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DARZALEX® (daratumumab)
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DARZALEX - GRIFFIN Study

Last Updated: 07/22/2026

Click on the following links to related sections within the document: GRIFFIN (MMY2004) Study Overview, Part 1: Results, Part 2: Primary and Updated Analyses Results, and Part 2: Final Analysis Results.
Abbreviations: AE, adverse event; ASCT, autologous stem cell transplant; CR, complete response; ≥CR, complete response or better; CrCl, creatinine clearance; DLT, dose-limiting toxicity; ECOG PS, Eastern Cooperative Oncology Group performance status; HDT, high-dose therapy; IMWG, International Myeloma Working Group; IRR, infusion-related reaction; IV, intravenous; MM, multiple myeloma; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; NGS, next-generation sequencing; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; R, lenalidomide; Rd, lenalidomide and dexamethasone; sCR, stringent complete response; TEAE, treatment-emergent AE; VGPR, very good partial response; VRd, bortezomib, lenalidomide, and dexamethasone.
aVoorhees (2017).1 bVoorhees (2019).2 cVoorhees (2020).3 d21-day cycles. e28-day cycles. fVoorhees (2021).4 gLaubach (2021).5 hIncludes the preferred terms of peripheral neuropathy and peripheral sensory neuropathy. iVoorhees (2023).6 jThere were no grade 4/5 IRRs.

SUMMARY

  • DARZALEX for intravenous (IV) use is not approved by the regulatory agencies for use in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of multiple myeloma (MM). Johnson & Johnson does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
  • GRIFFIN was a 2-part, phase 2 study that evaluated the safety and efficacy of DARZALEX when administered in combination with VRd (D-VRd) in patients with newly diagnosed multiple myeloma (NDMM) eligible for high-dose therapy (HDT) and autologous stem cell transplant (ASCT).1-3
    • Voorhees et al (2021)4 reported the final analysis of the safety run-in cohort (Part 1) of the GRIFFIN study with a median follow-up of 40.8 months. By the end of D-VRd consolidation, 56.3% patients achieved stringent complete response (sCR). After maintenance, 93.8% patients achieved sCR. Grade 3/4 treatment-emergent adverse events (TEAEs) were reported in 93.8% of patients. One death from progressive disease (PD) occurred in the patient who did not achieve sCR.
    • Voorhees et al (2020)2,3 presented the primary analysis of the randomized phase (Part 2) of this study at a median follow-up of 13.5 months. By the end of consolidation, 42.4% of patients in the D-VRd group vs 32.0% in the VRd group achieved sCR (odds ratio [OR], 1.57; 95% confidence interval [CI], 0.87-2.82; 1-sided P=0.068). The most common (≥20%) grade 3/4 TEAEs were neutropenia (D-VRd, 41.4%; VRd, 21.6%) and lymphopenia (D-VRd, 23.2%; VRd, 21.6%).
    • Voorhees et al (2023)6 reported the final efficacy and safety results of Part 2 after all patients completed ≥1 year of follow-up after the end-of-study treatment, died, or withdrew from study participation. The median follow-up was 49.6 months. In the D-VRd vs VRd arm, respectively, sCR was achieved in 67% vs 48% of patients (OR, 2.18; 95% CI, 1.22-3.89; 2-sided P=0.0079) and complete response or better (≥CR) in 83% vs 60% of patients (P=0.0005). In the D-VRd vs VRd arm, the most common (≥10%) grade 3/4 TEAEs were neutropenia (46% vs 23%), lymphopenia (23% in both arms), leukopenia (17% vs 8%), thrombocytopenia (16% vs 9%), pneumonia (12% vs 14%), and hypophosphatemia (10% vs 11%).
  • Nooka et al (2024)7 reported an updated post hoc analysis results by race at the time of final analysis in the overall population with ~2 years of additional follow-up. The median follow-up was 49.6 months. In the D-VRd vs VRd arm, the rate of sCR was 92.9% vs 38.9% in Black patients and 65.1% vs 50.0% in White patients, the rate of MRD-negativity (at 10-5 threshold) was 64.3% vs 22.2% in Black patients and 65.9% vs 31.6% in White patients, and the estimated 48-month progression-free survival (PFS) rate was 79.1% vs 64.6% in Black patients and 89.4% vs 74.2% in White patients. The most common grade 3/4 TEAEs were neutropenia (D-VRd vs VRd: Black, 50.0% vs 22.2%; White, 47.0% vs 17.6%) and lymphopenia (Black, 28.6% vs 38.9%; White, 22.9% vs 16.2%). No deaths due to TEAEs were reported among Black patients in either arm, and 1 death due to pneumonia was reported among White patients in the D-VRd arm.

CLINICAL DATA

GRIFFIN (MMY2004; NCT02874742) was a 2-part, phase 2, randomized, active-controlled, open-label, multicenter, United States (US) study that evaluated the safety and efficacy of D-VRd in patients with NDMM eligible for HDT and ASCT.1-3

Study Design/Methods

  • The study enrolled 16 patients in the safety run-in phase (Part 1), which assessed potential dose-limiting toxicities (DLTs) during cycle 1, and 207 patients in the randomized phase 2 portion (Part 2).
  • DLTs were defined as reported adverse events (AEs) of:
    • Grade 4 neutropenia lasting >7 days
    • Grade 4 thrombocytopenia lasting >7 days despite transfusion support
    • Grade ≥3 nonhematological toxicity, except:
      • Grade 3 nausea, vomiting, or diarrhea that can be controlled within 48 hours with maximal supportive care
      • Grade 3 hyperglycemia that can be controlled within 48 hours with supportive care
      • Asymptomatic grade ≥3 electrolyte disturbances that can be controlled with repletion within 24 hours
      • Grade 3 maculopapular rash attributable to lenalidomide
    • Infusion-related reactions (IRRs):
      • Any grade 4 IRR occurring within 48 hours of infusion of DARZALEX
      • Any grade 3 IRR occurring within 48 hours of infusion of DARZALEX that does not resolve with a reduced infusion rate or temporarily stopping the infusion, as well as administration of supportive care and symptomatic therapy such as a steroid and an antihistamine
  • The safety run-in phase consisted of an induction phase (cycles 1-4; 21-day cycles), followed by ASCT, followed by a consolidation phase (cycles 5-6; 21-day cycles), that was initiated 60-100 days after ASCT, followed by a maintenance phase (cycles 7-32; 28-day cycles).
    • From the induction phase through the consolidation phase, patients received:
      • DARZALEX 16 mg/kg intravenously (IV) weekly in cycles 1-4 and every 3 weeks in cycles 5-6
      • Lenalidomide 25 mg orally (PO) on days 1-14
      • Bortezomib 1.3 mg/m2 subcutaneously (SC) on days 1, 4, 8, and 11
      • Dexamethasone 40 mg PO weekly (20 mg PO on days 1, 2, 8, 9, 15, and 16)
    • During the maintenance phase, patients received:
      • DARZALEX 16 mg/kg IV every 4 weeks or 8 weeks.
      • Lenalidomide 10 mg PO daily on days 1-21, then 15 mg PO daily beginning cycle 10 (if no tolerability issues)
      • Dexamethasone 20 mg PO every 8 weeks on days 1, 2, 8, 9, 15, and 16
    • One interim safety analysis was performed as planned for the safety run-in patients after they were treated for ≥4 cycles or discontinued study participation.
  • Following successful completion of the safety run-in phase, in part 2 of the study patients were randomized 1:1 to an induction phase (D-VRd or VRd [cycles 1-4; 21-day cycles]), followed by ASCT, followed by a consolidation phase (D-VRd or VRd [cycles 5-6; 21-day cycles]), followed by a maintenance phase (DARZALEX + lenalidomide or lenalidomide monotherapy [cycles 7-32; 28-day cycles]), following the dosing illustrated above, +/- DARZALEX.
  • A data review committee was established to review safety data after 8, 12, and 16 patients in the safety run-in phase completed cycle 1, and to determine if the study should proceed to the randomized phase 2 portion or stop.
  • Key inclusion criteria: age 18-70 years; documented MM per International Myeloma Working Group (IMWG) 2015 criteria; eligible for HDT/ASCT; Eastern Cooperative Oncology Group performance score of 0 to 2; adequate organ function; no prior systemic therapy for MM; measurable disease; creatinine clearance (CrCl) ≥30 mL/min
  • Primary objective: determine if the addition of DARZALEX to VRd will increase the sCR rate by the end of the post-ASCT consolidation therapy
  • Primary endpoints: sCR (by end of post-ASCT consolidation)
  • Secondary endpoints: MRD (10-5 via next-generation sequencing [NGS]), CR, overall response rate (ORR), ≥VGPR, duration of response (DOR), time to CR or sCR, PFS, and overall survival (OS)

Final Analysis of Part 1: Safety Run-in Phase

Voorhees et al (2021)4 reported the final analysis of the safety run-in cohort of the GRIFFIN study at a median follow-up of 40.8 months (range, 20.6-43.0) after patients completed D-VRd treatment and 24 months of D-R maintenance therapy.

Results

Baseline Characteristics
  • Demographics and baseline characteristics are presented in Table: Baseline Characteristics.
  • All patients in the safety run-in phase (N=16) completed induction therapy, stem cell mobilization, ASCT, consolidation, and entered maintenance therapy.
  • A total of 87.5% (n=14) of patients completed study therapy, and 2 (12.5%) discontinued the therapy because of progressive disease (PD; n=1) or AE (n=1; neuralgia or thrombocytopenia) during maintenance therapy.

Baseline Characteristics4
Characteristic
D-VRd (n=16)
Age, years
   Median (range)
62.5 (46-65)
      <65 years, n (%)
14 (87.5)
      ≥65 years, n (%)
2 (12.5)
Sex, n (%)
   Male
8 (50.0)
   Female
8 (50.0)
Race, n (%)
   White
11 (68.8)
   Black or African American
4 (25.0)
   Asian
1 (6.3)
ECOG PS, n (%)a
   0
3 (18.8)
   1
10 (62.5)
   2
3 (18.8)
ISS disease stage, n (%)b
   I
12 (75.0)
   II
2 (12.5)
   III
2 (12.5)
Cytogenetic risk profile, n (%)c
   Standard
12 (75.0)
   High risk
4 (25.0)
Median (range) time since diagnosis of MM, months
1.6 (0-5)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MM, multiple myeloma; t, translocation.
aECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
cCytogenetic risk was assessed by fluorescence in situ hybridization (locally tested); high risk was defined as the presence of del(17p), t(4;14), or t(14;16) in those patients with cytogenetic risk data available.
Safety
  • During cycle 1, 3 of 16 patients developed 4 DLTs: fatigue, gastroenteritis, hypotension, and pneumonitis. All DLTs were grade 3 and none resulted in treatment discontinuation during induction or consolidation therapy.
  • One patient had a TEAE leading to discontinuation of study treatment.
  • Fourteen patients (87.5%) experienced any-grade infections and 5 patients (31.3%) experienced grade 3/4 infections.
    • During the maintenance phase, 31.3% of patients (n=5) experienced any-grade infections, the most common being upper respiratory tract infections. One patient (6.3%) experienced a grade 3/4 infection (pneumonia and bronchitis).
  • Grade 1/2 IRRs occurred in 31.3% of patients (n=5). IRRs included pruritus, chills, flushing, maculo-papular rash, and vascular access site swelling; all occurred during cycle 1 except vascular access site swelling.
  • Eleven patients (68%) experienced a serious AE. For the incidences of grade 3/4 TEAEs, please see Table: Most Common Grade 3/4 TEAEs.

Most Common Grade 3/4 TEAEs4
Events, n (%)
D-VRd (n=16)
Grade 3/4a
Total
15 (93.8)
Most commonly occurring
   Neutropenia
7 (43.8)
   Pneumonia
5 (31.3)
   Lymphopenia
5 (31.3)
   Thrombocytopenia
4 (25.0)
   Hypertension
3 (18.8)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone, TEAE, treatment-emergent adverse event.
aNo grade 5 TEAEs were reported.
Efficacy
  • At a median follow-up of 40.8 months (range, 20.6-43.0), disease progression occurred in 3 patients.
  • Median time to first response was 0.77 months (range, 0.1-2.1), and median DOR was not estimable.
  • Median time to ≥CR was 7.36 months (range, 2.8-18.5), and median duration of ≥CR was not estimable.
  • Estimated 24-months PFS and OS rates was 93.8%.
  • Estimated 36-month PFS and OS rates were 78.1% and 93.8%, respectively.
  • MRD-negativity rates at 10-5 sensitivity threshold and 10-6 sensitivity threshold, respectively:
    • By end of D-VRd induction: 18.8% (n=3) vs 0%.
    • By end of D-VRd consolidation: 50% (n=8) vs 0%.
    • At the last follow-up: 81.3% (n=13) vs 31.3% (n=5)
  • MRD-negativity rates of 10-5 were sustained for ≥12 months in 8 patients (50.0%).
  • Response rates are presented in Table: Updated Response Rates Over Time for the Safety Run-in Cohort.

Updated Response Rates Over Time for the Safety Run-in Cohorta,4
Patients, %
By End of
D-VRd Induction
By End of
D-VRd Consolidation
By Last Follow-up
D-R Maintenance
sCR
-
56.3
93.8
CR
12.5
12.5
-
≥CR
12.5
68.8
93.8
VGPR
56.3
31.3
6.3
PR
31.3
-
-
Abbreviations: CR, complete response; ≥CR, complete response or better; D-R, DARZALEX + lenalidomide; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
Response data are shown for the response-evaluable population (N=16).
aPercentages do not add up to 100% due to rounding.

Updated and Final Analysis of Part 2: Randomized Phase

Voorhees et al (2020)2,3 presented the primary analysis and updated analysis of the randomized portion of this study at a median follow-up of 13.5 months in the primary analysis and 22.1 months in the updated analysis.

Results

Baseline Characteristics
  • A total of 207 patients were randomized (D-VRd, n=104; VRd, n=103).
  • Ninety percent of patients in the D-VRd arm underwent ASCT compared to 76% in the VRd arm (ASCT rate lower due to early discontinuations).
  • Baseline patient characteristics are summarized in Table: Patient Demographics in the Randomized Phase (ITT).

Patient Demographics in the Randomized Phase (ITT)3
Characteristic
D-VRd (n=104)
VRd (n=103)
Age
   Median (range), years
59 (29-70)
61 (40-70)
   ≥65 years
28 (26.9)
28 (27.2)
Male, n (%)
58 (55.8)
60 (58.3)
ECOG PS,a n (%)
n=101
n=102
   0
39 (38.6)
40 (39.2)
   1
51 (50.5)
52 (51)
   2
11 (10.9)
10 (9.8)
ISS stage,b n (%)
   I
49 (47.1)
50 (48.5)
   II
40 (38.5)
37 (35.9)
   III
14 (13.5)
14 (13.6)
Baseline CrCl, n (%)
  30-50 mL/minute
9 (8.7)
9 (8.7)
   >50 mL/minute
95 (91.3)
94 (91.3)
Cytogenetic profile,c n (%)
n=98
n=97
   Standard risk
82 (83.7)
83 (85.6)
   High risk
16 (16.3)
14 (14.4)
Time since diagnosis of MM
n=103
n=102
   Median (range), months
0.7 (0-12)
0.9 (0-61)
Abbreviations: CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intent-to-treat; MM, multiple myeloma; VRd, bortezomib + lenalidomide + dexamethasone.
aECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bISS disease stage is based on the combination of serum-β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
cCytogenetic risk was assessed by fluorescence in situ hybridization, high risk was defined as the presence of del17p, t(4:14), or t(14:16) among patients with available cytogenetic risk data.
Efficacy
  • The primary endpoint was met with D-VRd improving the sCR rate by end of consolidation (D-VRd vs VRd: 42.4% vs 32.0%; OR, 1.57; 95% CI, 0.87-2.82; 1-sided P=0.068). The study had 80% power to detect a 15% improvement with a 1-sided alpha of 0.1.
  • A significantly higher proportion of patients achieved an ORR following consolidation in the D-VRd arm vs the VRd arm (99.0% vs 91.8%; 2-sided P=0.0160).
  • The rate of ≥VGPR was 90.9% with D-VRd vs 73.2% with VRd.
  • The rate of ≥CR was 51.5% with D-VRd vs 42.3% with VRd.
  • The percentage of patients achieving ≥CR at the end of induction, ASCT, consolidation, and clinical cutoff in the D-VRd arm was 19.2%, 27.3%, 51.5%, and 79.8%, respectively, vs 13.4%, 19.6%, 42.3%, and 60.8% in the VRd arm.
  • MRD (10-5 via NGS) among patients achieving ≥CR greater with D-VRd vs VRd: 58.8% vs 24.4% (OR, 4.65; 95% CI, 1.76-12.28; P=0.0014).
  • In the intent-to-treat (ITT) population, 51% of patients in the D-VRd arm achieved post-ASCT MRD-negativity vs 20.4% of patients in the VRd arm, regardless of response (OR, 4.70; 95% CI, 2.38-9.28; P<0.0001). Additional MRD results are presented in Table: Post-consolidation MRD-Negativity.

Post-consolidation MRD-Negativity3
MRD-Negative Status (10-5),a n (%); ITT
D-VRd (n=104)
VRd (n=103)
OR (95% CI)b
P valuec
MRD negative regardless of response
53/104 (51.0)
21/103 (20.4)
4.07 (2.18-7.59)
<0.0001
MRD negative with CR or better
49/104 (47.1)
19/103 (18.4)
3.89 (2.07-7.33)
<0.0001
In patients achieving CR or better
49/69 (62.0)
19/59 (32.2)
3.57 (1.72-7.44)
0.0006
MRD-evaluable population
53/77 (68.8)
21/65 (32.3)
4.47 (2.19-9.11)
<0.0001
Abbreviations: CI, confidence interval; CR, complete response; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aThe 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 International Myeloma Working Group criteria. MRD assessments occurred in patients who had both baseline (with clone identified/calibrated) and postbaseline MRD (with negative, positive, or indeterminate result) samples taken (D-VRd, n=71; VRd, n=55). Patients with a missing or inconclusive assessment were considered MRD positive.
bMantel-Haenszel estimate of the common OR for stratified tables is used. The stratification factors are ISS stage (I, II, III) and CrCl (30-50 mL/min or >50 mL/min) at randomization. An OR >1 indicates an advantage for the DARZALEX group.
cP values were calculated from the Fisher’s exact test.
  • At the median follow-up of 22.1 months, D-VRd achieved higher sCR (62.6% vs 45.4%; OR, 1.98; 95% CI, 1.12-3.49; 2-sided P=0.0177), CR (17.2% vs 15.5%), and ≥CR (79.8% vs 60.8%; OR, 2.53; 95% CI, 1.33-4.81; 2-sided P=0.0045) vs VRd.
  • In the ITT population, median PFS and OS were not reached (NR) in the D-VRd and VRd arms. In the D-VRd and VRd arms, respectively (Kaplan-Meier estimates):
    • 12-month PFS rates were 96.9% and 95.3%.
    • 24-month PFS rates were 95.8% and 89.8%.
    • 12-month OS rates were 99.0% and 97.9%.
    • 24-month OS rates were 95.8% and 93.4%.
Safety
  • In the updated safety and efficacy analysis, any-grade infections occurred in 91% of patients in the D-VRd arm and 62% of patients in the VRd arm, the most common being grade 1/2 upper respiratory tract infections; grade 3/4 infections were seen in 23% of patients in the D-VRd arm vs 22% of patients in the VRd arm.
  • Pneumonia was reported in 13% of patients in the D-VRd arm and 15% of patients in the VRd arm.
  • TEAEs are summarized in Table: Most Common TEAEs.

Most Common TEAEsa,3,8
TEAEs, n (%)
D-VRd (n=99)
VRd (n=102)
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)
   Peripheral neuropathyb
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)
   Edema peripheral
34 (34.3)
2 (2.0)
35 (34.3)
3 (2.9)
   Arthralgia
33 (33.3)
0
33 (32.4)
2 (2.0)
IRRs
42 (42.4)
6 (6)c
-
-
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone.
aAny-grade TEAEs are listed that occurred in ≥30% of patients in either arm. The safety analysis population included all randomized patients who received ≥1 dose of study treatment; analysis was according to treatment received.
bIncludes patients with neuropathy peripheral and peripheral sensory neuropathy.
cNo grade 4 IRRs were reported.

Final Efficacy and Safety Analysis of Maintenance Therapy

Voorhees et al (2023)6 reported the final efficacy and safety results after all patients completed ≥1 year of follow-up after the end-of-study treatment, died, or withdrew from study participation.

Results

Patient Characteristics
  • At the time of the final analysis, all patients completed ≥1 year of follow-up after the end-of-study treatment, died, or withdrew from the study.
  • The median follow-up was 49.6 months (interquartile range [IQR], 47.4-52.1).
  • By the final analysis, 25% of patients in the D-VRd arm and 51% in the VRd arm discontinued treatment. See Table: Patient Disposition.
  • The median duration of treatment in the D-VRd and VRd arms was 32.5 months (IQR, 31.1-33.4) and 27.5 months (IQR, 2.9-32.7), respectively.
    • In the D-VRd arm, among the 90 patients who received DARZALEX and lenalidomide maintenance therapy, 21% (n=19) switched from DARZALEX to DARZALEX FASPRO and received ≥1 cycle of DARZALEX FASPRO (median number, 3.0 [IQR, 3.0-5.0]).

Patient Disposition6
Patients, n
D-VRd (n=104)
VRd (n=103)
Treated with maintenance therapy
90
70
Completed maintenance therapy
74
48
Discontinued treatment during maintenance therapy
16
22
   AE
6
7
   PD
3
8
   Patient withdrawal
2
4
   Lost to follow-up
2
0
   Death
1
1
   Other
2
2
Discontinued treatment by final analysis
26
53
Abbreviations: AE, adverse event; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; PD, progressive disease; VRd, bortezomib + lenalidomide + dexamethasone.
Efficacy
  • At the final analysis, among response-evaluable patients in the D-VRd (n=100) vs VRd (n=98) arm, respectively, sCR was achieved in 67% vs 48% of patients (OR, 2.18; 95% CI, 1.22-3.89; 2-sided P=0.0079) and ≥CR in 83% vs 60% of patients (P=0.0005). Response data over time are summarized in Table: Summary of Response Over Time.6,9

Summary of Response Over Time6
Timepoint, %
D-VRd
VRd
sCR
CR
≥CR
VGPR
PR
SD/PD/
NE
sCR
CR
≥CR
VGPR
PR
SD/PD/
NE
End of inductiona
12
7
19
53
26
2
7
6
13
43
35
8
End of post-ASCT consolidationa
42
9
52
39
8
1
32
10
42
31
19
8
Final analysisb
67
16
83
13
3
1
48
12
60
17
14
8
Abbreviations: ASCT, autologous stem cell transplant; CR, complete response; ≥CR, complete response or better; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; NE, not evaluable; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
Rates shown are the number of patients with each type of response divided by the response-evaluable population.aResponse rates were from the primary analysis cutoff (median follow-up, 13.5 months) and the response-evaluable population comprised 196 patients (D-VRd, n=99; VRd, n=97).
bResponse rates were also evaluated at the time of the final analysis (median follow-up 49·6 months; IQR 47.4-52·1), and the response-evaluable population comprised 198 patients (D-VRd, n=100; VRd, n=98).

Response Duration Among Patients in the D-VRd vs VRd Arm6
Parameter
D-VRd
VRd
Median duration to first response (ORR), months (95% CI)
0.8 (0.8-0.8)
0.8 (0.8-1.0)
Median duration to sCR, months (95% CI)
10.2 (8.8-13.0)
14.3 (9.2-21.7)
   HR (95% CI)
1.26 (0.86-1.83)
   P value
0.2339
Median duration to ≥VGPR, months (95% CI)
2.2 (2.1-2.7)
3.0 (2.2-6.3)
Median duration to ≥CR, months (95% CI)
8.9 (7.9-9.4)
9.6 (8.4-12.2)
Median DOR
NR
NR
   Estimated 48-month DOR, % (95% CI)
89 (79.9-94.3)
71 (55.8-81.4)
Abbreviations: CI, confidence interval; ≥CR, complete response or better; DOR, duration of response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; NR, not reached; ORR, overall response rate; sCR, stringent complete response; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.

Final Analysis of Best Response and MRD-Negativity Rates at the End of Maintenance6,9
Parameter
D-VRd
VRd
P value
Response,a n
100
98
-
   ORR, n (%)
99 (99)
90 (92)
0.016b
      ≥CR
83 (83)
59 (60)
0.0005b
      CR
16 (16)
12 (12)
-
      sCR
67 (67)
47 (48)
0.0079b
      ≥VGPR
96 (96)
76 (78)
0.0002b
      VGPR
13 (13)
17 (17)
-
      PR
3 (3)
14 (14)
-
   SD, n (%)
1 (1)
8 (8)
-
   PD, n (%)
0
0
-
MRD negative
   ITT population, n
104
103
-
      10-5 sensitivity, n (%)
67 (64)
31 (30)
<0.0001c
         OR (95% CI)
4.23 (2.35-7.62)
      10-6 sensitivity, n (%)
37 (36)
16 (16)
0.0013c
         OR (95% CI)
2.95 (1.52-5.75)
   In patients achieving ≥CR, n
83
59
-
      10-5 sensitivity, n (%)
64 (77)
28 (47)
0.0004c
      10-6 sensitivity, n (%)
35 (42)
14 (24)
0.031c
Durable MRD negativity
   Lasting ≥12 months, n
104
103
-
      10-5 sensitivity, n (%)
46 (44)
14 (14)
<0.0001c
         OR (95% CI)
5.00 (2.50-9.99)
      10-6 sensitivity, n (%)
10 (10)
4 (4)
0.16c
         OR (95% CI)
2.48 (0.76-8.07)
Abbreviations: CI, confidence interval; CR, complete response; ≥CR, complete response or better; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MM, multiple myeloma; MRD, minimal residual disease; NGS, next-generation sequencing; OR, odds ratio; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
The predefined per protocol final analysis occurred after all patients completed ≥1 year of long-term follow-up after the end-of-study treatment, died, or withdrew from study participation, whichever occurred first.
aResponse rate is based on the response-evaluable population, which included randomized patients who had a confirmed diagnosis of MM, had measurable disease at baseline, received ≥1 dose of study treatment, and had ≥1 postbaseline disease assessment. The response-evaluable population for the primary analysis included 99 patients in the D-VRd group and 97 patients in the VRd group.
bP value was calculated using the Cochran-Mantel-Haenszel Chi-square test stratified by ISS disease stage (I, II, or III) and baseline CrCl (30-50 mL/min or >50 mL/min) at randomization.
cP value was calculated using Fisher’s exact test.
  • By the end of the 2-year maintenance therapy, 14% (n/N=15/104) and 10% (n/N=10/103) of patients in the D-VRd and VRd arms, respectively, who were previously MRD positive at the end of the consolidation phase, converted to MRD negative (10-5). MRD-negativity rates continuously improved over time and were consistently higher in the D-VRd vs VRd arm. See Table: Summary of MRD-Negativity Rates Over Time (ITT Population).

Summary of MRD-Negativity Rates Over Time (ITT Population)a, 6,9
Timepoint, %
D-VRd
VRd
MRD-Negativity (10-5)
MRD-Negativity (10-6)
MRD-Negativity (10-5)
MRD-Negativity (10-6)
End of induction
22
1
8
0
Post-ASCT consolidation
50
11
20
3
End of study
64
36
30
16
Abbreviations: ASCT, autologous stem cell transplant; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; VRd, bortezomib + lenalidomide + dexamethasone. aMRD was evaluated by NGS using the clonoSEQ assay. MRD assessments occurred at the first evidence of suspected CR or sCR, after induction (but before stem cell collection), after consolidation, and after 12 and 24 months of maintenance, regardless of response.
  • No patient in either treatment arm with sustained MRD-negativity 10-5 lasting ≥12 months became MRD positive later.
  • The median time to MRD-negativity in the D-VRd vs VRd arm at sensitivity thresholds of 10-5 and 10-6, respectively, was 8.5 vs 34.6 months (HR, 2.70; 95% CI, 1.72-4.23; P<0.0001) and 33.9 months vs NR (HR, 1.93; 95% CI, 1.05-3.54; P=0.031).
  • Efficacy and survival outcomes are summarized in Table: Efficacy and Survival Outcomes (ITT Population).

Efficacy and Survival Outcomes (ITT Population)6,9
Parameter
D-VRd
VRd
Median PFS, months
NR
NR
   3-year PFS rate, %
89
80.7
   4-year PFS rate, %
87.2
70
   PFS HR (95% CI); P value
0.45 (0.21-0.95); 0.032
Median PFS in patients who received lenalidomide therapy as per SoC after study completion, months
NR
NR
4-year PFS rate in patients who received SoC lenalidomide therapy after study completion, %
96
80
Median PFS in patients who did not receive lenalidomide therapy as per SoC after study completion, months
NR
NR
4-year PFS rate in patients who did not receive SoC lenalidomide therapy after study completion, %
100
86
Median OS, months
NR
NR
   3-year OS rate, %
92.7
92.2
   4-year OS rate, %
92.7
92.2
   OS HR (95% CI); P value
0.90 (0.31-2.56); 0.84a
Disease progression or death, n/N (%)
11/104 (11)
18/103 (17)
   HR (95% CI)
0.45 (0.21-0.95)
   P value
0.032
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; HR, hazard ratio; ISS, International Staging System; ITT, intention-to-treat; NR, not reached; OS, overall survival; PFS, progression-free survival; SoC, standard of care; VRd, bortezomib + lenalidomide + dexamethasone.
aHR and 95% CI are from a Cox proportional hazards model with treatment as the sole explanatory variable and stratified with ISS staging (I, II, and III) and baseline CrCl (30-50 mL/min or >50 mL/min) at randomization.
An HR <1 indicates an advantage for D-VRd. P value is based on the log-rank test stratified with ISS staging and baseline CrCl at randomization.
Safety
  • Among safety-evaluable patients in the D-VRd (n=99) vs VRd (n=102) arms, grade 3/4 TEAEs occurred in 86% (n=85) vs 79% (n=81), respectively.
  • In the D-VRd vs VRd arm, serious TEAEs occurred in 46% (n=46) vs 52% (n=53) of patients, respectively.
    • The most common serious TEAEs included pneumonia (15% vs 14%) and pyrexia (11% vs 10%).
  • TEAEs leading to treatment discontinuation were similar across treatment arms (D-VRd, 33% [n=33]; VRd, 31% [n=32]). One patient in each arm died due to TEAEs unrelated to study treatment.
  • Any-grade infections were more common in the D-VRd vs VRd arm (93% [n=92] vs 66% [n=67]). Similar incidence rates were reported across treatment arms for grade 3/4 infections (D-VRd, 29%; VRd, 26%) and infections leading to treatment discontinuation (D-VRd, 2%; VRd, 3%).
    • During maintenance therapy (cycle 7 and onwards) in the D-VRd vs VRd arm, any-grade infections occurred in 35% (n/N=31/89) vs 32% (n/N=23/71) of patients and grade 3/4 infections occurred in 18% (n=16) vs 21% (n=15) of patients.
    • In the D-VRd vs VRd arm, Coronavirus Disease 2019 (COVID-19) infections were reported in 5% (n=5) vs 2% (n=2) of patients, respectively. Of these, 1 patient in each arm had a grade 3 COVID-19-related event (including 1 serious event in the D-VRd arm).
  • TEAEs occurring in the safety population are summarized in Table: Most Common TEAEs in the Safety Population.

Most Common TEAEs in the Safety Populationa,6,9
TEAEs, n (%)
D-VRd (n=99)
VRd (n=102)
Grade 1/2
Grade 3
Grade 4
Grade 1/2
Grade 3
Grade 4
Hematologic
   Anemia
28 (28)
9 (9)
0
27 (26)
5 (5)
1 (1)
   Thrombocytopenia
28 (28)
4 (4)
12 (12)
27 (26)
4 (4)
5 (5)
   Leukopenia
22 (22)
8 (8)
9 (9)
22 (22)
6 (6)
2 (2)
   Neutropenia
17 (17)
32 (32)
14 (14)
18 (18)
21 (21)
2 (2)
   Lymphopenia
8 (8)
13 (13)
10 (10)
6 (6)
20 (20)
3 (3)
Nonhematologic
   Hypokalemia
24 (24)
3 (3)
1 (1)
24 (24)
3 (3)
0
   Hypocalcemia
17 (17)
0
0
12 (12)
2 (2)
1 (1)
   Pneumoniab
11 (11)
11 (11)
1 (1)
4 (4)
14 (14)
0
   Hyperkalemia
6 (6)
1 (1)
0
1 (1)
0
1 (1)
   Cellulitis
6 (6)
0
1 (1)
3 (3)
1 (1)
0
   Hypophosphatemia
5 (5)
9 (9)
1 (1)
6 (6)
11 (11)
0
   Hyperuricemia
4 (4)
0
0
6 (6)
0
1 (1)
   Acute kidney injury
2 (2)
2 (2)
2 (2)
4 (4)
3 (3)
0
   Atrial fibrillation
1 (1)
0
1 (1)
3 (3)
0
0
   Increased blood creatine phosphokinase
1 (1)
0
0
0
0
1 (1)
   Atrial tachycardia
1 (1)
0
0
0
0
1 (1)
   Sepsis
0
1 (1)
2 (2)
0
1 (1)
0
   Drug reaction with eosinophilia and systemic symptoms
0
0
0
0
1 (1)
1 (1)
   Septic shock
0
0
0
0
0
1 (1)
   Cerebrovascular accident
0
0
0
0
0
1 (1)
   Systemic inflammatory
   response syndrome
0
0
0
0
0
1 (1)
   Death
0
0
0
0
0
0
IRRsc
49 (49)
7 (7)
0
-
-
-
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone.
aThe maximum intensity for each preferred term is listed, and TEAEs are listed for all grade 4 or 5 events and any grade 3 events occurring in ≥10% of patients in either treatment arm (corresponding grade 1-2 events are listed).
bOne grade 5 event was recorded in the D-VRd group.
cThere were no grade 4/5 IRRs. Data pertaining to IRRs are not available for the VRd arm.
  • During maintenance therapy, second primary malignancies with first onset after the start of maintenance therapy were reported in 4% (n/N=4/89) evaluable patients in the D-VRd arm and 4% (n/N=3/71) evaluable patients in the VRd arm.
  • A total of 14 (D-VRd, n=7; VRd, n=7) patients died, of whom 9 (D-VRd, n=5; VRd, n=4) patients died due to PD.
  • There were 39% (n=39) IRRs reported at the initial infusion, 2% (n=2) IRRs at the second infusion, and 14% (n=14) IRRs at the subsequent infusions.9

Subgroup Analysis of the GRIFFIN Study in Black vs White Patients

Nooka et al (2024)7 reported updated post hoc analysis results by race at the time of final analysis in the overall population with ~2 years of additional follow-up. The median duration of follow-up was 49.6 months.

Study Design/Methods

  • The study design is consistent with the randomized portion of the GRIFFIN Study Design/Methods.
  • This analysis was conducted at the time of final analysis, with an additional ~2-year follow-up.
  • Patients self-reported race and ethnicity.

Results

Patient Characteristics
  • Of the 207 randomized patients included in the study, 15.5% were Black (D-VRd, n=14; VRd, n=18), 77.8% were White (D-VRd, n=85; VRd, n=76), 1% were Asian (VRd, n=2), 1.5% reported “other” race (D-VRd, n=2; VRd, n=1), 0.5% reported multiple races (VRd, n=1), and 3.4% reported unknown race (D-VRd, n=2; VRd, n=5).
    • Additionally, 7.2% were Hispanic or Latino (D-VRd, n=9; VRd, n=6), 89.4% were non-Hispanic or Latino (D-VRd, n=92; VRd, n=93), and 3.4% did not know or did not report ethnicity (D-VRd, n=3; VRd, n=4).
  • The median duration of follow-up was 49.6 months.
  • The baseline patient and disease characteristics are presented in Table: Baseline Patient and Disease Characteristics According to Race.

Baseline Patient and Disease Characteristics According to Racea,13
Characteristic
Black
White
D-VRd
(n=14)
VRd
(n=18)
D-VRd
(n=85)
VRd
(n=76)
Median age (range), years
58.5 (29-67)
57.0 (48-67)
59.0 (35-70)
61.5 (41-70)
Sex, n (%)
   Male
5 (35.7)
8 (44.4)
52 (61.2)
46 (60.5)
   Female
9 (64.3)
10 (55.6)
33 (38.8)
30 (39.5)
Median weight (range), kg
82.6
(66.0-147.5)
93.8
(57.0-123.8)
78.4
(48.8-158.6)
82.4
(37.4-150.1)
Median height (range), cm
168.3
(152.0-190.5)
168.9
(154.9-190.0)
171.3
(152.4-203.2)
173.0
(150.6-200.0)
BMI
   Median (range), kg/m2
30.7
(23.5-40.6)
31.4
(23.8-43.8)
26.5
(19.7-41.4)
27.3
(15.8-45.0)
   ≥30 kg/m2, n (%)
7 (50.0)
11 (61.1)
29 (34.1)
20 (26.3)
Comorbidities
   Median (range) number of
   comorbiditiesb
7.0 (3-13)
5.5 (1-38)
7.0 (1-24)
7.0 (1-27)
   Diabetes mellitus, n (%)
3 (21.4)
4 (22.2)
9 (10.6)
7 (9.2)
   Pre-existing neuropathies, n (%)c
4 (28.6)
3 (16.7)
4 (4.7)
12 (15.8)
ECOG PS score, n (%)d
n=13
n=18
n=84
n=75
   0
6 (46.2)
7 (38.9)
32 (38.1)
30 (40.0)
   1
6 (46.2)
10 (55.6)
42 (50.0)
37 (49.3)
   2
1 (7.7)
1 (5.6)
10 (11.9)
8 (10.7)
Type of myeloma, n (%)e
n=13
n=18
n=82
n=74
   IgG
8 (61.5)
11 (61.1)
46 (56.1)
40 (54.1)
   IgA
1 (7.7)
2 (11.1)
17 (20.7)
16 (21.6)
   IgD
0
0
1 (1.2)
1 (1.4)
   IgM
0
0
1 (1.2)
0
   Light chain
3 (23.1)
4 (22.2)
17 (20.7)
14 (18.9)
   Biclonal
1 (7.7)
1 (5.6)
0
3 (4.1)
ISS disease stage, n (%)f
   I
9 (64.3)
11 (61.1)
40 (47.1)
37 (48.7)
   II
3 (21.4)
4 (22.2)
32 (37.6)
27 (35.5)
   III
2 (14.3)
3 (16.7)
12 (14.1)
10 (13.2)
   Missing
0
0
1 (1.2)
2 (2.6)
Cytogenetic risk, n (%)g
n=14
n=16
n=80
n=73
   Standard risk
11 (78.6)
14 (87.5)
68 (85.0)
63 (86.3)
   High risk
3 (21.4)
2 (12.5)
12 (15.0)
10 (13.7)
      del(17p)
2 (14.3)
0
6 (7.5)
6 (8.2)
      t(4;14)
1 (7.1)
2 (12.5)
6 (7.5)
3 (4.1)
      t(14;16)
0
0
1 (1.3)
2 (2.7)
Revised cytogenetic risk, n (%)h
n=14
n=16
n=80
n=73
   Standard risk (0 HRCAs)
10 (71.4)
9 (56.3)
44 (55.0)
46 (63.0)
   High risk
4 (28.6)
7 (43.8)
36 (45.0)
27 (37.0)
      gain/amp(1q21)
2 (14.3)
4 (25.0)
30 (37.5)
23 (31.5)
      t(14;20)
0
1 (6.3)
1 (1.3)
0
      1 HRCA
3 (21.4)
6 (37.5)
28 (35.0)
20 (27.4)
      ≥2 HRCAs
1 (7.1)
1 (6.3)
8 (10.0)
7 (9.6)
Abbreviations: BMI, body mass index; D-VRd, DARZALEX + lenalidomide + bortezomib + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; Ig, immunoglobulin; ISS, International Staging System; VRd, lenalidomide + bortezomib + dexamethasone.
aDemographic and clinical characteristics were taken from electronic case report forms completed by study sites.
bMedian (range) number of comorbidities was calculated from data of patients with medical histories available in which comorbidities were reported, which included 32 Black patients (D-VRd, n=14; VRd, n=18) and 153 White patients (D-VRd, n=81; VRd, n=72). A value of “0” was not automatically applied in the event a medical history did not report the presence of a comorbidity.
cNeuropathies included peripheral sensory neuropathy, neuralgia, peripheral neuropathy, and/or diabetic neuropathy.
dECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
eType of myeloma by immunofixation or serum free light-chain assay.
fISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
gCytogenetic risk was assessed by FISH (local testing); high risk was defined as the presence of del(17p), t(4;14), or t(14;16) among patients with available cytogenetic risk data.
hRevised cytogenetic risk was assessed by FISH testing; revised high risk was defined as ≥1 of the following: del(17p), t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21).

Summary of Treatment Duration and Exposure According to Racea,13
Parameter
Black
White
D-VRd
(n=14)
VRd
(n=18)
D-VRd
(n=83)
VRd
(n=74)
Median duration of therapy (range), months
32.3
(19.4-36.9)
26.5
(2.6-35.3)
32.5
(1.1-37.7)
31.1
(0.5-36.3)
Median dose intensity (range)
   D (mg/kg/cycle)b
20.3
(19.4-22.7)
-
20.3
(18.9-48.5)
-
   R (mg/cycle)c
245.5
(136.6-311.7)
253.6
(102.2-350.0)
245.0
(71.7-350.0)
274.2
(85.5-350.0)
   V (mg/m2/cycle)d
4.8 (3.1-5.1)
4.8 (3.6-5.3)
5.0 (2.8-5.4)
4.8 (2.5-5.4)
   d (mg/cycle)e
38.4
(33.4-73.3)
114.2
(40.0-120.0)
36.8
(26.6-113.3)
111.7
(44.5-120.0)
Cycle delays, n (%)
9 (64.3)
10 (55.6)
52 (62.7)
34 (45.9)
   D
9 (64.3)
-
50 (60.2)
-
   R
7 (50.0)
9 (50.0)
43 (51.8)
34 (45.9)
   V
1 (7.1)
5 (27.8)
16 (19.3)
14 (18.9)
   d
8 (57.1)
5 (27.8)
38 (45.8)
17 (23.0)
Dose adjusted, n (%)
   D
9 (64.3)
-
39 (47.0)
-
   R
7 (50.0)
11 (61.1)
43 (51.8)
32 (43.2)
   V
4 (28.6)
6 (33.3)
17 (20.5)
14 (18.9)
   d
1 (7.1)
1 (5.6)
9 (10.8)
12 (16.2)
Abbreviations: D, DARZALEX; d, dexamethasone; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; R, lenalidomide; V, bortezomib; VRd, bortezomib + lenalidomide + dexamethasone.
aThe safety analysis population included all randomized patients who received ≥1 dose of study treatment.
bDose intensity (mg/kg/cycle) was calculated as the sum of total doses (mg/kg) received in all cycles divided by the number of treatment cycles on D.
cDose intensity (mg/cycle) was calculated as the sum of total doses (mg) received in all cycles divided by the number of treatment cycles on R.
dDose intensity (mg/m2/cycle) was calculated as the sum of total doses (mg/m2) received in all cycles divided by the number of treatment cycles on V.
eDose intensity (mg/cycle) was calculated as the sum of total doses (mg) received in all cycles divided by the number of treatment cycles on d.
Efficacy
  • Among Black vs White patients, efficacy response rates were evaluable in 32 vs 155, and MRD-negativity was evaluable in 32 vs 161. The efficacy outcomes are summarized in Table: Response, MRD, and Survival Outcomes According to Race.
  • D-VRd reduced the risk of disease progression or death compared with VRd by 55% (HR, 0.45; 95% CI, 0.21-0.95) in the overall population.
    • The risk of disease progression or death was reduced by 61% in Black patients (HR, 0.39; 95% CI, 0.07-2.24; P=0.2767) vs 53% in White patients (HR, 0.47; 95% CI, 0.19-1.18; P=0.1003) in the D-VRd vs VRd arm.

Response, MRD, and Survival Outcomes According to Racea, 7,13
Parameter
Black
White
D-VRd
VRd
D-VRd
VRd
Response evaluable population, n
14
18
83
72
   ≥CR, n (%)
14 (100)
10 (55.6)
67 (80.7)
44 (61.1)
      OR (95% CI)
NE (NE-NE)
2.66 (1.29-5.49)
   sCR, n (%)
13 (92.9)
7 (38.9)
54 (65.1)
36 (50.0)
      OR (95% CI)
20.43 (2.17-192.64)
1.86 (0.98-3.55)
   ≥VGPR, n (%)
14 (100)
16 (88.9)
79 (95.2)
53 (73.6)
      OR (95% CI)
NE (NE-NE)
7.08 (2.28-21.98)
   PR, %
-
5.6
3.6
18.1
   SD/PD/NE, %
-
5.6
1.2
8.3
MRD-evaluable populationb, n
14
18
85
76
   MRD at 10-5 threshold, n (%)
9 (64.3)
4 (22.2)
56 (65.9)
24 (31.6)
      OR (95% CI)
6.30 (1.33-29.94)
4.18 (2.16-8.09)
   MRD at 10-6 threshold, n (%)
4 (28.6)
2 (11.1)
33 (38.8)
11 (14.5)
      OR (95% CI)
3.20 (0.49-20.81)
3.75 (1.73-8.13)
Estimated 48-month PFS rate, %
79.1
64.6
89.4
74.2
Abbreviations: CI, confidence interval; CR, complete response; ≥CR, complete response or better; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; MRD, minimal residual disease; NE, not evaluable; NGS, next-generation sequencing; OR, odds ratio; PD, progressive disease; PFS, progression-free survival; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
aPercentages may not add to 100 due to rounding.
bThe threshold of MRD negativity was defined as 1 tumor cell per 105 or per 106 white cells. MRD status is based on the assessment of bone marrow aspirates by NGS in accordance with International Myeloma Working Group criteria. Bone marrow aspirates were assessed at baseline, at first evidence of suspected CR or sCR (including patients with ≥VGPR and suspected daratumumab interference), at the end of induction and consolidation, and after 1 and 2 years (±3 weeks) of maintenance, regardless of response.
Safety

Most Common (≥30%) TEAEs in Black or White Patientsa,7
Adverse Event, n (%)
Black
White
D-VRd
(n=14)
VRd
(n=18)
D-VRd
(n=83)
VRd
(n=74)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
8 (57.1)
7 (50.0)
6 (33.3)
4 (22.2)
54 (65.1)
39 (47.0)
26 (35.1)
13 (17.6)
   Anemia
8 (57.1)
2 (14.3)
7 (38.9)
3 (16.7)
29 (34.9)
7 (8.4)
22 (29.7)
3 (4.1)
   Thrombocytopenia
6 (42.9)
4 (28.6)
7 (38.9)
2 (11.1)
38 (45.8)
12 (14.5)
26 (35.1)
6 (8.1)
   Leukopenia
6 (42.9)
3 (21.4)
8 (44.4)
1 (5.6)
32 (38.6)
14 (16.9)
17 (23.0)
4 (5.4)
   Lymphopenia
5 (35.7)
4 (28.6)
9 (50.0)
7 (38.9)
26 (31.3)
19 (22.9)
16 (21.6)
12 (16.2)
Nonhematologic
   Upper respiratory tract
   infection
11 (78.6)
0
9 (50.0)
0
55 (66.3)
4 (4.8)
38 (51.4)
2 (2.7)
   Constipation
9 (64.3)
0
7 (38.9)
0
40 (48.2)
2 (2.4)
28 (37.8)
1 (1.4)
   Peripheral oedema
9 (64.3)
0
9 (50.0)
0
27 (32.5)
2 (2.4)
27 (36.5)
3 (4.1)
   Peripheral
   neuropathy/peripheral
   sensory neuropathy
8 (57.1)
1 (7.1)
12 (66.7)
1 (5.6)
53 (63.9)
5 (6.0)
58 (78.4)
6 (8.1)
   Nausea
8 (57.1)
1 (7.1)
9 (50.0)
1 (5.6)
42 (50.6)
1 (1.2)
37 (50.0)
0
   Fatigue
8 (57.1)
1 (7.1)
8 (44.4)
0
61 (73.5)
6 (7.2)
45 (60.8)
5 (6.8)
   Headache
7 (50.0)
0
2 (11.1)
0
26 (31.3)
5 (6.0)
17 (23.0)
1 (1.4)
   Vomiting
7 (50.0)
1 (7.1)
5 (27.8)
0
25 (30.1)
2 (2.4)
21 (28.4)
0
   Arthralgia
7 (50.0)
1 (7.1)
5 (27.8)
0
31 (37.3)
0
28 (37.8)
2 (2.7)
   Cough
7 (50.0)
0
5 (27.8)
0
45 (54.2)
0
21 (28.4)
0
   Insomnia
7 (50.0)
0
2 (11.1)
0
37 (44.6)
2 (2.4)
26 (35.1)
1 (1.4)
   Rash maculopapular
6 (42.9)
1 (7.1)
2 (11.1)
0
18 (21.7)
2 (2.4)
19 (25.7)
2 (2.7)
   Pyrexia
6 (42.9)
0
3 (16.7)
0
41 (49.4)
3 (3.6)
26 (35.1)
2 (2.7)
   Diarrhea
6 (42.9)
0
6 (33.3)
0
59 (71.1)
7 (8.4)
46 (62.2)
4 (5.4)
   Decreased appetite
6 (42.9)
0
2 (11.1)
0
18 (21.7)
0
8 (10.8)
0
   Back pain
5 (35.7)
0
9 (50.0)
0
35 (42.2)
2 (2.4)
22 (29.7)
3 (4.1)
   Pain in extremity
5 (35.7)
0
7 (38.9)
0
17 (20.5)
1 (1.2)
15 (20.3)
0
   Myalgia
5 (35.7)
0
4 (22.2)
0
21 (25.3)
0
15 (20.3)
2 (2.7)
   Hypokalemia
5 (35.7)
0
6 (33.3)
1 (5.6)
23 (27.7)
4 (4.8)
16 (21.6)
2 (2.7)
   Dizziness
4 (28.6)
0
7 (38.9)
0
19 (22.9)
0
15 (20.3)
0
   Dysgeusia
4 (28.6)
0
6 (33.3)
0
19 (22.9)
0
12 (16.2)
0
   Dyspnea
3 (21.4)
0
6 (33.3)
2 (11.1)
21 (25.3)
2 (2.4)
21 (28.4)
2 (2.7)
   Hyperglycemia
1 (7.1)
0
6 (33.3)
0
11 (13.3)
2 (2.4)
11 (14.9)
1 (1.4)
   Muscle spasms
3 (21.4)
0
2 (11.1)
0
26 (31.3)
2 (2.4)
15 (20.3)
1 (1.4)
Abbreviations: D-VRd, daratumumab + lenalidomide + bortezomib + dexamethasone; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event; VRd, lenalidomide + bortezomib + dexamethasone.aThe safety analysis population included all randomized patients who received ≥1 dose of study treatment.bIRRs (not shown in table) occurred in 28.6% of Black patients and 53.0% of White patients who received D-VRd; 1 (7.1%) Black patient and 6 (7.2%) White patients had grade 3 IRRs (none were grade 4 or 5).

Summary of TEAEs Leading to Discontinuation of Study Treatment According to Race Occurring in ≥2 Patients in Any Treatment Group or Those Attributed to Neuropathy-Related Eventsa,b,13
Black
D-VRd
(n=14)
VRd
(n=18)
Discontinuation of
Discontinuation of
Any Study Treatment
D
R
V
d
Any Study Treatment
R
V
d
6Patients with TEAEs leading to study treatment discontinuation, n (%)
9 (64.3)
1 (7.1)
2 (14.3)
8 (57.1)
1 (7.1)
7 (38.9)
2 (11.1)
5 (27.8)
1 (5.6)
   Occurring in ≥2 patients or attributable to neuropathy-related events
      Peripheral sensory
      neuropathy
3 (21.4)
0
0
3 (21.4)
0
4 (22.2)
0
4 (22.2)
0
      Neuralgia
2 (14.3)
0
0
2 (14.3)
0
1 (5.6)
1 (5.6)
0
0
      Hypoesthesia
1 (7.1)
0
0
1 (7.1)
0
0
0
0
0
      Peripheral
      neuropathy
1 (7.1)
0
1 (7.1)
1 (7.1)
0
0
0
0
0
      Paresthesia
0
0
0
0
0
1 (5.6)
0
1 (5.6)
0
White
D-VRd
(n=83)
VRd
(n=74)
Discontinuation of
Discontinuation of
Any Study Treatment
D
R
V
d
Any Study Treatment
R
V
d
Patients with TEAEs leading to study treatment discontinuation, n (%)
24 (28.9)
5 (6.0)
12 (14.5)
15 (18.1)
7 (8.4)
19 (25.7)
11 (14.9)
12 (16.2)
9 (12.2)
   Occurring in ≥2 patients or attributable to neuropathy-related events
      Peripheral sensory
      neuropathy
8 (9.6)
0
0
8 (9.6)
0
3 (4.1)
1 (1.4)
3 (4.1)
1 (1.4)
      Neuralgia
2 (2.4)
0
0
2 (2.4)
0
2 (2.7)
0
2 (2.7)
0
      Neutropenia
2 (2.4)
0
2 (2.4)
0
0
0
0
0
0
      Rash
2 (2.4)
0
2 (2.4)
0
0
0
0
0
0
      Peripheral
      neuropathy
1 (1.2)
0
0
1 (1.2)
0
4 (5.4)
2 (2.7)
3 (4.1)
2 (2.7)
      Fall
0
0
0
0
0
1 (1.4)
0
1 (1.4)
0
Abbreviations: D, daratumumab; d, dexamethasone; D-VRd, daratumumab + lenalidomide + bortezomib + dexamethasone; R, lenalidomide; TEAE, treatment-emergent adverse event; V, bortezomib; VRd, lenalidomide + bortezomib + dexamethasone.
aThe safety analysis population included all randomized patients who received ≥1 dose of study treatment.
bNeuropathy-related events included peripheral sensory neuropathy, neuralgia, paresthesia, peripheral neuropathy, hypoesthesia, and/or falls.
  • No deaths were reported in Black patients during the whole duration of the study (treatment period and post-treatment observation combined); 12 deaths were reported in White patients (D-VRd, n=6; VRd, n=6) due to PD (D-VRd, n=4; VRd, n=4) and AEs (D-VRd, n=2 [1 event occurred outside the reporting interval, which was >30 days after the last dose of study treatment]; VRd, n=2 [both events occurred outside the reporting interval]).
  • No deaths due to TEAEs were reported among Black patients in either arm, and 1 death due to pneumonia was reported among White patients in the D-VRd arm.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 17 July 2026.

 

References

Show
1 Voorhees P, Costa L, Reeves B, et al. Interim safety analysis of a phase 2 randomized study of daratumumab (Dara), lenalidomide (R), bortezomib (V), and dexamethasone (d; Dara-RVd). vs. RVd in patients (pts) with newly diagnosed multiple myeloma (MM) eligible for high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) (GRIFFIN). Poster presented at: The Annual Meeting of the American Society of Hematology (ASH); December 9-12, 2017; Atlanta, GA.  
2 Voorhees PM, Kaufman J, Laubach J, et al. Daratumumab + lenalidomide, bortezomib & dexamethasone improves depth of response in transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Oral Presentation presented at: The 17th International Myeloma Workshop (IMW); September 12-15, 2019; Boston, MA.  
3 Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;136(8):936-945.  
4 Voorhees PM, Rodriguez C, Reeves B, et al. Daratumumab plus RVd for newly diagnosed multiple myeloma: final analysis of the safety run-in cohort of GRIFFIN. Blood Adv. 2021;5(4):1092-1096.  
5 Laubach J, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Oral Presentation presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual Meeting.  
6 Voorhees PM, Sborov DW, Laubach J, et al. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837.  
7 Nooka AK, Kaufman JL, Rodriguez C, et al. Post hoc analysis of daratumumab plus lenalidomide, bortezomib, and dexamethasone in black patients from final data of the GRIFFIN study. Br J Haematol. 2024;00:1-6.  
8 Voorhees P, Kaufman J, Laubach J, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): GRIFFIN study update. Oral Presentation presented at: 61st American Society of Hematology (ASH) Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL.  
9 Voorhees PM, Sborov DW, Laubach J, et al. Supplement to: Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): final analysis of an open-label, randomised, phase 2 trial. Lancet Haematol. 2023;10(10):e825-e837.  
10 Nooka A, Kaufman J, Rodriguez C, et al. Daratumumab + lenalidomide/bortezomib/dexamethasone in African American/Black patients with transplant eligible newly diagnosed multiple myeloma: subgroup analysis of GRIFFIN. Poster presented at: 8th Annual Meeting of the Society of Hematologic Oncology; September 9-12, 2020; Virtual Meeting.  
11 Nooka AK, Kaufman JL, Rodriguez C, et al. Daratumumab plus lenalidomide/bortezomib/dexamethasone in Black patients with transplant-eligible newly diagnosed multiple myeloma in GRIFFIN. Blood Cancer J. 2022;12(4):63.  
12 Nooka A, Kaufman J, Rodriguez C, et al. Daratumumab (DARA) + lenalidomide/bortezomib/dexamethasone (RVd) in black patients with transplant-eligible newly diagnosed multiple myeloma (NDMM): an updated subgroup analysis of GRIFFIN. Poster presented at: 19th International Myeloma Society (IMS) Annual Meeting; August 25-27, 2022; Los Angeles, CA.  
13 Nooka AK, Kaufman JL, Rodriguez C, et al. Supplement to: Post hoc analysis of daratumumab plus lenalidomide, bortezomib, and dexamethasone in black patients from final data of the GRIFFIN study. Br J Haematol. 2024;00:1-6.  

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