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(daratumumab)

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DARZALEX® (daratumumab)
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DARZALEX - Minimal Residual Disease in Clinical Trials

Last Updated: 10/08/2026

SUMMARY

  • Johnson & Johnson does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
  • CASSIOPEIA: phase 3 study evaluating the safety and efficacy of DARZALEX + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM).1-3
    • Moreau et al (2024)4 reported long-term outcomes of the CASSIOPEIA study after a median follow-up of 80.1 months from the first randomization and at a median follow-up of 70.6 months from the second randomization. At any time point in the D-VTd cohort, minimal residue disease (MRD)-negativity at 10-5 threshold was achieved by 65.1% of patients in the DARZALEX subgroup and by 58.1% of patients in the observation subgroup (P=0.080), respectively. At any time point in the VTd cohort, MRD-negativity at 10-5 sensitivity threshold was achieved by 53.5% of patients in the DARZALEX subgroup and by 36.3% of patients in the observation subgroup (P=0.0001), respectively.
    • Corre et al (2026)5 presented an interim analysis of the CASSIOPEIA Registry data at a median follow-up of approximately 102.9 months from the first randomization and median follow-ups of approximately 93.5 months and 93.4 months from the second randomization in the DARZALEX maintenance and observation groups, respectively. In the maintenance population, 5-year sustained MRD negativity (10-5) in patients with complete response or better (≥CR) was achieved in 23.1% of patients in the D-VTd + DARZALEX maintenance group vs 17.9% of patients in the D-VTd + observation group (odds ratio [OR], 1.40; 95% confidence interval [CI], 0.88-2.22; P=0.1589).  
  • MAIA: phase 3 study evaluating the safety and efficacy of DARZALEX in combination with lenalidomide and dexamethasone (D-Rd) compared to Rd in transplant-ineligible NDMM patients.6
    • Facon et al (2025)7 reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months. As of the clinical cutoff date of October 21, 2021, the D-Rd vs Rd arm showed a significantly higher (all P<0.0001) MRD-negativity (10-5) rate (32.1% vs 11.1%) and sustained MRD-negativity rate (≥12 months: 18.8% vs 4.1%; ≥18 months: 16.8% vs 3.3%).
    • Moreau et al (2025)8 reported the efficacy and safety results in clinically important subgroups of patients from the MAIA study. Treatment with D-Rd generally resulted in a greater improvement in MRD-negativity (10-5) rate, and sustained MRD-negativity (10-5) rate for ≥12 months across subgroups, compared with Rd.
  • ALCYONE: phase 3 study evaluating the safety and efficacy of DARZALEX, bortezomib, melphalan, and prednisone (D-VMP) and bortezomib, melphalan, and prednisone (VMP) in NDMM patients ineligible for high-dose chemotherapy with autologous stem-cell transplantation (ASCT).9
    • Mateos et al (2025)10 reported the final efficacy and safety analysis results of the ALCYONE study at a median follow-up of 86.7 months. D-VMP vs VMP group showed a significantly higher MRD-negativity (10-5 sensitivity) rate (28% vs 7%, respectively [OR, 5.23; 95% CI, 3.27-8.36; P<0.0001]) and durable MRD-negativity (10-5) rate (≥6 months: 16% vs 4%,respectively [OR, 4.05; 95% CI, 2.27-7.21; P<0.0001]; ≥12 months: 14% vs 3%, respectively [OR, 5.63; 95% CI, 2.80-11.31; P<0.0001]).
    • San-Miguel et al (2022)11 evaluated the predictive and prognostic role of MRD-negativity and durability in patients treated in the ALCYONE study. The MRD-negativity (10-5 sensitivity) rates for D-VMP vs VMP were 26.9% vs 7% (P<0.0001) in the intention-to-treat (ITT) population, and 58.8% vs 27.8% (P<0.0001) in patients who achieved ≥CR.
  • GRIFFIN: phase 2 study evaluating the safety and efficacy of DARZALEX in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients with NDMM eligible for high-dose therapy (HDT) and ASCT.12
    • Part 1: Voorhees et al (2021)13 reported the final analysis of the safety run-in cohort of the GRIFFIN study with a median follow-up of 40.8 months. By the end of D-VRd consolidation, 50% of patients were MRD-negative (10-5). After maintenance, 81.3% of patients were MRD-negative (10-5).
    • Part 2: Voorhees et al (2023)14 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. The median duration of follow-up was 49.6 months. At the end of the study, 14% and 10% of patients in the D-VRd and bortezomib, lenalidomide, and dexamethasone (VRd) arms, respectively, who were previously MRD-positive at the end of the consolidation phase, converted to MRD-negative (10-5).
  • POLLUX: phase 3 study evaluating the safety and efficacy of D-Rd vs Rd in patients with relapsed or refractory multiple myeloma (RRMM).15
    • Dimopoulos et al (2023)16 reported the updated efficacy and safety results of the POLLUX study at a median follow-up of 79.7 months. The MRD-negativity rate (10-5) in the D-Rd vs Rd arm was 33.2% vs 6.7%, respectively (P<0.0001).
  • CASTOR: phase 3 study evaluating the safety and efficacy of bortezomib and dexamethasone (Vd) alone and DARZALEX + Vd (D-Vd) in patients with RRMM.17
    • Sonneveld et al (2022)18 reported updated efficacy and safety results from CASTOR at a median follow-up of 72.6 months. The MRD-negativity rates (10-5) were for D-Vd vs Vd were 15.1% vs 1.6%, respectively.
  • CANDOR: phase 3 study evaluating the efficacy and safety of DARZALEX use in combination with carfilzomib and dexamethasone (D-Kd) vs carfilzomib and dexamethasone (Kd) in patients with RRMM.19
    • Usmani et al (2023)20 reported the final efficacy and safety results of the CANDOR study after a median follow-up of approximately 50 months. The MRD-negativity rate was 18.3% in the D-Kd arm and 5.2% in the Kd arm.
  • Several subgroup analyses that reported on MRD outcomes with the use of DARZALEX were identified. These analyses are listed in the References section for your information.21-29

CLINICAL DATA

Phase 3 Study of DARZALEX in Combination with VTd in Previously Untreated MM

CASSIOPEIA (MMY3006; NCT02541383) is a phase 3, randomized, open-label, 2-arm, multicenter, study evaluating the safety and efficacy of D-VTd in patients with NDMM who are eligible for high-dose chemotherapy and ASCT.1-3

Long-term Analysis of the CASSIOPEIA Study

Moreau et al (2024)4 reported long-term outcomes of the CASSIOPEIA study after a median follow-up of 80.1 months from the first randomization and at a median follow-up of 70.6 months from the second randomization.

Results

Patient Disposition
  • Between September 22, 2015, and August 1, 2017, a total of 1085 patients were enrolled and randomized to receive D-VTd (n=543) and VTd (n=542).4
  • Overall, 458 patients (84%) in the D-VTd group and 428 patients (79%) in the VTd group, who completed consolidation and achieved a partial response or better (≥PR), were re-randomized to either DARZALEX maintenance (n=442) or observation (n=444).4
    • At a clinical data cutoff of September 1, 2023, 339 patients (77%) had completed DARZALEX maintenance, and 317 patients (71%) had completed observation during the maintenance phase.
    • A total of 61 patients (14%) in the DARZALEX maintenance group and 118 patients (27%) in the observation group had discontinued treatment due to disease progression during the maintenance phase.
Efficacy

PFS in MRD-Positive/MRD-Negative Subgroups30
Subgroup
DARZALEX
Observation
HR (95% CI)
n/N
Median PFS, Months
n/N
Median PFS, Months
All patients in the maintenance-specific ITT population
186/442
NE
279/444
45.8
0.54 (0.45-0.65)
MRD
   MRD-positive
66/105
46.5
95/107
24.2
0.44 (0.32-0.60)
   MRD-negative
120/337
NE
184/337
61.1
0.55 (0.40-0.70)
Abbreviations: CI, confidence interval; HR, hazard ratio; ITT, intent-to-treat; MRD, minimal residual disease; NE, not estimable; PFS, progression-free survival.

Proportion of Patients With a ≥CR and Sustained MRD-Negativity at Any Timepoint From Post-induction Onwards in the Maintenance-Specific ITT Population4
MRD- Negativity Sensitivity Threshold
D-VTd
OR
(95% CI)
P Value
VTd
OR
(95% CI)
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
At any time point
   10-5, %
65.1
58.1
1.47
(0.95-2.26)
0.080
53.5
36.3
2.33
(1.51-3.60)
0.0001
   10-6, %
58.1
48.9
1.56
(1.04-2.34)
0.031
43.7
26.5
2.44
(1.56-3.81)
<0.0001
≥12 Months
   10-5, %
56.3
46.3
1.61
(1.08-2.41)
0.020
44.1
24.7
2.71
(1.73-4.23)
<0.0001
   10-6, %
47.6
36.2
1.68
(1.13-2.50)
0.0096
31.9
14.9
2.92
(1.77-4.82)
<0.0001
≥24 Months
   10-5, %
49.8
36.7
1.82
(1.23-2.71)
0.0028
36.2
16.7
3.15
(1.94-5.12)
<0.0001
   10-6, %
41
27.9
1.87
(1.25-2.81)
0.0023
24.9
10.2
3.11
(1.78-5.44)
<0.0001
Abbreviations: CI, confidence interval; CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.

MRD-Negativity Rates at 10-5 Sensitivity Threshold Following Induction and Consolidation in the ITT Population30
Post-Induction
Post-Consolidation
D-VTd
(n=543)
VTd
(n=542)
D-VTd
(n=543)
VTd
(n=542)
MRD-negativity rate, %
9.2
5.4
33.7
20.3
   P value
0.015
<0.0001
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; VTd, bortezomib + thalidomide + dexamethasone.

Long-term MRD Analysis from the CASSIOPEIA Registry

Corre et al (2026)5 presented an interim analysis of the CASSIOPEIA Registry data at a median follow-up of approximately 102.9 months from the first randomization and median follow-ups of approximately 93.5 months and 93.4 months from the second randomization in the DARZALEX maintenance and observation groups, respectively.

Study Design

  • This analysis included patients from the CASSIOPEIA study who received D-VTd or VTd during induction and consolidation and were subsequently randomized to DARZALEX maintenance or observation.5
  • After maintenance and follow-up, patients were included in the CASSIOPEIA Registry study (N=886).5

Results

Efficacy

5-Year Sustained MRD Negativity (≥CR) in the mITTa Population5
Sustained MRD-Negativity Sensitivity Threshold
D-VTd
OR (95% CI)
P Value
VTd
OR (95% CI)
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
10-5, n (%)
53 (23.1)
41 (17.9)
1.40 (0.88-2.22)
0.1589
33 (15.5)
12 (5.6)
3.23 (1.60-6.53)
0.0007
10-6, n (%)
25 (10.9)
21 (9.2)
1.22 (0.66-2.25)
0.5333
16 (7.5)
5 (2.3)
3.44 (1.23-9.63)
0.0132
Abbreviations: CI, confidence interval; CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance-specific intent-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.
aMRD analysis by NGS. Percentages are calculated with the number of patients in each group as denominator. The analysis period of MRD results is considered from post-induction up to end of follow-up, no imputation for missing value. Patients with ≥60 months of consistent MRD negativity (MRD negative at both the starting and ending point and no positive MRD between them) during the analysis period (and prior to subsequent antimyeloma therapy or disease progression if applicable) are considered as 5-year sustained MRD negativity. Patients are considered as sustained MRD negativity and ≥CR while both sustained MRD negativity and ≥CR have been achieved during the MRD negativity period.
  • The rate of ≥5-year sustained MRD negativity (10-5, ≥CR) was 34.8% in the DVTd + DARZALEX maintenance group, 32.6% in the DVTd + observation group, 23.9% in the VTd + DARZALEX maintenance group, and 7.6% in the VTd + observation group.5
    • Among patients with ≥5 years of sustained MRD negativity, 86.7% (95% CI, 77.2-97.4) remained progression free at a landmark analysis of 42 months after achieving ≥5 years of sustained MRD negativity.
  • Of 702 evaluable patients at day 100, 218 (31.1%) achieved MRD negativity at the 10-6 sensitivity threshold. Sustained MRD negativity was maintained in 90 (41.3%) and 71 (32.6%) patients at 12 and 24 months post-consolidation, respectively.5

CASSIOPEIA Landmark Analyses: Sustained MRD Negativity at 10-6 Sensitivity Threshold by Treatment Group vs D-VTd + DARZALEX Maintenance5
Timepoint
Comparator Groupa
Sustained MRD Negativity, %
OR (95% CI)
P Value
12 months
D-VTd + Obs
47.7
1.21 (0.61-2.37)
0.586
VTd + DARZALEX maintenance
48.6
1.25 (0.56-2.81)
0.591
VTd + Obs
29.7
0.56 (0.24-1.30)
0.178
24 months
D-VTd + Obs
33.8
0.68 (0.34-1.35)
0.270
VTd + DARZALEX maintenance
34.3
0.69 (0.30-1.60)
0.386
VTd + Obs
16.2
0.26 (0.10-0.69)
0.007
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.
aAmong patients who were MRD-negative at Day 100 (N=218), the D-VTd + DARZALEX maintenance group (43.1% sustained MRD negativity) served as the reference for odds ratio comparisons at 12 and 24 months post- consolidation.

Phase 3 Study of DARZALEX in Combination with Rd in Patients with NDMM

MAIA (MMY3008; NCT02252172) is a phase 3, randomized, international, open-label, active-controlled, multicenter study in patients with NDMM not eligible for high-dose chemotherapy and ASCT (N=737).6

Updated Efficacy and Safety Results of the MAIA Study

Facon et al (2025)7 reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months.

Results

Patient Characteristics
  • A total of 737 (D-Rd, n=368; Rd, n=369) patients were randomized in this study.7
  • The median follow-up was 64.5 months (range, 0-77.6).7
  • The median treatment duration was 47.5 months (range, 0.1-77.3) vs 22.6 months (range, 0.03-77.5) in the D-Rd vs Rd arm, respectively.31 
Efficacy
  • The D-Rd vs Rd arm showed a significantly higher (all P<0.0001) MRD-negativity rate (10-5 sensitivity; 32.1% [n=118] vs 11.1% [n=41]) and sustained MRD-negativity rate (≥12 months, 18.8% [n=69] vs 4.1% [n=15]; ≥18 months, 16.8% [n=62] vs 3.3% [n=12]).7
    • The MRD-negativity response rate deepened over time, increasing from 12.8% at 12 months to 20.4% at 18 months, 24.2% at 24 months, 27.4% at 30 months, 29.3% at 36 months, 31.5% at 48 months, and 31.8% at 60 months.
    • The D-Rd vs Rd arm was associated with an increased MRD-negativity rate across all age subgroups.
      • Patients aged <70 years: 35.9% (n=28) vs 11.7% (n=9); P=0.0006
      • Patients aged ≥70 to <75 years: 36.2% (n=47) vs 12.2% (n=16); P<0.0001
      • Patients aged ≥75 years: 26.9% (n=43) vs 9.9% (n=16); P<0.0001
      • Patients aged ≥80 years: 25.8% (n=17) vs 5.6% (n=4); P=0.0016
    • PFS and OS improved in patients who achieved MRD-negativity vs those who were MRD-positive in both treatment arms, with more patients in the D-Rd arm achieving MRD-negativity.

Analysis of Clinically Important Subgroups of MAIA

Moreau et al (2025)8 presented efficacy and safety results in clinically important subgroups of patients from the MAIA study.

Results

Patient Characteristics
  • Overall, 737 patients (D-Rd, 368; Rd, 369) were included in the ITT population.
  • The median follow-up was 64.5 months.8
Efficacy

Subgroup Analysis of MRD-Negativity (10-5) Rates in the ITT Population of MAIA8
Subgroup
D-Rd
n/N (%)
Rd
n/N (%)
OR (95% CI)a
ITT (overall)
118/368 (32.1)
41/369 (11.1)
3.78 (2.55-5.59)
Patient characteristics
   Age ≥75 years
43/160 (26.9)
16/161 (9.9)
3.33 (1.79-6.21)
   Frail
44/172 (25.6)
22/169 (13.0)
2.30 (1.31-4.04)
   Renal insufficiency
48/162 (29.6)
11/142 (7.7)
5.01 (2.49-10.11)
Disease-related characteristics
   ISS stage III
29/107 (27.1)
12/110 (10.9)
3.04 (1.46-6.34)
   Revised ISS stage III
13/43 (30.2)
3/40 (7.5)
5.34 (1.39-20.50)
   Extramedullary plasmacytomas
5/15 (33.3)
0/9 (0)
NE (NE-NE)
   Cytogenetic risk
      Standard cytogenetic risk
93/271 (34.3)
33/279 (11.8)
3.89 (2.50-6.06)
      High cytogenetic risk
12/48 (25.0)
1/44 (2.3)
14.33 (1.78-115.59)
      Revised standard cytogenetic risk
60/176 (34.1)
21/187 (11.2)
4.09 (2.36-7.09)
      Revised high cytogenetic risk
49/156 (31.4)
15/152 (9.9)
4.18 (2.22-7.86)
      Gain(1q21)
19/53 (35.8)
6/44 (13.6)
3.54 (1.27-9.89)
      Amp(1q21)
23/74 (31.1)
8/76 (10.5)
3.83 (1.59-9.27)
      Gain(1q21) or amp(1q21)
42/127 (33.1)
14/120 (11.7)
3.74 (1.92-7.30)
      1 HRCA
44/137 (32.1)
15/137 (10.9)
3.85 (2.02-7.34)
      ≥2 HRCAs
5/19 (26.3)
0/15 (0)
NE (NE-NE)
      Isolated gain(1q21)
17/47 (36.2)
6/42 (14.3)
3.40 (1.19-9.71)
      Isolated amp(1q21)
20/61 (32.8)
8/65 (12.3)
3.48 (1.39-8.66)
      Isolated gain(1q21) or amp(1q21)
37/108 (34.3)
14/107 (13.1)
3.46 (1.74-6.89)
      Gain(1q21) or amp(1q21) plus
      ≥1 HRCA
5/19 (26.3)
0/13 (0)
NE (NE-NE)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; Rd, lenalidomide + dexamethasone.
aOR >1 indicates an advantage for D-Rd.

Subgroup Analysis of Rates of Sustained MRD-Negativity (10-5) Lasting ≥12 Months in the ITT Population8
Subgroup
D-Rd
n/N (%)
Rd
n/N (%)
OR (95% CI)a
ITT (overall)
69/368 (18.8)
15/369 (4.1)
5.45 (3.05-9.72)
Patient characteristics
   Age ≥75 years
22/160 (13.8)
5/161 (3.1)
4.97 (1.83-13.49)
   Frail
27/172 (15.7)
7/169 (4.1)
4.31 (1.82-10.19)
   Renal insufficiency
30/162 (18.5)
2/142 (1.4)
15.91 (3.73-67.89)
Disease-related characteristics
   ISS stage III
17/107 (15.9)
3/110 (2.7)
6.74 (1.91-23.73)
   Revised ISS stage III
7/43 (16.3)
0/40 (0)
NE (NE-NE)
   Extramedullary plasmacytomas
2/15 (13.3)
0/9 (0)
NE (NE-NE)
   Cytogenetic risk
      Standard cytogenetic risk
55/271 (20.3)
11/279 (3.9)
6.20 (3.17-12.14)
      High cytogenetic risk
6/48 (12.5)
0/44 (0)
NE (NE-NE)
      Revised standard cytogenetic risk
31/176 (17.6)
5/187 (2.7)
7.78 (2.95-20.52)
      Revised high cytogenetic risk
32/156 (20.5)
7/152 (4.6)
5.35 (2.28-12.53)
      Gain(1q21)
14/53 (26.4)
3/44 (6.8)
4.91 (1.31-18.40)
      Amp(1q21)
13/74 (17.6)
4/76 (5.3)
3.84 (1.19-12.38)
      Gain(1q21) or amp(1q21)
27/127 (21.3)
7/120 (5.8)
4.36 (1.82-10.44)
      1 HRCA
31/137 (22.6)
7/137 (5.1)
5.43 (2.30-12.83)
      ≥2 HRCAs
1/19 (5.3)
0/15 (0)
NE (NE-NE)
      Isolated gain(1q21)
14/47 (29.8)
3/42 (7.1)
5.52 (1.46-20.86)
      Isolated amp(1q21)
12/61 (19.7)
4/65 (6.2)
3.73 (1.13-12.31)
      Isolated gain(1q21) or amp(1q21)
26/108 (24.1)
7/107 (6.5)
4.53 (1.87-10.97)
      Gain(1q21) or amp(1q21) plus ≥1 HRCA
1/19 (5.3)
0/13 (0)
NE (NE-NE)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; Rd, lenalidomide + dexamethasone.
aOR >1 indicates an advantage for D-Rd.

Phase 3 Study of DARZALEX in Combination with VMP in Patients with NDMM

ALCYONE (MMY3007; NCT02195479) is a phase 3, multicenter, randomized, open-label, active-controlled study which evaluated the safety and efficacy of D-VMP compared with VMP alone for the treatment of NDMM in patients (N=706) who were ineligible for high-dose chemotherapy with ASCT.9

Final Efficacy and Safety Analysis of the ALCYONE Study

Mateos et al (2025)10 reported the final efficacy and safety results study at a median follow-up of 86.7 months.

Results

Efficacy
  • The MRD-negativity rates (at 10-5 and 10-6) were higher in the D-VMP group than in the VMP group. The D-VMP group had higher durable MRD-negativity rates (10-5) for ≥6 months and ≥12 months compared with the VMP group. The MRD status of the D-VMP and VMP groups is summarized in Table: Summary of MRD-Negativity Rates and Durable MRD-Negativity Rates.10
  • In the D-VMP and VMP groups, longer OS was observed in patients who had MRD-negativity (HR, 0.60; 95% CI, 0.31-1.14) compared with those who did not have MRD-negativity (HR, 0.77; 95% CI, 0.62-0.95).10

Summary of MRD-Negativity Rates and Durable MRD-Negativity Rates10
Parameter
D-VMP
(n=350)
VMP
(n=356)
OR (95% CI)a,b
P Valuec
MRD-negativity, n (%)
   10-5
99 (28)
25 (7)
5.23 (3.27-8.36)
<0.0001
   10-6
33 (9)
3 (1)
12.96 (3.85-43.57)
<0.0001
Durable MRD-negativity (10-5)d, n (%)
   ≥6 months
56 (16)
16 (4)
4.05 (2.27-7.21)
<0.0001
   ≥12 months
49 (14)
10 (3)
5.63 (2.80-11.31)
<0.0001
Abbreviations: CI, confidence interval; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; VMP, bortezomib + melphalan + prednisone.
Data are for the intent-to-treat population.
aMantel-Haenszel estimate of the common OR for stratified tables was used for MRD status. The stratification factors were ISS disease stage (I, II, or III), region (Europe vs other), and age (<75 years vs ≥75 years) as randomized. An OR >1 indicates an advantage for D-VMP.
bA Mantel-Haenszel estimate of the common OR without stratification was used for durable MRD status.
An OR >1 indicates an advantage for D-VMP.
cP values were derived from Fisher’s exact test.
dDurable MRD-negativity was defined as the absence of MRD confirmed at least 6 months or at least 12 months apart without any instances of MRD-positivity in between assessments.

Phase 2 Study of DARZALEX in Combination with VRd in Patients with NDMM

GRIFFIN (MMY2004; NCT02874742) is a phase 2, 2-part, randomized, active-controlled, US study evaluating the safety and efficacy of DARZALEX in combination with VRd in patients with NDMM eligible for HDT and ASCT.12

Final Analysis of Part 1 (Safety Run-in Phase) of the GRIFFIN Study

Voorhees et al (2021)13 reported the final analysis of the safety run-in cohort (N=16) of the GRIFFIN study.

Results

Efficacy

  • Median follow-up was 40.8 months (range, 20.6-43) after patients completed D-VRd treatment and 24 months of D-R maintenance therapy.
  • 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 sensitivity was sustained for ≥12 months in 8 (50%) patients.

Final Analysis of Part 2 (Randomized Phase) of the GRIFFIN Study

Voorhees et al (2023)14 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

Efficacy


Final Analysis of MRD-Negativity Rates at the End of Maintenance14,32
Parameter
D-VRd
VRd
P Value
MRD-negative
   ITT population, n
104
103
-
      10-5 sensitivity, n (%)
67 (64)
31 (30)
<0.0001a
         OR (95% CI)
4.23 (2.35-7.62)
      10-6 sensitivity, n (%)
37 (36)
16 (16)
0.0013a
         OR (95% CI)
2.95 (1.52-5.75)
   In patients achieving ≥CR, n
83
59
-
      10-5 sensitivity, n (%)
64 (77)
28 (47)
0.0004a
      10-6 sensitivity, n (%)
35 (42)
14 (24)
0.031a
Durable MRD-negativity
   Lasting ≥12 months, n
104
103
-
      10-5 sensitivity, n (%)
46 (44)
14 (14)
<0.0001a
         OR (95% CI)
5 (2.5-9.99)
      10-6 sensitivity, n (%)
10 (10)
4 (4)
0.16a
         OR (95% CI)
2.48 (0.76-8.07)
Abbreviations: CI, confidence interval; ≥CR, complete response or better; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aP value was calculated using the Fisher’s exact test.
Note: The predefined per protocol final analysis was performed 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.
  • 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). The 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).14,32

Summary of MRD-Negativity Rates Over Time (ITT Population)a,14,32
Timepoint, %
D-VRd
VRd
MRD-Negativity (10-5 Sensitivity)
MRD-Negativity (10-6 Sensitivity)
MRD-Negativity (10-5 Sensitivity)
MRD-Negativity (10-6 Sensitivity)
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; CR, complete response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; sCR, stringent complete response; VRd, bortezomib + lenalidomide + dexamethasone.
aMRD was evaluated by NGS using the clonoSEQ assay. MRD assessments were performed at the first evidence of suspected CR or sCR after induction (but before stem cell collection), consolidation, and 12 and 24 months of maintenance, regardless of response.
  • No patient in either treatment arm with sustained MRD-negativity 10-5 sensitivity lasting ≥12 months became MRD-positive later.14
  • The median time to MRD-negativity in the D-VRd vs VRd arm at the 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).14

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 25 September 2026. For purposes of streamlining, this scientific response has been limited to phase 2/3 clinical studies.

In response to your specific request, summarized in this response are the relevant data from company-sponsored studies pertaining to this topic.

References

Show
1 Moreau P, Attal M, Hulin C, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394(10192):29-38.  
2 Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390.  
3 Corre J, Vincent L, Moreau P, et al. Daratumumab/bortezomib/thalidomide/dexamethasone in newly diagnosed myeloma: CASSIOPEIA minimal residual disease results. [published online ahead of print March 24, 2025]. Blood. 2025. doi:10.1182/blood.2024027620.  
4 Moreau P, Hulin C, Perrot A, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024;25(8):1003-1014.  
5 Corre J, Sonneveld P, Zweegman S, et al. 5-year sustained minimal residual disease negativity and survival with daratumumab maintenance in transplant-eligible NDMM: CASSIOPEIA registry. Oral Presentation presented at: the 23rd International Myeloma Society (IMS) Annual Meeting; September 23-26, 2026; Glasgow, Scotland.  
6 Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115.  
7 Facon T, Moreau P, Weisel K, et al. Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. Leukemia. 2025;39(4):942-950.  
8 Moreau P, Facon T, Usmani SZ, et al. Daratumumab plus lenalidomide/dexamethasone in untreated multiple myeloma: analysis of key subgroups of the MAIA study. Leukemia. 2025;39(3):710-719.  
9 Mateos MV, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518-528.  
10 Mateos MV, San-Miguel J, Cavo M, et al. Bortezomib, melphalan, and prednisone with or without daratumumab in transplant-ineligible patients with newly diagnosed multiple myeloma (ALCYONE): final analysis of an open-label, randomised, multicentre, phase 3 trial. Lancet Oncol. 2025;26(5):596-608.  
11 San-Miguel J, Avet-Loiseau H, Paiva B, et al. Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE. Blood. 2022;139(4):492-501.  
12 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.  
13 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.  
14 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.  
15 Dimopoulos M, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.  
16 Dimopoulos MA, Oriol A, Nahi H, et al. Overall survival with daratumumab, lenalidomide, and dexamethasone in previously treated multiple myeloma (POLLUX): a randomized, open-label, phase III trial. J Clin Oncol. 2023;41(8):1590-1599.  
17 Palumbo A, Chanan-Khan A, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.  
18 Sonneveld P, Chanan-Khan A, Weisel K, et al. Overall survival with daratumumab, bortezomib, and dexamethasone in previously treated multiple myeloma (CASTOR): a randomized, open-label, phase III trial. J Clin Oncol. 2023;41(8):1600-1609.  
19 Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open-label, phase 3 study. Lancet. 2020;396(10245):186-197.  
20 Usmani S, Quach H, Mateos M, et al. Supplement to: Final analysis of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in the CANDOR Study. Blood Adv. 2023;7(14):3739-3748.  
21 Rodriguez C, Kaufman J, Laubach J, et al. Daratumumab + lenalidomide, bortezomib, and dexamethasone in transplant-eligible newly diagnosed multiple myeloma: a post hoc analysis of sustained minimal residual disease negativity from GRIFFIN. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL/Virtual Meeting.  
22 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.  
23 Chari A, Kaufman JL, Laubach J, et al. Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN. Blood Cancer J. 2024;14(1).  
24 Spencer A, Moreau P, Mateos MV, et al. Daratumumab in combination with bortezomib plus dexamethasone (D-Vd) or lenalidomide plus dexamethasone (D-Rd) in relapsed or refractory multiple myeloma (RRMM): subgroup analysis of the phase 3 CASTOR and POLLUX studies in patients with early or late relapse after initial therapy. presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL/Virtual Meeting.  
25 Spencer A, Moreau P, Mateos MV, et al. Daratumumab for patients with myeloma with early or late relapse after initial therapy: subgroup analysis of CASTOR and POLLUX. Blood Adv. 2024;8(2):388-398.  
26 Spencer A, Moreau P, Mateos MV, et al. Daratumumab for patients with myeloma with early or late relapse after initial therapy: subgroup analysis of CASTOR and POLLUX. Blood Advances. 2024;8(2):388-398.  
27 Rodriguez-Otero P, Voorhees PM, Boccadoro M, et al. Daratumumab for newly diagnosed multiple myeloma: pooled analysis of patients aged ≥65 years from GRIFFIN and PERSEUS. Clin Lymphoma Myeloma Leuk. 2025.  
28 Rodriguez-Otero P, Voorhees P, Boccadoro M, et al. Daratumumab for newly diagnosed multiple myeloma: pooled analysis of patients aged ≥65 years from GRIFFIN and PERSEUS. [Published online ahead of print April 11, 2025]. Clin Lymphoma Myeloma Leuk. doi:10.1016/j.clml.2025.04.007.  
29 Mian H, Facon T, Cook G, et al. Dynamic frailty analysis of transplant-ineligible patients with NDMM in the phase 3 MAIA and CEPHEUS trials of daratumumab (Dara) + lenalidomide-dexamethasone (Rd) and bortezomib-Rd (VRd). Oral Presentation presented at: 22nd International Myeloma Society (IMS) Annual Meeting; September 17-20, 2025; Toronto, Canada.  
30 Moreau P, Hulin C, Perrot A, et al. Supplement to: Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol. 2024;25(8):1003-1014.  
31 Facon T, Moreau P, Weisel K, et al. Supplement to: Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. Leukemia. 2025;39(4):942-950.  
32 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.   

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