Regular Article

CLINICAL TRIALS AND OBSERVATIONS

Daratumumab, lenalidomide, bortezomib, and

dexamethasone for transplant-eligible newly diagnosed
multiple myeloma: the GRIFFIN trial
Peter M. Voorhees,1 Jonathan L. Kaufman,2 Jacob Laubach,3 Douglas W. Sborov,4 Brandi Reeves,5 Cesar Rodriguez,6 Ajai Chari,7
Rebecca Silbermann,8 Luciano J. Costa,9 Larry D. Anderson Jr,10 Nitya Nathwani,11 Nina Shah,12 Yvonne A. Efebera,13 Sarah A. Holstein,14

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Caitlin Costello,15 Andrzej Jakubowiak,16 Tanya M. Wildes,17 Robert Z. Orlowski,18 Kenneth H. Shain,19 Andrew J. Cowan,20 Sean Murphy,21
Yana Lutska,21 Huiling Pei,22 Jon Ukropec,23 Jessica Vermeulen,24 Carla de Boer,24 Daniela Hoehn,21 Thomas S. Lin,21 and Paul G. Richardson,3
for the GRIFFIN Trial Investigators
1
Levine Cancer Institute, Atrium Health, Charlotte, NC; 2Winship Cancer Institute, Emory University, Atlanta, GA; 3Dana-Farber Cancer Institute, Boston, MA;
4
Huntsman Cancer Institute, School of Medicine, University of Utah, Salt Lake City, UT; 5Division of Hematology/Oncology, Department of Medicine, The University
of North Carolina at Chapel Hill, Chapel Hill, NC; 6Department of Hematology and Oncology, School of Medicine, Wake Forest University, Winston-Salem, NC;
7
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY; 8Knight Cancer Institute, Oregon Health & Science University, Portland, OR;
9
University of Alabama at Birmingham, Birmingham, AL; 10Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX; 11Judy and
Bernard Briskin Center for Multiple Myeloma Research, City of Hope Comprehensive Cancer Center, Duarte, CA; 12Department of Medicine, University of California
San Francisco, San Francisco, CA; 13The Ohio State University Comprehensive Cancer Center, Columbus, OH; 14Division of Oncology & Hematology, University of
Nebraska Medical Center, Omaha, NE; 15Moores Cancer Center, University of California San Diego, La Jolla, CA; 16University of Chicago Medical Center, Chicago,
IL; 17Section of Medical Oncology, Division of Oncology, School of Medicine, Washington University in St. Louis, St. Louis, MO; 18Department of
Lymphoma-Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; 19Department of Malignant Hematology, H. Lee Moffitt Cancer Center,
Tampa, FL; 20Division of Medical Oncology, University of Washington, Seattle, WA; 21Janssen Scientific Affairs, LLC, Horsham, PA; 22Janssen Research & De-
velopment, LLC, Titusville, NJ; 23Janssen Global Medical Affairs, Horsham, PA; and 24Janssen Research & Development, LLC, Leiden, The Netherlands

KEY POINTS Lenalidomide, bortezomib, and dexamethasone (RVd) followed by autologous stem cell
transplantation (ASCT) is standard frontline therapy for transplant-eligible patients with
l D-RVd improved sCR
rates and MRD newly diagnosed multiple myeloma (NDMM). The addition of daratumumab (D) to RVd
negativity vs RVd, (D-RVd) in transplant-eligible NDMM patients was evaluated. Patients (N 5 207) were
both of which randomized 1:1 to D-RVd or RVd induction (4 cycles), ASCT, D-RVd or RVd consolidation
deepened over time.
(2 cycles), and lenalidomide or lenalidomide plus D maintenance (26 cycles). The primary end
l No new safety point, stringent complete response (sCR) rate by the end of post-ASCT consolidation, fa-
concerns were vored D-RVd vs RVd (42.4% vs 32.0%; odds ratio, 1.57; 95% confidence interval, 0.87-2.82;
observed with D-RVd,
1-sided P 5 .068) and met the prespecified 1-sided a of 0.10. With longer follow-up (median,
and no clinically
significant impact on 22.1 months), responses deepened; sCR rates improved for D-RVd vs RVd (62.6% vs 45.4%;
stem cell mobilization P 5 .0177), as did minimal residual disease (MRD) negativity (1025 threshold) rates in the
or engraftment intent-to-treat population (51.0% vs 20.4%; P < .0001). Four patients (3.8%) in the D-RVd
was noted.
group and 7 patients (6.8%) in the RVd group progressed; respective 24-month progression-
free survival rates were 95.8% and 89.8%. Grade 3/4 hematologic adverse events were more
common with D-RVd. More infections occurred with D-RVd, but grade 3/4 infection rates were similar. Median CD341 cell
yield was 8.2 3 106/kg for D-RVd and 9.4 3 106/kg for RVd, although plerixafor use was more common with D-RVd.
Median times to neutrophil and platelet engraftment were comparable. Daratumumab with RVd induction and con-
solidation improved depth of response in patients with transplant-eligible NDMM, with no new safety concerns. This trial
was registered at www.clinicaltrials.gov as #NCT02874742. (Blood. 2020;136(8):936-945)

Introduction strategies with manageable toxicity are needed to improve

Recommended frontline treatment of transplant-eligible newly depth of response, progression-free survival (PFS), and overall
diagnosed multiple myeloma (MM; NDMM) includes induction survival (OS). The combination of lenalidomide, bortezomib, and
therapy, high-dose melphalan and autologous stem cell trans- dexamethasone (RVd) is a standard induction regimen for
plantation (ASCT), and maintenance.1-3 However, this approach NDMM.4,5 This regimen improved PFS and OS in NDMM pa-
is noncurative in the vast majority of patients. Therefore, novel tients not undergoing ASCT6 and demonstrated a median PFS of

936 blood® 20 AUGUST 2020 | VOLUME 136, NUMBER 8 © 2020 by The American Society of Hematology
50 months and a 4-year OS rate of 81% when used as induction Trial treatments
and consolidation therapy with frontline ASCT.7 We randomly assigned patients in a 1:1 ratio to D-RVd or RVd
(supplemental Figure 1). Randomization was stratified by In-
Although advances in frontline therapy have yielded unprece- ternational Staging System (ISS) disease stage (I, II, or III) and
dented improvement in long-term patient outcomes, surrogate creatinine clearance (30-50 or .50 mL/min).
markers of PFS and OS are needed. In this regard, achievement
of stringent complete response (CR; sCR) after ASCT is associ- All patients received four 21-day induction cycles and two
ated with improvement in median PFS and OS.8,9 Similarly, 21-day consolidation cycles of oral lenalidomide (25 mg daily
minimal residual disease (MRD) testing has emerged as a sen- on days 1-14), subcutaneous bortezomib (1.3 mg/m2 on days 1,
sitive measure of depth of response that strongly correlates with 4, 8, and 11), and oral dexamethasone (20 mg on days 1, 2, 8,
PFS and OS.7,10-13 9, 15, and 16). Patients in the D-RVd group received IV
daratumumab (16 mg/kg) on days 1, 8, and 15 of cycles 1 through
Daratumumab is a human immunoglobulin G kappa (IgGk) 4 and day 1 of post-ASCT consolidation cycles (cycles 5 and 6).
monoclonal antibody targeting CD38.14-20 In randomized phase Starting at cycle 7, all patients received maintenance therapy
3 studies in NDMM and relapsed/refractory MM, daratumumab- (28-day cycles) consisting of oral lenalidomide (10 mg daily

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based regimens improved depth of response, including MRD on days 1-21; increasing to 15 mg after 3 cycles, if tolerated).
negativity, which translated into longer median PFS.21-27 Re- Patients in the D-RVd group also received IV daratumumab
cently, the CASSIOPEIA study demonstrated the benefit of (16 mg/kg) on day 1 every 8 weeks or every 4 weeks per protocol
adding daratumumab to triplet induction and consolidation amendment 2 (approved 5 February 2018), based on emerging
therapy consisting of a proteasome inhibitor (bortezomib), im- pharmacokinetic results from other studies. Maintenance ther-
munomodulatory agent (thalidomide), and dexamethasone in apy on study will continue until disease progression or up to
transplant-eligible NDMM.21 2 years. Following completion of study maintenance therapy,
patients can continue lenalidomide per local standard of care.
The GRIFFIN study was designed to examine whether the ad- The supplemental Appendix includes details regarding pre- and
dition of daratumumab to RVd (D-RVd) and ASCT improves postinfusion medications and dose modifications.
depth of response, including rates of sCR and MRD negativity, in
NDMM patients. The safety run-in phase demonstrated that After induction cycle 4, patients underwent stem cell mobili-
D-RVd was safe and well-tolerated, and depth of response zation with granulocyte colony-stimulating factor with or without
continued to improve over the course of therapy.28 Herein, we plerixafor, according to institutional standards; if unsuccessful,
report the primary efficacy and updated secondary efficacy and cyclophosphamide-based mobilization was permitted. Patients
safety results of the randomized phase of the trial. then received high-dose therapy (melphalan 200 mg/m2) fol-
lowed by ASCT. Consolidation began 60 to 100 days after ASCT,
when the patient had recovered sufficiently per investigator’s
Methods discretion. Maintenance therapy began within 14 days following
Trial design and oversight postconsolidation disease evaluation.
This multicenter, randomized, open-label, active-controlled,
phase 2 study was designed by Janssen Oncology in partnership End points and assessments
with Alliance Foundation Trials and enrolled patients between The primary end point was the sCR rate by the end of post-ASCT
20 December 2016 and 10 April 2018 at 35 sites across the consolidation, systematically assessed by a validated computer
United States. The protocol and all amendments were approved algorithm in accordance with IMWG criteria9,29 (supplemental
by the institutional review board or independent ethics com- Table 1) within 7 days after completion of consolidation. As
mittee at each participating site, and all patients gave written daratumumab may interfere with serum immunofixation, reflex
informed consent. The study was conducted in accordance with assays were performed to confirm responses of CR or better.30
the International Conference on Harmonization Good Clinical Patients with confirmed daratumumab interference on serum
Practice guidelines, the principles originating from the Decla- M-protein electrophoresis and immunofixation who demon-
ration of Helsinki, and study site-specific regulations. strated all other criteria for CR or sCR were regarded as having
CR or sCR, respectively.
Patients
Eligible patients were 18 to 70 years of age at study entry, had The secondary end point of the MRD-negativity rate was defined
NDMM as defined by International Myeloma Working Group as the proportion of patients who achieved MRD negativity,
(IMWG) criteria,29 had an Eastern Cooperative Oncology Group using a minimum sensitivity threshold of 1 in 105 nucleated cells
(ECOG) performance status score of 0 to 2, and were candidates or higher, in accordance with IMWG criteria.9 MRD was evalu-
for high-dose therapy and ASCT. Other inclusion criteria in- ated by next-generation sequencing (NGS; clonoSEQ Assay
cluded: absolute neutrophil count, $1.0 3 109/L; hemoglobin 2.0)31 of bone marrow aspirates at baseline and first evidence of
level, .7.5 g/dL; platelet count, $75 3 109/L ($50 3 109/L if suspected CR or sCR as recommended per IMWG criteria (in-
$50% of the bone marrow was infiltrated with MM cells); alanine cluding patients with very good partial response [VGPR] or better
aminotransferase and aspartate aminotransferase levels ,2.5 and suspected daratumumab interference). Following protocol
times the upper limit of normal; total bilirubin level, ,1.5 times amendment 2, MRD assessments were scheduled for the end of
the upper limit of normal; creatinine clearance, $30 mL/min; induction and consolidation, and after 12 and 24 months of
and corrected serum calcium, #14.0 mg/dL (#3.5 mmol/L). maintenance, regardless of response. Patients were considered
Additional eligibility criteria are listed in the supplemental MRD positive if the MRD assessment was positive, indetermi-
Appendix (available on the Blood Web site). nate, or unavailable. MRD was analyzed in the intent-to-treat

D-RVd FOR TRANSPLANT-ELIGIBLE MULTIPLE MYELOMA blood® 20 AUGUST 2020 | VOLUME 136, NUMBER 8 937
population, in the subgroup of patients who achieved a re- Table 1. Patient demographic and disease characteristics
sponse of CR or better, and in the MRD-evaluable population in the intent-to-treat population at baseline
(patients who had both baseline [clone identified/calibrated] and
post-baseline MRD [with negative, positive, or indeterminate D-RVd RVd
result] samples taken). Additional secondary end points, in-
cluding complete definitions, are provided in the supplemental Age, y n 5 104 n 5 103
Appendix. Median (range) 59 (29-70) 61 (40-70)
Category, n (%)
,65 76 (73.1) 75 (72.8)
Adverse events (AEs) were monitored continuously from in- $65 28 (26.9) 28 (27.2)
formed consent through 30 days after last study treatment and
graded according to National Cancer Institute Common Ter- Sex, n (%) n 5 104 n 5 103
minology Criteria for Adverse Events Version 4.03. Male 58 (55.8) 60 (58.3)
Female 46 (44.2) 43 (41.7)

Statistical analysis ECOG performance status, n (%)* n 5 101 n 5 102

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The prespecified primary analysis occurred after all randomized 0 39 (38.6) 40 (39.2)
patients completed the post-ASCT consolidation disease 1 51 (50.5) 52 (51.0)
evaluation or discontinued from study treatment before this 2 11 (10.9) 10 (9.8)
time point. A second protocol-specified analysis will be per-
formed after all randomized patients complete the mainte- ISS disease stage, n (%)† n 5 104 n 5 103
nance phase or discontinue from study treatment before I 49 (47.1) 50 (48.5)
completing maintenance. II 40 (38.5) 37 (35.9)
III 14 (13.5) 14 (13.6)
Missing 1 (1.0) 2 (1.9)
The primary hypothesis was that patients in the D-RVd group
would have an improved rate of sCR by the end of post-ASCT Baseline creatinine clearance, n 5 104 n 5 103
consolidation compared with the RVd group (primary end point), mL/min, n (%)
tested at a 1-sided a of 0.10. All secondary analyses were 30-50 9 (8.7) 9 (8.7)
evaluated using a 2-sided P value (a 0.05) and were not adjusted .50 95 (91.3) 94 (91.3)
for multiplicity. Historical data suggest that the sCR rate by the
Cytogenetic risk profile, n (%)‡ n 5 98 n 5 97
end of consolidation is ;35% for RVd therapy. To detect an
Standard 82 (83.7) 83 (85.6)
absolute 15% increase in the sCR rate with 80% power using
High risk 16 (16.3) 14 (14.4)
a 1-sided likelihood ratio test with a 0.1 significance level,
200 patients were required for 1:1 randomization, assuming a Time since diagnosis of MM, mo n 5 103 n 5 102
5% nonevaluable rate. Median (range) 0.7 (0-12) 0.9 (0-61)

The intent-to-treat population was defined as all randomized patients. Informal testing
showed no differences between the 2 treatment groups in the characteristics evaluated at
Results baseline.
*ECOG performance status is scored on a scale from 0 to 5, with 0 indicating no symptoms
Patients and treatment and higher scores indicating increasing disability.
Among 292 patients screened, 16 were enrolled in the safety †The ISS disease stage is based on the combination of serum b2-microglobulin and albumin
levels. Higher stages indicate more advanced disease.
run-in phase28 (results previously reported) and 207 were ran-
‡Cytogenetic risk was assessed by FISH (local testing); high risk was defined as the presence
domized in part 2 and are reported in this analysis (D-RVd, of del17p, t(4;14), or t(14;16) among patients with available cytogenetic risk data.
n 5 104; RVd, n 5 103; supplemental Figure 2). Patients who failed
screening (n 5 69) did not meet inclusion and/or exclusion
criteria predefined by the protocol; the most common reasons
Ninety-eight patients (94.2%) in the D-RVd group and 94 (91.3%)
(occurring in .5 patients) were failure to provide signed in-
in the RVd group completed induction, 95 (91.3%) and
formed consent, inability to demonstrate documented MM/
80 (77.7%) underwent stem cell mobilization, 94 (90.4%) and
measurable disease at baseline, clinically significant cardiac
disease, and abnormal laboratory test results. In part 2 of 78 (75.7%) underwent ASCT, and 91 (87.5%) and 72 (69.9%)
GRIFFIN, 201 patients received $1 dose of study treatment and completed consolidation, respectively (supplemental Figure 2).
were analyzed for safety (D-RVd, n 5 99; RVd, n 5 102). The Ninety patients (86.5%) and 70 patients (68.0%) in the D-RVd and
primary efficacy analysis group consisted of 196 patients (D-RVd, RVd groups, respectively, entered maintenance. Seventeen
n 5 99; RVd, n 5 97) who had measurable disease at baseline, patients (16.3%) in the D-RVd group discontinued study treat-
received $1 study treatment dose, and underwent $1 disease ment, compared with 44 (42.7%) in the RVd group. The most
assessment. Demographics and clinical characteristics were common reasons for discontinuation were investigator-assessed
well balanced between randomized groups (Table 1). Median progressive disease (PD; D-RVd, 6.7%; RVd, 10.7%), patient
age was 60 years (range, 29-70 years); median time since withdrawal (3.8%; 9.7%), AEs (2.9%; 10.7%), and investigator
diagnosis was 0.8 months (range, 0-61 months). Nearly one- discretion (2.9%; 8.7%). In the D-RVd group, fewer patients
half of all patients (47.8%) had ISS stage I disease, and discontinued during induction (1.9% vs 6.8%) and after induction
30 patients (15.4%) had high-risk cytogenetic abnormalities but before mobilization (2.9% vs 13.6%) than in the RVd group
(del17p, t[4;14], or t[14;16] by fluorescence in situ hybridization (supplemental Figure 2). All 4 response-evaluable patients in the
[FISH]). D-RVd group who completed induction but did not undergo

938 blood® 20 AUGUST 2020 | VOLUME 136, NUMBER 8 VOORHEES et al

Table 2. Primary analysis: summary of responses by the end of consolidation

D-RVd, n (%) RVd, n (%) Odds ratio (95% CI)* P

Best response† n 5 99 n 5 97

ORR 98 (99.0) 89 (91.8) 8.75 (1.08, 71.01) .0160‡

sCR 42 (42.4) 31 (32.0) 1.57 (0.87, 2.82) .0680‡,§
$CR 51 (51.5) 41 (42.3)
CR 9 (9.1) 10 (10.3)
$VGPR 90 (90.9) 71 (73.2) 3.53 (1.55, 8.00) .0014‡
VGPR 39 (39.4) 30 (30.9)
PR 8 (8.1) 18 (18.6)

SD 1 (1.0) 7 (7.2)

PD 0 1 (1.0)

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The primary analysis occurred on 25 January 2019 (median follow-up, 13.5 months) after all randomized patients completed the post-ASCT disease evaluation or discontinued from study
treatment by this time point.
*Mantel-Haenszel estimate of the common odds ratio for stratified tables is used. The stratification factors are ISS stage (I, II, III) and creatinine clearance (CrCl [30-50 mL/min or .50 mL/min]) at
randomization. An odds ratio .1 indicates an advantage for the daratumumab group.
†Responses were assessed according to the IMWG recommendations by computer algorithm (details on the response criteria are provided in supplemental Table 1). This analysis included all
patients in the response-evaluable population of all randomized patients who had a confirmed diagnosis of MM, measurable disease at baseline, received $1 dose of study treatment, and
had $1 postbaseline disease assessment.
‡P values were calculated with the use of the Cochran-Mantel-Haenszel x2 test.
§A 1-sided P value is reported for the primary end point (postconsolidation sCR); all other responses were calculated using a 2-sided P value not adjusted for multiplicity.

ASCT achieved VGPR or better. Of the 15 response-evaluable 20.4% [21 of 103 patients]; P , .0001), as well as among patients
patients in the RVd group who completed induction but did not who achieved CR or better (62.0% [49 of 79 patients] vs 32.2%
undergo ASCT, 3 achieved VGPR or better, 4 had a partial re- [19 of 59 patients]; P 5 .0006), and among the MRD-evaluable
sponse (PR), and 8 had stable disease (SD). Most patients who population (68.8% [53 of 77 patients] vs 32.3% [21 of 65 patients];
discontinued study treatment with RVd received subsequent P , .0001; Table 3). The proportion of patients in the intent-to-
therapy (supplemental Table 2). treat population who were MRD negative (1025) and achieved CR
or better also favored the D-RVd group (47.1% [49 of 104 patients]
The prespecified primary analysis occurred at a median follow- vs 18.4% [19 of 103 patients]; P , .0001; Table 3).
up of 13.5 months. At the last follow-up, with a median of
22.1 months (range, 0-30.0 months), the median duration of To assess the impact of the higher rate of early treatment dis-
treatment was 21.9 months (range, 1.1-29.7 months) in the continuation in the RVd group on MRD negativity, an analysis
D-RVd group and 19.5 months (range, 0.5-29.7 months) in the was performed for patients who underwent ASCT. MRD-
RVd group. Median relative dose intensities for RVd were 91.6% negativity (1025) rates were higher in D-RVd patients undergo-
or greater and similar in both groups (supplemental Table 3). ing ASCT compared with RVd patients undergoing ASCT (55.3%
[52 of 94 patients] vs 25.6% [20 of 78 patients]; P , .0001).
Efficacy
The primary end point of sCR by the end of post-ASCT con- The higher MRD-negativity (1025) rates of the D-RVd regimen
solidation was achieved in 42 patients (42.4%) in the D-RVd were observed as early as the end of induction in the intent-
group and 31 patients (32.0%) in the RVd group (odds ratio, 1.57; to-treat population (21.2% [22 of 104 patients] vs 5.8% [6 of
95% confidence interval [CI], 0.87-2.82; 1-sided P 5 .068; 103 patients]; P 5 .0019; Figure 1B) and among patients
Table 2), which was statistically significant at the preset 1-sided a who achieved CR or better by the end of induction (47.4% [9 of
of 0.10. Secondary end points of overall response rate (ORR; 19 patients] vs 7.7% [1 of 13 patients]; P 5 .0237). Moreover,
99.0% vs 91.8%; P 5 .0160) and rate of VGPR or better (90.9% vs MRD-negativity rates using a higher sensitivity threshold of
73.2%; P 5 .0014) by the end of consolidation were higher in the 1026 also favored the D-RVd group at a median of 22.1 months
D-RVd group (Table 2). Responses continued to deepen over follow-up: 18.3% (19 of 104 patients) vs 6.8% (7 of 103 patients;
time, and at the last follow-up (median follow-up, 22.1 months; P 5 .0197), including among patients who reached CR or
Figure 1A), the percentage of patients with sCR was 62.6% in the better (24.1% [19 of 79 patients] vs 10.2% [6 of 59 patients];
D-RVd group and 45.4% in the RVd group (odds ratio, 1.98; 95% P 5 .0447).
CI, 1.12-3.49; P 5 .0177). Moreover, the rate of CR or better was
79.8% in the D-RVd group vs 60.8% in the RVd group (odds ratio, Subgroup analyses for prespecified factors were conducted
2.53; 95% CI, 1.33-4.81; P 5 .0045). for the primary efficacy end point at a median follow-up of
13.5 months (Figure 2A) and for MRD negativity at a median
At a median follow-up of 22.1 months, the MRD-negativity (1025) follow-up of 22.1 months (Figure 2B). For the prespecified pri-
rate was higher in the D-RVd group than in the RVd group in mary end point, D-RVd vs RVd improved the sCR rate by the end
the intent-to-treat population (51.0% [53 of 104 patients] vs of post-ASCT consolidation in all subgroups except for patients

D-RVd FOR TRANSPLANT-ELIGIBLE MULTIPLE MYELOMA blood® 20 AUGUST 2020 | VOLUME 136, NUMBER 8 939
 A B
100 60
7.2
12.1 14.4
90 21.2 6.2 51.0
7.1 32.0 50

Patients with MRD negativity, %

5.2 47.1
80 42.4
6.1 45.4
70 62.6
43.3 40
10.3
Patients, %

60
46.4
52.5 9.1
50 30
15.5
59.6 30.9
40 21.2 20.4
20 16.5
30 39.4 17.2 18.6
35.1
20 25.8
18.6 10
26.3 13.4 5.8
16.2
10
12.1
8.1 8.2 8.2 8.2 7.2
2.0 1.0 1.0 3.0 1.0
0 0
induction

consolidation

follow-up

induction

consolidation

follow-up

induction

consolidation

follow-up

induction

consolidation

follow-up
End of

End of
ASCT

ASCT
End of

End of

End of

End of

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Last

Last

Last

Last
End of

End of

End of

End of
D-RVd RVd D-RVd RVd

sCR CR VGPR PR SD/PD/NE

Figure 1. Summary of response rates and MRD-negativity (1025) rates over time. (A) Response rates over time are shown. Data for the end of induction, end of ASCT, and
end of consolidation are from the primary analysis. Response data with longer median follow-up of 22.1 months are also shown (last follow-up). (B) MRD-negativity (1025) rates in
the intent-to-treat population by the end of induction therapy, end of consolidation, and last follow-up. All MRD data are from the analysis with a median follow-up of
22.1 months. MRD was evaluated at baseline, first evidence of suspected CR or sCR, at the end of induction and consolidation, and after 12 and 24 months of maintenance,
regardless of response (per protocol amendment 2).

with ISS stage III disease or high-risk cytogenetic abnormal- Safety

ities (Figure 2A). At both the time of the primary analysis (data The most common AEs of any grade (occurring in $30% of
not shown) and after 22.1 months of median follow-up, the patients in either group) are summarized in Table 4. The most
subgroup analysis of MRD negativity (1025) favored D-RVd in common ($10%) grade 3/4 AEs were neutropenia (D-RVd,
all analyzed subgroups (Figure 2B) but was not statistically 41.4%; RVd, 21.6%), lymphopenia (23.2%; 21.6%), thrombocy-
significant for ISS stage III disease or high-risk cytogenetic topenia (16.2%; 8.8%), leukopenia (16.2%; 6.9%), and pneu-
abnormalities. monia (8.1%; 10.8%; Table 4).

At a median follow-up of 22.1 months, 4 events (3.8%) of disease Serious AEs were reported in 39 patients (39.4%) in the D-RVd
progression occurred in the D-RVd group compared with group and 52 (51.0%) in the RVd group; the most common
7 events (6.8%) for the RVd group. Median PFS was not reached (occurring in $5% in either group) were pyrexia (D-RVd, 10.1%;
in either group. The Kaplan-Meier estimate of the 24-month PFS RVd, 7.8%) and pneumonia (9.1%; 10.8%). The percentage of
rate was 95.8% (95% CI, 89.2-98.4) in the D-RVd group and patients with AEs leading to treatment discontinuation was
89.8% (95% CI, 77.1-95.7) in the RVd group (Figure 3). Median 15.2% in the D-RVd group and 20.6% in the RVd group, most
OS was not reached in either group, and follow-up for long-term commonly ($5%) peripheral sensory neuropathy (D-RVd, 5.1%;
survival is ongoing. RVd, 3.9%). One AE in the RVd group had an outcome of death,

Table 3. MRD status at last follow-up

MRD-negative (1025) status* D-RVd, n (%) RVd, n (%) Odds ratio (95% CI)† P‡

Intent-to-treat population
MRD-negative 53/104 (51.0) 21/103 (20.4) 4.07 (2.18-7.59) ,.0001
MRD-negative with $CR 49/104 (47.1) 19/103 (18.4) 3.89 (2.07-7.33) ,.0001

In patients achieving $CR 49/79 (62.0) 19/59 (32.2) 3.57 (1.72-7.44) .0006

MRD-evaluable population 53/77 (68.8) 21/65 (32.3) 4.47 (2.19-9.11) ,.0001

MRD data are from last follow-up at a median follow-up of 22.1 months.
*The threshold of MRD negativity was defined as 1 tumor cell per 105 white cells. MRD status is based on assessment of bone marrow aspirates by NGS in accordance with IMWG criteria.9
The MRD-evaluable population included patients who had both baseline (with clone identified/calibrated) and postbaseline MRD (with negative, positive, or indeterminate result)
samples taken (D-RVd group, n 5 77; RVd group, n 5 65). Patients with a missing or inconclusive assessment were considered positive for MRD.
†Mantel-Haenszel estimate of the common odds ratio for stratified tables is used. The stratification factors are ISS stage (I, II, III) and creatinine clearance (CrCl [30-50 mL/min or . 50 mL/min])
at randomization. An odds ratio .1 indicates an advantage for the daratumumab group.
‡P values were calculated from the Fisher exact test.

940 blood® 20 AUGUST 2020 | VOLUME 136, NUMBER 8 VOORHEES et al

 A Median follow-up, 13.5 months B Median follow-up, 22.1 months
RVd D-RVd RVd D-RVd
Subgroup stringent complete response, n (%) Odds Ratio (95% CI) Subgroup minimal residual disease negative, n (%) Odds Ratio (95% CI)
Sex Sex
Male 18/55 (32.7) 21/55 (38.2) 1.27 (0.58-2.78) Male 10/60 (16.7) 26/58 (44.8) 4.06 (1.73-9.54)
Female 13/42 (31.0) 21/44 (47.7) 2.04 (0.84-4.92) Female 11/43 (25.6) 27/46 (58.7) 4.13 (1.68-10.19)
Age Age
<65 yr 22/70 (31.4) 30/72 (41.7) 1.56 (0.78-3.10) <65 yr 16/75 (21.3) 38/76 (50.0) 3.69 (1.81-7.52)
≥65 yr 9/27 (33.3) 12/27 (44.4) 1.60 (0.53-4.82) ≥65 yr 5/28 (17.9) 15/28 (53.6) 5.31 (1.57-17.97)
ISS disease stage ISS disease stage
I 11/48 (22.9) 19/48 (39.6) 2.20 (0.91-5.35) I 6/50 (12.0) 25/49 (51.0) 7.64 (2.75-21.19)
II 12/35 (34.3) 17/37 (45.9) 1.63 (0.63-4.22) II 10/37 (27.0) 20/40 (50.0) 2.70 (1.04-7.01)
Ill 7/13 (53.8) 6/14 (42.9) 0.64 (0.14-2.94) Ill 5/14 (35.7) 8/14 (57.1) 2.40 (0.52-10.99)
Type of multiple myeloma Type of multiple myeloma
lgG 8/51 (15.7) 15/51 (29.4) 2.24 (0.85-5.88) lgG 11/52 (21.2) 29/55 (52.7) 4.16 (1.78-9.73)
Non-lgG 23/46 (50.0) 25/45 (55.6) 1.25 (0.55-2.85) Non-lgG 10/51 (19.6) 22/46 (47.8) 3.76 (1.53-9.26)

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Cytogenetic risk Cytogenetic risk
High risk 4/13 (30.8) 3/16 (18.8) 0.52 (0.09-2.90) High risk 4/14 (28.6) 6/16 (37.5) 1.50 (0.32-6.99)
Standard risk 26/80 (32.5) 39/79 (49.4) 2.03 (1.06-3.85) Standard risk 17/83 (20.5) 45/82 (54.9) 4.72 (2.37-9.40)
ECOG PS score ECOG PS score
0 13/39 (33.3) 16/38 (42.1) 1.45 (0.58-3.67) 0 5/40 (12.5) 21/39 (53.8) 8.17 (2.64-25.25)
1 or 2 18/58 (31.0) 25/60 (41.7) 1.59 (0.74-3.38) 1 or 2 16/62 (25.8) 32/62 (51.6) 3.07 (1.44-6.53)

0.1 1 10 1 10 100

RVd better D-RVd better RVd better D-RVd better

Figure 2. Subgroup analysis of sCR by the end of post-ASCT consolidation (primary end point; median follow-up, 13.5 months) and subgroup analysis of MRD
negativity (1025) by last follow-up (median follow-up, 22.1 months). (A) sCR by the end of post-ASCT consolidation (primary end point; median follow-up, 13.5 months).
Analysis of sCR for the primary end point in prespecified subgroups of the response-evaluable population that were defined according to baseline characteristics. (B) MRD
negativity by last follow-up (median follow-up, 22.1 months). Analysis of MRD by last follow-up in subgroups of the intent-to-treat population. The ISS disease stage is derived
based on the combination of serum b2-microglobulin and albumin levels, with higher stages indicating more advanced disease. The subgroup analysis for the type of multiple
myeloma was performed on data from patients who had measurable disease in serum. A high-risk cytogenetic profile was defined by the detection of a del17p, t(4;14), and/or
t(14;16) cytogenetic abnormality on FISH testing. ECOG performance status (PS) is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating
increasing disability.

which was not related to study drug. In the D-RVd group, no AEs for both groups; the median number of days for neutrophil and
led to death. platelet engraftment were 12 and 13 for the D-RVd group, and
12 and 12 for the RVd group, respectively. More patients un-
Infections of any grade were more common in the D-RVd group dergoing stem cell mobilization and collection in the D-RVd
compared with the RVd group (90.9% vs 61.8%), largely due to group received plerixafor compared with the RVd group (69.5%
more grade 1/2 upper respiratory tract infections in the D-RVd [66 of 95 patients] vs 56.3% [45 of 80 patients]); cyclophos-
group (supplemental Table 4); however, the incidence of phamide use was low in both groups (#5.3%).
grade 3/4 infections was similar between groups (23.2% vs
21.6%), as was the percentage of patients with infections
leading to discontinuation (D-RVd, 2.0%; RVd, 2.9%). Four 95.8%
100
second primary malignancies were observed in the D-RVd D-RVd
89.8%
% surviving without progression

group (3 squamous cell carcinoma and 1 prostate cancer) and RVd

80
1 secondary primary malignancy was observed in the RVd
group (melanoma).
60
Infusion-related reactions (IRRs) to daratumumab occurred in
42 patients (42.4%) and were generally mild, with grade 3 events 40
occurring in 6 patients (6.1%); no grade 4/5 events occurred
(Table 4). Most patients with an IRR experienced the reaction 20
during the first infusion (35 of 99; 35.4%), with 2 patients (2.0%)
and 11 patients (11.1%) experiencing reactions during the 0
second and subsequent infusions, respectively. Three patients 0 3 6 9 12 15 18 21 24 27 30
(3.0%) experienced an IRR in the first D-RVd consolidation cycle Months
following ASCT. No IRRs led to treatment discontinuation. No. at risk
RVd 103 93 77 71 69 67 64 46 20 6 0
Median CD341 cell yield was 8.2 3 106/kg (range, 2.6 3 106 to D-RVd 104 98 93 89 89 88 86 59 27 5 0
33.0 3 106) for the D-RVd group and 9.4 3 106/kg (range, 4.1 3
106 to 28.7 3 106) for the RVd group. Median CD341 cells Figure 3. PFS. Results of the Kaplan-Meier estimates of PFS are shown among
transplanted were 4.2 3 106 in the D-RVd group and 4.8 3 106 in patients in the intent-to-treat population. Median PFS was not reached for either
the RVd group. Hematopoietic reconstitution was comparable group, and Kaplan-Meier estimates of 24-month PFS rates are shown.

D-RVd FOR TRANSPLANT-ELIGIBLE MULTIPLE MYELOMA blood® 20 AUGUST 2020 | VOLUME 136, NUMBER 8 941
Table 4. Most common adverse events reported during treatment in the safety population

D-RVd, n 5 99 RVd, n 5 102

Adverse event, n (%) Any grade Grade 3/4 Any grade Grade 3/4

Hematologic
Neutropenia 57 (57.6) 41 (41.4) 36 (35.3) 22 (21.6)
Thrombocytopenia 43 (43.4) 16 (16.2) 36 (35.3) 9 (8.8)
Leukopenia 36 (36.4) 16 (16.2) 29 (28.4) 7 (6.9)
Anemia 35 (35.4) 9 (9.1) 33 (32.4) 6 (5.9)
Lymphopenia 30 (30.3) 23 (23.2) 28 (27.5) 22 (21.6)

Nonhematologic
Fatigue 68 (68.7) 6 (6.1) 62 (60.8) 6 (5.9)
Upper respiratory tract infection 62 (62.6) 1 (1.0) 45 (44.1) 2 (2.0)

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Peripheral neuropathy* 59 (59.6) 7 (7.1) 74 (72.5) 8 (7.8)
Diarrhea 59 (59.6) 7 (7.1) 51 (50.0) 4 (3.9)
Constipation 51 (51.5) 2 (2.0) 40 (39.2) 1 (1.0)
Cough 50 (50.5) 0 27 (26.5) 0
Nausea 49 (49.5) 2 (2.0) 50 (49.0) 1 (1.0)
Pyrexia 45 (45.5) 2 (2.0) 28 (27.5) 3 (2.9)
Insomnia 42 (42.4) 2 (2.0) 31 (30.4) 1 (1.0)
Back pain 36 (36.4) 1 (1.0) 34 (33.3) 4 (3.9)
Peripheral edema 34 (34.3) 2 (2.0) 35 (34.3) 3 (2.9)
Arthralgia 33 (33.3) 0 33 (32.4) 2 (2.0)

Infusion-related reaction 42 (42.4) 6 (6.1)† NA NA

The safety analysis population included all randomized patients who received $1 dose of study treatment; analysis was according to treatment received. Adverse events of any grade that are
listed are those that occurred in 30% or more of the patients in either group. The safety analysis occurred at a median follow-up of 22.1 months.
NA, not applicable.
*Includes patients with neuropathy peripheral and peripheral sensory neuropathy.
†There were no grade 4 infusion-related reactions.

Discussion $CR) rates ranged from 50% to 78% after consolidation.7,33,34

However, it is difficult to make cross-trial comparisons due to
In this randomized phase 2 study, addition of daratumumab
differences in study designs, patient populations, and assessment
to RVd for transplant-eligible NDMM improved response rates
methodologies. For example, these studies varied in the duration
and depth of response, including sCR and MRD-negativity (1025)
of induction therapy (ranging from three 21-day cycles to six
rates. Responses deepened with continued therapy in both
28-day cycles), use of chemomobilization with cyclophosphamide
groups, in accordance with previous observations.21,22,25,27,32
(permitted in GRIFFIN only if mobilization with granulocyte
colony-stimulating factor with or without plerixafor was not suc-
These findings are consistent with the benefit demonstrated in cessful), and the duration and timing of initiation of consolidation.
CASSIOPEIA, in which addition of daratumumab to bortezomib, Differences in duration and timing of induction and consolidation
thalidomide, and dexamethasone improved the rates of sCR and impact the duration of follow-up at the postconsolidation as-
MRD negativity (1025) in transplant-eligible NDMM.21 In GRIFFIN sessment, which is an important point, as responses are expected
and CASSIOPEIA, the odds ratios for sCR were nearly identical to deepen over time. Nevertheless, the randomized GRIFFIN
(1.57 and 1.60, respectively), indicating that the addition of dar- study demonstrates that the addition of daratumumab to RVd
atumumab to a standard-of-care regimen including an immuno- improves and deepens responses compared with RVd therapy.
modulatory drug, proteasome inhibitor, and dexamethasone
achieves deeper responses. Improved long-term outcomes of OS Achievement of MRD negativity has also been associated with
and PFS have been previously reported with the achievement of superior long-term patient outcomes, resulting in increasing
sCR after ASCT in MM patients.8 It should be noted that the im- interest in this end point as a surrogate marker for PFS and
provement in sCR seen in the daratumumab arm of CASSIOPEIA OS.7,10-13 Importantly, GRIFFIN demonstrated that addition of
was associated with an improvement in median PFS; however, daratumumab to RVd and ASCT improved MRD negativity at the
differences in study design, including a second randomization to standard sensitivity threshold of 1025 and the more stringent
maintenance or observation in CASSIOPEIA, confound any com- threshold of 1026. Improvements in MRD-negativity rates for the
parisons between the 2 studies. Longer follow-up is needed to D-RVd group vs the RVd group were seen as early as at the end
confirm whether a PFS benefit will be achieved in GRIFFIN. of induction (21.2% vs 5.8%), and continued to deepen at
the end of consolidation (47.1% vs 16.5%) and by the last
Reported CR rates from prior clinical studies including RVd for follow-up (51.0% vs 20.4%). The results from GRIFFIN confirm
induction and/or consolidation therapy with ASCT were generally previous findings that the addition of daratumumab to standard-
higher compared with the rate in the RVd arm of GRIFFIN; CR (or of-care regimens across lines of therapy improves MRD negativity

942 blood® 20 AUGUST 2020 | VOLUME 136, NUMBER 8 VOORHEES et al

in myeloma,21-23,25,27 which has consistently translated into im- observations from the safety run-in.28 The D-RVd group had higher
proved PFS, whether the backbone regimen was used for a de- rates of grade 3/4 hematologic events, consistent with previous
fined duration21,22,26,27 or until disease progression.23-25 phase 3 studies. Interestingly, the RVd group experienced a larger
number of serious AEs. There is no clear explanation for this
One limitation of our study is that the proportion of patients with finding, as no single serious AE or group of serious AEs occurred
ISS stage I disease in GRIFFIN was higher than in other studies of more frequently in the RVd group vs the D-RVd group. However, it
NDMM patients eligible for transplant.7,21,33 Additionally, the is possible that the open-label study design and relatively small
number of patients with high-risk cytogenetics was low. None- number of patients in this randomized phase 2 study may have
theless, the proportions of high-risk patients in GRIFFIN were been contributing factors. The rate of discontinuation was lower in
well balanced between treatment groups and similar to other the D-RVd group, and no AEs led to death in the D-RVd group.
clinical studies that evaluated patients with transplant-eligible The incidence and severity of IRRs was consistent with other
NDMM.7,21,34 In this context, subgroup analyses in GRIFFIN daratumumab studies.35,36 Although more neutropenia and grade
demonstrated that D-RVd improved sCR rates across most of the 1/2 infections were observed in the D-RVd arm, there was no
subgroups for both the primary end point and at a median follow- difference in grade 3/4 infections or treatment discontinuations
up time of 22.1 months, except for patients with ISS stage III due to infection, confirming previous study findings that any in-

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disease or high-risk cytogenetics. The subgroup analysis for MRD creased infection risk with daratumumab is clinically manageable.
negativity showed that D-RVd favored all subgroups. Although
these findings are informative, the small number of patients in The results from GRIFFIN demonstrate that stem cell mobili-
these categories limits interpretation of the effect of daratumumab zation and ASCT are feasible when daratumumab is added to
for these groups. Additional studies of D-RVd as therapy for patients induction therapy for myeloma. These results are consistent
with high-risk NDMM are needed to better understand its potential with those in CASSIOPEIA; however, differences in mobilization
impact in these patients. strategies in these 2 studies limit direct comparison of stem cell
yield data. Stem cell mobilization in GRIFFIN occurred as per
The MRD-negativity rate for the RVd arm of the GRIFFIN trial was institutional guidelines but without chemotherapy unless the initial
lower than that reported in the IFM 2009 trial, although direct mobilization was unsuccessful. The study allowed centers to follow
comparisons are confounded by differences in the methods and institutional guidelines for the use of plerixafor, which was more
timing of MRD assessments, as well as eligibility criteria and study common in patients undergoing stem cell mobilization in the
design. The primary IFM 2009 analysis reported an MRD-negativity D-RVd group compared with the RVd group (69.5% vs 56.3%). A
rate of 79% but used a flow cytometric-based MRD assay with a similarly low number of patients in both treatment groups re-
sensitivity of 1024.7 A subsequent IFM 2009 MRD analysis using ceived cyclophosphamide for mobilization (5.3% vs 5.0%), in-
NGS (1026 threshold) by the end of lenalidomide therapy reported dicating that mobilization without chemotherapy was successful.
an MRD-negativity rate of 30%, but this included only a subset The median stem cell yield, although numerically lower for the
of patients who entered the maintenance phase of the trial.13 D-RVd group (8.2 vs 9.4 3 106 cells/kg), was sufficient to allow
Moreover, all IFM 2009 patients in VGPR or better were tested for cryopreservation of enough stem cells for a potential future
MRD, whereas testing in GRIFFIN was initially only performed at the second transplant. In addition, time to engraftment and hema-
time of suspected CR or sCR in accordance with IMWG guidelines topoietic recovery were not impacted by daratumumab.
(additional time points added in amendment 2). Although GRIFFIN
critically demonstrates that the addition of daratumumab to RVd Study results from GRIFFIN are promising and practice
improves the rate of MRD negativity in transplant-eligible NDMM informing; this randomized phase 2 study was designed to ex-
patients, longer follow-up is needed to determine whether this pediently provide efficacy and safety information on a new regimen
results in a survival advantage, as in other studies. of great interest to myeloma clinicians. The aim of this study was to
inform clinical decision-making, as well as design of a definitive
A lower percentage of patients underwent transplant in the RVd registrational trial. As a phase 2 study, GRIFFIN was not intended to
arm (75.7%) vs the D-RVd arm (90.4%). It is worth noting that this evaluate and does not provide sufficient power to analyze small
imbalance was due to a higher rate of treatment discontinuation patient subgroups, such as those with high-risk cytogenetics. The
in the RVd group compared with the D-RVd group. Thirteen positive, practice-informing results from GRIFFIN support and
patients (12.6%) assigned to RVd discontinued therapy prior to provide a strong rationale for the ongoing phase 3 PERSEUS
ASCT due to investigator-assessed PD or investigator discretion, registration study (ClinicalTrials.gov Identifier, NCT03710603),
both of which can be viewed as treatment failures. The high which will determine whether subcutaneous daratumumab in
proportion of RVd patients with SD or PR who did not undergo combination with RVd improves PFS in transplant-eligible NDMM.
ASCT on study further highlights the increased rate of suboptimal
responses in the RVd arm of the trial. Furthermore, D-RVd In summary, the addition of daratumumab to RVd in transplant-
already achieved higher rates of sCR (12.1% vs 7.2%), VGPR or eligible NDMM patients resulted in improved rates of sCR and
better (71.7% vs 56.7%), and MRD negativity (21.2% vs 5.8%) MRD negativity, an acceptable safety profile, and no clinically
at the end of induction. Lastly, in an analysis of patients who significant impact on stem cell mobilization or engraftment.
completed ASCT, MRD negativity remained superior for These results indicate that the combination of D-RVd may be a
D-RVd (55.3% vs 25.6%). These results suggest that dar- potential new standard of care for transplant-eligible NDMM.
atumumab played a critical role in deepening responses.

Adding daratumumab to RVd did not lead to unexpected safety Acknowledgments

concerns. AEs were consistent with the known safety profiles The GRIFFIN team acknowledges the contributions of all princi-
for RVd4-7 as well as daratumumab,21-24,26,35,36 and consistent with pal investigators who participated in the study: Carlos Alemany,

D-RVd FOR TRANSPLANT-ELIGIBLE MULTIPLE MYELOMA blood® 20 AUGUST 2020 | VOLUME 136, NUMBER 8 943
Larry D. Anderson Jr, Ashraf Badros, Ajai Chari, Robert Cornell, Luciano Bluebird Bio, Sutro Biopharma, and Poseida; has served in an advisory role
J. Costa, Caitlin Costello, Andrew J. Cowan, Binod Dhakal, Yvonne or held membership on an entity’s board of directors for Bristol-Myers
A. Efebera, Laura Finn, Cristina Gasparetto, Sarah A. Holstein, Andrzej Squibb, Amgen, Kite, Nkarta, TeneoBio, Genentech, Seattle Genetics,
Jakubowiak, Jonathan L. Kaufman, Hakan Kaya, Sarah Larson, Jacob Oncopeptides, Karyopharm, Surface Oncology, Precision BioSciences,
Laubach, Tomer Mark, Nitya Nathwani, Ruben Niesvizky, Joanne Filicko-O’Hara, GlaxoSmithKline, Nektar, Amgen, Indapta Therapeutics, and Sanofi; owns
Robert Z. Orlowski, Brandi Reeves, Paul G. Richardson, Cesar Rodriguez, stock in Indapta Therapeutics; and has received research funding from
Douglas W. Sborov, Nina Shah, Kenneth H. Shain, Leyla Shune, Rebecca Celgene, Janssen, Bluebird Bio, and Sutro Biopharma. Y.A.E. has served on
Silbermann, Pallawi Torka, Peter M. Voorhees, Andrew Whiteley, Tanya a speakers’ bureau for Janssen; received honoraria from and served on an
M. Wildes, and Jeffrey Zonder. The team also acknowledges the independent adjudication committee for Takeda; and served on an ad-
Alliance Multiple Myeloma Committee, particularly Phil McCarthy visory board and speakers’ bureau for Akcea. S.A.H. has served in a
and patient advocate Jim Omel, for their input and support of the consultancy or advisory role for and received honoraria from Adaptive
study. Lastly, the team thanks the Alliance Foundation Trials team for Biotechnologies, Bristol-Myers Squibb, Celgene, Genentech, Oncopep-
their key role in the conduct of this trial (https://acknowledgments. tides, Sorrento, and Takeda; and has received research funding from
alliancefound.org). The authors thank the patients who volunteered to Oncopeptides. C.C. has received honoraria from Takeda and Celgene; has
participate in this trial, their families, and the staff members at the trial served as a consultant for Celgene; and has received research funding from
sites who cared for them; the members of the data review committee Takeda, Janssen, and Celgene. A.J. served as a consultant for, received
(Tracy McGowan [Chair], Leslie Killion, Daniela Hoehn, and Wayne honoraria from, or held membership on an entity’s board of directors or
Langholff) and safety monitoring committee (Carol Ann Huff [Chair], advisory committee for AbbVie, Amgen, Bristol-Myers Squibb, Celgene,
Adam Cohen, Weichung Shih, and Parexel International, LLC [Sta- GlaxoSmithKline, Janssen, Karyopharm Therapeutics, Millennium Phar-

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tistical Support Group]); representatives of the sponsor who were maceuticals, Sanofi, SkylineDx, and Takeda; and has served as a consultant
involved in data collection and analyses; and Charlotte Majerczyk and for and received honoraria from Adaptive Biotechnologies and Juno.
Melissa Brunckhorst of MedErgy for editorial assistance funded by the T.M.W. has received research funding from Janssen and served as a
sponsor. consultant for Carevive. R.Z.O. has received honoraria from or held
membership on an entity’s board of directors or advisory committees for
This work was supported by research funding from Janssen Oncology. Amgen, Janssen, Bristol-Myers Squibb, Kite Pharma, Celgene, Ionis
Pharmaceuticals, Legend Biotech, Molecular Partners, Sanofi-Aventis,
Servier, Takeda, and Pharmaceuticals North America; and received re-
search funding from Amgen, BioTheryX, and Spectrum Pharmaceuticals.
Authorship K.H.S. has received research funding from AbbVie; has served as a con-
Contribution: P.M.V., N.S., A.J., D.H., J.U., and P.G.R. contributed to sultant for Adaptive Biotechnologies; and has held membership on an
study design and data acquisition and contributed to data analysis or entity’s board of directors or served in an advisory role for Celgene, Bristol-
interpretation; J.L.K., D.W.S., C.R., A.C., R.S., L.J.C., L.D.A., Y.A.E., Myers Squibb, Amgen, Takeda, Janssen, and Sanofi Genzyme. A.J.C. has
S.A.H., C.C., T.M.W., R.Z.O., K.H.S., A.J.C., and J.V. contributed to data received research funding from and served as a consultant for Janssen and
acquisition and contributed to data analysis or interpretation; S.M. and Celgene; has received research funding from AbbVie and Juno Thera-
T.S.L. contributed to study design and contributed to data analysis or peutics, a subsidiary of Celgene; and served in a consultancy role for
interpretation; Y.L., H.P., and C.d.B. contributed to data analysis or in- Cellectar and Sanofi. Y.L. is an employee of Janssen. S.M., H.P., J.U., J.V.,
terpretation; J.L. contributed to study design; B.R. and N.N. contributed C.d.B., D.H., and T.S.L. are employees of Janssen and have equity own-
to data acquisition; and all authors reviewed the manuscript, approved ership. P.G.R. has received research funding from Oncopeptides, Celgene,
the final version, decided to publish this report, and vouch for the data Takeda, and Bristol-Myers Squibb; and has served as a member of an
accuracy and completeness. advisory committee or received honoraria from Karyopharm, Oncopep-
tides, Celgene, Takeda, Amgen, Janssen, and Sanofi. The remaining au-
Conflict-of-interest disclosure: P.M.V. served in a consultancy or advisory thors declare no competing financial interests.
role and received honoraria from Adaptive Biotechnologies, Bristol-
Myers Squibb, Celgene, Janssen, Takeda, and TeneoBio; served in a A complete list of investigators in the GRIFFIN trial is provided in the
consultancy or advisory role for Novartis, and Oncopeptides; served on supplemental appendix.
a speakers’ bureau for Janssen and Amgen; and received research
funding from Amgen, Celgene, Janssen, GlaxoSmithKline, Takeda, and ORCID profiles: L.J.C., 0000-0001-5362-2469; L.D.A., 0000-0002-6531-
TeneoBio. J.L.K. has held membership on an entity’s board of directors 9595; S.A.H., 0000-0002-9342-5635; R.Z.O., 0000-0002-5723-4129.
or advisory committee for Pharmacyclics and Karyopharm; has received
honoraria from Janssen; served as a consultant for AbbVie, Takeda,
Correspondence: Peter M. Voorhees, Levine Cancer Institute, Atrium
Celgene, Amgen, Bristol-Myers Squibb, Incyte, and TG Therapeutics;
Health, 1021 Morehead Medical Dr, Charlotte, NC 28204; e-mail:
and is an employee of Winship Cancer Institute of Emory University.
peter.voorhees@atriumhealth.org.
D.W.S. served in a consultancy or advisory role for Amgen, Celgene, and
Janssen; and received honoraria from Celgene. B.R. has served as a
consultant for Incyte, Takeda, and Seattle Genetics; received honoraria
from Celgene, Incyte, Takeda, and Seattle Genetics; and served on a
speakers’ bureau for Celgene. C.R. has served in a consultancy role or on a Footnotes
speakers’ bureau for Celgene, Takeda, Janssen, Kite, Sanofi, and Bristol- Submitted 13 February 2020; accepted 3 April 2020; prepublished online
Myers Squibb. A.C. has received research funding from, served as a on Blood First Edition 23 April 2020. DOI 10.1182/blood.2020005288.
consultant for, and served on an advisory board for Janssen, Celgene,
Novartis, and Amgen; has served in a consultancy role for Bristol-Myers The data-sharing policy of Janssen Pharmaceutical Companies of
Squibb; has served on an advisory board for Karyopharm, Sanofi, and Johnson & Johnson is available at https://www.janssen.com/clinical-trials/
Oncopeptides; has received research funding and served on an advisory transparency. As noted on this site, requests for access to the study data
board for Seattle Genetics and Millennium Pharmaceuticals/Takeda; and can be submitted through the Yale Open Data Access (YODA) Project
has received research funding from Pharmacyclics. R.S. has served on an site at http://yoda.yale.edu.
advisory committee for Janssen and on an advisory board for Sanofi. L.J.C.
has received research funding from Janssen, Celgene, GlaxoSmithKline, The online version of this article contains a data supplement.
and Amgen; received honoraria from Amgen, Celgene, Sanofi,
GlaxoSmithKline, and Janssen; has served in a consultancy or advisory role
for AbbVie, Amgen, Celgene, Sanofi, GlaxoSmithKline, and Karyopharm; There is a Blood Commentary on this article in this issue.
and has served on a speakers’ bureau for Amgen, Sanofi, and Janssen.
L.D.A. has served in a consultancy or advisory role for, served on a speakers’ The publication costs of this article were defrayed in part by page charge
bureau for, and received honoraria from Celgene, Takeda, Janssen, and payment. Therefore, and solely to indicate this fact, this article is hereby
Amgen. N.S. has received research funding from Celgene, Janssen, marked “advertisement” in accordance with 18 USC section 1734.

944 blood® 20 AUGUST 2020 | VOLUME 136, NUMBER 8 VOORHEES et al

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