Multiple Myeloma and Related Disorders

Kumar Rajagopalan

Outline
Biology Plasma Cell Dyscrasia
MGUS Plasmacytoma

Multiple myeloma
Smoldering POEMS

Waldenstroms Macroglobulinemia Amyloidosis

The Continuum of Plasma Cell Disorders

Normal

MGUS

Indolent Myeloma

Multiple Myeloma

Myeloma, Malpas et al. 2004

 The hallmark of plasma cell disorders is the presence of a paraprotein in the serum and/or urine.

Paraproteinemias
Normal immunoglobulin pattern
Polyclonal reflects progeny of different plasma cells

Paraproteinemia
Monoclonal immunoglobulin band in sera reflects synthesis from single plasma cell clone

SPEP Polyclonal Gammopathy

Monoclonal Gammopathy

Normal Immunoelectrophoresis

Presentation of Plasma Cell Disorders

Increased protein on a routine chemistry panel Anemia Bone pain Renal dysfunction Hypercalcemia

Pathophysiology: Monoclonal BCells/Plasma Cell Dyscrasia

Marrow replacement
Cytopenias Constitutional symptoms

Decreased quantitative immunoglobulins

Infections

Lytic bone lesions

Fractures Hypercalcemia

Extramedullary involvement
Plasmacytomas Organomegaly

Pathophysiology: Monoclonal Immunoglobulin Proteins

Heavy chains or Light chains in serum, urine, kidney or other tissues
Renal insufficiency Neurologic disease Hyperviscosity Cold Agglutinin disease AL Amyloidosis POEMS: Polyneuropathy, Organomegaly, Endocrine disturbances, M-protein, Skin changes

MGUS: Monoclonal Gammopathy of Undetermined Significance

MGUS
Diagnosis
Serum M-protein
Usually IgG or IgA, usually <3 g/dL Stable over time

Marrow plasma cells <10% No lytic bone lesions, unexplained anemia, hypercalcemia, or renal insufficiency

Incidence
1-2% of adults Increases with age
6% aged 62-79 y/o, 14% >90 y/o

MGUS Progression
1384 patients at Mayo MGUS: 1% per year progression
Relative risk 25x (myeloma), 46x (Waldenstroms), 8.4x (amyloid), 2.4x (lymphoma)

IgM MGUS: 1.5% per year Predictors

Size of M-spike (> 2.5 g/dL, 41% at 10 yr) Serum albumin
NEJM 2002;346:564. Kyle ASH 2002 #384.

MGUS Progression: 1% per Year

NEJM 2002;346:564

MGUS: Management
Testing
CBC, calcium, creatinine, SPEP with immunofixation, quantitative immunoglobulins, 24-hour urine protein (with UPEP and immunofixation if positive) If M-protein 2-3 g/dl, add bone marrow and skeletal survey

F/U
SPEP/H&P repeated in 6 months, then annually

Multiple Myeloma and Related Disorders

Definition: A group of diseases that involve malignant proliferation of Ig-secreting cells of B-cell lineage that are usually associated with paraproteinemia or paraproteinuria.

Multiple Myeloma
US Incidence: 15,000 new cases/year
1% of malignancies

US Prevalence: 65,000 cases/year Double incidence rate in African Americans Median age 65
3% <40 years old

Unknown cause
Radiation, benzene, solvents, pesticides, insecticides

Etiology
Etiology is not known. Risk factors: Race, sex. Increased risk with ionizing radiation and exposure to pesticides like Dioxin. Recently viruses like HHV-8 and SV-40, have been linked to myeloma development.

Pathogenesis
Bone marrow microenvironment very important for proliferation and chemotherapy resistance. BM stromal cells produce IL-6, responsible for pathogenesis and progression. IL-6 inhibits apoptosis of plasma cells. IL-6 contributes to bone loss by stimulating osteoclasts and inhibiting bone formation. Interaction with extracellular matrix proteins protect cells from chemo and radiation.

MM: Clinical Features

Disease of the elderly (7th decade) Bone pain
most commonly vertebra and long bones lytic lesions fractures

Multiple Myeloma Typical Punched Out Lesions

Multiple Myeloma

Multiple Myeloma Diagnosis

(1 major+1 minor or 3 minor)

Major Criteria
Plasmacytoma on tissue biopsy 30% Marrow plasmacytosis M-protein
3.5 g/dL IgG 2 g/dL IgA 1g/24 hr urine Bence Jones

Minor Criteria
10-29% Marrow plasmacytosis M-protein
Less than major

Lytic bone lesions Low immunoglobuins

IgM <50 mg/dL IgA <100 mg/dL IgG <600 mg/dL

Newly Diagnosed Multiple Myeloma: 1985-1998

N=1027 Median age: 66 years Median survival: 33 months
Did not improve 1985 through 1998

Multivariate analysis
Age, plasma cell labeling index, thrombocytopenia, serum albumin, creatinine (log value)
Kyle, Mayo Clin Proc, 2003.

Newly Diagnosed Multiple Myeloma: 1985-1998

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Ca Cr >2 Anemia Skel Surv UPEP SPEP

Kyle, Mayo Clin Proc, 2003.

Myeloma Diagnostic Work-Up

SPEP and UPEP (24 collection) with immunofixation
3% nonsecretory: check serum free light chains

Skeletal survey (not a bone scan) Quantitative serum immunoglobulins (IgA, IgG, IgM) Bone Marrow Aspirate and Biopsy
Other tests (calcium, creatinine, beta-2 microglobulin, CRP, albumin, plasma cell labeling index, etc, etc) are only for staging/prognosis

M-Protein Tests
Urine Dipstick not sensitive to Bence Jones proteins, need sulfosalicylic acid (SSA) Screening (SPEP/UPEP)
Gamma-globulins
Polyclonal gammopathy: liver disease, connective tissue disease, chronic infection, others Hypogammaglobulinemia: Immunodeficiency, nephrotic syndrome (amyloidosis), myeloma/CLL

Monoclonality
Immunofixation with monospecific antibodies Immunoelectrophoresis Immunoassay for serum free light chains (Mayo Clinic)

Myeloma Prognostic Work-Up

Hemoglobin Calcium Serum creatinine Beta-2 microglobulin Albumin Bone Marrow cytogenetics
FISH chromosome 13 and 11?

C-reactive protein?? Plasma cell labeling index?? Serum IL-6??

Myeloma Renal Disease

Myeloma kidney
Normal glomerular function Concentrated light chains precipitate in tubules Monoclonal light chains seen in UPEP with immunofixation

Glomerular lesions
Deposits of amyloid or light chain deposition disease Nonselective leakage of all serum proteins UPEP preponderance of albumin

Renal Manifestations
Myeloma Kidney Cast Formation

Light chain Deposition

Amyloidosis

Pierre Ronco JNEPHROL 2000; 13 (suppl. 3):

Pathology

Myeloma: Durie-Salmon Staging

Stage I
Hemoglobin >10 g/dL Normal calcium No lytic bone lesions Low M-protein IgG <5 g/dL IgA <3 g/dL Bence Jones <4 g/24h

Stage III
Hemoglobin <8.5 Calcium >12 (adjusted) >3 lytic bone lesions High M-protein IgG >7 g/dL IgA >5 g/dL Bence Jones >12 g/24h

Stage II (not Stage I/III)

A) Creatinine <2 B) Creatinine >2

Myeloma: Median Survival

Durie-Salmon stage
Stage I 60 months

Stage II
Stage III

40 months
15 months

International Myeloma Working Group Staging System

Stage I II 2Microglobulin < 3.5 <3.5 3.5 5.5 III > 5.5 Albumin > 3.5 <3.5 any any

Therapy of Newly Diagnosed Multiple Myeloma: 1985-1998

Kyle, Mayo Clin Proc, 2003.

Myeloma: Therapy Principles

Observation for stage I Incurable despite conventional chemotherapy and high-dose therapy Bisphosphonates Chemotherapy
Conventional High-dose with stem cell rescue New agents

Graft-versus-myeloma

Myeloma: Therapy
Alkylating agents
Melphalan: low-dose oral to high-dose myeloablative

Steroids
Alone (pulse Dexamethasone) or combination (M&P, VAD, Thal/Dex)

Cyclophosphamide Thalidomide and the IMiDs Bortezomib (Velcade): proteosome inhibitor Graft-versus-myeloma effect
Mini-allogeneic transplantation

Interferon: maintenance

Therapy of Multiple Myeloma

Chemotherapy
pulse dexamethasone pulse dexamethasone+ thalidomide pulse dexamethasone +lenalidomide (revlimid) pulse dexamethasone + bortezimib (velcade) melphalan+prednisone + imid (not transplant candidate)

Autologous stem cell transplant Radiation

Major Classes of Drugs Used in the Treatment of Myeloma

Kyle, R. A. et al. N Engl J Med 2004;351:1860-1873

Autologous Transplantation

NEJM 2003; 348: 1875.

Myeloma: Supportive Therapy

Bisphosphonates
Phase III: monthly pamidronate (JCO 1998;16:593)
Skeletal-related events 38% versus 51%, p=0.015 Median survival 21 versus 14 months

Compression fractures: vertebroplasty DVT risk: steroids, steroids + thalidomide Hypercalcemia Renal insufficiency: ?Plasmapheresis Infections Anemia: Eyrthropoietins

Myeloma Bone Marrow Microenvironment

Interactions
Myeloma cell adhesion molecules react with stroma Release of osteoclast activating factors (IL-1B, IL-6, TNFB) Vascular endothelial growth factor (VEGF) secreted by myeloma cells

Myeloma Bone Disease

New Agents

Smoldering Myeloma
Serum M-protein >3 g/dL Marrow plasma cells >10% No lytic bone lesions, unexplained anemia, hypercalcemia, or renal insufficiency Evolve to overt multiple myeloma
3.3% per year Greatest for IgA
JCO 2002;20:1625.

Plasmacytoma

Extramedullary Plasmacytoma
~3% of plasma cell neoplasms Isolated plasma cell tumors of soft tissues
Upper respiratory tract common

Uninvolved marrow, negative skeletal survey M-protein present ~25% cases

Disappears following treatment

Curable with local radiation therapy

Solitary Plasmacytoma of Bone

~3% of plasma cell neoplasms One isolated bony lesion of plasma cells Uninvolved marrow <5% plasma cells M-protein present ~25% cases
Disappears following treatment

Curable with local radiation therapy

Median OS 10 years Multiple myeloma develops in 50-60%

Osteosclerotic Myeloma (POEMS)

Polyneuropathy
Sensorimotor peripheral neuropathy in 75%

Organomegaly
Lymphadenopathy, hepatomegaly, splenomegaly

Endocrinopathy
Adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic

M-Protein Skin changes

Hyperpigmentation, hypertrichosis, plethora, hemangiomata, white nails

Osteosclerotic Myeloma

Lymphoplasmacytic Lymphoma
(Waldenstroms Macroglobulinemia)
Malignant proliferation of plasmacytoid lymphocytes secreting IgM M-protein 1400 cases/year Organomegaly/Peripheral neuropathies Cryoglobulinemia
Type I: Raynauds phenomenon, cold urticaria, etc. Type II: Purpura, arthralgias, renal failure, mononeuritis

IgM tissue infiltration/AL amyloidosis Coagulation abnormalities

Hyperviscosity
Usually IgM >5 g/dL, viscosity >4.0 Eyes
Sausage link conjunctival and retinal veins Retinal hemorrhages, Papilledema

CNS
Ataxia, nystagmus, vertigo, confusion, altered consciousness

Increased intravascular volume

Dilutional anemia Risk congestive heart failure with transfusion

Therapy: plasmapheresis/chemotherapy

Waldenstroms Macroglobulinemia: Therapy

Plasmapheresis for hyperviscosity 2-Chlorodeoxyadenosine (2-CdA, cladribine) Fludarabine Rituximab Other myeloma-like therapies

Monoclonal IgM: DDx

MGUS Multiple myeloma Waldenstroms CLL Chronic cold agglutinin disease
No evidence of neoplasia Hemolytic anemia aggravated by cold exposure 90% have kappa light chains

Amyloidosis
Extracellular tissue deposition of low molecular weight fibrils
Beta-pleated sheets, bind Congo red

Precursor proteins involved

Monoclonal immunoglobulin light chains: Primary (AL) Amyloidosis Serum amyloid A protein: Reactive or Secondary (AA) Amyloidosis Beta-2 microglobulin: Dialysis (DA) Amyloidosis Transthyretin, apolipoprotein A-I, Alzheimer amyloid precursor protein, prion protein, Prolactin, Atrial natriuretic protein, Procalcitonin, Insulin, Keratin

Amyloidosis: Presentation
Nephrotic syndrome Refractory CHF, Arrhythmia, Heart block Orthostatic hypotension, Peripheral neuropathy Bleeding diathesis (Raccoon eyes)
Factor X deficiency, liver disease

GI bleeding, Gastroparesis/Dysmotility, Malabsorption Macroglossia, Shoulder pad sign, Carpal tunnel syndrome, Organomegaly Skin thickening/waxy, easy bruising

Amyloidosis

Amyloidosis: Work-up
Biopsy
Involved organs or bone marrow Fat pad, salivary glands, rectal mucosa: 50-70% success for diagnosis

Echocardiography suggestive
Speckled myocardium Interventricular septal thickening

Distinguish from hereditary forms (10%) Evaluate for myeloma (rare)

AL Amyloidosis: Course
Rare progression to multiple myeloma (0.4%) Poor long-term prognosis
Cardiac, renal, hepatic failure, and infection Prognostic factors: circulating plasma cells, high beta-2 microglobulin, marrow plasmacytosis >10%, dominant cardiac involvement High B2M, marrow plasmacytosis: median survival
0: 54 months 1: 19 months 2: 13.5 months

AL Amyloidosis: Therapy
Chemotherapy
Dexamethasone with Dex/IFN maintenance

High-dose melphalan with Auto transplantation

Risky with cardiac, renal, GI involvement

Dhodapkar, Blood 2004;104:3520. Skinner, Annals 2004;140:85

Summary
Spectrum of mature B-cell neoplasms/plasma cell dyscrasias Clinical manifestations:
Tumor growth, marrow and tissue infiltration M-protein accumulation or infiltration Immune dysfunction Kidney and bone disease

Therapy not curative, but increasingly effective