in Version 1.2023 of the NCCN Guidelines for Multiple Myeloma from Version 5.2022 include:
MYEL-1
• Initial Diagnostic Workup:
11th bullet modified: Plasma cell fluorescence in situ hybridization (FISH) panel on bone marrow [del(13), del(17p13), t(4;14), t(11;14), t(14;16),
t(14:20), 1q21 gain/1q21 amplification, 1p deletion]
12th bullet added: NT-proBNP/BNP
• Footnote d modified: Skeletal survey is acceptable in certain circumstances. However, it is significantly less sensitive than whole-body low-dose CT
and FDG PET/CT. If whole-body FDG PET/CT or low-dose CT has been performed, then skeletal survey is not needed. FDG PET should always be
performed with CT. (Also on MYEL-4)
• Footnote g added: 1q21 amplification is defined as ≥4 copies detected by FISH, and a gain is defined as 3 copies of 1q21.
• Footnote h added: If NT-proBNP is not available, BNP can be performed.
MYEL-2
• Follow-up/Surveillance, 2nd bullet, 5th sub-bullet modified: Bone marrow aspirate and biopsy as indicated
• Footnote j modified: Whole-body MRI (or PET/CT if MRI is not available) is the first choice for initial evaluation of solitary osseous plasmacytoma (MRI
of the spine and pelvis, whole-body FDG PET/CT, or low-dose whole-body CT under certain circumstances). Whole-body FDG PET/CT is the first
choice for initial evaluation of solitary extraosseous plasmacytoma.
• Footnote o added: Systemic therapy may be considered in patients with high risk of progression based on the clinical context.
• Footnote p modified: Reassess after at least 3 months following radiation as the assessment of response with imaging may not be accurate if the scans
are performed sooner. Patients with soft tissue and head/neck plasmacytoma could be followed less frequently after initial 3-month follow-up.
MYEL-4
• Primary Treatment:
Modified: Initiate Myeloma therapy and bone-targeting therapy + bisphosphonates, or denosumab + Supportive treatment as indicated for symptom
management
Added: Assess for candidacy for transplant after starting therapy and reassess for transplant as performance status improves
The following bullets have been moved from Follow-Up/Surveillance to Primary Treatment:
◊ Refer to HCT center
◊ Harvest hematopoietic stem cells (consider for 2 transplants if appropriate)
• Follow-Up/Surveillance, modified: No response Progression
• Footnote bb added: Patients with stable disease can be considered for autologous HCT.
MYEL-5
• This page has been extensively revised.
CONTINUED
Note: All recommendations are category 2A unless otherwise indicated.
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
UPDATES

Table of Contents
MYEL-6
• The former page has been removed. The content from this page has been incorporated into other pages of the algorithm.
• Multiple Myeloma (Symptomatic), Additional Treatment, Relapse or Progressive disease, added:
Clinical trial, if eligible
Consider referral to CAR T-cell therapy specialist for consideration for CAR T-cell therapies.
Consider referral to palliative care specialist for symptom management (See NCCN Guidelines for Palliative Care)
Discuss patient preferences and goals of care through a shared decision-making process
• Multiple Myeloma (Symptomatic), Additional Treatment, Refractory disease and lack of treatment options, modified:
Continue palliative care; consider re-evaluation of goals of care and hospice initiation
• Footnote cc added: Folllow up with the tests listed on MYEL-4 under follow-up/surveillance.
• Footnote gg added: Donor lymphocyte infusion can be considered in patients relapsing after allogeneic HCT.
MYEL-A
• Page heading modified: Disease Staging and Risk Stratification Systems for Multiple Myeloma
• New table added: Factors Considered High Risk for MM
• Footnote c added: Presence of ≥5% of plasma cells in circulation is defined as plasma cell leukemia.
MYEL-B
• Imaging of Solitary Plasmacytoma, 1st bullet modified: Whole-body imaging with MRI (or FDG PET/CT if MRI is not available)...
MYEL-D
• Solitary Plasmacytoma, Treatment Information/Dosing, 1st bullet, 1st sub-bullet modified: RT (40–50 Gy in 1.8–2.0 Gy fractions [20–25 total fractions])
to involved field site.
• Palliative RT Dosing for MM, 1st bullet modified: Low-dose RT (8 Gy x 1 fraction or 10–30 Gy in 2.0–3.0 Gy fractions [5–10 total fractions]) can be
used as palliative treatment for uncontrolled pain, for impending pathologic fracture, or for impending cord compression. Consider RT postoperatively if
urgent surgical intervention is indicated.
• Palliative RT Dosing for MM, 2nd bullet modified: Limited involved fields sites should be used to limit the impact of irradiation on hematopoietic stem cell
harvest or impact on potential future treatments.
CONTINUED
UPDATES

Table of Contents
MYEL-F
• General Principles, 1st bullet modified: Patients should receive at least a triplet regimen (2 drug classes and steroids) if they can tolerate it. Triplet
regimens (2 drug classes and steroids) should be used as the standard therapy for patients with MM; however,
• General Principles, 3rd bullet added: Clinical trials with these triplet regimens primarily included patients who were naïve or sensitive to the novel drug
in the doublet comparator arm. Patients with disease refractory to the novel drug in the doublet backbone should be considered for triplet therapy that
does not contain the drug they are progressing on.
• Candidates for Hematopoietic Cell Transplant, 2nd bullet modified: Consider harvesting peripheral blood stem cells after several cycles of therapy prior
to prolonged exposure to lenalidomide and/or daratumumab in patients for whom transplant is being considered.
• Screening Recommendations, 1st bullet modified: Test for hepatitis B before starting daratumumab or carfilzomib as clinically indicated.
• Prophylaxis Recommendations, 1st bullet modified: Pneumocystis jiroveci pneumonia (PJP), herpes zoster, and antifungal prophylaxis should be given
if receiving high-dose dexamethasone steroids.
• Side Effects and Lab Interference, 4th bullet added: In patients intended to receive CAR T-cell therapy, bendamustine should be used with caution
unless after leukapheresis prior to CAR T-cell therapy, since it could impact the success of the patient's T-cell collection.
MYEL-G 1 of 5
• Primary Therapy for Transplant Candidates:
The following regimen was moved from Other Recommended Regimens to Preferred Regimens:
◊ Carfilzomib/lenalidomide/dexamethasone
The following regimen was moved from Other Recommended Regimens to Useful in Certain Circumstances:
◊ Ixazomib/lenalidomide/dexamethasone (category 2B)
• Maintenance Therapy:
The following regimen was added to Other Recommended Regimens:
◊ Daratumumab
The following regimen was added to Useful in Certain Circumstances as an option for high risk MM:
◊ Carfilzomib/lenalidomide
• Footnote a has been modified: Selected, but not inclusive of all regimens. The regimens under each preference category are listed by order NCCN
Category of Evidence and Consensus alphabetically. (Also on MYEL-G 2 of 5, MYEL-G 3 of 5, MYEL-G 4 of 5, MYEL-G 5 of 5)
CONTINUED
UPDATES

Table of Contents
MYEL-G 3 of 5
• This page has been reformatted.
• Therapy for Previously Treated Multiple Myeloma:
The following regimens have been added for Bortezomib-Inhibitor Refractory, and Lenalidomide-Refractory:
◊ Carfilzomib/pomalidomide/dexamethasone (previously this regimen was listed under: Other Recommended Regimens for Early Relapse (1–3
prior therapies)
◊ After one prior therapy including lenalidomide and a PI
– Daratumumab/pomalidomide/dexamethasone (category 1)
• Footnote removed: Clinical trials with these regimens primarily included patients who were naïve or sensitive to the novel drug in the doublet
comparator arm. Patients with disease refractory to the novel drug in the doublet backbone should be considered for triplet therapy that does not
contain the drug they are progressing on. lenalidomide-naive or with lenalidomide-sensitive MM. Patients with lenalidomide refractory disease
should be considered for a lenalidomide free triplet regimen.
MYEL-G 4 of 5
• The following regimens have been moved from Other Recommended Regimens for Early Relapse (1–3 prior therapies) to Therapies for Patients
with Late Relapses (>3 prior therapies) on MYEL-G 5 of 5:
Bendamustine/bortezomib/dexamethasone
Bendamustine/lenalidomide/dexamethasone
• The following regimens have been moved from Useful in Certain Circumstances (1-3 prior therapies) to Therapies for Patients with Late Relapses
(>3 prior therapies) on MYEL-G 5 of 5:
Bendamustine
High-dose or fractionated cyclophosphamide
• The following regimen has been removed from Useful in Certain Circumstances for Early Relapse (1–3 prior therapies):
Ixazomib/dexamethasone
MYEL-G 5 of 5
• The following regimen has been added to Therapies for Patients with Late Relapses (>3 prior therapies):
Bendamustine/carfilzomib/dexamethasone
CONTINUED
UPDATES

Table of Contents
MYEL-H
• Bone Disease
1st bullet, 5th sub-bullet added: Patients receiving denosumab for bone disease who and subsequently discontinue therapy should be given
maintenance denosumab every 6 months or a single dose of bisphosphonate to mitigate risk of rebound osteoporosis.
1st bullet, 2nd sub-bullet added: Assess Vitamin D status
• Infection:
2nd bullet modified: Intravenous immunoglobulin therapy should be considered in the setting of recurrent serious (<400 mg/dL) infection and/or
hypogammaglobulinemia (IgG ≤400 mg/dL).
4th bullet added: Influenza vaccination recommended. Consider two doses of the high-dose inactivated quadrivalent influenza vaccine.
5th bullet added: Consider 12 weeks of levofloxacin 500 mg daily at the time of initial diagnosis for MM.
6th bullet added: See NCCN Guidance on Cancer and COVID-19 Vaccination
Bullet added: Assess Vitamin D status
Bullet removed: Consider 3 months of antibiotic prophylaxis at diagnosis for patients at high risk for infection.
• Footnote c added: This is based on observations with denosumab discontinuation in non-myeloma settings. Cummings SR, Ferrari S, Eastell R, et al.
Vertebral fractures after discontinuation of denosumab: A post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J
Bone Miner Res 2018;33:190-198.
MYEL-I 1 of 3
• IMPEDE Score for Risk Stratification (points assigned), Myeloma Risk Factors:
Modified: Low-dose Dexamethasone <160 mg/cycle)
Modified: High dose Dexamethasone >160 mg/cycle
MYEL-J
• Treatment Options:
2nd bullet modified: Regimens containing bortezomib and/or daratumumab-based regimen
3rd bullet added: Can switch to other regimen once renal function has improved or stabilized
Bullet removed: Consider third drug: cyclophosphamide, thalidomide, anthracycline, or daratumumab
• Supportive Care:
6th bullet modified: Mechanical removal of serum FLCs ; goal removal of 50% with high cutoff dialysis filters or plasmapheresis may have a limited
role. Systemic therapy should not be delayed if performing this procedure.
◊ 6th bullet, 1st and 2nd sub-bullets removed:
– High cutoff dialysis filters
– Plasmapheresis
• Footnote b added: Consider other diagnosis such as amyloid and light chain disease for patients with significant proteinuria.
MGRS-2
• Treatment, 1st bullet modified: For IgG, IgA, or FLC plasma cell-related MGRS, use the management algorithm for MM...
• Treatment, 2nd bullet modified: For IgM lymphoplasmacytic-related MGRS...
ABBR-1
• New page added: Abbreviations
CONTINUED
UPDATES

Table of Contents
INITIAL DIAGNOSTIC WORKUPa CLINICAL FINDINGS

• History and physical (H&P) exam Useful In Certain Circumstances
• CBC, differential, and platelet count • If whole-body low-dose CT or FDG PET/
• Peripheral blood smear CT is negative, consider whole-body MRI Solitary See Primary
• Serum BUN/creatinine, electrolytes, liver without contrast to discern smoldering plasmacytoma Treatment
function tests, albumin,b calcium, serum uric myeloma from multiple myeloma (MM) (MYEL-2)
acid, serum LDH,b and beta-2 microglobulinb • Tissue biopsy to confirm suspected
• Creatinine clearance (calculated or measured plasmacytoma
directly)c • Plasma cell proliferation
• Serum quantitative immunoglobulins, serum • Serum viscosity Smoldering See Primary
protein electrophoresis (SPEP), and serum • Human leukocyte antigen (HLA) typing myeloma Treatment
immunofixation electrophoresis (SIFE) • Hepatitis B and hepatitis C testing and (asymptomatic)i (MYEL-3)
• 24-h urine for total protein, urine protein HIV screening as required
electrophoresis (UPEP), and urine • Echocardiogram
immunofixation electrophoresis (UIFE) • Evaluation for light chain amyloidosis,
if appropriate (See NCCN Guidelines for See Primary
• Serum free light chain (FLC) assay
Systemic Light Chain Amyloidosis) MM (symptomatic)i Treatment
• Whole-body low-dose CT scan or FDG PET/
• Single nucleotide polymorphism (SNP) (MYEL-4)
CTd,e
• Unilateral bone marrow aspirate and biopsy, array on bone marrow,f and/or next-
generation sequencing (NGS) panel on For Monoclonal
including immunohistochemistry (IHC) and/or Gammopathy
multi-parameter flow cytometry bone marrowf
• Consider baseline clone identification of Renal
• Plasma cell fluorescence in situ hybridization Significance see
and storage of aspirate sample for future Monoclonal
(FISH)b panel on bone marrowf [del(13), del MGRS-1
minimal residual disease (MRD) testing gammopathies
(17p13), t(4;14), t(11;14), t(14;16), t(14:20), 1q21
by NGS of clinical
gain/1q21 amplification, 1p deletion]g For Monoclonal
• Assess for circulating plasma cells as significance
• NT-proBNP/BNPh Gammopathy
clinically indicated
of Neurological
a Frailty assessment should be considered in older adults. See NCCN Guidelines for Older Adult Oncology.
Significance see
b These tests are essential for R-ISS staging. See Disease Staging and Risk Stratification for Multiple Myeloma (MYEL-A).
c See Management of Renal Disease in Multiple Myeloma (MYEL-J).
MGNS-1
d Skeletal survey is acceptable in certain circumstances. However, it is significantly less sensitive than whole-body low-dose
CT and FDG PET/CT. If
whole-body FDG PET/CT or low-dose CT has been performed, then skeletal survey is not needed. FDG PET should always be performed with CT.
e See Principles of Imaging (MYEL-B).
f CD138-positive selected sample is strongly recommended for optimized yield.
g 1q21 amplification is defined as ≥4 copies detected by FISH, and a gain is defined as 3 copies of 1q21.
h If NT-proBNP is not available, BNP can be performed.
i See Definitions of Smoldering and Multiple Myeloma (MYEL-C).

MYEL-1

Table of Contents
CLINICAL PRIMARY FOLLOW-UP/SURVEILLANCE

FINDINGS TREATMENT
• Follow-up interval, every 3–6 mo:p

CBC, differential, and platelet count
Serum chemistry for creatinine, albumin, and
corrected calcium
• Tests as needed:
Solitary
Serum quantitative immunoglobulins, SPEP,
plasmacytoma Primary
RTm ± with SIFE
or progressiveq Restage See Multiple
surgeryn,o 24-h urine for total protein and UPEP with UIFE
Solitary or with Myeloma
or Consider Serum FLC assay
plasmacytoma Response myeloma (symptomatic)
clinical trial Serum LDH and beta-2 microglobulin
with minimal followed by workup (MYEL-4)
Bone marrow aspirate and biopsy as indicated
marrow progressionq
All plasmacytomas should be imaged yearly,
involvementk,l
preferably with the same technique used at
diagnosis, for at least 5 yearse,j
• See NCCN Guidelines for Survivorship

j Whole-body MRI (or PET/CT if MRI is not available) is the first choice for initial evaluation of solitary osseous plasmacytoma (MRI of the spine and pelvis, whole-body
FDG PET/CT, or low-dose whole-body CT under certain circumstances). Whole-body FDG PET/CT is the first choice for initial evaluation of solitary extraosseous
plasmacytoma.
k All criteria must be present for the diagnosis. For diagnostic criteria, please refer to Rajkumar SV, et al. Lancet Oncol 2014;15:e538-e548.
l Solitary plasmacytoma with 10% or more clonal plasma cells is regarded as active (symptomatic) MM and systemic therapy should be considered.
m See Principles of Radiation Therapy (MYEL-D).
n Consider surgery if structurally unstable or if there is neurologic compromise due to mass effect.
o Systemic therapy may be considered in patients with high risk of progression based on the clinical context.
p Reassess after at least 3 months following radiation as the assessment of response with imaging may not be accurate if the scans are performed sooner. Patients with
soft tissue and head/neck plasmacytoma could be followed less frequently after initial 3-month follow-up.
q See Response Criteria for Multiple Myeloma (MYEL-E).

MYEL-2

Table of Contents

FINDINGS TREATMENT
• Every 3–6 months:

Clinical trials
CBC, differential, platelet count
Creatinine, corrected calcium
Low riskr or
Serum quantitative
immunoglobulins, SPEP, SIFE
Observe at 3- to 6-mo
24-h urine for total protein,
intervalst (category 1)
UPEP, and UIFE at baseline and
as clinically indicated or if there
Smoldering is a significant change in FLC Progression See Multiple
myeloma Clinical trials levels to Myeloma
(asymptomatic)i (preferred) Serum FLC assay symptomatic (symptomatic)
• Bone marrow aspirate and biopsy myeloma (MYEL-4)
or with FISH, SNP array, NGS, or
multi-parameter flow cytometry as
Observe at 3-mo needed
intervals as clinically • Whole-body imaging with MRI
High riskr,t indicatedt without contrast, low-dose CT
scan, FDG PET/CT annually or
or as needed, ideally with the same
technique used at diagnosise
Lenalidomide in select • See NCCN Guidelines for
patients (category 2B) Survivorship

r Bone marrow plasma cells (BMPCs) > 20%, M-protein > 2 g/dL, and serum FLC ratio (FLCr) > 20 are variables used to risk stratify patients at diagnosis. Patients with
two or more of these risk factors are considered to have high risk of progression to MM. Lakshman A, et al. Blood Cancer J 2018;8:59.
s The NCCN Panel strongly recommends enrolling eligible patients with smoldering myeloma in clinical trials.
t Patients with rising parameters are considered high risk and should be closely monitored.

MYEL-3

Table of Contents

FINDINGS TREATMENT
• Laboratory assessments appropriate for monitoring

Initiate myeloma
treatment toxicities may include: CBC, differential,
therapy,v,w and bone-
platelet count, blood glucose and electrolytes, and
targeting treatmentx
metabolic panel
+ See
• Serum quantitative immunoglobulins, SPEP, and SIFEy
Supportive care treatment Response
• 24-h urine for total protein, UPEP, and UIFEy at baseline
as indicated for symptom Responseq,bb after primary
and as clinically indicated or if there is a significant
managementc,x therapy
change in FLC levels
• Serum FLC assay (MYEL-5)
Assess for candidacy for
• Whole-body imaging with MRI without contrast, low-dose
MM (symptomatic)i,u transplant after starting
CT scan, FDG PET/CT annually or as clinically indicated,
therapy and reassess for
ideally with the same technique used at diagnosise,d
transplant as performance
• Bone marrow aspirate and biopsy at relapse with FISH as
status improvesz,aa
clinically indicated
• Refer to HCT center
• Consider MRD as indicated for prognostication after
• Harvest hematopoietic See
shared decision with patient
stem cells (consider Progressionq Additional
• See NCCN Guidelines for Survivorship
for 2 transplants if Treatment
appropriate) (MYEL-6)
c See Management of Renal Disease in Multiple Myeloma (MYEL-J).

d Skeletal survey is acceptable in certain circumstances. However, it is
significantly v See Myeloma Therapy (MYEL-G).
less sensitive than whole-body low-dose CT and FDG PET/CT. If whole-body FDG w See General Considerations for Myeloma Therapy (MYEL-F).
PET/CT or low-dose CT has been performed, then skeletal survey is not needed. x See Supportive Care Treatment for Multiple Myeloma (MYEL-H).
FDG PET should always be performed with CT. y Needed only if protein electrophoresis is negative during follow-up.
e See Principles of Imaging (MYEL-B). z Autologous transplantation: Category 1 evidence supports proceeding directly
after induction therapy to high-dose therapy and HCT. See Discussion.
q See Response Criteria for Multiple Myeloma (MYEL-E). aa Renal dysfunction and advanced age are not contraindications to transplant.
u See Disease Staging and Risk Stratification for Multiple Myeloma (MYEL-A). bb Patients with stable disease can be considered for autologous HCT.

MYEL-4

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MULTIPLE MYELOMA (SYMPTOMATIC) FOLLOW-UP/SURVEILLANCE
Response or Maintenance therapy

Progressionq
stable diseaseq (category 1)v,w,ee
Autologousz,aa HCT (category 1)cc
Progressionq
Response
For relapse or
after Continuous myeloma therapy or
Progressionq progression
primary maintenance therapyv,w,cc
(see MYEL-6)
therapyq
Response or Maintenance therapy Progressionq

Tandem autologous or allogeneic stable diseaseq (category 1)v,w,ee
HCT,dd for high-risk patients
under certain circumstancescc
Progressionq

v See Myeloma Therapy (MYEL-G).
w See General Considerations for Myeloma Therapy (MYEL-F).
z Autologous transplantation: Category 1 evidence supports proceeding directly after induction therapy to high-dose therapy and HCT. See Discussion.
aa Renal dysfunction and advanced age are not contraindications to transplant.
cc Follow up with the tests listed on MYEL-4 under Follow-up/Surveillance.
dd Allogeneic HCT should preferentially be done in the context of a trial when possible.
ee The length of therapy should be balanced with toxicity and depth of response and disease status.

MYEL-5

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MULTIPLE MYELOMA ADDITIONAL TREATMENT

(SYMPTOMATIC) (FOR PATIENTS TREATED WITH OR WITHOUT A PRIOR TRANSPLANT)
Clinical trial, if eligible

or
Therapy for previously treated myelomav,w
or
Autologous HCTff
Relapse or Continue palliative care;
Allogeneic HCTdd,ff,gg Refractory diseasecc and
or consider re-evaluation
and lack of treatment options
Progressive diseaseq,cc of goals of care and
• Consider referral to CAR T-cell therapy hospice initiation
specialist for consideration for CAR T-cell (See NCCN Guidelines
therapies for Palliative Care)
• Consider referral to palliative care specialist for
symptom management (See NCCN Guidelines
for Palliative Care)
• Discuss patient preferences and goals of care
through a shared decision-making process

v See Myeloma Therapy (MYEL-G).
w See General Considerations for Myeloma Therapy (MYEL-F).
cc Folllow up with the tests listed on MYEL-4 under Follow-up/Surveillance.
dd Allogeneic HCT should preferentially be done in the context of a trial when possible.
ff Assess for HCT candidacy.
gg Donor lymphocyte infusion can be considered in patients relapsing after allogeneic HCT.

MYEL-6

Table of Contents
DISEASE STAGING AND RISK STRATIFICATION SYSTEMS FOR MULTIPLE MYELOMAa
Stage International Staging System (ISS) Revised-ISS (R-ISS)

ISS stage I and standard-risk
Serum beta-2 microglobulin <3.5 mg/L, chromosomal abnormalities by FISHb
I
Serum albumin ≥3.5 g/dL and
Serum LDH ≤ the upper limit of normal
II Not ISS stage I or III Not R-ISS stage I or III
ISS stage III and either high-risk

chromosomal abnormalities by FISHb
III Serum beta-2 microglobulin ≥5.5 mg/L
or
Serum LDH > the upper limit of normal
Factors Considered High Risk for MM

Cytogenetic t(4;14) MYC translocation
abnormalities t(14;16) TP53 mutation [with del(17p)]
Del(17p)/monosomy 17 Tetrasomies
1q21 gain/1q21 amplification Complex karyotype (when
done) or karyotypic del(13)
Other risk High-risk gene expression Renal failure
factors signature Thrombocytopenia
Extramedullary disease High serum FLC
Circulating plasma cellsc Lymphopenia
High plasma cell proliferation Immunoparesis
Frailty Elevated LDH
a Palumbo A, Avet-Loiseau H, Oliva S, et al. Revised International Staging System for Multiple Myeloma: A Report from International Myeloma Working Group. J Clin
Oncol 2015;33:2863-2869.
b Standard-risk: No high-risk chromosomal abnormality. High-risk: Presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16).
c Presence of ≥5% of plasma cells in circulation is defined as plasma cell leukemia.

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PRINCIPLES OF IMAGING
Imaging for Initial Diagnostic Workup (for patients suspected of having myeloma/solitary plasmacytoma)
• Whole-body imaging with low-dose CT or FDG PET/CT is recommended for initial diagnostic workup of patients suspected of having MM
or solitary plasmacytoma. Skeletal survey is acceptable in certain circumstances. However, skeletal survey is significantly less sensitive
than whole-body low-dose CT and FDG PET/CT in detecting osteolytic lesions in patients with monoclonal plasma cell disorders. A small
percentage of patients may have a negative PET/CT with active MM.1-5
• If whole-body low-dose CT or FDG PET/CT is negative, whole-body MRI without contrast may be considered to discern smoldering myeloma
from MM.
Imaging of Solitary Plasmacytoma
• Whole-body imaging with MRI (or FDG PET/CT if MRI is not available) is the first choice for initial evaluation of solitary osseous
plasmacytoma, and whole-body FDG PET/CT is the first choice for initial evaluation of solitary extraosseous plasmacytoma. The sensitivity
of FDG PET/CT for areas of increased metabolism and the high soft-tissue resolution of MRI enable both techniques to provide information
on the presence or absence of solitary plasmacytomas. While the sensitivity of both techniques for the detection of focal lesions is
similar, MRI provides a higher sensitivity for a diffuse infiltration.6,7 No data exist on the comparison of FDG PET/CT and MRI in solitary
plasmacytoma. In retrospective analyses, the risk of progression to MM within 2 years of diagnosis has been shown to be higher with
osseous plasmacytoma (35%) compared with extramedullary lesions (7%).8 This might, at least in part, be due to undetected diffuse
infiltration reflecting systemic disease, which makes the superior sensitivity of MRI significant in this regard.
• Since the risk of progression of solitary plasmacytoma into MM or relapse is relatively high (14%–38% within the first 3 years of diagnosis),
yearly follow-up with the same imaging technique used at first diagnosis should be performed for the first 5 years and subsequently only in
case of clinical or laboratory signs or symptoms.9
Imaging for Follow-up of Smoldering Myeloma
• Advanced whole-body imaging (ie, MRI without contrast, low-dose CT scan, FDG PET/CT) is recommended annually or as clinically
indicated. A retrospective analysis of 63 patients with smoldering myeloma with sequential whole-body MRI revealed that only 49%
progressed over a follow-up period of 5.4 years. Patients with disease progression seen on MRI had a 16.5-time higher risk of clinical
progression compared to those with no change on MRI.10 Therefore, if imaging findings are the only parameters indicating initiation of
treatment and if findings are doubtful, the same imaging technique should be repeated after 3–6 months. If only an MRI had been performed,
whole-body low-dose CT should be done to exclude lytic lesions.
Imaging for Follow-up of MM
• Advanced whole-body imaging (ie, FDG PET/CT, low-dose CT scan, whole-body MRI without contrast) is recommended as needed. Residual
focal lesions detected by either FDG PET/CT or MRI have been shown to be of adverse prognostic significance.11-14 Zamagni et al reported
progression-free survival (PFS) of 44 months in patients with residual focal lesions on PET/CT versus 84 months for those without residual
focal lesions on PET/CT after systemic treatment (P = .0009).13 In the IMAJEM trial, both PFS and overall survival (OS) were significantly
better in patients with negative PET/CT results before initiation of maintenance therapy (P = .011 and P = .033, respectively).14 An analysis
by Walker et al showed that conventional MRI normalizes over a prolonged period of time making PET/CT superior in this regard.11 However,
in small cohorts, functional imaging sequence for MRI called diffusion-weighted imaging was shown to have superior sensitivity to detect
residual disease compared with FDG PET/CT.15-17Furthermore, unlike FDG PET/CT, MRI does not expose the patient to radiation.

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PRINCIPLES OF IMAGING
References
1 Hillengass J, Moulopoulos LA, Delorme S, et al. Findings of whole body computed tomography compared to conventional skeletal survey in patients with monoclonal
plasma cell disorders - a study of the International Myeloma Working Group [Abstract]. Blood 2016;128:4468.
2 Hinge M, Andersen KT, Lund T, et al. Baseline bone involvement in multiple myeloma - a prospective comparison of conventional X-ray, low-dose computed
tomography, and 18flourodeoxyglucose positron emission tomography in previously untreated patients. Haematologica 2016;101:e415-e418.
3 Kropil P, Fenk R, Fritz LB, et al. Comparison of whole-body 64-slice multidetector computed tomography and conventional radiography in staging of multiple myeloma.
Eur Radiol 2008;18:51-58.
4 Wolf MB, Murray F, Kilk K, et al. Sensitivity of whole-body CT and MRI versus projection radiography in the detection of osteolyses in patients with monoclonal plasma
cell disease. Eur J Radiol 2014;83:1222-1230.
5 Siontis B, Kumar S, Dispenzieri A, et al. Positron emission tomography-computed tomography in the diagnostic evaluation of smoldering multiple myeloma:
identification of patients needing therapy. Blood Cancer J 2015;5:e364.
6 Zamagni E, Nanni C, Patriarca F, et al. A prospective comparison of 18F-fluorodeoxyglucose positron emission tomography-computed tomography, magnetic
resonance imaging and whole-body planar radiographs in the assessment of bone disease in newly diagnosed multiple myeloma. Haematologica 2007;92:50-55.
7 Fonti R, Salvatore B, Quarantelli M, et al. 18F-FDG PET/CT, 99mTc-MIBI, and MRI in evaluation of patients with multiple myeloma. J Nucl Med 2008;49:195-200.
8 Nahi H, Genell A, Walinder G, et al. Incidence, characteristics, and outcome of solitary plasmacytoma and plasma cell leukemia. Population-based data from the
Swedish Myeloma Register. Eur J Haematol 2017;99:216-222.
9 Paiva B, Chandia M, Vidriales MB, et al. Multiparameter flow cytometry for staging of solitary bone plasmacytoma: new criteria for risk of progression to myeloma.
Blood 2014;124:1300-1303.
10 Merz M, Hielscher T, Wagner B, et al. Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma.
Leukemia 2014;28:1902-1908.
11 Walker R, Barlogie B, Haessler J, et al. Magnetic resonance imaging in multiple myeloma: diagnostic and clinical implications. J Clin Oncol 2007;25:1121-1128.
12 Bartel TB, Haessler J, Brown TL, et al. F18-fluorodeoxyglucose positron emission tomography in the context of other imaging techniques and prognostic factors in
multiple myeloma. Blood 2009;114:2068-2076.
13 Zamagni E, Nanni C, Mancuso K, et al. PET/CT improves the definition of complete response and allows to detect otherwise unidentifiable skeletal progression in
multiple myeloma. Clin Cancer Res 2015;21:4384-4390.
14 Moreau P, Attal M, Caillot D, et al. Prospective evaluation of magnetic resonance imaging and [(18)F]fluorodeoxyglucose positron emission tomography-computed
tomography at diagnosis and before maintenance therapy in symptomatic patients with multiple myeloma included in the IFM/DFCI 2009 trial: Results of the IMAJEM
study. J Clin Oncol 2017;35:2911-2918.
15 Pawlyn C, Fowkes L, Otero S, et al. Whole-body diffusion-weighted MRI: a new gold standard for assessing disease burden in patients with multiple myeloma?
Leukemia 2016;30:1446-1448.
16 Rasche L, Angtuaco E, McDonald JE, et al. Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple
myeloma. Blood 2017;130:30-34.
17 Rasche L, Alapat D, Kumar M, et al. Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia 2019;33:1713-
1722.

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DEFINITIONS OF SMOLDERING AND MULTIPLE MYELOMA
Smoldering Myeloma (Asymptomatic)a,b Multiple Myeloma (Symptomatic)a,c
• Serum monoclonal protein ≥3 g/dL Clonal BMPCs ≥10% or biopsy-proven bony or extramedullary
or plasmacytoma
• Bence-Jones protein ≥500 mg/24 h and
and/or Any one or more of the following myeloma-defining events:
• Clonal bone marrow plasma cells (BMPCs) 10%–59% • Calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of
and normal or >2.75 mmol/L (>11 mg/dL)
• Absence of myeloma-defining events or amyloidosis • Renal insufficiency (creatinine >2 mg/dL) [>177 µmol/L] or
If skeletal survey negative, assess for bone disease with whole- creatinine clearance <40 mL/min
body MRI, FDG PET/CT, or low-dose CT scan • Anemia (hemoglobin <10 g/dL or hemoglobin >2 g/dL below the
lower limit of normal)
• One or more osteolytic bone lesions on skeletal radiography, CT, or
FDG PET/CT
• Clonal BMPCs ≥60%
• Involved:uninvolved serum FLC ratio ≥100 and involved FLC
concentration 10 mg/dL or higher
• >1 focal lesions on MRI studies ≥5 mm
a Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol
2014;15:e538-e548.
b BMPCs >20%, M-protein >2 g/dL, and FLCr >20 are variables used to risk stratify patients at diagnosis. Patients with two or more of these risk factors are considered
to have a high risk of progression to MM. Lakshman A, et al. Blood Cancer J 2018;8:59.
c Other examples of active disease include: repeated infections, amyloidosis, light chain deposition disease, or hyperviscosity.

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PRINCIPLES OF RADIATION THERAPY

Solitary Plasmacytoma
General Principle:
• Radiation therapy (RT) is the intervention of choice for solitary plasmacytoma.
Treatment Information/Dosing:
• Solitary plasmacytoma (MYEL-2)
RT (40–50 Gy in 1.8–2.0 Gy fractions [20–25 total fractions]) to involved site.
MM
General Principles:
• RT is primarily used for palliation in patients with MM.
• RT should be used judiciously in patients with MM who are undergoing or being considered for systemic therapy.
• Systemic therapy should not be delayed for RT.
• When systemic therapy and palliative RT are used concurrently, patients must be carefully monitored for toxicities.
Palliative RT Dosing for MM:

• Low-dose RT (8 Gy x 1 fraction or 10–30 Gy in 2.0–3.0 Gy fractions [5–10 total fractions]) can be used as palliative treatment for uncontrolled
pain, for impending pathologic fracture, or for impending cord compression. Consider RT postoperatively if urgent surgical intervention is
indicated.
• Limited involved sites should be used to limit the impact of irradiation on hematopoietic stem cell harvest or impact on potential future
treatments.

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RESPONSE CRITERIA FOR MULTIPLE MYELOMA

(Revised based on the new criteria by International Myeloma Working Group [IMWG])
IMWG criteria for response assessment including criteria for minimal residual disease (MRD)
Response Categorya Response Criteria
IMWG MRD criteria (requires a complete response as defined below)
MRD negativity in the marrow (next-generation flow [NGF], next-generation sequencing [NGS], or both) and by
Sustained MRD-negative imaging as defined below, confirmed minimum of 1 year apart. Subsequent evaluations can be used to further
specify the duration of negativity (eg, MRD-negative at 5 years).b
Absence of phenotypically aberrant clonal plasma cells by NGFc on bone marrow aspirates using the EuroFlow
Flow MRD-negative standard operation procedure for MRD detection in multiple myeloma (or validated equivalent method) with a
minimum sensitivity of 1 in 105 nucleated cells or higher.
Absence of clonal plasma cells by NGS on bone marrow aspirate in which presence of a clone is defined as less
Sequencing MRD-negative than two identical sequencing reads obtained after DNA sequencing of bone marrow aspirates using a validated
equivalent method with a minimum sensitivity of 1 in 105 nucleated cellsd or higher.
MRD negativity as defined by NGF or NGS plus disappearance of every area of increased tracer uptake found at
Imaging plus MRD-negative baseline or a preceding FDG PET/CT or decrease to less mediastinal blood pool standardized uptake value (SUV) or
decrease to less than that of surrounding normal tissue.e
Standard IMWG response criteriaf
Complete response as defined below plus normal FLC ratiog and absence of clonal cells in bone marrow biopsy by
Stringent complete response immunohistochemistry (κ/λ ratio ≤4:1 or ≥1:2 for κ and λ patients, respectively, after counting ≥100 plasma cells).h
Complete responsei Negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and <5%
plasma cells in bone marrow aspirates.
Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum
Very good partial response M-protein plus urine M-protein level <100 mg per 24 h.
≥50% reduction of serum M-protein plus reduction in 24-h urinary M-protein by ≥90% or to <200 mg per 24 h.
If the serum and urine M-protein are unmeasurable, a ≥50% decrease in the difference between involved and
uninvolved FLC levels is required in place of the M-protein criteria.
Partial response If serum and urine M-protein are unmeasurable, and serum-free light assay is also unmeasurable, ≥50% reduction
in plasma cells is required in place of M-protein, provided baseline bone marrow plasma-cell percentage was ≥30%.
In addition to these criteria, if present at baseline, a ≥50% reduction in the size (sum of the products of the maximal
perpendicular diameters [SPD] of measured lesions)j of soft tissue plasmacytomas is also required.
≥25% but ≤49% reduction of serum M-protein and reduction in 24-h urine M-protein by 50%–89%. In addition to
Minimal response the above listed criteria, if present at baseline, a 25%–49% reduction in SPDj of soft tissue plasmacytomas is also
required.
Reprinted from The Lancet Oncology, 17: Kumar S, Paiva B, Anderson K, et al. International Myeloma Working Group consensus criteria for response and minimal
residual disease assessment in multiple myeloma, e328-e346, Copyright (2016), with permission from Elsevier.
Continued
Note: All recommendations are category 2A unless otherwise indicated. Footnotes
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Version 1.2023, 09/14/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
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(Revised based on the new criteria by International Myeloma Working Group [IMWG])
Response Categorya Response Criteria
Not recommended for use as an indicator of response; stability of disease is best described by providing the time-to-
Stable disease progression estimates. Not meeting criteria for complete response, very good partial response, partial response, minimal
response, or progressive disease.
Any one or more of the following criteria:
Increase of 25% from lowest confirmed response value in one or more of the following criteria:
Serum M-protein (absolute increase must be ≥0.5 g/dL);
Serum M-protein increase ≥1 g/dL, if the lowest M component was ≥5 g/dL;
Urine M-protein (absolute increase must be ≥200 mg/24 h);
Progressive diseasek,l In patients without measurable serum and urine M-protein levels, the difference between involved and uninvolved FLC levels
(absolute increase must be >10 mg/dL);
In patients without measurable serum and urine M-protein levels and without measurable involved FLC levels, bone marrow
plasma-cell percentage irrespective of baseline status (absolute increase must be ≥10%);
Appearance of a new lesion(s), ≥50% increase from nadir in SPDj of >1 lesion, or ≥50% increase in the longest diameter of a
previous lesion >1 cm in short axis;
≥50% increase in circulating plasma cells (minimum of 200 cells per μL) if this is the only measure of disease.
Clinical relapse requires one or more of the following criteria:
Direct indicators of increasing disease and/or end organ dysfunction (calcium elevation, renal failure, anemia, lytic bone
lesions [CRAB features]) related to the underlying clonal plasma cell proliferative disorder. It is not used in calculation of
time to progression or progression-free survival but is listed as something that can be reported optionally or for use in
clinical practice;
Development of new soft tissue plasmacytomas or bone lesions (osteoporotic fractures do not constitute progression);
Clinical relapse Definite increase in the size of existing plasmacytomas or bone lesions. A definite increase is defined as a 50% (and ≥1 cm)
increase as measured serially by the SPDj of the measurable lesion;
Hypercalcemia (>11 mg/dL);
Decrease in hemoglobin of ≥2 g/dL not related to therapy or other non–myeloma-related conditions;
Rise in serum creatinine by 2 mg/dL or more from the start of the therapy and attributable to myeloma;
Hyperviscosity related to serum paraprotein.
Relapse from complete Any one or more of the following criteria:
response (to be used only Reappearance of serum or urine M-protein by immunofixation or electrophoresisi;
if the endpoint is Development of ≥5% plasma cells in the bone marrow;
disease-free survival) Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia) (see above).
Any one or more of the following criteria:
Relapse from MRD Loss of MRD negative state (evidence of clonal plasma cells on NGF or NGS, or positive imaging study for recurrence of
negative (to be used only myeloma);
if the endpoint is Reappearance of serum or urine M-protein by immunofixation or electrophoresis;
disease-free survival) Development of ≥5% clonal plasma cells in the bone marrow;
Appearance of any other sign of progression (ie, new plasmacytoma, lytic bone lesion, or hypercalcemia).
Footnotes
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Footnotes
a All response categories require two consecutive assessments made any f Derived from international uniform response criteria for multiple myeloma. Minor response
time before starting any new therapy; for MRD there is no need for two definition and clarifications derived from Rajkumar and colleagues. When the only
consecutive assessments, but information on MRD after each treatment method to measure disease is by serum FLC levels: complete response can be defined
stage is recommended (eg, after induction, high-dose therapy/ Autologous as a normal FLC ratio of 0.26 to 1.65 in addition to the complete response criteria listed
stem cell transplants (ASCT), consolidation, maintenance). MRD tests should previously. Very good partial response in such patients requires a ≥90% decrease in the
be initiated only at the time of suspected complete response. All categories difference between involved and uninvolved FLC levels. All response categories require
of response and MRD require no known evidence of progressive or new two consecutive assessments made at any time before the institution of any new therapy;
bone lesions if radiographic studies were performed. However, radiographic all categories also require no known evidence of progressive or new bone lesions or
studies are not required to satisfy these response requirements except for the extramedullary plasmacytomas if radiographic studies were performed. Radiographic
requirement of FDG PET if imaging MRD-negative status is reported. studies are not required to satisfy these response requirements. Bone marrow
b Sustained MRD negativity when reported should also annotate the method assessments do not need to be confirmed. Each category, except for stable disease, will
used (eg, sustained flow MRD-negative, sustained sequencing MRD- be considered unconfirmed until the confirmatory test is performed. The date of the initial
negative). test is considered as the date of response for evaluation of time dependent outcomes such
c Bone marrow MFC should follow NGF guidelines. The reference NGF method as duration of response. Durie BG, Harousseau JL, Miguel JS, et al, for the International
is an eight-color two-tube approach, which has been extensively validated. Myeloma Working Group. International uniform response criteria for multiple myeloma.
The two-tube approach improves reliability, consistency, and sensitivity Leukemia 2006; 20:1467-73.
because of the acquisition of a greater number of cells. The eight-color g All recommendations regarding clinical uses relating to serum FLC levels or FLC ratio are
technology is widely available globally and the NGF method has already based on results obtained with the validated serum FLC assay.
been adopted in many flow laboratories worldwide. The complete eight-color h Presence/absence of clonal cells on immunohistochemistry is based upon the κ/λ/L ratio.
method is most efficient using a lyophilised mixture of antibodies, which An abnormal κ/λ ratio by immunohistochemistry requires a minimum of 100 plasma cells
reduces errors, time, and costs. Five million cells should be assessed. The for analysis. An abnormal ratio reflecting presence of an abnormal clone is κ/λ of >4:1 or
Flow Cytometry Method (FCM) method employed should have a sensitivity of <1:2.
detection of at least 1 in 10⁵ plasma cells. Paiva B, Gutierrez NC, Rosinol L, et i Special attention should be given to the emergence of a different monoclonal protein
al, for the GEM (Grupo Españolde MM)/PETHEMA (Programa para el Estudio following treatment, especially in the setting of patients having achieved a conventional
de la Terapéutica en Hemopatías Malignas) Cooperative Study Groups. High- complete response, often related to oligoclonal reconstitution of the immune system.
risk cytogenetics and persistent minimal residual disease by multiparameter These bands typically disappear over time and in some studies have been associated with
flow cytometry predict unsustained complete response after autologous stem a better outcome. Also, appearance of monoclonal IgG κ in patients receiving monoclonal
cell transplantation in multiple myeloma. Blood 2012;119: 687-91. antibodies should be differentiated from the therapeutic antibody.
d DNA sequencing assay on bone marrow aspirate should use a validated j Plasmacytoma measurements should be taken from the CT portion of the PET/CT, or MRI
assay. scans, or dedicated CT scans where applicable. For patients with only skin involvement,
e Criteria used by Zamagni and colleagues, and expert panel (IMPetUs; Italian skin lesions should be measured with a ruler. Measurement of tumor size will be
Myeloma Criteria for PET Use). Baseline positive lesions were identified by determined by the SPD.
presence of focal areas of increased uptake within bones, with or without any k Positive immunofixation alone in a patient previously classified as achieving a complete
underlying lesion identified by CT and present on at least two consecutive response will not be considered progression. For purposes of calculating time to
slices. Alternatively, an SUVmax = 2.5 within osteolytic CT areas >1 cm progression and progression-free survival, patients who have achieved a complete
in size, or SUVmax = 1.5 within osteolytic CT areas ≤1 cm in size were response and are MRD-negative should be evaluated using criteria listed for progressive
considered positive. Imaging should be performed once MRD negativity is disease. Criteria for relapse from a complete response or relapse from MRD should be
determined by MFC or NGS. Zamagni E, Nanni C, Mancuso K, et al. PET/CT used only when calculating disease-free survival.
improves the definition of complete response and allows to detect otherwise l In the case where a value is felt to be a spurious result per physician discretion (eg, a
unidentifiable skeletal progression in multiple myeloma. Clin Cancer Res possible laboratory error), that value will not be considered when determining the lowest
2015;21:4384-90. value.

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GENERAL CONSIDERATIONS FOR MYELOMA THERAPY

General Principles
• Patients should receive at least a triplet regimen (2 drug classes and steroids) if they can tolerate it. Patients with poor performance status or who are
frail can be started on a 2-drug regimen, with a third drug added once performance status improves.
• A new triplet regimen should preferably include drugs or drug classes patients have not been exposed to, or not exposed to for at least 6 months.
• Clinical trials with these triplet regimens primarily included patients who were naïve or sensitive to the novel drug in the doublet comparator arm.
Patients with disease refractory to the novel drug in the doublet backbone should be considered for triplet therapy that does not contain the drug they
are progressing on.
• Frailty assessment should be considered in older adults. See NCCN Guidelines for Older Adult Oncology.
• For the Myeloma Frailty Score Calculator developed by International Myeloma Working Group for the prognosis of elderly myeloma patients, see http://
www.myelomafrailtyscorecalculator.net/a
• Consider dose modifications based on functional status and age.
• For additional supportive care while on myeloma therapy, see Supportive Care Treatment for Multiple Myeloma (MYEL-H).
Candidates for HCT

• Exposure to myelotoxic agents (including alkylating agents and nitrosoureas) should be limited to avoid compromising stem cell reserve prior to stem
cell harvest in patients who may be candidates for transplant.
• Consider harvesting peripheral blood stem cells after several cycles of therapy prior to prolonged exposure to lenalidomide and/or daratumumab in
patients for whom transplant is being considered.
Screening Recommendations
• Test for hepatitis B as clinically indicated.
• Screen for HIV and hepatitis C as clinically indicated.
Prophylaxis Recommendations
• Pneumocystis jiroveci pneumonia (PJP) should be given if receiving steroids.
• Administer herpes zoster prophylaxis for all patients treated with proteasome inhibitors (PIs), daratumumab, isatuximab-irfc, or elotuzumab.
Dosing and Administration

• Subcutaneous bortezomib is the preferred method of administration.
• Both weekly and twice-weekly dosing schemas of bortezomib may be appropriate; weekly preferred.
• Carfilzomib may be used once or twice weekly and at different doses.
• For any regimen that includes daratumumab, this could be daratumumab for intravenous infusion or daratumumab and hyaluronidase-fihj for
subcutaneous injection. Daratumumab and hyaluronidase-fihj for subcutaneous injection has different dosing and administration instructions
compared to daratumumab for intravenous infusion.
Side Effects and Lab Interference

• Daratumumab and isatuximab-irfc may interfere with serologic testing and cause false-positive indirect Coombs test.
• Type and screen should be performed before using daratumumab or isatuximab-irfc.
• Carfilzomib can potentially cause cardiac and pulmonary toxicity, especially in elderly patients.
• Agents such as bendamustine can impact the ability to collect T cells for CAR T-cell therapy.
a Palumbo A, Bringhen S, Mateos MV, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group
report. Blood 2015;125:2068-2074.
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PRIMARY THERAPY FOR TRANSPLANT CANDIDATESa-d

Preferred Regimens
• Bortezomib/lenalidomide/dexamethasone (category 1)
• Carfilzomib/lenalidomide/dexamethasone
Other Recommended Regimens
• Daratumumab/lenalidomide/bortezomib/dexamethasone
Useful In Certain Circumstances
• Bortezomib/thalidomide/dexamethasone (category 1)
• Bortezomib/cyclophosphamide/dexamethasonee
• Bortezomib/doxorubicin/dexamethasone
• Carfilzomib/cyclophosphamide/dexamethasonef
• Cyclophosphamide/lenalidomide/dexamethasone
• Daratumumab/bortezomib/thalidomide/dexamethasone
• Daratumumab/carfilzomib/lenalidomide/dexamethasone
• Daratumumab/cyclophosphamide/bortezomib/dexamethasone
• Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide/bortezomibg (VTD-PACE)
• Ixazomib/cyclophosphamide/dexamethasonef
• Ixazomib/lenalidomide/dexamethasone (category 2B)
MAINTENANCE THERAPY
Preferred Regimens
• Lenalidomideh (category 1)
• Bortezomib
• Daratumumab
• Ixazomib (category 2B)i
• Bortezomib/lenalidomide ± dexamethasonej
• Carfilzomib/lenalidomidej
a Selected, but not inclusive of all regimens. The regimens under each preference
category are listed by order NCCN Category of Evidence and Consensus f Treatment option for patients with renal insufficiency and/or peripheral neuropathy.
alphabetically. g Generally reserved for the treatment of aggressive MM.
b See Supportive Care Treatment for Multiple Myeloma (MYEL-H). h There appears to be an increased risk for secondary cancers, especially with lenalidomide
c See General Considerations for Myeloma Therapy (MYEL-F).
maintenance following transplant. The benefits and risks of maintenance therapy vs.
d See Management of Renal Disease in Multiple Myeloma (MYEL-J).
secondary cancers should be discussed with patients.
e Preferred primarily as initial treatment in patients with acute renal insufficiency or i Results from interim analyses of TOURMALINE MM3 and MM4 trials of ixazomib in the
those who have no access to bortezomib/lenalidomide/dexamethasone. Consider maintenance setting suggest a potential decrease in overall survival (OS).
switching to bortezomib/lenalidomide/dexamethasone after renal function improves. j Dual maintenance recommended for high-risk MM.
Continued
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PRIMARY THERAPY FOR NON-TRANSPLANT CANDIDATESa-d

Preferred Regimens
• Bortezomib/lenalidomide/dexamethasone (category 1)
• Daratumumab/lenalidomide/dexamethasone (category 1)
• Daratumumab/bortezomib/melphalan/prednisone (category 1) • Daratumumab/cyclophosphamide/bortezomib/dexamethasone
• Carfilzomib/lenalidomide/dexamethasone • Ixazomib/lenalidomide/dexamethasone
• Lenalidomide/low-dose dexamethasone (category 1)k • Bortezomib/lenalidomide/dexamethasone (VRD-lite) for frail
• Bortezomib/dexamethasone patients
• Bortezomib/cyclophosphamide/dexamethasonee • Carfilzomib/cyclophosphamide/dexamethasonef
MAINTENANCE THERAPY
Preferred Regimens
• Lenalidomide (category 1)
• Bortezomib
• Ixazomib (category 2B)i
• Bortezomib/lenalidomidej
category are listed by order NCCN Category of Evidence and Consensus
alphabetically.
b See Supportive Care Treatment for Multiple Myeloma (MYEL-H). f Treatment option for patients with renal insufficiency and/or peripheral neuropathy.
c See General Considerations for Myeloma Therapy (MYEL-F). i Results from interim analyses of TOURMALINE MM3 and MM4 trials of ixazomib in
the maintenance setting suggest a potential decrease in OS.
e Preferred primarily as initial treatment in patients with acute renal insufficiency j Dual maintenance recommended for high-risk MM.
or those who have no access to bortezomib/lenalidomide/dexamethasone. k Continuously until progression. Benboubker L, Dimopoulos MA, Dispenzieri A,
Consider switching to bortezomib/lenalidomide/dexamethasone after renal et al. Lenalidomide and dexamethasone in transplant-ineligible patients with
function improves. myeloma. N Engl J Med 2014;371:906-917.
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THERAPY FOR PREVIOUSLY TREATED MULTIPLE MYELOMAa-d,l-m

Preferred Regimens for Early Relapses (1–3 prior therapies)
Order of regimens does not indicate comparative efficacy
• If relapse is >6 months, the regimen used for primary therapy may be repeated.
• For patients still sensitive to bortezomib and/or lenalidomide, any of the regimens listed on this page may be appropriate.
• Ixazomib/lenalidomide/dexamethasone (category 1)
• Bortezomib/lenalidomide/dexamethasone
Bortezomib-Refractory Lenalidomide-Refractory
• Daratumumab/lenalidomide/dexamethasone (category 1) • Daratumumab/carfilzomib/dexamethasone (category 1)
• Daratumumab/carfilzomib/dexamethasone (category 1) • Daratumumab/bortezomib/dexamethasone (category 1)
• Carfilzomib/lenalidomide/dexamethasone (category 1) • Isatuximab-irfc/carfilzomib/dexamethasone (category 1)
• Isatuximab-irfc/carfilzomib/dexamethasone (category 1) • Carfilzomib/pomalidomide/dexamethasone
• Carfilzomib/pomalidomide/dexamethasone
After one prior therapy including lenalidomide and a PI After one prior therapy including lenalidomide and a PI
Daratumumab/pomalidomide/dexamethasone (category 1) Daratumumab/pomalidomide/dexamethasone (category 1)
After two prior therapies including lenalidomide and a PI After two prior therapies including lenalidomide and a PI
Isatuximab-irfc/pomalidomide/dexamethasone (category 1) Isatuximab-irfc/pomalidomide/dexamethasone (category 1)
After two prior therapies including an IMiD and a PI and with disease After two prior therapies including an IMiD and a PI and with disease
progression on/within 60 days of completion of last therapy progression on/within 60 days of completion of last therapy
Ixazomib/pomalidomide/dexamethasone Pomalidomide/bortezomib/dexamethasone (category 1)
Ixazomib/pomalidomide/dexamethasone
For Other Recommended Regimens and for regimens Useful in

Certain Circumstances for Early Relapses (1–3 prior therapies),
see MYEL-G 4 of 5
a
Selected, but not inclusive of all regimens. The regimens under each preference category are listed by order NCCN Category of Evidence and Consensus alphabetically.
b See Supportive Care Treatment for Multiple Myeloma (MYEL-H).
l Consideration for appropriate regimen in previously treated myeloma should be based on the context of clinical relapse.
m Regimens included under 1–3 prior therapies can also be used later in the disease course. Attempt should be made to use drugs/drug classes the patients have not been
exposed to or exposed to >1 line prior.
n Autologous HCT should be considered in an eligible patient who had not previously received transplant or had a prolonged response to initial transplant.
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THERAPY FOR PREVIOUSLY TREATED MULTIPLE MYELOMAa-d,l-o

• If relapse is >6 months, the regimen used for primary therapy may be repeated.
• For patients still sensitive to bortezomib and/or lenalidomide, any of the regimens listed on this page may be appropriate.
Other Recommended Regimens for Early Relapses (1–3 prior therapies)
• Bortezomib/liposomal doxorubicin/dexamethasone (category 1) After two prior therapies including an IMiD and a PI and disease progression
• Carfilzomib (twice weekly)/dexamethasone (category 1) on/within 60 days of completion of last therapy
• Elotuzumab/lenalidomide/dexamethasone (category 1) Pomalidomide/cyclophosphamide/dexamethasone
• Selinexor/bortezomib/dexamethasone (once weekly) (category 1)
• Bortezomib/cyclophosphamide/dexamethasone After two prior therapies including lenalidomide and a PI
• Carfilzomib/cyclophosphamide/dexamethasone Elotuzumab/pomalidomide/dexamethasone
• Daratumumab/cyclophosphamide/bortezomib/dexamethasone
• Elotuzumab/bortezomib/dexamethasone
• Ixazomib/cyclophosphamide/dexamethasone
Useful in Certain Circumstances for Early Relapses (1–3 prior therapies)
• Bortezomib/dexamethasone (category 1) After two prior therapies including IMiD and a PI and with disease progression
• Lenalidomide/dexamethasone (category 1) on/within 60 days of completion of last therapy
• Carfilzomib/cyclophosphamide/thalidomide/dexamethasone Pomalidomide/dexamethasone (category 1)
• Carfilzomib (weekly)/dexamethasone Selinexor/pomalidomide/dexamethasone
• Selinexor/daratumumab/dexamethasone
• Selinexor/carfilzomib/dexamethasone For treatment of aggressive MM
• Venetoclax/dexamethasone only for t(11;14) patients Dexamethasone/cyclophosphamide/etoposide/cisplatin (DCEP)
Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/
etoposide (DT-PACE) ± bortezomib (VTD-PACE)
After at least three prior therapies including a PI and an IMiD or are double-
refractory to a PI and an IMiD
Daratumumab
a Selected, but not inclusive of all regimens. The regimens under each preference m Regimens included under 1–3 prior therapies can also be used later in the disease
b
category are listed by order NCCN Category of Evidence and Consensus alphabetically.
See Supportive Care Treatment for Multiple Myeloma (MYEL-H). course. Attempt should be made to use drugs/drug classes the patients have not been
c See General Considerations for Myeloma Therapy (MYEL-F). exposed to or exposed to >1 line prior.
d See Management of Renal Disease in Multiple Myeloma (MYEL-J). n Autologous HCT should be considered in an eligible patient who had not previously
l Consideration for appropriate regimen in previously treated myeloma should be based on the received transplant or had a prolonged response to initial transplant.
o Consider single-agent lenalidomide or pomalidomide for patients with steroid intolerance.
context of clinical relapse.
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THERAPY FOR PREVIOUSLY TREATED MULTIPLE MYELOMAa-d,l-n

Therapies for Patients with Late Relapses (>3 prior therapies)
• Bendamustine
• Bendamustine/bortezomib/dexamethasone
• Bendamustine/carfilzomib/dexamethasone
• Bendamustine/lenalidomide/dexamethasone
• High-dose or fractionated cyclophosphamide
After at least four prior therapies, including an anti-CD38 monoclonal antibody, a PI, and an IMiD
Belantamab mafodotin-blmf
Idecabtagene vicleucel
Ciltacabtagene autoleucel
After at least four prior therapies and whose disease is refractory to at least two PIs, at least two immunomodulatory agents, and an anti-CD38
monoclonal antibody
Selinexor/dexamethasone
category are listed by order NCCN Category of Evidence and Consensus
alphabetically. m Regimens included under 1–3 prior therapies can also be used later in the disease
b See Supportive Care Treatment for Multiple Myeloma (MYEL-H).
course. Attempt should be made to use drugs/drug classes the patients have not
been exposed to or exposed to >1 line prior.
d See Management of Renal Disease in Multiple Myeloma (MYEL-J). n Autologous HCT should be considered in an eligible patient who had not previously
l Consideration for appropriate regimen in previously treated myeloma should be
received transplant or had a prolonged response to initial transplant.
based on the context of clinical relapse.

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SUPPORTIVE CARE FOR MULTIPLE MYELOMA
Bone Disease Anemia

• All patients receiving primary myeloma therapy should be given • See NCCN Guidelines for Hematopoietic Growth Factors.
bone-targeting treatment (bisphosphonates (category 1)a or • Consider erythropoietin for anemic patients.
denosumab.b)
A baseline dental exam is strongly recommended. Infection
Assess Vitamin D status • See NCCN Guidelines for Prevention and Treatment of Cancer-
Monitor for renal dysfunction with use of bisphosphonate therapy. Related Infections.
Monitor for osteonecrosis of the jaw. • Intravenous immunoglobulin therapy should be considered in the
Continue bone-targeting treatment (bisphosphonates or setting of recurrent serious infection and/or hypogammaglobulinemia
denosumab) for up to 2 years. The frequency of dosing (monthly (IgG ≤400 mg/dL).
vs. every 3 months) would depend on the individual patient criteria • The pneumococcal conjugate vaccine should be given followed by
and response to therapy. Continuing beyond 2 years should be the pneumococcal polysaccharide vaccine one year later.
based on clinical judgment. • Influenza vaccination recommended. Consider two doses of the high-
Patients receiving denosumab for bone disease who subsequently dose inactivated quadrivalent influenza vaccine.
discontinue therapy should be given maintenance denosumab • Consider 12 weeks of levofloxacin 500 mg daily at the time of initial
every 6 months or a single dose of bisphosphonate to mitigate risk diagnosis for MM.
of rebound osteoporosis.c • See NCCN Guidance on Cancer and COVID-19 Vaccination
• RT (See Principles of Radiation Therapy [MYEL-D]) • See MYEL-F for myeloma therapy-specific prophylaxis
• Orthopedic consultation should be sought for impending or actual
long-bone fractures or bony compression of spinal cord or vertebral Renal Dysfunction
column instability. • See Management of Renal Disease in Multiple Myeloma (MYEL-J)
• Consider vertebroplasty or kyphoplasty for symptomatic vertebral
compression fractures. Venous Thromboembolism (VTE)
Hypercalcemia • For management of VTE, risk stratification, and VTE prophylaxis, See
• Hydration, bisphosphonates (zoledronic acid preferred), MYEL-I
denosumab, steroids, and/or calcitonin are recommended.
Hyperviscosity
• Plasmapheresis should be used as adjunctive therapy for
symptomatic hyperviscosity.
a Both pamidronate and zoledronic acid have shown equivalence in terms of reducing risk of skeletal-related events in randomized trials.
b Denosumab is preferred in patients with renal insufficiency.
c This is based on observations with denosumab discontinuation in non-myeloma settings. Cummings SR, Ferrari S, Eastell R, et al. Vertebral
fractures after
discontinuation of denosumab: A post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 2018;33:190-198.

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MANAGEMENT OF VENOUS THROMBOEMBOLISM (VTE) IN MULTIPLE MYELOMA
VTE RISK STRATIFICATION USING IMPEDE OR SAVED SCORING SYSTEM
IMPEDE Scorea for Risk Stratification (points assigned)

Individual Risk Factors Points Myeloma Risk Factors Points
Positive Factors
Central venous catheter/Tunneled central line +2 Immunomodulatory drug (IMiD) +4
Pelvic, hip, or femur fracture +4 Erythropoiesis-stimulating agent +1
Obesity (Body Mass Index ≥25) +1 Dexamethasone <160 mg/month +2
Previous VTE +5 Dexamethasone >160 mg/month +4
Doxorubicin or multiagent chemotherapy +3
Negative Factors
Ethnicity/Race = Asian/Pacific Islander -3
Existing thromboprophylaxis: prophylactic -3
LMWH (low-molecular-weight heparin) or aspirin
Existing thromboprophylaxis: therapeutic -4
LMWH or warfarin
SAVED Scoreb for Risk Stratification

Variable Points
Surgery within 90 days +2
Asian Race -3
VTE history +3
Age ≥80 years +1
Dexamethasone (regimen dose)
• Standard dose (120–160 mg/cycle) +1
• High dose (>160 mg/cycle) +2
a Adapted from Sanfilippo KM, et al. Am J Hematol 2019;94:1176-1184.
b Adapted from: Li A, et al. J Natl Compr Canc Netw 2019;17:840-847.
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General Principles:
• Highest risk for VTE is in the first 6 months following new diagnosis of MM.
• VTE prophylaxis is administered assuming there are no contraindications to anticoagulation agents or anti-platelets (Please see page
VTE-A of the NCCN Guidelines for Cancer-Associated Venous Thromboembolic Disease.)
• All anticoagulants carry increased risk of bleeding; careful consideration needs to be made regarding risks and benefits for each
patient.
• Warfarin at international normalized ratio (INR) 2–3 is not directly comparable to the other agents listed at prophylactic doses with
respect to bleeding and thrombotic risks.
• Patients already on therapeutic anticoagulants for other reasons (eg, atrial fibrillation) should continue anticoagulation therapy.
• If no other coagulopathy, full-dose anticoagulation is contraindicated with thrombocytopenia <50,000/μL; in patients with high risk for
VTE, prophylactic anticoagulation may be appropriate even if platelet count is as low as 25,000/μL.
• Indications for long-term anticoagulation include unprovoked VTE or provoked VTE in the presence of a risk factor that is still present.
• For any patients who develop VTE on IMiD-based therapy, continue using therapeutic dose anticoagulants for as long as IMiD-based
therapy is indicated.
Factors Impacting the Choice of Optimal VTE Prophylaxis Agent:

• Bleeding risk (eg, concurrent coagulopathy, disseminated intravascular coagulation, hyperviscosity)
• Cytopenias (eg, platelet count ± hemoglobin)
• Concurrent medications (eg, strong cytochrome P inducers/inhibitors, single/dual anti-platelets)
• Current renal function (eg, creatinine clearance)
• Patient choice (eg, preference for mode of administration, dietary restrictions)
• Insurance coverage/restrictions (including cost of therapy)
• Availability of reversal agents in case of emergency bleeding
• History of heparin-induced thrombocytopenia
• Extremes of body weight
• Carfilzomib + IMiD therapy
References:
Palumbo A. Leukemia 2008;22:414-423.
Kristinsson SY. Hematology Am Soc Hematol Educ Program 2010;2010:437-444.
Carrier M. N Engl J Med 2019;380:711-719.
Khorana AA. N Engl J Med 2019;380:720-728.
Piedra K. Br J Haematol. 2022;196:105-109.
Wang T-F. J Thromb Haemost 2019;17:1772-1778. Note: The AVERT apixaban trial had only 2.6% myeloma patients, and myeloma patients were excluded from the
CASSINI rivaroxaban trial.

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. Continued
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RECOMMENDATIONS FOR VTE PROPHYLAXIS

VTE Prophylaxis Recommendations
≤3 Points by IMPEDE Score or <2 Points by SAVED Score ≥4 Points by IMPEDE Score or ≥2 SAVED Scorec
• Aspirin 81–325 mg once daily • LMWH (equivalent to enoxaparin 40 mg daily) OR
• Rivaroxaban 10 mg daily OR
• Apixaban 2.5 mg twice daily OR
• Fondaparinux 2.5 mg daily OR
• Warfarin (target INR 2.0–3.0)
Duration of VTE Prophylaxis

• Indefinite while on myeloma therapy
• 3–6 months followed by aspirin (longer periods of anticoagulation may be considered in the presence of additional patient, treatment-
specific, or transient VTE risk factors)
c A less common choice of agent includes dalteparin 5,000 units subcutaneously (SC) daily (category 2B).

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MANAGEMENT OF RENAL DISEASE IN MULTIPLE MYELOMAa

Testsb Supportive Care
• Serum creatinine, electrolytes, and uric acid • Provide hydration to dilute tubular light chains; goal urine output
• Urinalysis, electrolytes, and sediment is 100–150 cc/h
• 24-h urine collection for protein and UPEP/UIFE • Monitor fluid status
• SPEP/SIFE and serum FLCs • Treat hypercalcemia, hyperuricemia, and other metabolic
• Consider renal ultrasound and renal biopsy
abnormalities
Treatment Options • Discontinue nephrotoxic medications
• Pulse dexamethasone • Dialysis
• Regimens containing bortezomib and/or daratumumab Refractory electrolyte disturbances, uremia, and fluid overload
• Can switch to other regimen once renal function has improved or • Mechanical removal of serum FLCs with high cutoff dialysis
stabilized filters or plasmapheresis may have a limited role. Systemic
• Use other plasma cell-directed therapy with caution therapy should not be delayed if performing this procedure.
• See Response Criteria for Multiple Myeloma (MYEL-E) • Renal dosing of all medications
• See Myeloma Therapy (MYEL-G)
Recommendations for Lenalidomide Dosing in Patients with Multiple Myeloma Who Have Renal Impairment
Category Renal Function (Cockcroft-Gault CLCr) Lenalidomide Dosing in Multiple Myeloma
Moderate renal impairment CLCr ≥30 mL/min to <60 mL/min 10 mg every 24 h
Severe renal impairment CLCr <30 mL/min (not requiring dialysis) 15 mg every 48 h
End-stage renal disease CLCr <30 mL/min (requiring dialysis) 5 mg once daily; on dialysis days,
dose should be administered after dialysis
CLCr= creatinine clearance
Bone-Modifying Agent Dosing in Patients with Multiple Myeloma Who Have Renal Impairment
Degree of Renal Impairment Pamidronate Zoledronic Acid Denosumab
(focal segmental glomerulosclerosis) (tubular cell toxicity)
None 90 mg IV over >2 h every 3–4 wks 4 mg IV over >5 min every 3–4 wks 120 mg SQ Q 4 weeks
Mild/moderate renal impairment Use standard dose Reduce dose 120 mg SQ Q 4 weeks
Severe renal impairment 60–90 mg over 4–6 h Not recommended 120 mg SQ Q 4 weeksc
a Defined as serum creatinine >2 mg/dL or established glomerular filtration rate (eGFR) <60 mL/min/1.73 sqm.
b Consider other diagnosis such as amyloid and light chain disease for patients with significant proteinuria.
c Patients with creatinine clearance <30 cc/min can experience severe hypocalcemia and should be monitored.

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MONOCLONAL GAMMOPATHY OF CLINICAL SIGNIFICANCE

MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE
CLINICIAL INITIAL WORKUP ADDITIONAL WORKUP
FINDINGS
Renal biopsy To confirm diagnosis of MGRS:
recommended if: • Light microscopy
• Acute kidney injury • Immunofluorescence staining for
(AKI) stage 3 IgG subclasses, IgA and IgM, and
• eGFR <60 mL/min and kappa and lambda
>2 mL/min per year Note: M protein detected in
decline serum and/or urine must
• Proteinuria (>1 g/day) match the one found in the
Albumin:creatinine >30 renal biopsy
mg/mmol • Electron microscopy
• Fanconi syndrome • FDG PET/CT, low-dose CT, or
MGRS
whole-body MRI as clinically
(Monoclonal
indicated
gammopathy Evaluate for kidney disease
Consider renal biopsy if: • Bone marrow biopsy if suspected
of renal • Kidney function: eGFR For management
• AKI stage 1 or 2 to have MM or Waldenström
significance) • Urinalysis See MGRS-2
• eGFR <60 mL/min and macroglobulinemia (WM)
suspected • Metabolic testing
<2 mL/min per year Additional workup as clinically
decline indicated:
• Albumin:creatinine • FISH panel for myeloma and
3–30 mg/mmol and polymerase chain reaction (PCR)
glomerular filtration rate assay for MYD88 L265P
(GFR) <60 mL/min • Excisional lymph node biopsy,
• Evidence of light chain if other B-cell lymphomas are
proteinuria suspected
• Peripheral blood flow cytometry for
diagnosis of Chronic Lymphocytic
Defer renal biopsy if: Leukemia (See NCCN Guidelines
• Stable established GFR for Chronic Lymphocytic Leukemia/
(eGFR) Small Lymphocytic Lymphoma)
• Normal urinalysis • Evaluate for light chain amyloidosis
• No evidence of light (See NCCN Guidelines for Systemic
chain proteinuria Light Chain Amyloidosis)

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MONOCLONAL GAMMOPATHY OF CLINICAL SIGNIFICANCE

MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE
TREATMENT RESPONSE ASSESSMENT
• For IgG- or IgA-associated MGRS, use the

response criteria for MMb
• For IgM-associated MGRS, use
the response criteria for WM (See
• For plasma cell-related MGRS, use the NCCN Guidelines for Waldenström Individualize
management algorithm for MM (See MYEL-4) Macroglobulinemia/Lymphoplasmacytic treatment based
• For lymphoplasmacytic-related MGRS, Lymphoma) on response and
See NCCN Guidelines for Waldenström • For FLC-associated MGRS, use the toxicity of prior
Macroglobulinemia/Lymphoplasmacytic response criteria for amyloidosis (See Relapse therapy, patient’s
Lymphomaa NCCN Guidelines for Systemic Light Chain performance
• For any MGRS with monoclonal B-cell Amyloidosis) status, and renal
lymphocytosis (MBL) features, See NCCN • For cases in which the causal monoclonal function at the
Guidelines for Chronic Lymphocytic paraprotein is not detectable or is difficult time of relapse
Leukemia/Small Lymphocytic Lymphoma to measure:
evaluate renal function
evaluate bone marrow involvement or
radiologic findings
a Systemic agents associated with neurotoxicity should be used with caution.

b See Response Criteria for Multiple Myeloma (MYEL-E).

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MONOCLONAL GAMMOPATHY OF CLINICAL SIGNIFICANCE (FOR MGRS, SEE MGRS-1)
MONOCLONAL GAMMOPATHY OF NEUROLOGICAL SIGNIFICANCE

INITIAL WORKUP CLINICAL FINDINGS
• Rule out other causes of neuropathy

Diabetes High suspicion
Cobalamin deficiency • Sensory predominant
Thyroid dysfunction • Length dependent
Lyme disease • Slow progression (years)
HIV infection • Bilateral and symmetrical
Syphilis • Antibodies present
Autoimmune disease • Demyelination by EMG/NCS See NCCN
Cryoglobulinemia OR intermediate suspicion (not Guidelines for
IgMa MGNS Evaluation for light chain amyloidosis, high or low suspicion) AND Waldenström
(Monoclonal (See NCCN Guidelines for Systemic Light affecting activities of daily Macroglobulinemia/
gammopathy Chain Amyloidosis), WM (See NCCN living (ADLs) Lymphoplasmacytic
of neurological Guidelines for WM/LPL), or POEMS (See Lymphoma
significance) POEMS-1), if appropriate.
suspected • Anti-MAG antibodiesa Low suspicion Observation
• Ganglioside antibody panel • Motor/pain predominant
• Nerve conduction study (NCS)/ • Non-length dependent
electromyogram (EMG)a • Rapid progression (weeks to
• Neurology consult months)
• MYD88b L265P allele-specific PCR (AS-PCR) • Unilateral/asymmetrical
testing of bone marrow • Antibodies not present
• Chest/abdominal/pelvic CT with contrast • No demyelination by EMG/NCS
when possible OR intermediate/high suspicion
AND not affecting ADLs
Useful in certain circumstances
• Sural nerve biopsy
• CXCR4 gene mutation testing
a Inpatients presenting with suspected disease related to peripheral neuropathy, rule out amyloidosis in patients presenting with nephrotic syndrome or unexplained
cardiac problems.
b MYD88 wild-type occurs in <10% of patients and should not be used to exclude diagnosis of WM if other criteria are met.

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POEMS (POLYNEUROPATHY, ORGANOMEGALY, ENDOCRINOPATHY, MONOCLONAL PROTEIN, SKIN CHANGES)

INITIAL WORKUP RECOMMENDED INITIAL TESTING ADDITIONAL TESTING DIAGNOSIS
AS INDICATED
• For criteria for

• Electrophysiologic (nerve
• Complete H&P diagnosis, see
conduction) studies
examination POEMS-3
• CT chest/abdomen/pelvis to
• Evaluate for • Sural nerve biopsy
document lymphadenopathy, For management of
organomegaly • Follicle-stimulating
organomegaly, ascites, pleural POEMS syndrome,
• Fundoscopic exam hormone,
effusion, edema see POEM-2
• Hyperhidrosis adrenocorticotropin
• Testosterone, estradiol, fasting
• Diarrhea hormone,
glucose, thyroid-stimulating
• Weight loss cosyntropin
hormone, parathyroid hormone,
• Menstrual and sexual stimulation test
prolactin, serum cortisol,
function • Biopsy of bone lesion
luteinizing hormone
• Skin examination for if needed
• CBC, complete metabolic panel, If diagnosis is MM,
POEMS hyperpigmentation,
serum immunoglobulins (IgG, follow MM algorithm
suspected hypertrichosis,
IgA, IgM), electrophoresis and
acrocyanosis, • Excisional lymph
immunofixation, serum FLC, If diagnosis is WM,
glomeruloid node biopsy, if
24-h urine total protein, vascular see NCCN Guidelines
hemangiomata, Castleman disease
endothelial growth factor (VEGF), for WM/LPL
plethora, flushing, or other B-cell
interleukin 6 (IL-6)
clubbing, etc. lymphomas are
• Bone marrow aspirate and biopsy, If diagnosis is
• Detailed neurologic suspected
FISH panel for myeloma, and PCR Castleman disease,
history (numbness, • FISH panel for
• Echocardiography to assess right See NCCN Guidelines
pain, weakness, myeloma
ventricular systolic and pulmonary for B-Cell Lymphomas
balance, orthostasis) • Evaluate for light
artery pressures
and exam (sensation chain amyloidosis,
• CT body bone windows and or FDG If diagnosis is
and motor function) if appropriate (See
PET/CT for sclerotic bone lesions Systemic Light Chain
NCCN Guidelines for
Amyloidosis, see
Systemic Light Chain
NCCN Guidelines for
Amyloidosis)
Systemic Light Chain
Amyloidosis
Adapted with permission: Dispenzieri A. Am J Hematol 2019;94:812-827.

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TREATMENT RESPONSE ASSESSMENT
• Radiation therapy alone to isolated

bone lesion (<3 sites) in patients
without clonal BMPC
• Autologous HCT in patients who
are eligible as sole therapy or as
consolidation after induction therapy
Induction therapy options include:
◊ Lenalidomide/dexamethasone
Individualize treatment based
◊ Bortezomiba/dexamethasone
on response and toxicity of
◊ Melphalan/dexamethasone
See POEMS-4 for Response Criteria Progression prior therapy and patient’s
◊ Cyclophosphamide/dexamethasone
performance status at the
◊ Pomalidomide/dexamethasone
time of progression
• In patients who are transplant ineligible,
options include:
Lenalidomide/dexamethasone
Bortezomiba/dexamethasone
Melphalan/dexamethasone
Cyclophosphamide/dexamethasone
Pomalidomide/dexamethasone
a Bortezomib may cause exacerbation of neuropathy.

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Table 1 Criteria for the Diagnosis of POEMS Syndromea
Mandatory major criteria 1. Polyneuropathy (typical demyelinating)
2. Monoclonal plasma cell-proliferative disorder (almost always λ)
Other major criteria (one required) 3. Castleman diseaseb
4. Sclerotic bone lesions
5. Vascular endothelial growth factor elevation
Minor criteria 6. Organomegaly (splenomegaly, hepatomegaly, lymphadenopathy)
7. Extravascular volume overload (edema, pleural effusion, or ascites)
8. Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
9. Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora,

acrocyanosis, flushing, white nails)
10. Papilledema
11. Thrombocytosis/polycythemiac
Other signs and symptoms Clubbing, weight loss, hyperhidrosis, pulmonary hypertension, restrictive lung disease, thrombotic
diatheses, diarrhea, low vitamin B12 levels
The diagnosis of POEMS syndrome is confirmed when both of the mandatory major criteria, one of the other three major criteria, and one of the six minor criteria are
present.
a There is a Castleman disease variant of POEMS that occurs without evidence of a clonal plasma cell disorder that is not accounted for in this table. This entity should
be considered separately.
b Because of the high prevalence of diabetes mellitus and thyroid abnormalities, this diagnosis alone is not sufficient to meet this minor criterion.
c Approximately 50% of patients will have bone marrow changes that distinguish it from a typical MGUS or myeloma bone marrow. Anemia and/or thrombocytopenia are
distinctively unusual in this syndrome unless Castleman disease is present.
Reprinted with permisson: Dispenzieri A. Am J Hematol 2019;94:812-827.

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Table 2 Response Criteria for POEMS Syndrome
Parameter Evaluable Complete Response Improvement Progressiona
Plasma VEGF 2x ULN Normalb 50% reduction from 50% increase from lowest level
baselineb
Hematologic M-spike 0.5 g/dL,c Negative serum and urine 50% reduction of M-spike 25% increase from lowest level,
1.0 g/dLd,e IFE and bone marrowb from baselinef which must be >0.5 g/dL
PET/CT At least one lesion with No FDG uptake 50% reduction in sum of 30% increase in sum of SUVmaxg
FDG SUVmaxg SUVmaxg from lowest level which must
be at least 4 SUVmaxg OR
appearance of new FDG avid
lesion
mNIS +7POEMS All patients ... 15% decrease from 15% increase from lowest value
baseline (a minimum of 10 (a minimum of 10 points)
points)
Ascites/effusion/edema Present Absent Improved by 1 CTCAE Worsened by 1 CTCAE grade
grade from baseline from lowest grade
ECHO RVSP ≥40 mm Hg ... <40 mm Hg
Papilledema Present Absent Worsening by 1 CTCAE grade
DLCO <70% predicted ≥70% predicted ... Worsening by 1 CTCAE grade
Abbreviations:CTCAE, common terminology criteria for adverse events, IFE, immunofixation electrophoresis, ECHO RVSP, echocardiogram right ventricular systolic pressure, DLCO, diffusing
capacity of carbon monoxide.
a Any progression event (VEGF, hematologic, or clinical will be considered progression, assuming d For PR evaluable.
change is attributable to disease and not an adverse event). To document progression, option e Quantitative IgA is acceptable surrogate for M-spike
exists for repeating value. If confirmed, progression date is first date of suspected progression. for proteins migrating in the beta region.
b For VEGF, M-spike, and IFE response documentation, blood values need to be repeated for f VGPR is defined as no measurable monoclonal protein
verification. on serum or urine electrophoresis, but positive IFE.
c For VGPR evaluable. g By body weight.
Reprinted with permisson: Dispenzieri A. Am J Hematol 2019;94:812-827.

POEMS-4

Table of Contents
ABBREVIATIONS
ADL activities of daily living H&P history and physical NGS next generation sequencing SNP single nucleotide
polymorphism
AKI acute kidney injury HCT hematopoietic cell transplant NGF next-generation flow
SPEP serum protein
electrophoresis
AS-PCR allele-specific polymerase chain HIV human immunodeficiency virus NT- N-terminal pro hormone B-type
reaction proBNP natriuretic peptide
SUV standardized uptake
Ig immunoglobulin value
BMPC bone marrow plasma cell NCS nerve conduction study
ISS International Staging System UIFE urine immunofixation

BUN blood urea nitrogen POEMS polyneuropathy, organomegaly, electrophoresis
edocrinopathy, monoclonal
IMiD Immunomodulatory drug protein, skin change
BNP b-type natriuretic peptide UPEP urine protein
electrophoresis
IMPEDE IMiD, BMI, Pathologic fracture, PFS progression free survival
CAR-T chimeric antigen receptor T-cell
ESA (erythropoietin stimulating
therapy ULN upper limit of normal
agent), Dexamethasone/
Doxorubicin, Ethnicity PI proteasome-inhibitor
CBC complete blood count VTE venous
LDH lactate dehydrogenase PR partial response thromboembolism
CLcr creatinine clearance
LMWH low-molecular-weight heparin PCR polymerase chain reaction VEGF vascular endothelial
growth factor
eGFR established glomerular filtration
rate MFC multicolor flow cytometry OS overall survival
VGPR very good partial
EMG electromyogram response
MGUS monoclonal gammopathy of R-ISS revised International Staging
undetermined significance System
FDG flurodeoxyglucose WM/LPL Waldenstrom
Macroglobulinemia/
MM multiple myeloma SAVED Surgery within 90 days, Asian
lymphoplasmacytic
MRD minimal residual disease race, Venous thromboembolism
FISH fluorescence in situ hybridization lymphoma
history, age over Eighty (80),
dexamethasone
FLC free light chain MGRS monoclonal gammopathy of renal
significance
SIFE serum immunofixation
FLCr serum free light chain ratio electrophoresis
MGNS monoclonal gammopathy of
neurological significance
GFR glomerular filtration rate
ABBR-1

Table of Contents
NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.
CAT-1
NCCN Guidelines Version 1.2023

Multiple Myeloma
Discussion This discussion corresponds to the NCCN Guidelines for Supportive Care for Multiple Myeloma ...................................... MS-39
Multiple Myeloma. Last updated: October 19th, 2020.
Note: Regimens containing panobinostat were removed Management of Renal Disease in Multiple Myeloma ................. MS-42
due to market withdrawal of the agent (Dec 14th, 2021).
Monoclonal gammopathy of Clinical significance (MGCS) ....... MS-44
Table of Contents
Monoclonal Gammopathy of Renal Significance (MGRS) ........... MS-44
Overview ........................................................................................ MS-2 Initial Workup ............................................................................ MS-44
Literature Search Criteria and Guidelines Update Methodology . MS-2 Treatment ................................................................................. MS-44
Diagnosis and Workup .................................................................. MS-2 Monoclonal Gammopathy of Neurological Significance (MGNS) MS-46
Solitary Plasmacytoma ................................................................. MS-5 POEMS Syndrome ...................................................................... MS-47
Primary Therapy for Solitary Plasmacytoma ............................ MS-6 References .................................................................................. MS-48
Surveillance/Follow-up Tests for Solitary Plasmacytoma ........ MS-6
Smoldering (Asymptomatic) Myeloma.......................................... MS-6
Primary Therapy for Smoldering (Asymptomatic) Myeloma .... MS-7
Surveillance/Follow-up Tests for Smoldering (Asymptomatic)

Myeloma ..................................................................................... MS-8
Active (Symptomatic) Multiple Myeloma ...................................... MS-8
Primary Therapy for Active (Symptomatic) Multiple Myeloma . MS-8
Monitoring After Primary Myeloma Therapy of Both Transplant

and Non-Transplant Candidates .............................................. MS-20
Hematopoietic Cell Transplantation ....................................... MS-20
Follow-Up After Hematopoietic Cell Transplantation ............. MS-25
Maintenance Therapy............................................................... MS-25
Therapy for previously treated Multiple Myeloma .................. MS-27
Version 1.2023 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
MS-1

Multiple Myeloma
Overview The complete details of the development and update of the NCCN
Multiple myeloma (MM) is a malignant neoplasm of plasma cells that Guidelines are available at www.NCCN.org.
accumulate in bone marrow, leading to bone destruction and marrow
Diagnosis and Workup
failure. MM accounts for about 1.8% of all cancers and 18% of
hematologic malignancies in the United States.1 MM is most frequently It is important to distinguish MM from other plasma cell
diagnosed among people aged 65 to 74 years, with the median age being neoplasms/dyscrasias in order to determine prognosis and provide
69 years.2 The American Cancer Society has estimated 32,270 new MM appropriate treatment.
cases in the United States in 2020, with an estimated 12,830 deaths.1
The initial diagnostic workup in all patients should include a history and
Literature Search Criteria and Guidelines Update physical examination. To differentiate symptomatic and asymptomatic MM
Methodology the following baseline laboratory studies are needed: a complete blood
count (CBC) with differential and platelet counts; examination of peripheral
An electronic search of the PubMed database was performed to obtain
blood smear; blood urea nitrogen (BUN); serum creatinine; creatinine
key literature in MM published since the last update of this Discussion
clearance (calculated or measured directly) and serum electrolytes; liver
section, using the following search terms: Smoldering Multiple Myeloma,
function tests, serum calcium; albumin; lactate dehydrogenase (LDH); and
Solitary Plasmacytoma, Multiple Myeloma, Monoclonal Gammopathy of
beta-2 microglobulin.
Undetermined Significance, POEMS syndrome. The PubMed database
was chosen as it remains the most widely used resource for medical Peripheral smear may show abnormal distribution of red blood cells such
literature and indexes biomedical literature.3 as the Rouleaux formation (red cells taking on the appearance of a stack
of coins) due to elevated serum proteins.4 Increased BUN and creatinine
The search results were narrowed by selecting studies in humans
indicate decreased kidney function, whereas LDH and beta-2
published in English. Results were confined to the following article types:
microglobulin levels reflect tumor cell characteristics.
Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;
Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic Serum and Urine Analysis: Serum analysis includes quantitative
Reviews; and Validation Studies. The results of the PubMed search were immunoglobulin levels (IgG, IgA, and IgM); serum protein electrophoresis
examined for their potential relevance. The data from key PubMed articles (SPEP) for quantitation of monoclonal protein; and serum immunofixation
as well as articles from additional sources deemed as relevant to these electrophoresis (SIFE) to obtain more specific information about the type
guidelines and discussed by the Panel have been included in this version of M-protein present. Assessing changes in levels of various proteins,
of the Discussion section (eg, e-publications ahead of print, meeting particularly the M-protein, helps track disease progression and response
abstracts). Any recommendations for which high-level evidence is lacking to treatment. Urine analysis as a part of the initial diagnostic workup
are based on the Panel’s review of lower-level evidence and expert includes evaluating 24-hour urine for total protein; urine protein
opinion. electrophoresis (UPEP), and urine immunofixation electrophoresis (UIFE).
MS-2

Multiple Myeloma
Free Light-chain Assay: The serum FLC assay along with serum analyses Metaphase cytogenetics may provide additional information. Specific
(SPEP and SIFE) yields high sensitivity while screening for MM and chromosomal abnormalities have been identified in patients with MM
related plasma cell disorders.5 It is also helpful in prognostication of involving translocations, deletions, or amplifications.
monoclonal gammopathy of undetermined significance (MGUS),
smoldering myeloma, active MM, immunoglobulin light chain amyloidosis, Deletion of 17p13 (the locus for the tumor-suppressor gene, p53) leads to
and solitary plasmacytoma.5,6 The serum FLC assay also allows for loss of heterozygosity of TP53 and is considered a high-risk feature in
quantitative monitoring of patients with light chain amyloidosis and light MM.10-12 Higher proportion of myeloma cells with the abnormality as well as
chain myeloma. In addition to all of the above, the FLC ratio (FLCr) is mutation of the remaining allele significantly enhances the risk. Other
required for documenting stringent complete response (sCR) according to high-risk chromosomal aberrations in MM are characterized by structural
the International Myeloma Working Group (IMWG) Uniform Response changes that include specific rearrangements involving the IGH gene
Criteria.7 The serum FLC assay cannot replace the 24-hour UPEP for (encoding immunoglobulin heavy chain), located at 14q32. Several
monitoring patients with measurable urinary M-protein and can also be subgroups of patients are identified on the basis of 14q32 translocations.
affected by renal function. Once the M-protein is quantified, it is important The main translocations are the t(11;14)(q13;q32), t(4;14)(p16;q32),
to use the same test for serial studies to ensure accurate relative t(14;16)(q32;q23), and t(14;20)(q32;q12). Several studies have confirmed
quantification. that MM patients with t(4;14), t(14;16), and t(14;20) have a poor prognosis,
while t(11;14) is believed to impart less risk.13-16 del(13q) is a common
Bone Marrow Evaluation: The percentage of clonal bone marrow plasma abnormality that is observed on FISH studies, but is a negative prognostic
cells (≥10%) is a major criterion for the diagnosis of MM. The percentage factor only when observed on metaphase cytogenetics. Abnormalities of
of plasma cells in bone marrow is estimated by unilateral bone marrow chromosome 1 are also among the frequent chromosomal alterations in
aspiration and biopsy. Immunohistochemistry and/or flow cytometry can MM.17 The short arm is most often associated with deletions and the long
be used to confirm presence of monoclonal plasma cells, and to more arm with amplifications.18 Gains/amplification of 1q21 as well as 1p
accurately quantify plasma cell involvement.8 The cytoplasm of abnormal deletion increases the risk of MM progression and incidence of the
plasma cells contain either kappa or lambda light chains, and amplification is higher in relapsed than in newly diagnosed patients.17,19
predominance of one or the other light chain expressing plasma cells
indicate clonality. Specific immunophenotypic profiles of the myeloma cells Stratification of patients into various risk groups based on the
may have prognostic implications.9 chromosomal markers is being utilized by some centers for prognostic
counseling, selection, and sequencing of therapy approaches.20,21
Cytogenetic Studies: Although MM may be morphologically similar, According to the NCCN Multiple Myeloma Panel members, the FISH panel
several subtypes of the disease have been identified at the genetic and for prognostic estimation of plasma cells should examine for del 13, del
molecular level. Bone marrow studies at initial diagnosis should include 17p13, t(4;14), t(11;14), t(14;16), t(14:20), 1q21 gain/amplification, and 1p
chromosome analysis by fluorescence in situ hybridization (FISH) deletion. The utility of this information is to determine biological subtype
performed on the plasma cells obtained from bone marrow aspiration.
MS-3

Multiple Myeloma
and for prognostic recommendations as well as candidacy for clinical bones is acceptable where advanced imaging is not available (eg. in low
trials. resource settings). CT contrast agents are not necessary for detection of
myeloma bone disease and should be generally avoided in myeloma
Imaging: A skeletal survey has been the standard for decades for patients whenever possible.
assessing bone disease for any individual with suspected MM.22 However,
this technique has significant limitations related to lower sensitivity Additional Diagnostic Tests
compared to advanced imaging. CT alone or in combination with FDG The NCCN Multiple Myeloma Panel recommends additional tests that may
PET has been shown to be significantly superior regarding the sensitivity be useful in some circumstances. MRI is useful for discerning smoldering
to detect osteolytic lesions in patients with monoclonal plasma cell myeloma from MM. Since the disease burden in patients with smoldering
disorders. In a multi-center analysis by the IMWG conventional skeletal myeloma is lower than those with MM, imaging techniques with high
survey was compared with whole-body CT scans from 212 patients with sensitivity need to be used and MRI is a sensitive technique for detecting
monoclonal plasma cell disorders. Whole-body CT was positive in 25.5% marrow infiltration by myeloma.30,31 According to the NCCN Panel, if
of patients with negative skeletal survey. The sensitivity of the skeletal whole-body low-dose CT or FDG PET/ CT is negative, consider whole-
survey and whole-body low-dose CT in the long bones is not significantly body MRI without contrast to discern smoldering myeloma from MM.
different, the difference is mainly in detection of abnormalities in spine and
pelvis.23,24 In a study of 29 patients, 5 (17%) showed osteolytic lesions in A tissue biopsy may also be necessary to confirm the presence of
CT while skeletal survey results were negative.25 Furthermore, studies plasmacytomas. Plasma cell proliferation assays may be helpful to identify
have shown whole-body low-dose CT is superior to skeletal survey the fraction of proliferating myeloma cell population.32 Also, if amyloidosis
radiographs in areas that are difficult to visualize with skeletal surveys is suspected, the diagnosis is established by following the
such as skull and ribs.26 recommendations outlined in the NCCN Guidelines for Systemic Light
Chain Amyloidosis.
FDG PET/CT too has been shown to identify more lesions than plain x-
rays and detect lesions in patients with negative skeletal surveys.27-29 It is Serum viscosity should be evaluated when clinical symptoms of
important to note that if PET/CT is chosen instead of whole-body low-dose hyperviscosity are suspected, particularly in those with high levels of M-
CT, the imaging quality of the CT part of the PET/CT should be equivalent protein.
to a whole-body low-dose CT. Usually the CT part is used only for
Human leukocyte antigen (HLA)-type must be obtained, if a patient is
attenuation correction, which may not be sufficient to assess bone disease
being considered for allogeneic transplant.
due to MM and stability of the spine. Whole body PET/CT is useful in
detecting extramedullary disease outside of the spine. Single nucleotide polymorphism (SNP) array and/or next generation
sequencing (NGS) panel on bone marrow help provide a more detailed
For initial diagnostic workup of patients suspected of having MM, the
evaluation of MM genetics allows for further risk categorization through the
NCCN Panel recommends, either whole-body low-dose CT or FDG
identification of additional abnormalities that may be of prognostic and/or
PET/CT. The Panel has also noted that skeletal survey including long
MS-4

Multiple Myeloma
therapeutic value.33 Therefore, the NCCN Multiple Myeloma Panel has focal marrow (non-osteolytic) lesion 34 All of these myeloma defining
included these tests as useful adjunct in certain circumstances. events are referred to as SLiM-CRAB.
The Panel also suggests baseline clone identification or storage of bone The criteria by the IMWG for smoldering (asymptomatic) patients include
marrow aspirate sample for clone identification for future minimal residual serum M-protein (IgG or IgA) ≥30 g/L and/or clonal bone marrow plasma
disease (MRD) testing by NGS if required, and also assessment for cells 10% to 59% and absence of CRAB features, myeloma-defining
circulating plasma cells in peripheral blood, as clinically indicated. events, or amyloidosis.34 The updated IMWG diagnostic criteria for MM
allow initiation of therapy before end-organ damage on the basis of
Clinical Findings specific biomarkers, and also allow the use of sensitive imaging criteria to
Based on the results of the clinical and laboratory evaluation, patients are diagnose MM, including whole-body FDG PET/CT and MRI.34 Recently, a
initially classified as either MGUS, solitary plasmacytoma, smoldering study analyzed clinical and laboratory information from 421 patients with
(asymptomatic) disease or active (symptomatic) disease. More recently, smoldering myeloma and identified monoclonal protein greater than 2g/dL,
patients with an MGUS who have systemic effect related to the FLCr of greater than 20, and greater than 20% plasma cells as important
monoclonal gammopathy have been variably classified as having risk factors for progression. Patients with 2 or more of these features had
monoclonal gammopathy of clinical significance or monoclonal a median time to progression (TTP) of 29 months.35
gammopathy of renal significance, depending on the nature of organ
involvement. Those with active MM can be staged using the International Staging
System (ISS).36 The ISS is based on easily obtained laboratory measures
The IMWG recently updated the disease definition of MM to include (serum beta-2 microglobulin and serum albumin) and is easier to use than
biomarkers in addition to existing requirements of CRAB features.34 The the Durie-Salmon Staging System for patients with previously untreated
CRAB criteria that define MM include: increased calcium levels (greater MM. The ISS has been revised (R-ISS) to include serum beta-2
than 11.5 mg/dL), renal insufficiency (creatinine greater than 2 mg/dL or microglobulin and serum albumin and prognostic information obtained
creatinine clearance less than 40 mL/min), anemia (hemoglobin less than from the LDH and high-risk chromosomal abnormalities [t(4;14), t(14;16),
10 g/dL or 2 g/dL less than normal), and presence of bone lesions. The 17p13 deletion] detected by FISH and is the preferred staging approach.37
IMWG has also clarified that presence of one or more osteolytic lesions Having del(17p) and/or translocation t(4;14) and/or translocation t(14;16)
seen on skeletal radiography, whole-body MRI, or whole-body FDG are considered as high-risk. Those with no high-risk chromosomal
PET/CT fulfills the criteria for bone disease.34 The MM-defining biomarkers abnormality are considered standard-risk.
identified by the IMWG SLiM features (SLiM- stands for Sixty, Light chain
ratio, MRI) features include one or more of the following: greater than or Solitary Plasmacytoma
equal to sixty percent clonal plasma cells in the bone marrow; The diagnosis of solitary plasmacytoma requires a thorough evaluation
involved/uninvolved free light chain ratio of 100 or more with the involved with advanced imaging studies to rule out the presence of additional
FLC being greater than or equal 100 mg/L; or MRI with more than one
MS-5

Multiple Myeloma
lesions or systemic disease, because many patients presumed to have and head/neck plasmacytoma could be followed less frequently after initial
solitary plasmacytomas are found to have additional sites38,39 3-month follow-up. According to the NCCN Panel, one should consider
using the same imaging modality used during the initial workup for the
Primary Therapy for Solitary Plasmacytoma follow-up assessments. Bone surveys are inadequate for this type of
The treatment and follow-up options for solitary plasmacytoma or solitary surveillance.
plasmacytoma with minimal marrow involvement (less than 10% plasma
cells in bone marrow) are similar. Radiation therapy has been shown to The blood tests include CBC with differential and platelet count; serum
provide excellent local control of solitary plasmacytomas.40-46 The largest chemistry for creatinine, albumin, and corrected calcium; serum
retrospective study (N = 258) included patients with solitary plasmacytoma quantitative immunoglobulins; and SPEP with SIFE as needed. Testing for
(n = 206) or extramedullary plasmacytoma (n = 52).47 Treatments included serum FLC assay, LDH, and beta-2 microglobulin may be useful in some
RT alone (n = 214), RT plus chemotherapy (n = 34), and surgery alone (n circumstances.
= 8). Five-year overall survival (OS) was 74%, disease-free survival was
The urine tests include 24-hour urine assay for total protein, UPEP, and
50%, and local control was 85%. Patients who received localized RT had
UIFE.
a lower rate of local relapse (12%) than those who did not (60%).46
Bone marrow aspirate and biopsy, and imaging studies using whole-body
The optimal radiation dose for treatment of solitary plasmacytomas is not
MRI or low-dose CT or whole-body FDG PET/CT are recommended as
known. The dose used in most published papers ranges from 30 to 60
clinically indicated. PET imaging may detect early bone marrow
Gy.45,46,48
involvement in patients with solitary plasmacytoma.50-52 Imaging studies
For those patients with osseous plasmacytoma, the NCCN Panel are recommended yearly, preferably with the same technique used at
recommends primary radiation therapy (40–50 Gy in 1.8–2.0 Gy/fraction) diagnosis, for at least 5 years.
to the involved field. Occasionally, surgery may be performed if a lesion
If progression to MM occurs, then the patient should be re-evaluated as
causes structural instability or neurologic compromise. For extraosseous
described in Diagnosis and Workup, and systemic therapy must be
plasmacytomas primary treatment is radiation therapy (40–50 Gy in 1.8–
administered as clinically indicated.
2.0 Gy/fraction)43 to the involved field with surgery,49 if clinically necessary.
Smoldering (Asymptomatic) Myeloma
Surveillance/Follow-up Tests for Solitary Plasmacytoma
Smoldering (asymptomatic) myeloma describes a stage of disease with no
Follow-up and surveillance tests for solitary plasmacytoma consist of
symptoms and no related organ or tissue impairment.53 Patients with
blood and urine tests and imaging. Serial measurements to check for re-
asymptomatic smoldering MM may have an indolent course for many
emergence or appearance of M-protein are required to confirm disease
years without therapy.
sensitivity to radiation therapy. The recommended follow-up interval for
these patients is every 3 to 6 months; however, patients with soft tissue
MS-6

Multiple Myeloma
Primary Therapy for Smoldering (Asymptomatic) Myeloma In a larger multicenter phase III randomized trial, patients with
Smoldering myeloma is a precursor to MM. All patients with smoldering smoldering myeloma (n= 182) were either treated with lenalidomide until
myeloma have a risk of progression to MM.54 However, the rate of progression or observed. The lenalidomide group experienced improved
progression varies from months to several years based on certain risk progression-free survival (PFS) and decreased end organ damage (eg,
features.54 renal failure, bone lesions) when compared with those who were
observed.57 Grade 3 or 4 adverse events were reported in 41% of
The historic approach for management of smoldering myeloma has been patients treated with lenalidomide.57 On subgroup analysis, the PFS
close observation. However, recently there has been mounting evidence benefit was seen in those with high-risk smoldering myeloma but was
that those with high-risk features may benefit from early intervention. less clear in those with low- or intermediate-risk disease.57
A relatively small, randomized, prospective, phase III study by the The Mayo 2018 20/2/20 criteria stratify patients based on risk. The criteria
PETHEMA group investigated whether early treatment with lenalidomide take into consideration the following risk factors: percentage of bone
and dexamethasone in patients (n = 119) with smoldering myeloma, at marrow plasma cells (BMPC) greater than 20%, M-protein greater than 2
high risk of progression to active MM, prolongs the TTP.55 The high-risk g/dL, and FLCr greater than 20. Patients with two or more of the above
group in the study was defined using the following criteria: plasma cell risk factors are considered to have high risk. These risk factors were
bone marrow infiltration of at least 10% and/or a monoclonal component developed from a retrospective study of patients with smoldering myeloma
(defined as an IgG level of greater than or equal to 3 g/dL, an IgA level of (n= 417). In those with high risk (≥ 2 factors present), the estimated
greater than or equal to 2 g/dL, or a urinary Bence Jones protein level of median TTP was 29 months, in those with intermediate risk (1 factor
great than 1 g per 24 hours); and at least 95% phenotypically aberrant present), the estimated median TTP was 68 months, and for those with
plasma cells in the bone marrow infiltrate. The OS reported in the trial at 3 low risk (none of the risk factors present), the estimated median TTP
years was higher in the group treated with the lenalidomide and was110 months.35
dexamethasone arm (94% vs. 80%; HR, 0.31; 95% CI, 0.10–0.91; P =
.03).55 At a median follow-up of 75 months (range, 27–57 months), The Mayo 2018 20/2/20 criteria were validated in a large retrospective
treatment with lenalidomide and dexamethasone delayed median TTP to analysis of 2004 patients with smoldering myeloma.58 The estimated
symptomatic disease compared to no treatment (TTP was not reached in progression rates at 2 years among those with low-, intermediate-, and
the treatment arm compared to 23 months in the observation arm; HR, high-risk disease were 5%, 17%, and 46% respectively.58
0.24; 95% CI, 0.14–0.41).56 The high OS rate seen after 3 years was also
The NCCN Panel suggests using the Mayo 2018/IMWG 20/2/20 criteria to
maintained (HR, 0.43; 95% CI, 0.20–0.90). According to the NCCN Panel,
stratify patients based on risk. According to the NCCN Panel, the low risk
the flow cytometry-based high-risk criteria specified in the study is not
group should be managed by enrolling in a clinical trial or observe at 3- to
uniformly available and participants did not receive advanced imaging.
6-month intervals (category 1). For the high-risk group, the NCCN Panel
Based on the criteria used in the trial, some patients with active myeloma
prefers enrollment in an ongoing clinical trial or treatment with single-agent
were classified as having high-risk smoldering myeloma.
lenalidomide only in carefully selected patients (category 2B)55,57 or
MS-7

Multiple Myeloma
observation at 3-month intervals, as clinically indicated. Those with rising Stem cell toxins, such as nitrosoureas or alkylating agents compromise
markers or high-risk factors must be monitored closely. stem cell reserve. Regimens with these agents (notably melphalan) should
be avoided in patients who are potential candidates for HCT until stem
Surveillance/Follow-up Tests for Smoldering (Asymptomatic) cells are collected.
Myeloma
The surveillance/follow-up tests for smoldering myeloma include CBC with One of the first steps in evaluating newly diagnosed patients with MM is to
differential and platelet count; serum chemistry for creatinine, albumin, determine whether they are candidates for high-dose therapy and
corrected calcium, serum quantitative immunoglobulins, SPEP, and SIFE; transplant, based on age and comorbidities. However, it should be noted
and serum FLC assay as clinically indicated. The urine tests include 24- that advanced age and renal dysfunction are not absolute
hour urine assay for total protein, UPEP, and UIFE. contraindications to transplant. Therefore, referral to an HCT center to
assess whether patient is eligible for HCT is important.
Bone marrow aspirate and biopsy with FISH, SNP array, NGS, or
multiparameter flow cytometry may be used as clinically indicated. The page titled Myeloma Therapy in the algorithm has a list of primary
therapy regimens recommended by the NCCN Multiple Myeloma Panel
Imaging studies with MRI without contrast, whole-body low-dose CT members for transplant eligible and non-transplant candidates and also
and/or CT and/or whole-body FDG PET/CT are recommended annually or lists drugs recommended for maintenance therapy in each setting. The list
as clinically indicated. The NCCN Panel recommends considering using is selected and is not inclusive of all regimens.
the same imaging modality used during the initial workup for the follow-up
assessments. The NCCN Multiple Myeloma Panel has categorized all myeloma therapy
regimens as: “preferred,” “other recommended,” or “useful in certain
If the disease progresses to symptomatic myeloma, then patients should circumstances.” The purpose of classifying regimens as such is to convey
be treated according to the guidelines for symptomatic MM. the sense of the Panel regarding the relative efficacy and toxicity of the
regimens. Factors considered by the Panel include evidence, efficacy,
Active (Symptomatic) Multiple Myeloma toxicity, pre-existing comorbidities such as renal insufficiency, and in some
Newly diagnosed MM is typically sensitive to a variety of classes of drugs: cases access to certain agents.
immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and
monoclonal antibodies. The NCCN Panel prefers 3-drug regimens as the standard for primary
treatment of all patients who are transplant eligible. This is based on
Primary Therapy for Active (Symptomatic) Multiple Myeloma improved response rates, depth of response, and rates of progression-free
Patients presenting with active (symptomatic) myeloma are initially treated survival (PFS) or OS seen with 3-drug regimens in clinical trials. The
with primary therapy and primary therapy is followed by high-dose doublet regimens are no longer recommended for transplant candidates
chemotherapy with autologous hematopoietic cell transplant (HCT) in with the rationale that doublets would be recommended for patients who
transplant-eligible patients. would not be considered for initial treatment with a three-drug regimen
MS-8

Multiple Myeloma
such as those not initially eligible for transplant. For non-transplant The NCCN Panel has noted that subcutaneous administration is the
patients, the 2- drug regimens are still listed as options with a note that a preferred route for bortezomib. This is based on the results of the MMY-
triplet regimen is the standard therapy but patients who cannot tolerate a 3021 trial. The trial randomized patients (n=222) to single-agent
3-drug regimen due to poor performance status, can be started with a 2- bortezomib administered either by the conventional intravenous (IV) route
drug regimen, and the third drug can be added if the performance status or by subcutaneous route.60 The findings from the study demonstrate non-
improves. inferior efficacy with subcutaneous versus IV bortezomib with regard to the
primary endpoint (overall response rate [ORR] after 4 cycles of single-
It is also important to consider supportive care for all patients at diagnosis. agent bortezomib). The results showed no significant differences in terms
For example, 80% of patients have bone disease and up to 33% have of PFS or 1-year OS between groups.60,61 However, patients receiving
renal compromise. In all patients, careful attention to supportive care is bortezomib subcutaneously had a significant reduction in peripheral
critical to avoid early complications that may compromise therapeutic neuropathy.
outcome.
Carfilzomib can potentially cause cardiac, renal, and pulmonary
Bone disease, renal dysfunction, and other complications such as toxicities.62 Careful assessment before initiating treatment with carfilzomib
infections, hypercalcemia, hyperviscosity, and coagulation/thrombosis and close monitoring during treatment is recommended.62 Regarding
should be treated with appropriate adjunctive measures (see Supportive dosing and administration, carfilzomib may be used once or twice weekly
Care Treatment for Multiple Myeloma in this Discussion). and at different doses.
While weekly and twice-weekly dosing schemas of bortezomib are A randomized trial has compared two formulations of daratumumab as
considered appropriate, weekly dosing is preferred. Twice-weekly monotherapy. The subcutaneous formulation of daratumumab and
bortezomib can be associated with neuropathy that may limit efficacy due hyaluronidase-fihj resulted in a similar ORR, PFS, and safety profile and
to treatment delays or discontinuation. Therefore, Reeder et al modified fewer infusion-related reactions compared with the IV daratumumab63.
the regimen to a once-weekly schedule of bortezomib.59 In the study, According to the NCCN Panel, daratumumab IV infusion or
patients treated with weekly bortezomib achieved responses similar to the daratumumab and hyaluronidase-fihj, subcutaneous injection may be
twice-weekly schedule (ORR, 93% vs. 88%; very good partial response used in all daratumumab-containing regimens. Some patients may not be
(VGPR), 60% vs. 61%). In addition, they experienced less grade 3/4 appropriate for subcutaneous treatment, for example those with
adverse events (37%/3% vs. 48%/12%). Fewer dose reductions of significant thrombocytopenia.
bortezomib/dexamethasone were required in the modified schedule and
neuropathy rates were the same in both cohorts, even though the total Preferred Primary Therapy Regimens for Newly Diagnosed Transplant
bortezomib dose per cycle was higher in the weekly versus the twice- Candidates
weekly schedule (6.0 mg/m2 vs. 5.2 mg/m2).59 The preferred primary therapy options for patients who are HCT eligible
include bortezomib/lenalidomide/dexamethasone and
bortezomib/cyclophosphamide/dexamethasone.
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Multiple Myeloma
Bortezomib/Lenalidomide/Dexamethasone Bortezomib/lenalidomide/dexamethasone was compared to

Phase II and III studies results have shown that primary therapy with lenalidomide/dexamethasone in the multicenter phase III SWOG S077
bortezomib/lenalidomide/dexamethasone is active and well tolerated in trial.67 Patients (n = 525) with previously untreated MM were randomly
newly diagnosed patients with MM, transplant eligible as well as transplant assigned to receive 6 months of induction therapy with either
ineligible. bortezomib/lenalidomide/dexamethasone (N = 264) or
lenalidomide/dexamethasone (N = 261), each followed by maintenance
In the first phase I/II prospective study of therapy with lenalidomide/dexamethasone until progression or
lenalidomide/bortezomib/dexamethasone in patients with newly diagnosed unacceptable. The triple-drug regimen group had significantly longer PFS
MM, the rate of partial response (PR) was 100%, with 74% very good (43 months vs. 30 months; HR, 0.712; 96% CI, 0.56–0.906) and improved
partial response (VGPR) or better and 52% complete response (CR)/near median OS (75 months vs. 64 months; HR, 0.709; 95% CI, 0.524–
CR.64 0.959).67 As expected, ≥ grade 3 neuropathy was more frequent in the
bortezomib-containing arm (24% vs. 5%; P < .0001) as bortezomib was
The benefits of bortezomib/lenalidomide/dexamethasone as primary
administered intravenously in this study.67
therapy were also seen in the results of the phase II IFM 2008 trial65 and
phase II EVOLUTION trial.66 In the phase II IFM 2008 trial, patients With longer-term follow up (median 84 months), the benefits of adding
received bortezomib, lenalidomide, and dexamethasone as induction bortezomib to lenalidomide and dexamethasone were seen to be
therapy followed by HCT.65 Patients subsequently received two cycles of maintained.68 The PFS with Bortezomib/lenalidomide/dexamethasone was
bortezomib/lenalidomide/dexamethasone as consolidation cycles and 1- 41 months versus 29 months for lenalidomide/dexamethasone.68 The OS
year lenalidomide maintenance. VGPR rate or better at the completion of was not yet reached (>84 months) with the bortezomib regimen versus 69
induction was 58%.65 After transplantation and consolidation therapy the months for lenalidomide/dexamethasone.68
rate of VGPR or better was 70% and 87%, respectively.65
A randomized multicenter phase 3 trial (ENDURANCE E1A11) studied
The phase II EVOLUTION trial was designed to examine the tolerability newly diagnosed patients (n=1053) with MM treated with either
and efficacy of combining bortezomib/lenalidomide/dexamethasone or
bortezomib/cyclophosphamide/lenalidomide/dexamethasone versus carfilzomib/lenalidomide/dexamethasone as induction therapy. Patients
bortezomib/lenalidomide/dexamethasone versus with high-risk features (with the exception of patients with t(4;14)) were
bortezomib/cyclophosphamide/dexamethasone in a randomized not included in this trial. After a median follow-up of 9 months, median
multicenter setting.66 The ORR after primary treatment with PFS was 34.4 months with the bortezomib-regimen versus 34.6 months
bortezomib/lenalidomide/dexamethasone followed by maintenance with with the carfilzomib regimen.69 A response of VGPR or better was seen
bortezomib was 85% (51% ≥ VGPR and 24% CR) and corresponding one- in 65% of patients treated with bortezomib/lenalidomide/dexamethasone
year PFS was 83% in the bortezomib/lenalidomide/dexamethasone arm.66 and 74% of patients treated with
carfilzomib/lenalidomide/dexamethasone (P =.0015). With respect to
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Multiple Myeloma
adverse events, the carfilzomib regimen was associated with less Analysis of the German DSMM XIa study also demonstrated high
peripheral neuropathy but more cardiac, pulmonary and renal toxicities.69 responses with CyBorD as primary treatment (ORR was 84%, with 71.5%
PR rate and 12.5% CR rate). High response rates were seen in patients
In order to minimize the toxicities seen with the standard-dose of with unfavorable cytogenetics.72
bortezomib/lenalidomide/dexamethasone, a phase II study evaluated
the efficacy of dose-adjusted bortezomib/lenalidomide/dexamethasone In the updated results of the phase II EVOLUTION study, primary
(VRd-lite). 70 The VRd-lite regimen included subcutaneous bortezomib treatment with CyBorD demonstrated an ORR of 75% (22% CR and 41%
(1.3 mg/m2) on days 1, 8, 15 and 22, and oral dexamethasone (20 mg) ≥ VGPR), and the 1-year PFS rate was 93%.66
on the day of and the day after bortezomib administration. Lenalidomide
was omitted on days 1, 8 and 15, which are the days of bortezomib Based on data from these and other phase II studies, the NCCN Multiple
administration. The ORR after four cycles of VRd-lite was 83%, including Myeloma Panel has now included the combination of
a CR of 25%. The ORR and VGPR or better were further improved to cyclophosphamide/bortezomib/dexamethasone to the list of primary
100% and 74%, in those who received autologous HCT.70 treatment available for transplant candidates. This is a preferred option,
especially in patients with acute renal insufficiency. According to the
Based on with the above results, NCCN Panel, one can consider switching to
bortezomib/lenalidomide/dexamethasone, the NCCN Panel included this bortezomib/lenalidomide/dexamethasone after renal function improves.
regimen as a category 1, preferred option for primary treatment of
Other Recommended Primary Therapy Regimens for Newly Diagnosed
transplant-eligible patients with MM.
Transplant Candidates
Bortezomib/Cyclophosphamide/Dexamethasone Carfilzomib/Lenalidomide/Dexamethasone
Data from three phase II studies involving newly diagnosed patients with Carfilzomib is a second-generation PI that binds highly selectively and
MM have demonstrated high response rates with cyclophosphamide, irreversibly to the proteasome. It is administered intravenously.
bortezomib, and dexamethasone (CyBorD) as primary treatment.66,71,72 The A multicenter phase I/II trial evaluated the combination of carfilzomib,
trial by Reeder et al carried out in the United States and Canada lenalidomide, and dexamethasone in newly diagnosed patients with MM.74
demonstrated an ORR of 88% including a VGPR or greater of 61% and In this trial, patients (n = 53) received carfilzomib with lenalidomide and
39% CR/near CR with CyBorD as the primary regimen.71 The depth of low-dose dexamethasone. After 4 cycles, Hematopoietic cells were
response seen after primary treatment was maintained after transplant in collected from eligible patients.74 Out of 35 patients from whom
those who underwent transplantation (70% rates of CR/near CR; rate of at hematopoietic cells were collected, 7 proceeded to transplantation, and
least VGPR or better was 74%).71 According to the long-term follow-up the remainder continued with carfilzomib/lenalidomide/dexamethasone.74
analysis, the 5-year PFS and OS rates were 42% (95% CI, 31–57) and With median follow-up of 13 months, 24-month PFS was estimated at
70% (95% CI, 59–82).73 92%.The most common grade 3 and 4 toxicities in ≥10% of patients
included hypophosphatemia (25%), hyperglycemia (23%), anemia (21%),
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Multiple Myeloma
thrombocytopenia (17%), and neutropenia (17%). Peripheral neuropathy cardiac adverse events were 4% for all grades (0% grade 3/4),
was limited to grade 1/2 (23%).74 hypertension was 16% (4% grade 3/4), and dyspnea was 32% (3% grade
3/4).77
Another phase II trial also evaluated the same regimen (carfilzomib in
combination with lenalidomide and dexamethasone) in newly diagnosed The results of the phase III ENDURANCE trial69 showed similar PFS with
patients (n = 45) with MM. After 8 cycles of treatment, patients with stable carfilzomib/lenalidomide/dexamethasone versus
disease (SD) received up to 24 cycles of lenalidomide 10 mg/day on days bortezomib/lenalidomide/dexamethasone. However, as mentioned
1 to 21.75 Thirty-eight patients were evaluable for response and previously, high risk patients were not included.
toxicity. After a median follow-up of 10 months, PFS was 83.3%. Twenty- Carfilzomib/lenalidomide/dexamethasone was associated with less
five patients completed 8 cycles of the carfilzomib, lenalidomide, and neuropathy but more dyspnea, hypertension, heart failure, and acute
dexamethasone regimen, of which 24 continued to lenalidomide therapy kidney injury compared with bortezomib/lenalidomide/dexamethasone.69
and 1 patient opted to exit the study after initial therapy. The most
common non-hematologic and hematologic toxicities (≥ grade 3) in >10% Based on the data from the above studies, the NCCN Panel has included
of patients included electrolyte disturbances (18%), liver function test the carfilzomib/lenalidomide/ dexamethasone regimen as an option for
elevation (13%), rash/pruritus (11%), fatigue (11%), lymphopenia (63%), primary treatment of transplant-eligible patients with MM.
anemia (16%), leukopenia (13%), and thrombocytopenia (11%).76
Daratumumab/Lenalidomide/Bortezomib/Dexamethasone
The results of another phase 2 trial multicenter study of The benefit of adding a fourth drug for the primary treatment transplant-
carfilzomib/lenalidomide/dexamethasone in newly diagnosed transplant- eligible patients is emerging. In the GRIFFIN trial, transplant-eligible
eligible patients (n = 76) showed that CR or better was seen in 86% of patients with MM (n= 207) were randomized to daratumumab
patients at the end of 18 cycles for bortezomib/lenalidomide/dexamethasone or
carfilzomib/lenalidomide/dexamethasone plus autologous HCT compared bortezomib/lenalidomide/dexamethasone followed by autologous HCT
to 59% for carfilzomib/lenalidomide/dexamethasone and no autologous plus consolidation and maintenance.78 The rate of stringent complete
HCT. The 3-year PFS was 80% for response rate after autologous HCT and consolidation with 4-drug
carfilzomib/lenalidomide/dexamethasone alone and 86% for regimen was 42% versus 32% with the 3-drug regimen.78 Follow-up after
carfilzomib/lenalidomide/dexamethasone with autologous HCT patients. median of 22 months showed further improved sCR rates for the
The three-year OS was 96% for carfilzomib/lenalidomide/dexamethasone daratumumab-containing 4 drug regimen (62.6% vs 45.4%; P = .0177).78
alone and 95% for carfilzomib/lenalidomide/dexamethasone with Although the hematological toxicities were higher with the 4-drug
autologous HCT. The grade ≥3 adverse events, with autologous HCT regimen, no major safety concerns were reported in the study.78
versus autologous HCT, included lymphopenia (25% vs. 45%),
The NCCN Panel has included
neutropenia (25% vs. 30%), and infection (16% vs. 8%). In the
daratumumab/lenalidomide/bortezomib/dexamethasone as an option for
carfilzomib/lenalidomide/dexamethasone with autologous HCT, the
primary treatment of transplant-eligible patients with MM.
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Multiple Myeloma
Ixazomib/Lenalidomide/Dexamethasone Regimens Useful In Certain Circumstances for Newly Diagnosed

Ixazomib is an oral PI that was approved by the FDA in combination with Transplant Candidates
lenalidomide and dexamethasone for the treatment of patients with MM Bortezomib/Doxorubicin/Dexamethasone
who have received at least one prior therapy. The updated results from the HOVON-65/GMMG-HD4 group phase III trial
of newly diagnosed patients with stage II/III MM demonstrated high
In a phase I/II trial, Kumar et al studied an all-oral combination of
response rates after primary therapy with
ixazomib/lenalidomide/dexamethasone in patients with newly diagnosed
bortezomib/doxorubicin/dexamethasone versus
MM.79 The results of this trial show that the regimen was well tolerated and
vincristine/doxorubicin/dexamethasone (VAD), and this superior response
active in the study population. Out of the 64 patients in whom the
rate (CR + near CR was 31% vs. 15%; P < .001) was maintained even
response could be evaluated, 37 (58%; 95% CI, 45–70) had a VGPR or
after HCT with significantly higher ORR.81 No unexpected toxicities
better. Grade 3 or higher adverse events related to any drug in the
occurred, and del(13q) did not have a significant impact on response.
combination were reported in 41 (63%) patients. These included skin and
Response rates improved with bortezomib maintenance (34% vs. 49%; P
subcutaneous tissue disorders (11 patients, 17%), neutropenia (8 patients,
< .001).81 After a median follow-up of 41 months, PFS in patients treated
12%), and thrombocytopenia (5 patients, 8%); drug-related peripheral
with bortezomib/doxorubicin/dexamethasone as primary therapy followed
neuropathy of grade 3 or higher occurred in 4 (6%) patients.
by HCT and bortezomib maintenance was 35 months versus 28 months in
A phase III trial (TOURMALINE-MM2) evaluated the addition of ixazomib patients treated with VAD followed by HCT and maintenance with
to lenalidomide and dexamethasone versus lenalidomide/dexamethasone thalidomide. Patients treated with bortezomib/doxorubicin/dexamethasone
plus placebo in newly diagnosed MM patients not eligible for autologous had a significantly better PFS (HR, 0.75; 95% CI, 0.62–0.90; P = .002).81
stem cell transplant.80 The results presented at the Eighth SOHO Annual The OS was also found to be better in the bortezomib, doxorubicin, and
Meeting reported higher CR with the addition of ixazomib (26% vs. 14%). dexamethasone arm (HR, 0.77; 95% CI, 0.60–1.00; P = .049). In high-risk
The median TTP was longer in the ixazomib arm (45.8 months vs. 26.8 patients presenting with increased creatinine more than 2 mg/dL,
months; HR, 0.738).80 The median PFS was increased by 13.5 months bortezomib significantly improved PFS from a median of 13 months to 30
with the addition of ixazomib (35.3 months vs. 21.8 months; HR, 0.830; P months (HR, 0.45; 95% CI, 0.26–0.78; P = .004) and OS from a median of
=.073).80 This trial did not meet its pre-specified primary endpoint of 21 months to 54 months (HR, 0.33; 95% CI, 0.16–0.65; P < .001). A
improved PFS as the data failed to meet the threshold for statistical benefit in terms of increased PFS was also observed in patients with
significance. deletion of 17p13.81 The rate of grade 2 to 4 peripheral neuropathy was
higher in those treated with the bortezomib-containing regimen versus
Based on the above data and pending publication of the phase III VAD (40% vs. 18%). In addition, newly developed grade 3 to 4 peripheral
TOURMALINE trial, the NCCN Panel has included neuropathy occurred in 8% of patients during thalidomide maintenance
ixazomib/lenalidomide/dexamethasone as an option (category 2B) for and 5% of patients during bortezomib maintenance.81
treatment of patients with newly diagnosed MM.
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Multiple Myeloma
Based on data from the HOVON-65/GMMG-HD4 trial and the uniform tolerated and effective in newly diagnosed patients with MM.86
consensus among the NCCN Multiple Myeloma Panel members, Subsequently, a multicenter, phase 2 trial investigated the efficacy and
bortezomib/doxorubicin/dexamethasone is a category 1 option for primary toxicity of ixazomib, cyclophosphamide and low-dose dexamethasone as
therapy for transplant-eligible patients with MM. induction, followed by single-agent ixazomib maintenance, in elderly,
transplant-ineligible newly diagnosed patients.87 The ORR after initial
Carfilzomib/Cyclophosphamide/Dexamethasone therapy with ixazomib/cyclophosphamide/dexamethasone was 73%. After
The carfilzomib/cyclophosphamide/dexamethasone regimen has been a median follow-up of 26.1 months, the PFS was 23.5 months.
studied in phase I/II trials of transplant-ineligible newly diagnosed patients
with MM. Trials have investigated both once-weekly and twice weekly NCCN Panel has included ixazomib/cyclophosphamide/dexamethasone
carfilzomib dosing combined with fixed dose cyclophosphamide and for both transplant and non-transplant settings as options useful in certain
dexamethasone.82,83 A pooled analysis of two phase I and II studies circumstances such as those with renal insufficiency and/or peripheral
comparing two alternative schedules of carfilzomib, transplant-ineligible neuropathy.
newly diagnosed patients with MM showed similar response rates in those
treated with once-weekly carfilzomib at a dose of 70 mg/m2 compared to Bortezomib/Thalidomide/Dexamethasone
those treated with twice weekly carfilzomib at a dose of 36 mg/m2. The The GIMEMA Italian Multiple Myeloma Network reported results of a
PFS and OS were also similar. The median PFS was 35.7 months in the phase III trial investigating bortezomib/thalidomide/dexamethasone (N =
once-weekly group and 35.5 months in the twice-weekly group (HR = 241) versus thalidomide/dexamethasone (N = 239) as primary therapy,
1.39; P = .26). The 3-year OS was 70% and 72%, respectively (HR = followed by tandem autologous HCT with high-dose melphalan and then
1.27; P = .5).84 consolidation therapy with the same primary regimen.88 The addition of
Consistent with the above results, a phase 1b study, CHAMPION-2 bortezomib to thalidomide and dexamethasone significantly improved
evaluated the safety and tolerability of twice-weekly carfilzomib (3 different ORR after primary treatment. After primary therapy, CR/near CR was
doses) in combination with cyclophosphamide and dexamethasone for the achieved in 73 patients (31%; 95% CI, 25.0–36.8) receiving
treatment of newly diagnosed MM patients. This study found that 56 bortezomib/thalidomide/dexamethasone, and 27 patients (11%; 95% CI,
mg/m2 carfilzomib combined with weekly cyclophosphamide and 7.3–15.4) receiving thalidomide/dexamethasone.88 Rates of CR/near CR
dexamethasone was effective and with manageable toxicity.85 and VGPR or better continued to be significantly higher in the
bortezomib/thalidomide/dexamethasone group than in the
The NCCN Panel has included thalidomide/dexamethasone group after the first and second autologous
carfilzomib/cyclophosphamide/dexamethasone for both transplant and HCT and subsequent consolidation therapy.88 Patients receiving the
non-transplant settings as an option useful in certain circumstances such bortezomib-containing regimen experienced grade 3/4 peripheral
as those with renal insufficiency and/or peripheral neuropathy. neuropathy.
Ixazomib/cyclophosphamide/dexamethasone: In a phase I trial, this
regimen was shown to be a convenient, all oral combination that is well
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Multiple Myeloma
Data from a single-institution retrospective study are similar to the interim Thalidomide is not widely used in the United States; however, it is more
data from the GIMEMA trial.89 The findings of this analysis demonstrate easily available and affordable in other resource-constrained parts of the
that ORR after primary therapy with world.
bortezomib/thalidomide/dexamethasone was 94% of the patients (32 of 34
patients showed some response, including a VGPR rate ≥56%).89 Cyclophosphamide/Lenalidomide/Dexamethasone
The efficacy and tolerability of
The results of the randomized phase III trial by the Spanish Myeloma cyclophosphamide/lenalidomide/dexamethasone in newly diagnosed
Group (PETHEMA/GEM) also demonstrated a significantly higher CR rate patients was demonstrated in a phase II study. Of the 53 patients enrolled
with bortezomib/thalidomide/dexamethasone as primary therapy overall in the trial, 85% had a PR or better including VGPR in 47%. The median
(35% vs. 14%, P = .001) and in patients with high-risk cytogenetics (35% PFS was 28 months (95% CI, 22.7–32.6) and at 2 years the OS was 87%
vs. 0%, P = .002).90 The CR rate continued to be significantly higher after (95% CI, 78–96).92
autologous HCT (46% vs. 24%) in patients treated with
bortezomib/thalidomide/dexamethasone versus The Myeloma XI trial compared responses to cyclophosphamide/
thalidomide/dexamethasone as primary therapy.90 lenalidomide/dexamethasone with cyclophosphamide/thalidomide/
dexamethasone.93 The preliminary results reported that the combination
The phase III IFM 2013-04 trial is evaluating 4 cycles of CyBorD versus 4 of lenalidomide/cyclophosphamide/dexamethasone is effective and has a
cycles of bortezomib/thalidomide/dexamethasone as induction therapy good safety profile in patients of all ages.93
before autologous HCT in patients (N = 340) with newly diagnosed MM.91
The NCCN Panel included
The results reported during the 2015 ASH meeting show that patients who
cyclophosphamide/lenalidomide/dexamethasone as a primary therapy
received bortezomib/thalidomide/dexamethasone as induction therapy
option for transplant-eligible patients with MM under the category “useful in
achieved higher ORR (92.3%) compared with those who received CyBorD
certain circumstances” (category 2A).
(84%). Those who received bortezomib/thalidomide/dexamethasone had
significantly greater VGPR (P = .04) and PR (P = .02) rates.91 The Daratumumab/Bortezomib/Thalidomide/Dexamethasone
hematologic toxicity was greater in the CyBorD arm; however, higher rates In the CASSIOPEIA trial, patients with newly diagnosed MM (n=1085)
of peripheral neuropathy were reported in the were first randomly assigned to receive induction with four cycles of
bortezomib/thalidomide/dexamethasone arm.91 No significant difference in bortezomib/thalidomide/dexamethasone with or without daratumumab,
OS was observed in any of the trials with followed by autologous HCT plus two cycles of consolidation with the
bortezomib/thalidomide/dexamethasone. A longer follow-up period is induction regimen.94 The primary endpoint of the first part of this trial was
required. assessment of response 100 days after transplantation. The second
randomization of this trial (randomization to maintenance with
Bortezomib/thalidomide/dexamethasone is listed as a primary treatment
daratumumab) is ongoing.
option (category 1) under the category “useful in certain circumstances.”
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Multiple Myeloma
At day 100 after transplantation, the daratumumab arm reported deeper therapy.96 This regimen is a potent combination of newer agents as well as
response rates (CR or better of 39% vs. 26%). Addition of traditional chemotherapy agents.
daratumumab increased neutropenia (28% vs 15%), lymphopenia (17%
vs 10%). Infusion reactions to daratumumab (mostly mild) were reported This regimen is listed under the category “useful in certain circumstances.”
in 35%. According to the NCCN Panel, VTD-PACE could be an option for newly
diagnosed patients presenting with high-risk and aggressive
The NCCN Panel has included extramedullary disease or plasma cell leukemia.
Daratumumab/bortezomib/thalidomide/dexamethasone as a primary
Preferred Primary Therapy Regimens for Newly Diagnosed Non-Transplant
therapy option for transplant-eligible patients with MM under the category Candidates
“useful in certain circumstances” (category 2A) based on the results of Many of the regimens described above for transplant candidates are also
CASSIOPEIA trial and FDA approval for this indication. options for non-transplant candidates. As in transplant-eligible patients,
three-drug regimens are preferred by the NCCN Panel as these regimens
Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone have been shown to induce higher response rates and depth of response
Patients with MM (n=101) including newly diagnosed patients (n=87) and
in clinical trials. The 2-drug regimens are reserved for elderly and/or frail
patients with relapsed MM (n=14) received
patients. The list of preferred options for non-transplant candidates
daratumumab,/bortezomib/cyclophosphamide/dexamethasone.95 In
includes: bortezomib/cyclophosphamide/dexamethasone,
newly diagnosed patients, after 4 cycles of induction therapy, VGPR or
bortezomib/lenalidomide/dexamethasone, and lenalidomide/low-dose
better was seen in 44.2% and the ORR was observed was 79.1%.95 The
dexamethasone.
median PFS was not reached and the 12‐month PFS rate was 87%. At
the time of clinical cut‐off, the 12‐month OS rate was 98.8% (95% CI,
Bortezomib/Lenalidomide/Dexamethasone
92.0–99.8%).95 Efficacy was also observed in patients with relapsed MM.
Phase II study results (discussed in the transplant setting) have shown
Based on the above results, NCCN Panel has included that primary therapy with bortezomib/lenalidomide/dexamethasone is
Daratumumab/cyclophosphamide/bortezomib/dexamethasone for newly active and well tolerated in all newly diagnosed patients with MM
diagnosed patients with MM (transplant eligible and ineligible patients) as regardless of autologous HCT status.64
an option useful in certain circumstances.
The randomized phase III SWOG S0777 trial, comparing
Bortezomib, Dexamethasone, Thalidomide, Cisplatin, Doxorubicin, bortezomib/lenalidomide/dexamethasone to lenalidomide/dexamethasone
Cyclophosphamide, and Etoposide (VTD-PACE) as induction therapy without an intent of immediate transplantation,
The total therapy 3 (TT3) trial evaluated induction therapy with the multi- reported superior results with the 3-drug regimen.67,68
agent regimen, VTD-PACE (bortezomib, dexamethasone, thalidomide,
cisplatin, doxorubicin, cyclophosphamide, and etoposide) prior to high- In transplant-ineligible newly diagnosed patients with MM, a phase II study
dose melphalan-based tandem auto-transplants and later as consolidation with the dose-adjusted VRd-lite regimen, showed that the dose-adjusted
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Multiple Myeloma
regimen had comparable efficacy and better tolerability than the standard years (range 66–90 years). After a median of 5 cycles, the ORR was 95%
dose regimen. The VRd-lite dosage included lenalidomide 15 mg days with 70% of patients achieving VGPR or better response. With respect to
orally on 1–21; bortezomib 1.3 mg/m2 subcutaneously days 1, 8, 15, and toxicity, 6 patients experienced non-hematologic grade 3/4 adverse events
22 and dexamethasone 20 mg orally on the day of and the day after (20%), including muscle weakness, sepsis, and pneumonia. Neutropenia
bortezomib for 9 cycles followed by 6 cycles of consolidation with and thrombocytopenia were seen in 2 patients (10%).99
lenalidomide and bortezomib. The ORR after 4 cycles of VRd-lite was
86%, with 66% achieving a VGPR or better.97 Based on the above and the results from the EVOLUTION trial66
(described earlier) that had included transplant-ineligible patients and the
The NCCN Panel included the bortezomib/lenalidomide/dexamethasone above phase II trial results,99 the NCCN Panel has included
regimen as a category 1, preferred option for patients with MM not eligible bortezomib/cyclophosphamide/dexamethasone as a preferred option for
for HCT. non-transplant candidates. This is a preferred option, especially in patients
with acute renal insufficiency. According to the NCCN Panel, one can
Daratumumab/lenalidomide/dexamethasone: In transplant-ineligible consider switching to bortezomib/lenalidomide/dexamethasone after renal
patients with newly diagnosed MM, results of a recently reported phase III function improves.
trial (MAIA) showed that daratumumab/lenalidomide/dexamethasone
significantly reduced the risk of disease progression or death by 44% (HR, Lenalidomide/Low-dose Dexamethasone
0.56 (95% CI = 0.43–0.73; P < .001).98 The addition of daratumumab to The results of the SWOG SO232 trial100 that included transplant-ineligible
lenalidomide/dexamethasone resulted in deeper responses compared with patients and the ECOG E4A03 trial101 that included elderly patients with
lenalidomide/dexamethasone, including increased rates of complete MM demonstrate that lenalidomide in combination with low-dose
response (CR) or better (48% vs 25%), VGPR or better (VGPR) (79% vs dexamethasone is a well-tolerated and effective regimen for these groups
53%), and ORR (93% vs 81%).98 The rates of pneumonia, neutropenia, of patients. In the ECOG E4A03 trial the OS rate was significantly higher
and leukopenia were higher in those receiving daratumumab.98 Based on in the lenalidomide plus low-dose dexamethasone arm compared with the
the results of this study, the FDA has approved the use of lenalidomide plus high-dose dexamethasone arm (also discussed under
daratumumab/lenalidomide/dexamethasone in this setting. Preferred Primary Therapy Regimens for Newly Diagnosed Transplant
Candidates).101 The inferior survival outcome seen with high-dose
The NCCN Panel has also included dexamethasone was greatest in patients aged 65 years and older. At 2
daratumumab/lenalidomide/dexamethasone as a category 1, preferred years, patients who did not proceed to transplant had an OS rate of 91%
option for newly diagnosed patients who are transplant ineligible. with lenalidomide and low-dose dexamethasone.101
Bortezomib/Cyclophosphamide/Dexamethasone The international, multicenter trial (FIRST trial) evaluated efficacy and
The role of bortezomib/cyclophosphamide/dexamethasone as initial safety of lenalidomide/dexamethasone given continuously or for 72 weeks
therapy for patients with MM ineligible for HCT was studied in a small with melphalan/prednisone/thalidomide (MPT) in elderly (n = 1623)
phase II trial (n = 20).99 The median age of patients in this study was 76 transplantation-ineligible patients with newly diagnosed MM.102 The
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Multiple Myeloma
primary endpoint of this trial was PFS, and secondary endpoints were OS treatment with continuous lenalidomide/dexamethasone until disease
and adverse events, including the incidence of secondary malignancies. progression for patients who are not eligible for transplant.
After a median of 37 months of follow-up, the risk of progression or death
Other Recommended Primary Therapy Regimens for Newly Diagnosed
was reduced by 28% in patients receiving continuous
Non-Transplant Candidates
lenalidomide/dexamethasone versus MPT (HR, 0.72; 95% CI, 0.61–0.85;
P < .001).102 Continuous lenalidomide/dexamethasone also reduced the Carfilzomib/Lenalidomide/Dexamethasone
risk of progression or death compared with 18 cycles of The results of a phase I/II trial demonstrated that the combination of
lenalidomide/dexamethasone (HR, 0.70; 95% CI, 0.89–1.20; P = .70). In carfilzomib/lenalidomide/dexamethasone is well-tolerated and is also
the interim analysis, an OS benefit was seen in the effective in all newly diagnosed patients.74 An updated follow-up analysis
lenalidomide/dexamethasone arm versus MPT (HR, 0.78; CI, 0.64–0.96; P of the subset of 23 elderly patients (aged ≥65 years) showed that use of
= .02).102 the carfilzomib, lenalidomide, and low-dose dexamethasone regimen for
an extended period of time resulted in deep and durable responses. All
There are several reports showing higher incidences of secondary patients achieved at least a PR. With a median follow-up of 30.5 months,
malignancies when lenalidomide is used as a maintenance therapy post- the reported PFS rate was 79.6% (95% CI, 53.5–92.0) and OS was
transplantation or in a melphalan-containing regimen.103-106 In the FIRST 100%.109
trial, the overall incidence of secondary malignancies, including The phase II trial by Korde et al76 also showed that treatment with the
hematologic malignancies, was lower in the continuous carfilzomib/lenalidomide/dexamethasone regimen results in high rates of
lenalidomide/dexamethasone arm. The overall rates of second primary deep remission. The results were very similar across age groups, with the
cancers were 3.0% in the continuous lenalidomide/dexamethasone arm, oldest patient on the trial being 88 years of age,76 and the regimen was
6.0% in the arm receiving 18 cycles of lenalidomide/dexamethasone, and found to be effective in individuals with high-risk disease.110
5.0% in the MPT arm.102 In an analysis based on renal function of patients
enrolled in the FIRST trial, continuous lenalidomide/low-dose Based on the above phase II studies that did not exclude transplant-
dexamethasone compared with MPT reduced the risk of progression or ineligible patients, the NCCN Panel has included carfilzomib/
death in patients with normal, mild, and moderate renal impairment by lenalidomide/dexamethasone as an option for treatment of all patients with
33%, 30%, and 35%, respectively.107 newly diagnosed MM, including those who are not eligible for HCT.
Lenalidomide/low-dose dexamethasone is considered a category 1, Ixazomib/Lenalidomide/Dexamethasone

preferred option by the NCCN Multiple Myeloma Panel for transplant- A phase I/II study (discussed in the previous section for HCT-eligible
ineligible patients with MM. The Panel recommends appropriate candidates) evaluated the safety and efficacy of the all-oral combination of
thromboprophylaxis for patients receiving this therapy. Based on the ixazomib with lenalidomide and dexamethasone in patients with newly
results of the FIRST trial,102,108 the NCCN Panel recommends considering diagnosed MM treated with combination lenalidomide and
dexamethasone.79 Both tolerability and activity of this regimen in older
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Multiple Myeloma
patients (those ≥65 years of age) was similar to that in younger patients in Regimens Useful In Certain Circumstances for Newly Diagnosed Non-
this study. Transplant Candidates
Bortezomib/Dexamethasone
Based on the above phase II study, the NCCN Panel has included
A U.S. community-based, randomized, open-label, multicenter, phase IIIb
ixazomib in combination with lenalidomide and dexamethasone as a
UPFRONT trial compared the safety and efficacy of three highly active
primary treatment option for all patients with newly diagnosed MM,
bortezomib-based regimens in previously untreated elderly patients with
including those not eligible for HCT.
MM ineligible for HCT.112 The patients with symptomatic, measurable MM
Daratumumab/Bortezomib/Melphalan/Prednisone were randomized (1:1:1) to one of the following regimens:
In the randomized phase III trial (ALCYONE), randomized patients (n bortezomib/dexamethasone (n = 168);
=706) with newly diagnosed MM ineligible for transplant were to receive bortezomib/thalidomide/dexamethasone (n = 167); or
bortezomib/melphalan/prednisone with or without daratumumab until melphalan/prednisone/bortezomib (n = 167) followed by maintenance
disease progression.111 The addition of daratumumab increased the ORR therapy with bortezomib. The primary endpoint was PFS; secondary
(90.9% vs. 73.9%) and PFS at 18 months was 72% versus 50%. With endpoints included ORR, CR/near CR and VGPR rates, OS, and safety.
respect to toxicity, there was an increased rate of grade 3 or 4 infections All three induction regimens exhibited substantial activity, with an ORR of
(23% vs. 15%) and daratumumab-related infusion reactions were seen in 73% (bortezomib/dexamethasone), 80%
27.7% of patients. (bortezomib/thalidomide/dexamethasone), and 70%
(melphalan/prednisone/bortezomib) during the treatment period.113 After a
Based on the results of the ALCYCLONE trial, the NCCN Panel has median follow-up of 42.7 months, the median PFS and OS were not
included daratumumab/bortezomib/melphalan/prednisone as a category 1 significantly different between the three treatment arms.112 Response
option for treatment of patients with newly diagnosed MM not eligible for rates, including CR and ≥VGPR, improved after bortezomib maintenance,
HCT. Since regimens containing melphalan are rarely used in North with no concomitant increase in the incidence of peripheral neuropathy.
America, the regimen daratumumab in combination with While the triple regimen with bortezomib/lenalidomide/dexamethasone is
bortezomib/lenalidomide/dexamethasone has now been listed under the preferred therapy for patients with newly diagnosed MM, elderly or frail
“Other Recommended Regimens” in this setting. patients may be treated with doublet regimens. The NCCN Multiple
Myeloma Panel has included bortezomib/dexamethasone as a primary
Daratumumab/cyclophosphamide/bortezomib/dexamethasone therapy as an option that is useful in certain circumstances for patients
Based on the results of the LYRA study (described above),95 the NCCN with MM who are ineligible for HCT.
Panel has included
Cyclophosphamide/lenalidomide/dexamethasone
Daratumumab/bortezomib/thalidomide/dexamethasone as a treatment
Based on results of the phase II trial by Kumar et al,92 and the Myeloma
option for both transplant and non-transplant settings as options useful in
X1,93 the NCCN Panel has included cyclophosphamide/
certain circumstances.
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Multiple Myeloma
lenalidomide/dexamethasone as an option for treatment of all patients with all clinical trials.116 According to the NCCN Panel, response should be
newly diagnosed MM, including those who are not eligible for HCT. assessed using the IMWG criteria.7
Carfilzomib/Cyclophosphamide/Dexamethasone The same imaging modality used during the initial workup should ideally
A phase II study examined the safety and efficacy of be used for the follow-up assessments. Follow-up tests after primary MM
carfilzomib/cyclophosphamide/dexamethasone in patients ≥65 years of therapy include those used for initial diagnosis: a CBC with differential and
age with newly diagnosed MM and ineligible for autologous HCT.82 Out of platelet counts; serum creatinine and corrected serum calcium; and
55 patients, 52 (95%) had at least a PR, 39 of 55 (71%) patients had at quantification of M-protein. The serum immunoglobulins and FLC
least a VGPR, 27 of 55 (49%) patients had a near CR or CR, and 11 of 55 (especially in patients with oligo- or non-secretory MM) may be assessed
(20%) patients had a stringent CR. After a median follow-up of 18 months, as clinically indicated.
the 2-year PFS and OS rates were 76% and 87%, respectively.82
Frequently reported grade 3 to 5 toxicities were neutropenia (20%), The NCCN Panel recommends considering harvesting peripheral blood
anemia (11%), and cardiopulmonary events (7%). Peripheral neuropathy hematopoietic stem cells prior to prolonged exposure to lenalidomide
was limited to grades 1 and 2 (9%). and/or daratumumab in patients for whom transplant is being considered.
The NCCN Panel has included Collecting enough hematopoietic stem cells for two transplants (depending
carfilzomib/cyclophosphamide/dexamethasone as an option for treatment on the intended number of transplants and age) in anticipation of a tandem
of patients with newly diagnosed MM not eligible for HCT. transplant or a second transplant as subsequent therapy is recommended.
Alternatively, all patients may consider continuation of primary therapy
Monitoring After Primary Myeloma Therapy of Both Transplant and until the best response is reached. The optimal duration of primary therapy
Non-Transplant Candidates after achieving maximal response is unknown; hence, maintenance
therapy (see section on Maintenance Therapy) or observation can be
Response Criteria
considered beyond maximal response.
Assessing the response to treatment is a key determinant of MM
treatment. Patients on treatment should be monitored for response to Hematopoietic Cell Transplantation
therapy and for symptoms related to disease and/or treatment.
Transplant Eligibility
The updated IMWG response criteria definitions for CR, stringent 7,114,115
All patients are assessed to determine eligibility for HCT. The NCCN
CR, immunophenotypic CR, molecular CR, VGPR, PR, minimal response Panel recommends that all patients eligible for HCT should be referred for
(MR) for relapsed/refractory MM, SD, and progressive disease (PD) are evaluation by HCT center and hematopoietic stem cells (for at least two
outlined in Response Criteria for Multiple Myeloma in the algorithm. This transplants, in younger patients) should be harvested.
has been recently updated to include measures of MRD assessments. It is
recommended that the IMWG uniform response criteria should be used in High-dose therapy with hematopoietic stem cell support is a critical
component in the treatment plan of eligible patients newly diagnosed with
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Multiple Myeloma
MM. The types of HCT may be single autologous HCT, a tandem HCT (a Another trial included 190 patients 55 to 65 years of age randomized to
planned second course of high-dose therapy and HCT within 6 months of standard or high-dose therapy.121 This study was specifically designed to
the first course), or an allogeneic HCT. include older patients, since the median age of the participants in other
trials ranged from 54 to 57 years and the median age in this trial was 61
The NCCN Guidelines for Multiple Myeloma indicate that all types of HCT years. After 120 months of follow-up, there was no significant difference in
are appropriate in different clinical settings; these indications are OS, although there was a trend toward improved EFS in the high-dose
discussed further below. In general, all candidates for high-dose group (P = .7). Additionally, the period of time without symptoms,
chemotherapy must have sufficient hepatic, renal, pulmonary, and cardiac treatment, or treatment toxicity was significantly longer in the high-dose
function. However, renal dysfunction is not an absolute contraindication to group. The study concluded that the equivalent survival suggests that the
transplant. treatment choice between high-dose and conventional-dose
chemotherapy should be based on personal choice in older patients. For
Autologous Hematopoietic Cell Transplantation
example, an early transplant may be favored because patients can enjoy a
Autologous HCT results in high response rates and remains the standard
longer interval of symptom-free time.
of care after primary therapy for eligible patients. In 1996, results of the
first randomized trial were reported; this trial demonstrated that autologous A phase III study compared high-dose melphalan followed by autologous
HCT is associated with statistically significantly higher response rates and HCT with MPR (melphalan, prednisone, and lenalidomide) consolidation
increased OS and event-free survival (EFS) when compared with the after induction. Patients (n = 402) were randomly assigned (in a 1:1:1:1
response of similar patients treated with conventional therapy.117 In 2003, ratio) to one of the four groups: high-dose therapy and autologous HCT
results of a second trial comparing high-dose therapy to standard therapy followed by maintenance with lenalidomide; high-dose therapy and HCT
showed an increase in the CR rate and an improvement in OS (54 months alone; primary therapy with MPR followed by lenalidomide; and primary
in the high-dose group compared to 42 months for standard therapy).118 therapy with lenalidomide alone.122 At a median follow-up of 51 months,
Barlogie and colleagues reported on the results of an American trial that HCT resulted in longer median PFS (43 vs. 22 months; HR 0.44; 95% CI,
randomized 510 patients to receive high-dose therapy with autologous 0.32–0.61) and OS (82% vs. 65% at 4 years; HR 0.55; 95% CI, 0.32–
hematopoietic cell transplant or standard therapy.119 With a median 0.93).122
follow-up of 76 months, there were no differences in response rates, PFS,
or OS between the two groups. The reason for the discrepant results is not Results from the IFM 2005/01 study of patients with symptomatic MM
clear, but may be related to differences in the specific high-dose and receiving primary therapy with bortezomib and dexamethasone versus
conventional regimens between the American and French study. For VAD showed a marked improvement in ORR with bortezomib and
example, the American study included total body irradiation (TBI) as part dexamethasone over VAD (see Preferred Primary Therapy Regimens for
of the high-dose regimen; TBI has subsequently been found to be inferior Newly Diagnosed Transplant Candidates).123 Responses were evaluated
to high-dose melphalan.120 after primary treatment and post-autologous HCT. After the first
autologous HCT, CR/near-CR rates were 35.0% in the bortezomib plus
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Multiple Myeloma
dexamethasone arm, compared with 18.4% in the VAD arm.123 The VGPR The OS of patients in the IFM 2009 phase III trial was high in both groups,
rates were 54.3% versus 37.2%. Median PFS was 36.0 months versus the one that received autologous HCT and the one that did not. 125
29.7 months (P = .064) with bortezomib plus dexamethasone versus VAD Although autologous HCT improved PFS it did not improve OS,
after a median follow-up of 32.2 months.123 Also, PFS was also suggesting that delaying HCT is an option and is not associated with
significantly longer in the patients achieving greater than or equal to a negative effects on OS.
VGPR after primary treatment than in patients achieving a less than VGPR
(median 36 vs. 29.7 months).123 According to the NCCN Guidelines, for transplant-eligible patients
autologous HCT is the preferred option after primary induction therapy
In another study, 474 patients were randomized to primary therapy with while a delayed HCT after early stem cell collection and storage is
bortezomib/dexamethasone/thalidomide (n = 236) or appropriate as well. (category 1) A repeat HCT can be considered for
thalidomide/dexamethasone (n = 238) before double autologous HCT and treatment of progressive/refractory disease after primary treatment in
as consolidation therapy after HCT.124 The 3-drug regimen yielded high patients with prolonged response to initial HCT.
response rates compared with the 2-drug regimen, with a CR rate of 19%
Tandem Hematopoietic Cell Transplantation
(vs. 5%) and greater than or equal to a VGPR of 62% (vs. 31%). After
HCT, improved incremental responses were still seen with Tandem HCT refers to a planned second course of high-dose therapy and
bortezomib/dexamethasone/thalidomide compared with thalidomide plus HCT within 6 months of the first course. Planned tandem transplants have
dexamethasone.124The IFM 2009 phase III trial compared the efficacy and been studied in several randomized trials. The IFM94 trial reported by
safety of bortezomib/lenalidomide/dexamethasone alone versus Attal et al randomized newly diagnosed patients with MM to single or
bortezomib/lenalidomide/dexamethasone plus autologous HCT for the tandem autologous transplants.126 A total of 78% of patients assigned to
treatment of newly diagnosed MM in patients 65 years or younger.125 The the tandem transplant group received the second transplant at a median
reported CR rate was 48% in the group that received induction therapy time of 2.5 months after the first. A variety of options for therapy of
alone versus 59% in the transplantation group (P = .03). No MRD was relapsed disease were provided. For example, relapsing patients in either
detected in 65% of the patients who received group underwent either no therapy, additional conventional therapy, or
bortezomib/lenalidomide/dexamethasone alone versus no MRD in 79% of another HCT. The probability of EFS for 7 years after the diagnosis was
the patients who received induction therapy plus autologous HCT (P < 10% in the single transplant group compared to 20% in the double
.001).125 There was a clear improvement in PFS with HCT (50 months vs. transplant group. In a subset analysis, those patients who did not achieve
36 months). These results clearly show the benefit of autologous HCT, a complete CR or VGPR within 3 months after the first transplant
with higher rates of durable responses in those with no MRD after initial appeared to benefit the most from a second transplant. The investigators
therapy.125 Taken together, the studies suggest that improved responses of the IFM94 study have suggested that the improvement in projected
with the primary regimen result in improved outcomes after transplantation survival associated with tandem transplant is related not to improved
even for patients receiving an IMiD and PI-based triplet regimen. response rates, but to longer durations of response. Four other
randomized trials have compared single versus tandem transplant.121,127-129
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Multiple Myeloma
None of these trials showed a significant improvement in OS. However, Panel, a tandem transplant with or without maintenance therapy can be
since the median follow-up in these trials ranged from 42 to 53 months, considered for all patients who are candidates for HCT and is an option for
the lack of significant improvement is not surprising. The trial by Cavo et patients who do not achieve at least a VGPR after the first autologous
al127 found that patients not in CR or near CR after the first transplant HCT and those with high-risk features. The support for use of
benefited the most from a second transplant. This confirms the maintenance therapy after tandem transplant comes from the study by
observations of the IFM94 trial using non-TBI–based high-dose regimens. Palumbo et al,122 which addressed the role of maintenance therapy with
In both the French and Italian trials, the benefit of a second autologous lenalidomide after autologous transplantation.122 Although associated with
HCT was seen in patients who do not achieve a CR or VGPR (>90% more frequent grade 3 or 4 neutropenia and infections, maintenance
reduction in M-protein level) with the first procedure. These two studies therapy with lenalidomide was found to significantly reduce risk of disease
were not adequately powered to evaluate the equivalence of one versus progression or death (HR, 0.47) after both single and tandem
two transplants in patients achieving a CR or VGPR after the first transplantation compared with no maintenance.122
transplantation.
A second autologous HCT can be considered at the time of disease
A review of long-term outcomes of several trials of autologous relapse. A retrospective case-matched control analysis was performed
transplantation by Barlogie et al found that tandem transplantations were comparing patients who underwent a second autologous HCT to those
superior to both single transplantations and standard therapies.130 Also, treated with conventional chemotherapy for relapsed MM.134 Similar to
post-relapse survival was longer when EFS was sustained for at least 3.5 previously published smaller studies,135-137 this retrospective analysis
years after tandem transplantation.130-131 Results of the multicenter, phase demonstrated that a second autologous HCT is associated with superior
III study (EMN02/HO95 MM trial) suggested that tandem autologous HCT relapse-associated mortality compared with conventional chemotherapy
for newly diagnosed MM may be superior in extending PFS compared with (68% vs. 78%), along with improved OS (32% vs. 22%) at 4 years. In this
single autologous HCT after induction therapy with a bortezomib-based analysis, factors associated with improved OS and PFS included younger
regimen.132 In another more recent study, after initial HCT patients were age (<55 years), beta-2 microglobulin <2.5 mg/L at diagnosis, a remission
randomly assigned to receive a second HCT followed duration of >9 months, and a greater than PR to their first autologous
by lenalidomide maintenance; or four cycles of bortezomib, lenalidomide, HCT. This analysis indicates that a second autologous transplant, for
and dexamethasone followed by lenalidomide maintenance; or relapsed or progressive MM, may be an option for carefully selected
lenalidomide maintenance alone.133 At 38 months, all three arms showed patients. Some of these patients can achieve durable complete or partial
similar PFS and OS.133 remission.137,138
The NCCN Multiple Myeloma Panel recommends collecting enough A multicenter, randomized phase III trial compared treatment with high-
hematopoietic stem cells for at least one HCT in all eligible patients, and dose melphalan plus second autologous HCT with cyclophosphamide in
for 2 transplants in the younger patients if tandem transplant or salvage patients with relapsed MM who had received autologous HCT as primary
transplant would be considered. According to the NCCN Multiple Myeloma treatment.139 The patients included in the study were greater than 18 years
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Multiple Myeloma
of age and needed treatment for progressive or relapsed disease at least transplants are designed to decrease the morbidity of the high-dose
18 months after a previous autologous HCT. All patients first received chemotherapy but preserve the beneficial graft-versus-tumor effect.
bortezomib/doxorubicin/dexamethasone induction therapy. Patients with Therefore, the principal difference between myeloablative and
adequately harvested hematopoietic stem cells were then randomized to nonmyeloablative transplants relates to the chemotherapy regimen used.
high-dose melphalan plus second autologous HCT (n = 89) or oral Specific preparatory regimens have not been a focus of the NCCN
cyclophosphamide (n = 85). The primary endpoint was time to disease Guidelines, and therefore these guidelines do not make a distinction
progression.139 After a median follow-up of 31 months, median TTP in between these approaches.
patients who underwent second autologous HCT after induction therapy
was 19 months versus 11 months for those treated with Given the small candidate pool, it is not surprising that there have been no
cyclophosphamide (HR, 0.36; 95% CI, 0.25–0.53; P < .0001). Grade 3-4 randomized clinical trials comparing myeloablative allogeneic to
neutropenia (76% vs. 13%) and thrombocytopenia (51% vs. 5%) were autologous HCT, but multiple case series have been published describing
higher in the group that underwent autologous HCT versus allogeneic HCT as an initial therapy or as therapy for relapsed/refractory
cyclophosphamide.139 Median OS in the HCT group was 67 months versus MM. In a 1999 review, Kyle reported a mortality rate of 25% within 100
52 months in the cyclophosphamide maintenance group.140 days and overall transplant-related mortality of approximately 40% and
few patients were cured.150 Other reviews have also reported increased
According to the NCCN Multiple Myeloma Panel, repeat autologous HCT morbidity without convincing proof of improved survival.151,152 However,
for relapsed disease may be considered either on or off clinical trial there are intriguing data from the SWOG randomized trial of autologous
depending on the time interval between the preceding HCT and transplant versus conventional chemotherapy.119 The original trial had an
documented progression. ablative, allogeneic transplant group consisting of patients with HLA
identical siblings. Thirty-six patients received allografts, and due to the
The prognosis of patients who relapse after autologous HCT appears to high 6-month mortality of 45%, the allogeneic arm was closed. After 7
differ depending on the timing of the relapse.141-145 Data from retrospective years of follow-up the OS of the conventional chemotherapy, autologous,
studies146-149 suggest 2 to 3 years as the minimum length of remission for and allogeneic arms were all identical at 39%. The autologous and
consideration of second autologous HCT for relapsed disease. conventional chemotherapy arms do not demonstrate a plateau, whereas
the allogenic curve was flat at 39%. This suggests that a proportion of
Allogeneic Hematopoietic Cell Transplantation
these patients are long-term survivors. Thus, there is ongoing interest in
Allogeneic HCT includes either myeloablative or nonmyeloablative (ie,
myeloablative allogeneic HCT, particularly given the lack of a significant
“mini” transplant) transplants. Allogeneic HCT has been investigated as an
cure rate for single or tandem autologous HCT.
alternative to autologous HCT to avoid the contamination of reinfused
autologous tumor cells, but also to take advantage of the beneficial graft- Patients whose disease either does not respond to or relapses after
versus-tumor effect associated with allogeneic transplants. However, lack allogeneic hematopoietic cell grafting may receive donor lymphocyte
of a suitable donor and increased morbidity has limited this approach,
particularly for the typical older MM population. Non-myeloablative
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Multiple Myeloma
infusions to stimulate a beneficial graft-versus-myeloma effect153-160 or disease progression or died. The median TTP in the lenalidomide group
other myeloma therapies on or off a clinical trial. was 46 months versus 27 months in the placebo group (P < .001). Second
primary cancers occurred in 18 patients who received lenalidomide (8%)
Follow-Up After Hematopoietic Cell Transplantation and in 6 patients who received placebo (3%).104
Follow-up tests after HCT are similar to those done after primary myeloma
therapy. In addition, MRD assessment is increasingly being incorporated Data from the international, randomized, double-blind phase III IFM
into post-treatment assessments. MRD has been identified as an 2005-02 trial (n = 614) show that patients treated with lenalidomide as
important prognostic factor. A prospective study of patients with newly consolidation therapy after an autologous HCT followed by lenalidomide
diagnosed MM evaluated MRD in bone marrow samples and showed that as maintenance therapy had upgraded responses. Of the 614 patients
at a median follow-up of 57 months, MRD negativity after autologous HCT enrolled in the trial, 307 were randomly assigned to lenalidomide
translated to significantly improved PFS and OS rates.161 Similarly, in maintenance therapy and 307 to placebo. Maintenance treatment was
another study, MRD negativity after autologous HCT was predictive of continued until the patient withdrew consent, the disease progressed, or
favorable PFS and OS.162 Similar results have also been reported in the unacceptable toxic effects occurred. The final analysis of the IFM 2005-02
allogeneic HCT setting where the presence of MRD after allogeneic HCT trial was performed after a median follow-up of 30 months and 264
has been associated with a significantly adverse PFS and OS.163 The patients had disease progression (104 in the lenalidomide group and 160
NCCN Panel recommends assessing for MRD during follow-up as in the placebo group). The median PFS was 41 months in the
indicated prognostication after shared decision with patient.116 lenalidomide group, compared with 23 months in the placebo group (HR,
0.50; P < .001; median follow-up period was 30 months). The probability of
Maintenance Therapy surviving without progression for 3 years after randomization was 59% in
The NCCN Panel has clarified in the algorithm section the maintenance those treated with lenalidomide and 35% in those who received the
regimens appropriate for those who received autologous HCT versus placebo. The benefit of lenalidomide maintenance therapy, evidenced by
those who did not and classified them as either preferred”; “other rate of PFS at 3 years after randomization, was higher in all patients who
recommended”; or “useful in certain circumstances” received lenalidomide maintenance therapy compared with those who
received placebo. This benefit was observed in patients who had a VGPR
Lenalidomide as Maintenance at randomization (64% vs. 49%, P = .006) and those who did not (51% vs.
Lenalidomide as maintenance therapy after autologous transplantation 18%, P < .001).103 An increased incidence of second primary cancers was
has been evaluated in two independent randomized phase III studies.103,104 observed in the lenalidomide group (32 had second primary cancers in the
lenalidomide group and 12 in the placebo group).103 The updated survival
In the CALGB 100104 trial, patients were randomized to maintenance analysis of the same study after 91 months for follow-up reported median
therapy with lenalidomide (n = 231) versus placebo (n = 229) after TTP of 57.3 months (95% CI, 44.2–73.3) with lenalidomide and 28.9
autologous HCT.104 At a median follow-up of 34 months, 37% of the months (23.0–36.3) with placebo (HR, 0.57; 95% CI, 0.46–0.71; P <
patients who received lenalidomide versus 58% who received placebo had .0001).164 The most common grade 3-4 adverse events in the lenalidomide
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Multiple Myeloma
group compared to placebo were neutropenia (50% vs. 18%) and melphalan/prednisone/lenalidomide (MPL) significantly reduced the risk of
thrombocytopenia (15% vs. 5%). An increased rate of second primary disease progression and also increased PFS.168 In this study, newly
malignancies (hematologic plus solid tumor) were diagnosed in the diagnosed patients with MM (n = 459) aged ≥ 65 years were randomized
lenalidomide group compared with placebo (14% vs. 4%).164 to receive MP followed by placebo, MPL, or MPL followed by lenalidomide
until progression. Maintenance with lenalidomide significantly prolonged
The study by Palumbo et al122 (discussed in Autologous Hematopoietic PFS. The PFS of patients treated with MPL followed by maintenance
Cell Transplantation) showed that although maintenance therapy with lenalidomide was significantly prolonged (n = 152; median, 31 months)
lenalidomide is associated with more frequent grade 3 or 4 neutropenia compared with the other two arms: MPL (n = 153; median, 14 months; HR,
and infections, it significantly reduced risk of disease progression or death 0.49; P < .001) or MP (n = 154; median, 13 months; HR, 0.40; P < .001).
(HR, 0.47) compared with no maintenance.122 Lenalidomide maintenance therapy improved PFS by 66% compared with
placebo, regardless of age.168 In the FIRST trial, use of lenalidomide
The benefit of lenalidomide maintenance was studied in a meta-analysis of
indefinitely until progression was associated with a superior PFS
data from 1209 patients enrolled in the trials discussed above randomized
compared with a fixed duration of 18 months.
to maintenance with lenalidomide or placebo.165 The study showed
improved median PFS with lenalidomide maintenance (52.8 vs. 23.5 Based on the evidence from the phase III trials,103,104,168 the NCCN Multiple
months; HR 0.48; 95% CI, 0.42–0.55). At 7 years, the OS was 62% in the Myeloma Panel lists single-agent lenalidomide as one of the preferred
group receiving lenalidomide maintenance versus 50% in the group maintenance regimens (category 1). Lenalidomide lacks the neurologic
receiving placebo. In those with high-risk cytogenetics, a PFS benefit, but toxicity seen with thalidomide. However, there seems to be an increased
not an OS benefit was seen with lenalidomide maintenance versus risk for secondary cancers, especially post-transplantation,103-105 or after a
placebo. melphalan-containing regimen.106 According to the results of the FIRST
trial, in the continuous lenalidomide/dexamethasone arm, the absence of
The lenalidomide group had higher rates of second primary malignancy
the alkylator melphalan seems to be more effective in terms of improving
occurring before progression, and the rates of PD were higher in the group
PFS and lowering incidence of second malignancies.102
receiving placebo.
A meta-analysis of 4 randomized controlled trials examined patients
A report from the HOVON 76 trial indicates that lenalidomide maintenance
treated with lenalidomide maintenance versus patients with no
may not be a feasible option after mini-allogeneic HCT.166 However,
maintenance or placebo in both the transplant and non-transplant
another recently reported study has shown the feasibility of maintenance
settings.169 The analysis showed that patients treated with lenalidomide
therapy with low-dose lenalidomide after allogeneic HCT in patients with
maintenance had significantly improved PFS (HR, 0.49; P < .001) and a
high-risk MM.167
trend toward OS (HR, 0.77; P = .071) versus no maintenance or
Data from the phase III MM-015 study show that lenalidomide placebo.169 There was significantly more grade 3/4 neutropenia with the
maintenance after primary therapy with use of lenalidomide and a 2-fold increased risk of secondary malignancies.
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Multiple Myeloma
The benefits of improved PFS with lenalidomide maintenance must be dexamethasone; bortezomib in combination with thalidomide and
weighed against the increased rate of severe (grade 3 and 4) neutropenia, dexamethasone; or bortezomib with melphalan and prednisone followed
risk of second cancers, and other toxicities.170 The NCCN Panel notes that by maintenance treatment with bortezomib. The results show that the
the benefits and risks of maintenance therapy with lenalidomide versus response rates, including CR and ≥VGPR, improved after bortezomib
secondary cancers should be discussed with patients. maintenance in all arms, with no concomitant increase in the incidence of
peripheral neuropathy.112
Bortezomib as Maintenance Therapy
The results from the HOVON study show that maintenance with single- The NCCN Multiple Myeloma Panel members have added bortezomib as
agent bortezomib after autologous HCT is well tolerated and is associated a maintenance therapy option for transplant eligible as well as ineligible
with improvement of ORR.81 Patients in the HOVON trial were randomly patients.
assigned to one of the two arms consisting of either primary treatment with
Ixazomib as Maintenance Therapy After Autologous HCT
VAD followed by autologous HCT and maintenance with thalidomide or
The TOURMALINE-MM3 trial studied two years of maintenance with
with bortezomib/doxorubicin/dexamethasone followed by autologous HCT
ixazomib versus placebo in patients who had achieved at least a partial
and bortezomib as maintenance therapy for 2 years. The study reported
response (PR) following induction therapy and a single autologous HCT.
high near-CR/CR rates after primary treatment with the bortezomib-based
Ixazomib improved PFS (median 26.5 [95% CI 23·7-33·8] vs.21.3 months;
regimen. Bortezomib as maintenance therapy was well tolerated and
HR 0.72, 95% CI 0.58-0.89).172 The risk of developing secondary
associated with additional improvement of response rates81 (see Preferred
malignancies was similar in control arm and with maintenance ixazomib.
Primary Therapy Regimens for Transplant Candidates).
Based on the results of the phase III TOURMALINE-MM3 trial, the NCCN
A multicenter phase III trial in newly diagnosed patients with MM showed Panel has included ixazomib as “other recommended” maintenance option
that consolidation with bortezomib after autologous HCT improved PFS for transplant-eligible patients.
only in patients not achieving at least VGPR after autologous HCT.171
Therapy for previously treated Multiple Myeloma
There was no difference in PFS in patients with ≥VGPR after autologous
HCT. A variety of therapies are available for previously treated MM. The choice
of appropriate therapy for a patient would depend on the context of
Bortezomib as Maintenance Therapy clinical relapse such as prior treatment and duration of response.
The results of the phase III UPFRONT study also show that maintenance Therapy for previously treated relapsed/refractory MM is considered in the
with single-agent bortezomib is well-tolerated when administered after following clinical situations: patients with relapsed disease after allogeneic
treatment with bortezomib-based primary therapy.112 Newly diagnosed or autologous HCT; patients with primary PD after initial autologous or
patients with MM ineligible for high-dose therapy and HCT enrolled in the allogeneic HCT; and patients ineligible for HCT with progressive or
UPFRONT trial were randomized (1:1:1) and treated with one of the relapsing disease after initial primary therapy.
following bortezomib-based primary regimens: bortezomib and
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Multiple Myeloma
A variety of therapies are available as options for previously treated MM After a median follow-up of 13.5 months, daratumumab in combination
depending on the prior therapy and duration of response. The options with lenalidomide and dexamethasone was associated with better PFS
include systemic therapy; HCT (for eligible patients who did not receive and ORR compared with lenalidomide/dexamethasone alone. After a
HCT as part of their initial treatment); or clinical trial. For those who had median follow-up of 25.4 months, a subsequent analysis reported that the
autologous HCT as part of initial treatment and had a durable response or higher ORR (92.9% versus 76.4%, P < .001), and PFS (83% vs. 60% at
had SD, consideration must be given to a second transplantation on or off 12 months; 68% vs. 41% at 24 months; HR 0.41, 95% CI 0.31-0.53) was
clinical trial at the time of relapse/disease progression. maintained in those who received daratumumab.175
If the relapse occurs at greater than 6 months after completion of the initial The most common adverse events of grade 3 or 4 in patients treated with
primary therapy, patients may be retreated with the same primary the daratumumab regimen versus lenalidomide/dexamethasone were
regimen. neutropenia (51.9 vs. 37.0%), thrombocytopenia (12.7% vs. 13.5%), and
anemia (12.4% vs. 19.6%). Daratumumab-associated infusion-related
Preferred Regimens for Previously Treated Multiple Myeloma
reactions (mostly grade 1 or 2) were reported in 47.7% of the patients.
Bortezomib/Lenalidomide/Dexamethasone
Data from preclinical studies showed lenalidomide sensitizes myeloma With an extended follow-up of 3.5 years, the improvements in PFS and
cells to bortezomib and dexamethasone. The results of phase I and phase ORR continued to be maintained in patients treated with the daratumumab
II studies show that bortezomib/lenalidomide/dexamethasone is well regimen (16.7 vs. 7.1 months; HR, 0.31; 95%; CI, 0.25-0.40; P < .0001).
tolerated and active, with durable responses in heavily pretreated patients In subgroup of patients with one prior line of therapy, the median PFS was
with relapsed and/or refractory MM, including patients who have had prior 27.0 months with daratumumab versus 7.9 months with bortezomib and
lenalidomide, bortezomib, thalidomide, and HCT.173,174 After a median lenalidomide (HR, 0.22; 95% CI, 0.15-0.32; P < .0001). The ORR rates for
follow-up of 44 months, the median PFS was 9.5 months and median OS patients with one prior line of therapy for those receiving daratumuab-
was 30 months (95% CI, 24–37).174 The NCCN Multiple Myeloma Panel regimen was 92% compared with 74% in those receiving
members have included bortezomib/lenalidomide/dexamethasone as a bortezomib/dexamethasone.176
preferred option for relapsed/refractory MM.
Based on the above data, the NCCN Panel has added
Daratumumab/Lenalidomide/Dexamethasone daratumumab/lenalidomide/dexamethasone as a category 1, preferred
In a multicenter, open-label phase 3 trial (POLLUX), patients (n= 569) option for the treatment of patients with relapsed/refractory MM.
with relapsed/refractory MM were randomized to
lenalidomide/dexamethasone with or without daratumumab until disease Carfilzomib/Lenalidomide/Dexamethasone
progression or unacceptable toxicity.175 A randomized, multicenter, phase III trial of 792 patients (ASPIRE) studied
the combination of lenalidomide and dexamethasone with or without
carfilzomib in patients with relapsed/refractory MM who had received one
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Multiple Myeloma
to three prior lines of therapy. The primary endpoint of the study was PFS. thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and
The results showed that addition of carfilzomib to lenalidomide and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively).178
dexamethasone significantly improved PFS by 8.7 months (26.3 months Grade 1 or 2 infusion-related reactions associated with daratumumab
for the carfilzomib arm vs. 17.6 months for lenalidomide and low-dose were reported in 45.3% of the patients in the daratumumab group and
dexamethasone; HR for progression or death, 0.69; 95% CI, 0.57–0.83; P grade 3 in 8.6% of the patients. These infusion-related reaction rates are
= .0001). The median duration of treatment was longer in the carfilzomib consistent with findings from previous trials of daratumumab.179,180
group (88.0 weeks vs. 57 weeks). The incidence of peripheral neuropathy
was nearly identical in both arms (17%). Non-hematologic adverse effects After a median follow-up of 40 months, patients receiving the
(≥ grade 3) that were higher in the carfilzomib group compared with daratumumab containing regimen demonstrated a 69% reduction in the
lenalidomide and dexamethasone included dyspnea (2.8% vs. 1.8%), risk of disease progression or death (median PFS, 16.7 months vs
cardiac failure (3.8% vs. 1.8%), and hypertension (4.3% and 1.8%). There 7.1 months; HR, 0.31; 95% CI, 0.25–0.40; P < .0001); showed
were fewer discontinuations due to side effects in the carfilzomib arm significantly better ORR (85% vs 63%; P < .0001).181 Patients who
(15.3% vs. 17.7%). Patients in the carfilzomib arm reported superior received a prior line of therapy demonstrated the greatest benefit with
health-related quality of life than those who received lenalidomide and daratumumab (median PFS, 27.0 months vs 7.9 months; HR, 0.22; 95%
dexamethasone.177 CI, 0.15–0.32; P <.0001).
Based on the above data, the NCCN Multiple Myeloma Panel has included Based on the above phase III data, the NCCN Panel has added
the combination of carfilzomib with lenalidomide and dexamethasone as a daratumumab/bortezomib/dexamethasone as a category 1, preferred
category 1, preferred option for patients with relapsed/refractory MM. option for the treatment of patients with relapsed/refractory MM.
Daratumumab/Bortezomib/Dexamethasone Daratumumab/carfilzomib/dexamethasone
A phase III trial showed that adding daratumumab to bortezomib and A phase 1b, open-label, non-randomized, multicenter trial first studied this
dexamethasone markedly improved outcomes for patients with regimen in patients (n= 82) with relapsed or refractory MM. At a median
follow-up of 16 months, the ORR was 84%. In the overall treatment
recurrent/refractory MM.178 Patients (n = 498) were randomized to receive
population, while the median PFS was not reached, the 12-month and 18-
daratumumab/bortezomib/dexamethasone or bortezomib/dexamethasone.
month PFS rates were 74% and 66%, respectively.182 In a multicenter,
The ORR in the daratumumab arm was 82.9% compared to 63.2% in the
open-label phase 3 trial (CANDOR), the addition of daratumumab to
control arm (P < .001).178 The rates of VGPR and CR were double in the
carfilzomib plus dexamethasone showed deeper responses and improved
daratumumab arm compared to the control arm (59.2% vs. 29.1%, P <
PFS. Based on the above data and the FDA approval, the NCCN Panel
.001 and 19.2% vs. 9.0%, P = .001, respectively). The 12-month estimated
has included this regimen as a category 1, preferred regimen option for
rate of PFS was significantly higher in the daratumumab arm compared to
relapsed/refractory MM, for patients with relapsed or refractory MM.
the control arm (60.7% vs. 26.9%).178 The most common grade 3 or 4
adverse events reported in the daratumumab and control groups were
Isatuximab-irfc/pomalidomide/dexamethasone
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Multiple Myeloma
In an open-label, multicenter, phase 3 trial (ICARIA-MM), patients (n= 307) high-risk cytogenetics enrolled in the trial receiving ixazomib had a similar
with MM who had received at least two lines of prior therapy, including HR for PFS as the entire study population (HR, 0.596 and 0.543,
lenalidomide and a PI were randomized to receive respectively).185 Grade ≥3 adverse events were reported in 74% and 69%
pomalidomide/dexamethasone with or without isatuximab-irfc.183 After a of patients in the ixazomib-treated and control groups, respectively. These
median follow-up of 12 months, a higher ORR (60% vs. 35%) and included anemia (9% with ixazomib/lenalidomide/dexamethasone vs. 13%
improved PFS (median 11.5 months vs. 6.5 months; HR 0.6, 95% CI 0.44- with lenalidomide/dexamethasone), thrombocytopenia (19% vs. 9%), and
0.81) was reported in the isatuximab-irfc/pomalidomide/dexamethasone neutropenia (23% vs. 24%).185 The addition of the
arm. In a prespecified subgroup analysis of this study, the addition of ixazomib/lenalidomide/dexamethasone group had a slightly higher rate of
isatuximab-irfc showed improved ORR and PFS in patients with renal peripheral neuropathy compared to lenalidomide/dexamethasone (27% vs.
impairment.184 22%).
The NCCN Panel has included Isatuximab- Based on the results of the phase III TOURMALINE MM1 trial185 the NCCN
irfc/pomalidomide/dexamethasone as a category 1, preferred option for Panel has included ixazomib/lenalidomide/dexamethasone as a category
the treatment of patients with relapsed/refractory MM 1, preferred regimen option for previously treated MM.
Ixazomib/Lenalidomide/Dexamethasone
Ixazomib/Pomalidomide/Dexamethasone
A double-blind, randomized, placebo-controlled, phase III TOURMALINE
In the phase I Alliance A061202 study (n= 22), 32% of patients were
MM1 trial randomized 722 patients with relapsed and/or refractory MM to a
refractory to a lenalidomide/PI combination and 68% were refractory to the
combination of ixazomib plus lenalidomide and dexamethasone or
sequential use of these drugs. The majority of patients (65%) had high-risk
lenalidomide and dexamethasone alone (control group). This trial was
cytogenetics. More than half of the patients experienced grade 3 and 4
designed based on the promising results of a phase I/II study (discussed
neutropenia, lymphopenia, and reductions in white blood cell count.
under Other Recommended Primary Therapy Regimens for Transplant
Peripheral neuropathy, rash, diarrhea, and other side effects were limited
Candidates).79
to grades 1 and 2. The ORR was 55% in those with PI- or lenalidomide-
The results of the TOURMALINE MM1 trial show a significant refractory disease and responses were found to be durable over time.186
improvement in PFS with the ixazomib-containing regimen. After a median
Another phase I/II study studied the safety and efficacy of
follow-up of almost 15 months, a 35% improvement in PFS was seen in
ixazomib/pomalidomide/dexamethasone in patients who had multiple prior
the group treated with the ixazomib regimen compared with the control
therapies, were refractory to lenalidomide alone, or were refractory to
group (HR, 0.74; P = .01).185 Median PFS was 20.6 months in the
lenalidomide and bortezomib, or lenalidomide, bortezomib, and
ixazomib-treated group versus 14.7 months in the group receiving
carfilzomib.187 The ORR was 33% and 40% with two different doses of
lenalidomide and dexamethasone alone. In the ixazomib-treated group
ixazomib.187
versus the control group, the ORR (78% vs. 72%, P = .035) and CR
(11.7% vs. 6.6%, P = .019) were also improved. Of note, patients with
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Multiple Myeloma
Considering promising preliminary response rates, especially in patients Other Recommended Regimens for Previously Treated MM
refractory to both lenalidomide and a PI, the NCCN Panel has included
Belantamab mafodotin-blmf
ixazomib/pomalidomide/dexamethasone as a treatment option for patients
Belantamab mafodotin-blmf is an anti-B cell maturation antigen (BCMA)
with relapsed/refractory MM who have received at least two prior therapies
antibody, conjugated to a microtubule disrupting agent— monomethyl
including an IMiD and a PI and have demonstrated disease progression
auristatin—via a stable, protease resistant linker. It is the first in its class.
on or within 60 days of completion of the last therapy.
In the open-label phase II trial (DREAMM-2), belantamab mafodotin was
Based on the above results the NCCN Panel has included evaluated in patients whose MM was refractory to multiple agents.
ixazomib/pomalidomide/dexamethasone as a preferred regimen option for Responses were seen in approximately one-third of patients.189 The most
previously treated MM. common grade 3/4 adverse events in the safety population were
keratopathy, thrombocytopenia, and anemia.189
Pomalidomide/Bortezomib/Dexamethasone
A phase 3 open-label, multicenter, randomized, trail (OPTIMISMM) Based on the results of the DREAMM-2 trial and FDA approval, the NCCN
evaluated pomalidomide/bortezomib/dexamethasone (n=281) versus Panel has included this as a treatment option for patients with relapsed
bortezomib/dexamethasone in patients (n= 278) MM who received at least four previous therapies (including a PI, an IMiD,
with relapsed or refractory MM who previously received lenalidomide.188 and an anti-CD38 monoclonal antibody).
After a median follow-up of 15.9 months, a significantly improved PFS was
Bendamustine/Bortezomib/Dexamethasone
seen in the pomalidomide arm (median 11.20 months vs. 7.10 months;
A phase II study evaluated bendamustine/bortezomib/dexamethasone
HR, 0.61; 95% CI, 0.49–0.77; P < .0001). The most common grade 3/4
administered over six 28-day cycles and then every 56 days for six more
treatment-related adverse events in the pomalidomide arm reported in this
cycles in patients (n = 75; median age 68 years) with relapsed/refractory
trial were neutropenia, infections, and thrombocytopenia.188
MM treated with multiple prior therapies and not refractory to bortezomib.
Based on the above data, NCCN Panel had included The PR rate was 71.5% (16% CR, 18.5% VGPR, 37% partial remission).
pomalidomide/bortezomib/dexamethasone as a category 1, preferred At 12-month follow-up, median TTP was 16.5 months and 1-year OS was
option in patients who have received at least two prior therapies, 78%.190
including an immunomodulator (IMiD) and bortezomib, and have
demonstrated disease progression on or within 60 days of completion of Bendamustine/Lenalidomide/Dexamethasone
the last therapy. A multicenter phase I/II trial investigated the combination of bendamustine,
lenalidomide, and dexamethasone as treatment for patients (n = 29) with
relapsed/refractory MM.191 PR rate was seen in 52% (n = 13) of patients,
with VGPR in 24% (n = 6) of patients. The median PFS in the trial was 6.1
months (95% CI, 3.7–9.4 months), and the one-year PFS rate was 20%
(95% CI, 6%–41%).191 The NCCN Panel has included lenalidomide in
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Multiple Myeloma
combination with bendamustine and dexamethasone as a treatment option reported carfilzomib/cyclophosphamide/dexamethasone as well tolerated
for relapsed/refractory MM. with the toxicity profile of carfilzomib being similar to that seen in other
trials.195 This regimen is included in the NCCN Guidelines for Multiple
Bortezomib/Liposomal Doxorubicin/Dexamethasone Myeloma as an option for patients with relapsed/refractory MM.
Bortezomib with liposomal doxorubicin (PLD) was approved by the FDA as
a treatment option for patients with MM who have not previously received Carfilzomib (twice weekly)/Dexamethasone
bortezomib and have received at least one prior therapy. The approval The results of the phase III ENDEAVOR trial in patients with
was based on a priority review of data from an international phase III trial relapsed/refractory MM treated with multiple prior lines of therapy showed
(n = 646) showing that use of the combination significantly extended the a two-fold improvement in median PFS with carfilzomib/dexamethasone
median time to disease progression compared with bortezomib alone (9.3 compared to bortezomib/dexamethasone (18.7 months vs. 9.4 months;
vs. 6.5 months).192 Median duration of response was increased from 7.0 HR, 0.53; P < .0001).196 ORR was 77% in the carfilzomib group versus
months to 10.2 months with the combination therapy. Based on these 63% in the bortezomib group; rates of CR or better were 13% and 6% and
results, the NCCN Multiple Myeloma Panel considers bortezomib with the rates of VGPR were 42% and 22%, respectively. Median duration of
PLD regimen as a category 1 option for patients with relapsed/refractory response was 21.3 months in the carfilzomib group and 10.4 months in the
MM. bortezomib group. Adverse events (grade 3 or higher) in the carfilzomib
arm compared to the bortezomib arm included hypertension (6% vs. 3%),
Bortezomib/Cyclophosphamide/Dexamethasone anemia (12% vs. 9%), thrombocytopenia (10% vs. 14%), and dyspnea
The effects of adding of an alkylating agent (such as cyclophosphamide) (5% vs. 2%). Rate of grade ≥2 peripheral neuropathy was 6% in the
and a novel agent (such as lenalidomide or bortezomib) to carfilzomib group and 32% in the bortezomib group.196
dexamethasone have been investigated for patients with
relapsed/refractory MM. The combination of bortezomib, dexamethasone, The OS analysis showed that those treated with carfilzomib/
and cyclophosphamide was found to be effective in patients with dexamethasone lived 7.6 months longer (median OS was 47.6 months in
relapsed/refractory MM with an acceptable toxicity profile.193,194 The NCCN the carfilzomib group vs. 40 months in the bortezomib group; HR, 0.791
Multiple Myeloma Panel members have included [95% CI, 0.648–0.964]; P = .010).197 The most frequent grade 3 or worse
bortezomib/cyclophosphamide/dexamethasone to the list of options for adverse events in the carfilzomib arm compared to the bortezomib arm
relapsed/refractory MM. included hypertension (15% vs. 3%), anemia (16 % vs. 10%), dyspnea
(6% vs. 2%), decreased lymphocyte count (6% vs. 2%), diarrhea (4% vs.
Carfilzomib/Cyclophosphamide/Dexamethasone 9%), and peripheral neuropathy (1% vs. 6%).197 Rates of
A phase II trial compared the safety and toxicity of thrombocytopenia, pneumonia, and fatigue were similar in both groups.197
carfilzomib/cyclophosphamide/dexamethasone with
bortezomib/cyclophosphamide/dexamethasone in patients who had Based on the above phase III data, the NCCN Multiple Myeloma Panel
received one prior regimen for relapsed/refractory MM.195 The study has included the combination of carfilzomib (twice weekly) and
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Multiple Myeloma
dexamethasone as a category 1, preferred option for patients with Based on the above data, the NCCN Panel has included
relapsed/refractory MM. daratumumab/pomalidomide/dexamethasone as a treatment option for
patients with relapsed/refractory MM who have received at least 2 prior
Cyclophosphamide/Lenalidomide/Dexamethasone therapies including an IMiD and a PI and have demonstrated disease
A retrospective analysis to assess the efficacy of lenalidomide in progression on or within 60 days of completion of the last therapy.
combination with cyclophosphamide and dexamethasone showed that this
regimen is effective in heavily pre-treated patients with manageable Elotuzumab/Bortezomib/Dexamethasone
adverse effects.198 Numerous randomized trials have shown that 3-drug combinations have
been shown to be consistently more effective than 2-drug combinations for
Daratumumab/Cyclophosphamide/Bortezomib/Dexamethasone the treatment of MM. A phase II trial studied the effect of addition of
In the LYRA study,95 among the small cohort of patients with relapsed elotuzumab to bortezomib/dexamethasone in patients with
MM (n = 14), after 4 cycles of induction therapy ORR was 12.3% and relapsed/refractory MM.200
VGPR or better was seen in 57.1% of patients.95 The ORR after 4
induction cycles was 71.4%. The median PFS was 13.3 months (95% CI, Interim analysis results demonstrated a 28% reduction in risk of disease
6.8–13.3). At 12‐months, the OS rate was 54.5% (95% CI, 8.6%– progression or death for patients in the elotuzumab-containing triple-drug
86.1%).95 arm compared to patients treated with bortezomib/dexamethasone (HR,
0.72; 70% CI, 0.59–0.88). Median PFS was significantly higher in the
Based on this, the NCCN Panel has included elotuzumab-containing arm (9.7 months vs. 6.9 months). After 2 years the
Daratumumab/bortezomib/thalidomide/dexamethasone as treatment addition of elotuzumab continued to show an efficacy benefit compared to
option for relapsed/refractory MM. bortezomib/dexamethasone alone with a 24% relative risk reduction in
PFS (HR, 0.76; 70% CI, 0.63–0.91).200
Daratumumab/Pomalidomide/Dexamethasone
The combination of daratumumab/pomalidomide/dexamethasone was Based on the above phase II trial data, the NCCN Panel has included
evaluated in an open-label, multicenter, phase 1b study (MMY1001). This elotuzumab/bortezomib/dexamethasone as a treatment option for patients
study included patients (n = 103 patients) who had received at least two with relapsed/refractory MM who have received at least one prior therapy.
prior lines of therapy (excluding daratumumab or pomalidomide).199 At a
median follow-up of 13.1 months, the ORR was 60%. The median PFS Elotuzumab/Lenalidomide/Dexamethasone
and median OS were 8.8 and 17.5 months, respectively, and estimated Elotuzumab is a humanized monoclonal antibody targeted against
survival at 1 year was 66%.199 Toxicities reported were similar to those signaling lymphocytic activation molecule F7 (SLAMF7). SLAMF7, also
seen in other trials of pomalidomide and daratumumab, except for called CS1 (cell-surface glycoprotein CD2 subset 1) is a glycoprotein
increase in neutropenia.199 expressed on myeloma and natural killer cells but not on normal tissues.201
The FDA has approved elotuzumab in combination with lenalidomide and
dexamethasone for the treatment of patients with MM who have received
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Multiple Myeloma
one to three prior therapies. This is based on the results of the phase III Elotuzumab/Pomalidomide/Dexamethasone
trial, ELOQUENT-2. The trial randomized 646 patients (1:1) to receive In a phase II study, patients (n= 117) with refractory/relapsed MM and
either elotuzumab in combination with lenalidomide and dexamethasone refractory to lenalidomide and a PI were randomized to receive
or lenalidomide and dexamethasone alone.202 pomalidomide/dexamethasone or
pomalidomide/dexamethasone/elotuzumab.205 After a follow-up of 9.1
The rates of PFS at the end of 1 and 2 years were higher for those
months, the median PFS and ORR were both more than double with
receiving the elotuzumab-containing regimen (68% at 1 year and 41% at 2
elotuzumab (PFS, 10.3 months vs. 4.7; ORR, 53% vs. 26%).
years) compared with those receiving lenalidomide and dexamethasone
alone (57% at 1 year and 27% at 2 years).202 Median PFS in the group The NCCN Panel has included the combination of
receiving the elotuzumab-containing regimen was 19.4 months versus pomalidomide/dexamethasone/elotuzumab as an option for patients who
14.9 months in those receiving lenalidomide and dexamethasone alone have received at least two prior therapies including an iMID and a PI.
(HR for progression or death in the elotuzumab group, 0.70; 95% CI,
0.57–0.85; P < .001) indicating a relative reduction of 30% in the risk of Ixazomib/cyclophosphamide/dexamethasone
disease progression or death.202 Common grade 3 or 4 adverse events in This regimen has been shown to be tolerable and efficacious in newly
both arms of the trial were lymphocytopenia, neutropenia, fatigue, and diagnosed patients.86, 87 A phase II study evaluated this regimen in the
pneumonia. Infusion reactions occurred in 33 patients (10%) in the relapsed/refractory setting in patients with a median age of 63.5 years and
elotuzumab group and were grade 1 or 2 in 29 patients.202 found that it is well tolerated. At a median follow-up of 15.2 months in the
phase II study, median PFS was 14.2 months. The PFS trend with this
Consistent with the above findings, a subset analysis of 3-year follow-up regimen was better in patients aged 65 and older compared with those
reported a reduced risk of progression by 27% with the less than 65 years (median 18.7 months vs. 12·0 months; HR 0.62,
elotuzumab/lenalidomide/dexamethasone combination compared with P = .14).206 The NCCN Panel has included this all oral regimen under the
lenalidomide/dexamethasone.203 list of “other recommended regimens” for relapsed/refractory MM.
The final results of the ELOQUENT-2 study have demonstrated that the Pomalidomide/Carfilzomib/Dexamethasone
addition of elotuzumab to lenalidomide/dexamethasone improved OS in Based on the encouraging results of the phase I study,207 a phase II study
patients with MM who received 1–3 prior lines of therapy (48.3 months vs was carried out to evaluate the safety and efficacy of pomalidomide,
39.6 months).204 carfilzomib, and dexamethasone in lenalidomide-refractory and
proteasome-naïve/sensitive patients with relapsed/refractory MM. After a
Based on the above data and FDA approval the NCCN Panel has included
median of 7.2 cycles (range = 0.6–27.1 cycles), PR was 84%, MR was
elotuzumab in combination with lenalidomide and dexamethasone as a
91%, VGPR was 26%, and CR/near CR was 12%.208 After a median
category 1 option for previously treated MM.
follow-up of 18 months (range = 1–39 months), the median PFS for all 55
patients was 12.9 months and the estimated 18-month OS was 86.5%.208
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Multiple Myeloma
The NCCN Panel has included this regimen Regimens Useful In Certain Circumstances for Previously Treated MM
pomalidomide/carfilzomib/dexamethasone as a therapeutic option in
Bendamustine: In a trial by Knop and colleagues, 31 patients who had
patients who have received at least two prior therapies, including an IMiD
experienced relapse after autologous transplantation were enrolled to
and bortezomib, and have demonstrated disease progression on or within
receive increasing doses of bendamustine.211 The ORR was 55%, with a
60 days of completion of the last therapy.
median PFS of 26 weeks for all patients and 36 weeks for patients who
Pomalidomide/Cyclophosphamide/Dexamethasone received higher doses of bendamustine (90–100 mg/m2). Toxicity was mild
A phase II study compared the combination of and mainly hematologic. A retrospective analysis of 39 patients has
pomalidomide/cyclophosphamide/dexamethasone to reported that bendamustine is effective and tolerable in patients with
pomalidomide/dexamethasone in patients (n = 70) with relapsed/refractory advanced progressive MM, with an ORR of 36%.212
MM who had received more than two prior therapies.209 The ECOG studied treatment with high-dose cyclophosphamide in
patients with poor-risk features who had disease that was refractory to
The triple-drug combination significantly improved the ORR (≥PR, 64.7% prior chemotherapy.213 The ORR reported was 43% (29% response rate in
vs. 38.9%; P = .0355). The median PFS reported was 9.5 months versus patients refractory to prior therapy with cyclophosphamide).213
4.4 months. There were no significant differences in adverse event reports Bendamustine is currently a treatment option for relapsed/refractory MM.
between the treatment arms; grade 3 and 4 anemia, neutropenia, and
thrombocytopenia, respectively, were reported in 11%, 31%, and 6% of Carfilzomib/cyclophosphamide/thalidomide/dexamethasone: The results of
patients treated with pomalidomide/dexamethasone and 24%, 52%, and the phase I/II trial (CYCLONE) showed that this 4-drug regimen is
15% of patients treated with the triplet regimen.209 Similar results were efficacious with an ORR of 91%, with 76% achieving VGPR or greater
reported by a single-center retrospective study of patients (n = 20) with after 4 cycles in patients with MM.214 This regimen has now been included
relapsed/refractory MM who received under the list of regimens “useful in certain circumstances” for
pomalidomide/cyclophosphamide/dexamethasone until transplant or relapsed/refractory MM.
disease progression was reported.210 Response to the triple-drug regimen
Bortezomib/Dexamethasone
was 63%, with nearly half of patients (42%) responding after 1 cycle with a
The addition of dexamethasone to bortezomib in patients with relapsed/
median time to response of 3 cycles. One-year median PFS was 80.7%
refractory MM who had PD during bortezomib monotherapy resulted in
and 65% of patients were relapse-free.210
improvement of response in 18% to 34% of patients.215-217 The NCCN
Based on the above phase II trial data, the NCCN Panel has included Multiple Myeloma Panel members have included the bortezomib and
pomalidomide/cyclophosphamide/dexamethasone as a treatment option dexamethasone regimen as an option for patients with relapsed/refractory
for patients with relapsed/refractory MM who have received at least one MM (category 1).
prior therapy.
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Lenalidomide/Dexamethasone A phase III, multicenter, randomized, open-label study (MM-003)

Lenalidomide combined with dexamethasone received approval from the conducted in Europe compared the efficacy and safety of pomalidomide
FDA as a treatment option for patients with MM who had received at least and low-dose dexamethasone (n = 302) versus high-dose dexamethasone
one prior treatment. This was based on the results of two studies of a total (n = 153) in patients with relapsed MM who were refractory to both
of 692 patients randomized to receive dexamethasone either with or lenalidomide and bortezomib.222 After a median follow-up of 10 months,
without lenalidomide. The primary efficacy endpoint in both studies was PFS, the primary endpoint of the study, was significantly longer in patients
TTP. A pre-planned interim analysis of both studies reported that the who received pomalidomide and low-dose dexamethasone compared with
median TTP was significantly longer in the lenalidomide arm compared to those who received high-dose dexamethasone (4 months vs. 1.9 months;
the control group.218,219 The updated clinical data from the pivotal North HR, 0.45; P < .0001).222 The median OS was significantly longer in the
American phase III trial (MM-009) in 353 previously treated patients with patients who received pomalidomide and low-dose dexamethasone as
MM reported increased OS and median time to disease progression in well (12.7 months vs. 8.1 months; HR, 0.74; P = .0285).222 The most
patients receiving lenalidomide plus dexamethasone compared to patients common hematologic grade 3 and 4 adverse effects found to be higher
receiving dexamethasone plus placebo.219 Similar results were seen in the with the low-dose dexamethasone compared with the high-dose
international trial MM-010.218 Patients in both of these trials had been dexamethasone were neutropenia and pneumonia.222 Other phase III
heavily treated before enrollment. Many had three or more prior lines of studies of pomalidomide plus low-dose dexamethasone in combination
therapies with other agents and more than 50% of patients having with other agents (eg, bortezomib) are currently ongoing (Clinical Trial ID:
undergone HCT.218,219 Most adverse events and grade 3/4 adverse events NCT01734928). A European multicenter, single-arm, open-label, phase
were more frequent in patients with MM who received the combination of IIIb trial evaluated the safety and efficacy of pomalidomide and low-dose
lenalidomide/dexamethasone compared to placebo and dexamethasone. dexamethasone in a large patient population (N = 604).223 The median
Thrombocytopenia (61.5%) and neutropenia (58.8%) were the most PFS reported was 4.2 months and OS was 11.9 months. Whether the
frequently reported adverse events observed. The NCCN Multiple patients received prior lenalidomide or bortezomib, the PFS, OS, and ORR
Myeloma Panel now considers this regimen as a category 1 option as reported were similar.223 The results of this trial are consistent with those
therapy for patients with relapsed/refractory MM. Lenalidomide observed in the pivotal MM-003 trial.222
monotherapy has also been investigated and found effective in patients
with relapsed/refractory MM.220 The NCCN Multiple Myeloma Panel In addition, several complementary phase II studies have been published
suggests considering lenalidomide monotherapy for steroid-intolerant evaluating the use of pomalidomide and dexamethasone in patients with
individuals. MM relapsed/refractory to lenalidomide and/or bortezomib. A phase II
study investigated two different dose regimens of pomalidomide and
Pomalidomide/Dexamethasone dexamethasone in 84 patients with advanced MM. Pomalidomide (4 mg)
Pomalidomide, like lenalidomide, is an analogue of thalidomide. It was given orally on days 1 to 21 or continuously over a 28-day cycle, and
possesses potent immunomodulatory and significant anti-myeloma dexamethasone (40 mg) was given orally once weekly.224 ORR was 35%
properties.221 and 34% for patients in the 21-day and 28-day groups, respectively. With
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Multiple Myeloma
a median follow-up of 23 months, median duration of response, PFS, and (3 sCR, 10 VGPR, and 18 PR). Median duration of response was 7.4
OS were 7.3, 4.6, and 14.9 months across both groups, respectively. All months and median TTP was 3.7 months. The estimated 1-year OS rate
patients experienced similar adverse events in both groups. The adverse was 65%.180 Adverse events reported were fatigue (39.6%), anemia
events were primarily due to myelosuppression.224 Another phase II trial (33.0%), nausea (29.2%), and thrombocytopenia (25.5%). Grade 1 and 2
evaluated two doses of pomalidomide 2 or 4 mg/day with dexamethasone infusion-related reactions were seen in 42.5% of patients, mainly during
40 mg weekly in heavily pre-treated patients (n = 35).225 The ORR in the 2- first infusion. No patients discontinued the study due to infusion-related
mg cohort was 49% versus 43% in the 4-mg cohort. OS at 6 months was reactions.180
78% and 67% in the 2- and 4-mg cohort, respectively. Myelosuppression
was the most common toxicity.225 Based on the above phase II results and FDA approval, the Panel has
added daratumumab as an option for the treatment of patients with MM
The FDA has approved pomalidomide for patients with MM who have who have received at least three prior lines of therapy including a PI and
received at least two prior therapies including lenalidomide and an IMiD or who are double refractory to a PI and IMiD.
bortezomib and have demonstrated disease progression on or within 60
days of completion of the last therapy. The FDA-recommended dose and Ixazomib/Dexamethasone
schedule of pomalidomide is 4 mg orally on days 1 to 21 of repeated 28- Data from two phase I studies of single-agent ixazomib in patients with
day cycles with cycles repeated until disease progression along with the relapsed/refractory MM established the maximum tolerated dose of
recommendation to monitor patients for hematologic toxicities, especially ixazomib to be 2.0 mg/m2 on a twice-weekly schedule and 2.97 mg/m2 on
neutropenia. a weekly schedule.226,227 The patients in these studies had multiple prior
lines of therapy (median of four prior lines of therapy in both studies). In
Based on the above data, the NCCN Panel has included pomalidomide the study with the weekly schedule,226 out of 30 evaluable patients the rate
plus dexamethasone as a therapeutic option in patients who have of PR or better (≥PR) was 27%. In the twice-weekly schedule, out of 55
received at least two prior therapies, including an IMiD and bortezomib, evaluable patients ≥PR rate was 15%.227 Adverse events, grade ≥3, were
and have demonstrated disease progression on or within 60 days of reported in 78% (drug-related in 62%) of patients on the twice-weekly
completion of the last therapy (category 1). For steroid-intolerant schedule227 and 65% (53%) of patients on the weekly schedule.226 These
individuals, the NCCN Multiple Myeloma Panel suggests considering included thrombocytopenia (37%), neutropenia (17%), and skin and
pomalidomide monotherapy. subcutaneous tissue disorders (8%) on the twice-weekly schedule, and
thrombocytopenia (33%), neutropenia (18%), and diarrhea (17%) on the
Daratumumab weekly schedule. Peripheral neuropathy was reported in 17% (drug-
Daratumumab is a human IgG kappa monoclonal antibody that targets the related in 12%) of patients, with no grade 3 events, on the twice-weekly
CD38 surface protein on myeloma cells.179 In a phase I/II study, patients schedule.227 On the weekly schedule drug-related peripheral neuropathy
who had received more than three lines of therapy including an IMiD and a was reported in 20% of patients (2% grade 3). 226
PI or were double refractory to PI and IMiD were randomized to two
different doses of daratumumab (8 mg/kg vs. 16 mg/kg). ORR was 29.2%
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Multiple Myeloma
Subsequently, phase II trials were designed to evaluate ixazomib with or inhibiting nuclear factor κB and the translation of oncoprotein mRNAs such
without dexamethasone in patients with MM who have limited prior as c-Myc and cyclin-D. Selinexor in combination with dexamethasone was
exposure to bortezomib.228,229 In one trial, patients (n = 33) with relapsed studied in a phase IIb trial (STORM) in patients with relapsed/refractory
MM received weekly ixazomib 5.5 mg and had dexamethasone added for MM.230 The patients in the trial had multiple prior therapies and were
suboptimal response or disease progression (in 67% of patients). Six refractory to IMIDs (lenalidomide and pomalidomide), PIs (bortezomib and
additional patients achieved a PR after the addition of dexamethasone.228 carfilzomib), and the CD38 antibody (daratumumab). A total of 122
The ORR (≥PR) with or without the addition of dexamethasone reported patients were included in the intent-to-treat population. PR or better was
was 34%.228 Adverse events, grade ≥3, were reported in 78%. The most observed in 26% of patients (95% confidence interval [CI], 19 to 35) with
common adverse events observed included thrombocytopenia, fatigue, stringent CR in 2%, VGPR in 5%, and PR in 20% of the patients.
nausea, and diarrhea.228
The most common adverse events reported during treatment were
Another phase II study evaluated two doses of weekly ixazomib (arm A, 4 thrombocytopenia in 73% of the patients, fatigue in 73%, nausea in 72%,
mg and arm B, 5.5 mg) plus weekly dexamethasone (40 mg) in patients (n and anemia in 67%.
= 70) with relapsed MM. The patients enrolled in the trial had not been
previously treated with a PI (including bortezomib) or had received less Based on the above results, the NCCN Panel has included
than 6 cycles of therapy with bortezomib and had a PR or better and no selinexor/dexamethasone under the list of regimens “Useful in Certain
progression at the time of discontinuation.229 The ORRs were 31% in arm Circumstances” as an option for patients with relapsed/refractory MM who
A (95% CI, 17–49) and 51% (95% CI, 34–69) in arm B. Among the have received at least four prior therapies and whose disease is refractory
patients with no prior bortezomib exposure the response rates were 38% to at least two proteasome inhibitors, at least two immunomodulatory
for arm A and 52% for arm B.229 The most common toxicities reported in agents, and an anti-CD38 monoclonal antibody.
this trial were fatigue, thrombocytopenia, diarrhea, and nausea with more
Venetoclax/dexamethasone only for t(11;14) patients
grade 3 toxicities among arm B. Peripheral neuropathy, possibly related to
A phase I study of patients (n=66) with relapsed/refractory MM who
ixazomib, was seen in 55% (only grade 1 or 2) in arm A and 43% (2
received a median of five prior lines of therapy reported an ORR in 21% of
patients with grade 3) in arm B.229
patients with the response rate being higher in patients (n=30) with
Based on the above phase I/II trial data, the NCCN Panel has included t(11;14) compared with those without the t(11:14) (40% versus 6%).231
ixazomib/dexamethasone as a treatment option for patients with Similar higher response rates have been in patients with t(11:14) in real-
relapsed/refractory MM who have received at least one prior therapy. world experience as well.232 The NCCN Panel had included venetoclax in
combination with dexamethasone as an option for patients with t(11:14)
Selinexor/dexamethasone: Selinexor was recently approved for treatment translocation.
of MM. Selinexor induces apoptosis of MM cells by selectively inhibiting
the nuclear export compound that blocks exportin 1 (XPO1), forcing Patients with an aggressive relapse may need multi-drug combinations
nuclear accumulation and activation of tumor suppressor proteins, and such as DCEP,233-235 TD-PACE (thalidomide, dexamethasone, cisplatin,
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Multiple Myeloma
doxorubicin, high-dose cyclophosphamide, and etoposide),236,237 and VTD- mortality and significantly improve PFS.245 Patients on clodronate and
PACE (bortezomib, thalidomide, dexamethasone, cisplatin, doxorubicin, zoledronic acid had similar occurrence of acute renal failure and
cyclophosphamide, and etoposide)238-240 for effective disease control. treatment-related serious adverse events. Zoledronic acid was associated
with higher rates of ONJ than was clodronic acid.246 An extended follow-up
Supportive Care for Multiple Myeloma (median, 5.9 years) of the MRC Myeloma IX showed significant
Important advances have been made in adjunctive treatment/supportive improvement in OS (52 vs. 46 months; HR, 0.86; P = .01) compared with
care of patients with MM. This involves careful patient education about the clodronic acid.247 The long-term rates of ONJ were also observed to be
probable side effects of each drug, the drug combinations being used, and higher with zoledronic acid compared with clodronate (3.7% vs. 0.5%; P =
the supportive care measures required. Supportive care can be .0001).247
categorized into those measures required for all patients and those that
address specific drugs. A recent meta-analysis of 20 randomized controlled trials comparing
bisphosphonates with either placebo or a different bisphosphonate as a
Bony manifestations in the form of diffuse osteopenia and/or osteolytic comparator concluded that adding bisphosphonates to the treatment of
lesions, develop in 85% of patients with MM. Related complications are MM reduces vertebral fractures and probably reduces pain.248 It did not
the major cause of limitations in quality of life and performance status in find a particular bisphosphonate to be superior to another.248 In a
patients with MM. A large, double-blind, randomized trial has shown that multicenter trial (CALGB 70604), patients with MM or bone metastases
monthly use of IV pamidronate (a bisphosphonate) can decrease pain and from a solid malignancy were randomly assigned to zoledronic acid
bone-related complications, improve performance status, and, importantly, either monthly or every three months for two years.249 The rates of
preserve quality of life in patients with Durie-Salmon stage III MM and at skeletal-related events were similar in both arms. Among the 278
least one lytic lesion.241,242 Zoledronic acid has equivalent benefits.243 patients with MM, rates of SRE were 26% in those receiving monthly
Results from the study conducted by Zervas et al244 show a 9.5-fold versus 21% in those receiving treatment every three months.249
greater risk for the development of osteonecrosis of the jaw (ONJ) with
zoledronic acid compared to pamidronate. Patients who are on A large, placebo-controlled, randomized trial compared denosumab with
bisphosphonates should have their renal function monitored. They should zoledronic acid in patients (n = 1718) with newly diagnosed MM with bone
have a dental exam prior to the start of bisphosphonate therapy and lesions. Time to first skeletal-related events (SREs) and OS was similar in
should be monitored for ONJ. both arms. The denosumab arm had lower rates of renal toxicity and
higher rates of hypocalcemia. ONJ was slightly higher in the denosumab
The Medical Research Council (MRC) Myeloma IX study examined effects arm (3% vs. 2%) but not statistically significant.250
of zoledronic acid versus clodronate (a bisphosphonate not currently FDA
approved) in patients with MM initiating chemotherapy regardless of bone The NCCN Guidelines for Multiple Myeloma recommend bisphosphonates
disease. The patients were randomized to receive zoledronic acid (n = (category 1) or denosumab for all patients receiving therapy for
981) or clodronic acid (n = 979). Zoledronic acid was reported to reduce symptomatic MM regardless of documented bone disease. Denosumab is
preferred by the NCCN Panel in patients with renal disease. The NCCN
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Multiple Myeloma
Panel recommends a baseline dental exam and monitoring for ONJ in all Plasmapheresis should be used as adjunctive therapy for symptomatic
patients receiving a bone-modifying agent and monitoring for renal hyperviscosity.254 Institutions differ in their use of plasmapheresis for
dysfunction with use of bisphosphonate therapy. adjunctive treatment of renal dysfunction.
With respect to duration of therapy, the Panel also recommends Erythropoietin therapy may be considered for anemic patients, especially
continuing bone-targeting treatment (bisphosphonates or denosumab) for those with renal failure. Measuring endogenous erythropoietin levels may
up to 2 years and continuing beyond 2 years would be based on clinical also be helpful in treatment planning255,256 (see NCCN Guidelines for
judgement. The frequency of dosing (monthly vs. every 3 months) would Prevention and Treatment of Cancer-Related Infections). Daratumumab
depend on the individual patient criteria and response to therapy. can interfere with cross-matching and red blood cell antibody screening.
The NCCN Panel recommends performing type and screen prior to
Low-dose (10–30 Gy) or single fraction (8 Gy) are used for the palliative receiving daratumumab to inform future matching.
treatment of uncontrolled pain, impending pathologic fracture, or
impending spinal cord compression.41,251 Limited involved fields should be Thrombosis is relatively common with the use of IMiDs (thalidomide,
used to limit the effect of irradiation on hematopoietic stem cell harvest or lenalidomide, or pomalidomide) with steroids, and is particularly frequent
its effect on potential future treatments; the radiation doses administered when treating newly diagnosed patients. Use of prophylactic
should not preclude hematopoietic stem cell collection in potential anticoagulation agents (see NCCN Guidelines for Venous
candidates for high-dose therapy and HCT. Orthopedic consultation Thromboembolic Disease) is recommended when IMiDs are used in
should be obtained for impending or actual fractures in weight-bearing combination therapy during induction.257-259 For those receiving an IMiD-
bones, bony compression of the spinal cord, or vertebral column based therapy, prophylaxis with aspirin (81–325 mg) is recommended. An
instability. Either vertebroplasty or kyphoplasty should be considered for anticoagulation agent is recommended for patients receiving an IMiD-
symptomatic vertebral compression fractures. based therapy and who are at high risk for thrombosis.
Excess bone resorption from bone disease can lead to excessive release To prevent infections, IV immunoglobulin therapy should be considered for
of calcium into the blood, contributing to hypercalcemia. Symptoms recurrent, life-threatening infections; pneumococcal conjugate vaccine
include polyuria and gastrointestinal disturbances, with progressive should be given followed by the pneumococcal polysaccharide vaccine
dehydration and decreases in glomerular filtration rate. Hypercalcemia one year later.
should be treated with hydration, bisphosphonates, denosumab,250
steroids, and/or calcitonin. Among the bisphosphonates (zoledronic acid, Reactivation of hepatitis B virus (HBV) is a complication in patients
pamidronate, and ibandronate), the NCCN Multiple Myeloma Panel receiving carfilzomib or daratumumab. Therefore, testing for hepatitis B in
members prefer zoledronic acid for treatment of hypercalcemia.243,252,253 these patients is recommended.
Pneumocystis jiroveci pneumonia (PJP), herpes zoster, and antifungal

prophylaxis is recommended if high-dose dexamethasone is used.
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Multiple Myeloma
Prophylactic antiviral therapy is recommended for all patients receiving PI-

based and antibody based therapies.260,261 This is because impaired
lymphocyte function that results from MM and/or its treatment-related
myelosuppression may lead to reactivation of herpes simplex infection or
herpes zoster.261-264 Herpes zoster prophylaxis is recommended all patients
treated with PIs, daratumumab, isatuximab-irfc, or elotuzumab. According
to the NCCN Panel, three months of antibiotic prophylaxis should be
considered at diagnosis for patients at high risk for infection (See NCCN
Guidelines for Prevention and Treatment of Cancer-Related Infections).
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Multiple Myeloma
Management of Renal Disease in Multiple Myeloma The initial treatment of cast nephropathy includes initiating appropriate MM
In patients with MM and monoclonal gammopathies, renal disease usually therapy and providing adequate supportive care.
results from the production of monoclonal immunoglobulin or light/heavy
Myeloma therapy: Myeloma therapy using bortezomib-containing
chains by a clonal proliferation of plasma cells or B cells. Renal disease is
regimens should be initiated as soon as possible to decrease the
seen in 20-50% of patients with MM and has been observed to negatively
production of nephrotoxic clonal immunoglobulin.268
affect outcomes.265-267 The NCCN Panel has added a new page outlining
Bortezomib/dexamethasone-based regimens can be administered in
management of renal disease in MM.
patients with severe renal impairment and also those on dialysis and does
Renal insufficiency defined as elevated serum creatinine greater than 2 not require renal dose adjustment.268 If two-drug regimen, bortezomib and
mg/dL or established glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 dexamethasone is used as initial treatment, a third drug that does not
in patients with MM is usually due to light chain cast nephropathy, but require dose adjustment can be added including cyclophosphamide,
other etiologies need to be considered including hypercalcemia, volume thalidomide, an anthracycline or daratumumab. Other agents used in
depletion, and hyperuricemia as well as nephrotoxic medications or IV myeloma therapy should be used with caution and with dose adjustments
contrast. In addition, concomitant amyloidosis and monoclonal based on the degree of renal function impairment as recommended by the
immunoglobulin deposition should be suspected when renal insufficiency IMWG.269 A retrospective study evaluated lenalidomide and
or albuminuria is present without high levels of light chains. dexamethasone based on two phase III trials of lenalidomide/low-dose
dexamethasone in patients with relapsed/refractory MM with a serum
Diagnostic tests creatinine of <2.5 mg/dL. Patients grouped by creatinine clearance >60
According to the NCCN Panel, diagnostic workup of patients with mL/min (n=243), 30-60 mL/min (n=82), and <30 mL/min (n=16) showed no
symptomatic MM should include serum creatinine, electrolytes difference in response rates to lenalidomide/low-dose dexamethasone.270
measurements, eGFR, electrophoresis of a sample from a 24-hour urine Patients with renal insufficiency had higher rates of thrombocytopenia and
collection, serum electrophoresis, and serum free light chain lenalidomide discontinuation than seen in patients without renal
measurement. If proteinuria predominantly consists of light chains with insufficiency. The NCCN Panel had outlined recommendations for
high serum levels of free light chain, and the cause of renal insufficiency lenalidomide dosing based on the degree of renal function in patients with
can be attributed to MM, a renal biopsy may not be necessary. However, MM and renal impairment. While prospective data to define optimal dosing
in patients without a clear and complete explanation for their renal are often lacking, pomalidomide has been studied in patients with relapsed
insufficiency should undergo renal biopsy to look for other pathophysiology MM in three different categories of renal insufficiency (eGFR 30-40
such as monoclonal immunoglobulin deposition disease (MIDD) or mL/min/1.73 sqm, eGFR <30 mL/min/1.73 sqm, and those requiring
membranoproliferative glomerulonephritis (MPGN). dialysis) and full dose pomalidomide of 4 mg daily was found to be safe in
all three groups.271
Treatment Options
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Multiple Myeloma
Supportive Care: Intravenous fluids should be started promptly to

decrease the renal tubular light chain concentration with a goal urine
output of 100 to 150 cc per hour. Careful assessment of the fluid status is
critical to avoid hypervolemia especially in patients with oliguria renal
failure.
In addition, nephrotoxic medications should be discontinued and other

metabolic abnormalities such as hypercalcemia and hyperuricemia should
be corrected. Hydration, bisphosphonates or denosumab, and calcitonin
are recommended to reduce calcium levels in the case of hypercalcemia.
In patients with renal disease, pamidronate and zoledronic acid should be
used with caution. The NCCN Panel has provided the recommended
dosing of these agents in those who have renal impairment.
Dialysis may be required in selected patients in addition to prompt

institution of anti-myeloma therapy. Mechanical removal of light chains
may be considered on a case by case basis. While the benefit of
mechanical removal of free light chains has not been established, there is
limited evidence for the use of plasmapheresis or high-cutoff dialysis to
reduce pathogenic light chains.
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Multiple Myeloma
Monoclonal gammopathy of Clinical significance (MGCS) urinalysis is normal or there is no evidence of proteinuria. (it’s not always
Monoclonal gammopathy of undetermined significance (MGUS) is defined light chain proteinuria).
by the absence of MM defining events, presence of monoclonal
gammopathy of <3 g/dL, and clonal population of bone marrow plasma The presence of monoclonal immunoglobulin deposits in the kidney
cells less than 10%. The prevalence of MGUS in the general population is indicates the existence of a plasma cell, B cell, or lymphoplasmacytic
about 0.7%, and it increases with age. clone that is responsible for the production of the monoclonal protein.
M-protein must be detected by electrophoresis and immunofixation in the

Monoclonal gammopathy of clinical significance (MGCS) refers to the
urine and serum and must be correlated with the one found in biopsy.
potentially organ-toxic properties of M-protein. Typically, the M-protein in
Immunofluorescence staining should be performed with the biopsy sample
MGCS does not meet the diagnostic criteria MM and Waldenström
for IgG subclasses, IgA and IgM, and kappa and lambda.
macroglobulinemia (WM). Previously MGCS were all grouped under
MGUS. Monoclonal gammopathy affects the renal function, it is referred to Imaging by PET/CT, low-dose CT, or whole-body MRI should be
as monoclonal gammopathy of renal significance (MGRS). Peripheral performed as clinically indicated. Bone marrow biopsy is carried out if
neuropathy mediated by a monoclonal protein in the serum and urine suspected to have MM or WM.
without any evidence of MM or WM is now defined as monoclonal
gammopathy of neurological significance (MGNS). Additional workup for appropriate diagnosis of suspected WM, CLL/SLL,
or systemic light chain amyloidosis maybe carried out as outlined in the
Monoclonal Gammopathy of Renal Significance (MGRS) respective NCCN Guidelines (see NCCN Guidelines for Waldenström
Macroglobulinemia/Lymphoplasmacytic Lymphoma, NCCN Guidelines for
The term MGRS was proposed by the International Kidney and
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, and
Monoclonal Gammopathy Research Group to collectively describe
NCCN Guidelines for Systemic Light Chain Amyloidosis).
patients who meet the criteria MGUS but demonstrate renal injury
attributable to the underlying monoclonal protein.272 Treatment
When the presence of monoclonal gammopathy affects the renal function, The treatment of MGRS is directed at the underlying plasma cell or B-cell
it is referred to as MGRS. Renal damage in the setting of symptomatic MM clones to improve or prevent further kidney damage in these patients. For
is not considered MGRS. IgG, IgA and FLC MGRS, use the management algorithms for MM; For
IgM MGRS, see NCCN Guidelines for Waldenström
Initial Workup Macroglobulinemia/Lymphoplasmacytic Lymphoma. For any MGRS with
In patients suspected of having MGRS, kidney biopsy is performed. A monoclonal B-cell lymphocytosis (MBL) features, see NCCN Guidelines
kidney biopsy is essential in demonstrating the nephrotoxicity of the for Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.
monoclonal protein. The biopsy may be deferred if the eGFR is stable, the
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Multiple Myeloma
The response assessment in patients with MGRS who are being actively
treated is as per the NCCN Guidelines listed above and includes SPEP
and immunofixation; 24-hour urine collection for total protein, protein
electrophoresis, and immunofixation; serum free light chain assay; and
serum creatinine.
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Multiple Myeloma
Monoclonal Gammopathy of Neurological Significance (MGNS)
MS-46

Multiple Myeloma
POEMS Syndrome
POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal
protein, Skin changes) syndrome is characterized by the presence of a
monoclonal plasma cell disorder, peripheral neuropathy, and one or more
of the following features: osteosclerotic myeloma, Castleman disease
(angiofollicular lymph node hyperplasia), increased levels of serum
vascular endothelial growth factor (VEGF), organomegaly,
endocrinopathy, edema, typical skin changes, and papilledema.
MS-47

Multiple Myeloma
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MS-61

Multiple Myeloma
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MS-67

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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Guidelines for Patients® available at www.nccn.org/patients

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

*Shaji K. Kumar, MD/Chair ‡ ξ Noura Elsedawy, MD † Hans C. Lee, MD † ‡

ξ Bone marrow transplantation † Medical oncology

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

NCCN Multiple Myeloma Panel Members

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

INITIAL DIAGNOSTIC WORKUPa CLINICAL FINDINGS

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

CLINICAL PRIMARY FOLLOW-UP/SURVEILLANCE

• Follow-up interval, every 3–6 mo:p

e See Principles of Imaging (MYEL-B).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

CLINICAL PRIMARY FOLLOW-UP/SURVEILLANCE

• Every 3–6 months:

e See Principles of Imaging (MYEL-B).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

CLINICAL PRIMARY FOLLOW-UP/SURVEILLANCE

• Laboratory assessments appropriate for monitoring

c See Management of Renal Disease in Multiple Myeloma (MYEL-J).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

MULTIPLE MYELOMA (SYMPTOMATIC) FOLLOW-UP/SURVEILLANCE

Response or Maintenance therapy

Response or Maintenance therapy Progressionq

q See Response Criteria for Multiple Myeloma (MYEL-E).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

MULTIPLE MYELOMA ADDITIONAL TREATMENT

Clinical trial, if eligible

q See Response Criteria for Multiple Myeloma (MYEL-E).

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

DISEASE STAGING AND RISK STRATIFICATION SYSTEMS FOR MULTIPLE MYELOMAa

Stage International Staging System (ISS) Revised-ISS (R-ISS)

II Not ISS stage I or III Not R-ISS stage I or III

ISS stage III and either high-risk

Factors Considered High Risk for MM

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

DEFINITIONS OF SMOLDERING AND MULTIPLE MYELOMA

Smoldering Myeloma (Asymptomatic)a,b Multiple Myeloma (Symptomatic)a,c

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 1.2023 NCCN Guidelines Index

PRINCIPLES OF RADIATION THERAPY

Palliative RT Dosing for MM:

Note: All recommendations are category 2A unless otherwise indicated.