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This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

DARZALEX® (daratumumab)

Medical Information

Use of DARZALEX + DARZALEX FASPRO in Newly Diagnosed Multiple Myeloma in Patients Eligible for Autologous Stem-Cell Transplantation

Last Updated: 06/17/2025

SUMMARY

  • Janssen does not recommend the use of DARZALEX/DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • PERSEUS is an ongoing, open-label, multicenter, randomized, phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (VRd; D-VRd) vs VRd induction and consolidation followed by maintenance with DARZALEX FASPRO + lenalidomide (D-R) in D-VRd group or lenalidomide (R) in VRd group in patients with newly diagnosed multiple myeloma (NDMM) eligible for autologous stem cell transplant (ASCT).1
    • Sonneveld et al (2023)1 reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT. The median follow-up duration of 47.5 months (range, 0-54.4), 14.1% (50/355) of patients in the D-VRd group vs 29.1% (103/354) of patients in the VRd group experienced disease progression or death (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.30-0.59; P<0.0001), respectively. Overall complete response or better (≥CR) rate (87.9% vs 70.1%; P<0.0001) and overall minimal residual disease (MRD)-negativity rate (75.2% vs 47.5%; P<0.0001) were higher with D-VRd vs VRd. The most common grade 3/4 adverse events (AEs) in the D-VRd vs VRd group were neutropenia (62.1% vs 51.0%), thrombocytopenia (29.1% vs 17.3%), diarrhea (10.5% vs 7.8%), pneumonia (10.5% vs 6.1%), and febrile neutropenia (9.4% vs 10.1%).
    • Moreau et al (2025)2 presented findings from the phase 3 PERSEUS study, highlighting the impact of sustained MRD-negativity on progression free survival (PFS) and the incidence of functionally high-risk disease. D-VRd vs VRd more than doubled the rates of sustained MRD-negativity ≥CR (10-5 sensitivity threshold) at ≥12 months (64.8% vs 29.7%; odds ratio [OR], 4.42; 95% CI, 3.22-6.08; P<0.0001) and ≥24 months (55.8% vs 22.6%; OR, 4.36; 95% CI, 3.15-6.05; P<0.0001), respectively. Among patients from the D-VRd vs VRd arm with doubled rates of sustained MRD-negativity ≥CR (10-5 sensitivity threshold; ≥12 months), the sustained 48-month PFS rates were ~95% in both arms (95.3% vs 94.2%; HR, 0.83; 95% CI, 0.3-2.3). Among patients from the D-VRd vs VRd arm with doubled rates of sustained MRD-negativity ≥CR (10-5 sensitivity threshold; ≥24 months), the sustained 48-month PFS rates exceeded 95% in both arms (97.8% vs 98.8%; HR, 2.08; 95% CI, 0.2-17.8). D-VRd vs VRd halved the incidence of functionally high-risk status (3.1% vs 6.8%) with lower rates of functionally high-risk patients or pre-progression deaths (5.4% vs 11.0%).
  • CASSIOPEIA is a phase 3 study evaluating the safety and efficacy of DARZALEX + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant eligible patients with previously untreated MM.3,4
    • Corre et al (2025)5 reported results on the long-term MRD status and PFS outcomes from the CASSIOPEIA study following DARZALEX addition in the induction/consolidation and maintenance vs observation phases after a median follow-up of 80.1 months. The overall MRD-negativity rate (10-5) improved with DARZALEX during post-induction (D-VTd vs VTd: 34.6% vs 23.1%, respectively [OR, 1.76; P<0.0001]) and post-ASCT consolidation (D-VTd vs VTd: ss63.7% vs 43.7%, respectively [OR, 2.26; P<0.0001]). The overall MRD-negativity rate (10-5 and 10-6) was significantly higher in the DARZALEX maintenance group than in the observation group and was the highest among patients who received DARZALEX in both the induction/consolidation and maintenance phases. During post-induction, patients with MRD-negativity achieved a longer PFS as compared with patients with MRD-positivity, regardless of induction/consolidation treatment (HR, 0.40; 95% CI, 0.32-0.49; P<0.0001). Maintenance with DARZALEX improved PFS irrespective of induction/consolidation treatment and the post-consolidation MRD status. Regardless of the cytogenetic risk status and revised International Staging System (ISS) disease stage, DARZALEX induction/consolidation and maintenance improved PFS in the intent-to-treat (ITT) and maintenance intent-to-treat (mITT) populations, respectively.5,6 
  • GRIFFIN is a phase 2 study evaluating the safety and efficacy of DARZALEX when administered in combination with VRd (D-VRd) for patients with NDMM who are eligible for high-dose therapy (HDT) and ASCT.7-9
    • Part 1: Voorhees et al (2021)10 reported the final analysis of the safety run-in cohort (N=16) 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), and 50.0% were MRD-negative (10-5 threshold). After maintenance, 93.8% patients achieved sCR, and 81.3% patients were MRD-negative (10-5 threshold). 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.
    • Part 2: Voorhees et al (2020)7 presented the primary analysis of the randomized portion of this study (N=207). Voorhees et al (2023)11 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. In the D-VRd vs VRd group, 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). At the end of the study, 14% (n/N=15/104) and 10% (n/N=10/103) of patients in the D-VRd and VRd groups, respectively, who were previously MRD-positive at the end of the consolidation phase, converted to MRD-negative (10-5). In the D-VRd vs VRd group, the most common (≥10%) grade 3/4 TEAEs were neutropenia (46% vs 23%), lymphopenia (23% in both groups), leukopenia (17% vs 8%), thrombocytopenia (16% vs 9%), pneumonia (12% vs 14%), and hypophosphatemia (10% vs 11%).
  • Costa et al (2023)12 reported the results from the final analysis of the MASTER study (N=123) at a median follow-up of 42.2 months. The overall MRD-negative remission rate (next-generation sequencing [NGS]; <10-5 threshold) in MRD-evaluable patients at any point in treatment was 81% (95% CI, 73-88). The 3-year PFS rates were 88% (95% CI, 78-95) for patients with standard risk (0 HRCA), 79% (95% CI, 67-88) for patients with high risk (1 HRCA), and 50% (95% CI, 30-70) for patients with ultra high-risk (≥2 HRCAs) cytogenetic abnormalities. The 3-year overall survival (OS) rates were 94% (95% CI, 88-98) for patients with 0 HRCA, 92% (95% CI, 86-96) for patients with 1 HRCA, and 75% (95% CI, 63-85) for patients with ≥2 HRCAs. The most common grade 3 TEAEs (≥5%) were neutropenia (29%), lymphopenia (15%), hypertension (11%), anemia (9%), fatigue (9%), thrombocytopenia (7%), hypophosphatemia (7%), bone pain (6%), and leukopenia (5%).
  • Callander et al (2024)13 reported the results of a post hoc analysis evaluating the clinical efficacy of DARZALEX-based quadruplet therapies, including DARZALEX used in combination with carfilzomib, lenalidomide, and dexamethasone (KRd; D-KRd) and
    D-VRd, in transplant-eligible patients with NDMM and HRCAs from the MASTER and GRIFFIN studies, respectively. In the MASTER study, in patients with 0, 1, and ≥2 HRCAs, respectively, ≥CR was achieved by 90.6%, 89.1%, and 70.8% of patients; the estimated 24-month PFS rate was 92.4%, 95.7%, and 65.5%; and MRD-negativity
    (10-5) was reported in 80.0%, 86.4%, and 83.3% of patients. In the GRIFFIN study, in patients with 0, 1, and ≥2 HRCAs, respectively, ≥CR was achieved by 90.9%, 78.8%, and 61.5% of patients; the 24-month PFS rate was 96.7%, 93.8%, and 64.2%; and MRD-negativity (10-5) was reported in 76.1%, 55.9%, and 61.5% of patients. The total number of deaths reported in MASTER and GRIFFIN studies were 3 and 8, respectively.
  • EQUULEUS is a phase 1b study evaluating the safety and efficacy of DARZALEX when administered in combination with various treatment regimens, including KRd, for the treatment of NDMM for transplant eligible and noneligible patients.14
  • Several subgroup analyses have been identified which discuss the use of DARZALEX or DARZALEX FASPRO in NDMM patients who were eligible for ASCT. These subgroup analyses are included in the References section for your information.3,4,15-22

PRODUCT LABELING

CLINICAL DATA

DARZALEX FASPRO in Combination With Bortezomib, Lenalidomide, and Dexamethasone

PERSEUS (MMY3014; NCT03710603) is an ongoing, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-VRd vs VRd induction and consolidation followed by maintenance with D-R in D-VRd group or R in VRd group in patients with NDMM eligible for ASCT.

Sonneveld et al (2023)1 reported efficacy and safety results from the PERSEUS study evaluating D-VRd vs VRd in patients with NDMM eligible for ASCT.

Study Design/Methods

  • A total of 709 patients were randomized 1:1 to into D-VRd (n=355) vs VRd (n=354) group.
    • Stratification was done based on the ISS disease stage (I, II, or III) and standard or high cytogenetic risk (defined as the absence or presence, respectively, of a del[17p], t[4;14], or t[14;16]).
  • Dosing:
    • Induction and consolidation: Total duration of induction and consolidation treatment was 6 cycles. Each cycle was 28 days.
      • D-VRd:
        • DARZALEX FASPRO: 1800 mg once weekly at cycles 1-2 and once every 2 weeks at cycles 3-4
        • Subcutaneous (SC) bortezomib: 1.3 mg/m2 on days 1, 4, 8, and 11 of each cycle
        • Oral (PO) lenalidomide: 25 mg on days 1-21 of each cycle
        • PO/IV dexamethasone: 40 mg on days 1-4 and days 9-12 of each cycle
      • VRd:
        • SC bortezomib: 1.3 mg/m2 on days 1, 4, 8, and 11 of each cycle
        • PO lenalidomide: 25 mg daily on days 1-21 of each cycle
        • PO/IV dexamethasone: 40 mg on days 1-4 and days 9-12 of each cycle
    • Maintenance: Total duration of maintenance (≥24 months) was cycle 7 until PD. Each cycle was 28 days.
      • D-VRd:
        • DARZALEX FASPRO: 1800 mg SC once every 4 weeks
        • PO lenalidomide: 10 mg until PD or unacceptable toxicity
        • Patients who achieved sustained MRD for 12 months after ≥24 months of maintenance discontinued DARZALEX FASPRO, but continued PO lenalidomide until PD or unacceptable toxicity. Once they experienced loss of MRD-negativity or complete response (CR), they restarted on DARZALEX FASPRO.
        • Patients who did not achieved sustained MRD for 12 months after ≥24 months of maintenance continued DARZALEX FASPRO and PO lenalidomide
      • VRd:
        • PO lenalidomide: 10 mg daily until PD or unacceptable toxicity
  • Primary endpoint: PFS.
  • Key secondary endpoints: Overall ≥CR, overall MRD-negativity, and OS.
  • Other secondary endpoints: Overall response rate (ORR), very good partial response (VGPR) or better (≥VGPR), sCR, and duration of MRD-negativity.

Results

Patient Characteristics

  • A total of 709 patients were randomized into the D-VRd (n=355) and VRd (n=354) groups.
  • Demographics and baseline clinical characteristics of the ITT population are presented in Table: Demographics and Baseline Clinical Characteristics of the ITT Population.
  • A total of 698 patients (D-VRd, n=351; VRd, n=347) received ≥1 dose of treatment.
  • As of the clinical data cutoff date of August 1, 2023, 322 (91.7%) vs 300 (86.5%) patients in the D-VRd vs VRd group who started the induction phase continued into the maintenance phase, respectively.
    • A total of 207/322 patients in the D-VRd group who were receiving maintenance treatment discontinued DARZALEX FASPRO per protocol after receiving ≥24 months of maintenance treatment and achieving ≥CR and sustained MRD-negativity for ≥12 months.
  • A total of 315 (89.7%) vs 302 (87.0%) patients in the D-VRd vs VRd group received ASCT, respectively.
  • The median duration of treatment and median relative dose intensities are presented in Table: Duration of Treatment and Relative Dose Intensities During Induction/Consolidation/Maintenance Treatment in the Safety Population.
  • The median duration of follow-up was 47.5 months (range, 0-54.4).

Demographics and Baseline Clinical Characteristics of the ITT Populationa,1
D-VRd (n=355)
VRd (n=354)
Median age (range), years
61.0 (32-70)
59.0 (31-70)
Male, n (%)
211 (59.4)
205 (57.9)
Race, n (%)
   Asian
4 (1.1)
6 (1.7)
   Black or African American
5 (1.4)
4 (1.1)
   White
330 (93.0)
323 (91.2)
   Other
4 (1.1)
3 (0.8)
   Missing data
12 (3.4)
18 (5.1)
ECOG PS, n (%)b
   0
221 (62.3)
230 (65.0)
   1
114 (32.1)
108 (30.5)
   2
19 (5.4)
16 (4.5)
   3
1 (0.3)
0
Type of measurable disease, n (%)
   IgG
204 (57.5)
185 (52.3)
   IgA
65 (18.3)
85 (24.0)
   Otherc
13 (3.7)
11 (3.1)
   Detected in urine only
43 (12.1)
46 (13.0)
   Detected in serum free light chains only
29 (8.2)
27 (7.6)
   NE
1 (0.3)
0
ISS disease stage,d n
355
353
   I, n (%)
186 (52.4)
178 (50.4)
   II, n (%)
114 (32.1)
125 (35.4)
   III, n (%)
55 (15.5)
50 (14.2)
Cytogenetic risk profile, n (%)e
   Standard risk
264 (74.4)
266 (75.1)
   High risk
76 (21.4)
78 (22.0)
   Indeterminate
15 (4.2)
10 (2.8)
Median time since diagnosis of multiple myeloma (range), months
1.2 (0.0-46.5)
1.1 (0.1-184.6)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; Ig, immunoglobulin; ISS, International Staging System; ITT, intent-to-treat; NE, not estimable; VRd, bortezomib + lenalidomide + dexamethasone.
aThe ITT population was defined as all patients who underwent randomization. Informal testing showed no significant differences between the 2 treatment groups in the characteristics evaluated at baseline.
bECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability. One patient had an ECOG PS score of 0 at the time of randomization that worsened to an ECOG PS score of 3 at baseline.
cIncludes IgD, IgM, IgE, and biclonal.
dThe ISS disease stage is based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
eCytogenetic risk was assessed by fluorescence in situ hybridization. High risk was defined as the presence of del(17p), t(4;14), and/or t(14;16).

Duration of Treatment and Relative Dose Intensities During Induction/Consolidation/Maintenance Treatment in the Safety Populationa,b,23
D-VRd (n=351)
VRd (n=347)
Median duration
of treatment (range), months
45.7 (0.5-54.3)
42.2 (0.1-53.9)
Median relative dose intensity (range), %
Induction
Consolidation
Maintenance
Induction
Consolidation
Maintenance
   Bortezomib
(n=351)
98.0
(25.3-104.8)
(n=243)
97.8
(12.3-114.2)
NA
(n=347)
97.8
(40.2-110.4)
(n=236)
98.2
(9.5-106.0)
NA
   Lenalidomide
(n=351)
100
(28.6-122.2)
(n=271)
100
(29.5-116.7)
(n=316)
85.2
(8.5-152.8)
(n=347)
100
(36.7-105.6)
(n=260)
100
(23.3-100.0)
(n=300)
97.1
(39.7-150.4)
   Dexamethasone
(n=351)
100
(20.8-183.3)
(n=263)
100
(1.6-100.0)
NA
(n=347)
100
(35.9-121.9)
(n=250)
100
(10.0-125.0)
NA
Induction Cycles 1-2
(n=351)
Induction Cycles 3-4
(n=343)
Consolidation
(n=274)
Maintenance
(n=322)
      DARZALEX FASPRO
100
(50.0-100.4)
100
(25.0-100.0)
100
(50.0-100.0)
100
(67.6-100.0)
NA
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; NA, not available; VRd, bortezomib + lenalidomide + dexamethasone.
aDose intensity was defined as the ratio of the total administered dose to the total planned dose.
bThe safety population included all patients who received ≥1 dose of the study treatment.

Efficacy

  • A total of 50 (14.1%) vs 103 (29.1%) patients experienced disease progression or deaths in the D-VRd vs VRd group of the ITT population (HR, 0.42; 95% CI, 0.30-0.59; P<0.0001), respectively, crossing the prespecified stopping boundary for superiority at the first interim analysis (P=0.0126).
  • The estimated 48-month PFS rate for the D-VRd vs VRd group was 84.3% (95% CI, 79.5-88.1) vs 67.7% (95% CI, 62.2-72.6), respectively.
  • A summary of response rates and MRD status in the ITT population is presented in Table: Summary of Response Rates and MRD Status in the ITT Population.
  • Analyses of overall ≥CR rates and overall MRD-negativity rates (at 10-5) in prespecified subgroups appeared to favor D-VRd over VRd across clinically relevant subgroups.
  • Information on PFS in prespecified subgroup analysis is summarized in Table: PFS in Prespecified Subgroups.

Summary of Response Rates and MRD Status in the ITT Populationa,1
Parameter
D-VRd (n=355)
VRd (n=354)
P Valueb
Overall response
   n
343
332
-
   % (95% CI)
96.6 (94.2-98.2)
93.8 (90.7-96.1)
-
Response, n (%)
   ≥CR
312 (87.9)
248 (70.1)
<0.0001
      sCRc
246 (69.3)
158 (44.6)
-
      CR
66 (18.6)
90 (25.4)
-
   ≥VGPR
338 (95.2)
316 (89.3)
-
      VGPR
26 (7.3)
68 (19.2)
-
   PR
5 (1.4)
16 (4.5)
-
   SD
4 (1.1)
9 (2.5)
-
   PD
2 (0.6)
1 (0.3)
-
   Response could not be evaluated
6 (1.7)
12 (3.4)
-
MRD-negativity, n (%)d
   10-5 sensitivity
267 (75.2)
168 (47.5)
<0.0001
   10-6 sensitivity
231 (65.1)
114 (32.2)
-
Sustained MRD-negativity (10-5) for ≥12 months, n (%)
230 (64.8)
105 (29.7)
-
Abbreviations: ≥CR, complete response or better; ≥VGPR, very good partial response or better; CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; FLC, free light chain; IMWG, International Myeloma Working Group; ITT, intent-to-treat; MRD, minimal residual disease; NGS, next-generation sequencing; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
aResponse rates and MRD-negativity rates at any time during the study. The responses were assessed based on the IMWG response criteria.
bP values were calculated with the use of the stratified Cochran-Mantel-Haenszel chi-squared test.
cCriteria for an sCR included the criteria for a CR plus a normal serum FLC ratio and the absence of clonal plasma cells in the bone marrow, as assessed by immunohistochemistry, immunofluorescence, or 2- to 4-color flow cytometry.
dThe MRD-negativity rate was defined as the proportion of patients who achieved both MRD-negativity and ≥CR. Sustained MRD-negativity for 12 months was defined as 2 consecutive MRD-negative results 12 months apart, without any MRD-positive results in between. The MRD status was assessed using bone marrow samples and evaluated using an NGS assay (clonoSEQ assay, version 2.0; Adaptive Biotechnologies) in accordance with the IMWG guidelines for assessing MRD.

PFS in Prespecified Subgroups1
Subgroups
PFS
D-VRd
VRd
D-VRd
VRd
HR (95% CI)
No. of Progression Events or Deaths/Total No.
Median PFS, Months
Sex
   Male
36/211
61/205
NE
NE
0.51 (0.34-0.77)
   Female
14/144
42/149
NE
NE
0.29 (0.16-0.53)
Age
   <65 years
30/261
84/267
NE
NE
0.30 (0.20-0.46)
   ≥65 years
20/94
19/87
NE
NE
0.97 (0.52-1.81)
Race
   White
47/330
95/323
NE
NE
0.42 (0.30-0.60)
   Other
3/25
8/31
NE
NE
0.40 (0.11-1.50)
ISS staging
   I
18/186
35/178
NE
NE
0.46 (0.26-0.81)
   II
19/114
43/125
NE
NE
0.37 (0.22-0.64)
   III
13/55
25/50
NE
41.9
0.42 (0.22-0.83)
Type of MM
   IgG
28/204
58/185
NE
NE
0.36 (0.23-0.57)
   Non-IgG
13/78
31/96
NE
NE
0.46 (0.24-0.88)
Cytogenetic risk
   Standard risk
25/264
62/266
NE
NE
0.35 (0.22-0.56)
   High risk
24/76
38/78
NE
44.1
0.59 (0.36-0.99)
   Intermediate risk
1/15
3/10
NE
NE
0.16 (0.02-1.56)
ECOG PS
   0
28/221
60/230
NE
NE
0.42 (0.27-0.66)
   ≥1
22/134
43/124
NE
NE
0.41 (0.25-0.69)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; Ig, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; NE, not estimable; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone.

Safety

  • The most common grade 3/4 AEs recorded in the D-VRd vs VRd group were neutropenia (62.1% vs 51.0%), thrombocytopenia (29.1% vs 17.3%), diarrhea (10.5% vs 7.8%), pneumonia (10.5% vs 6.1%), and febrile neutropenia (9.4% vs 10.1%). See Table: Most Common AEs During Treatment in the Safety Population.
  • Grade 3/4 peripheral neuropathy occurred in 6.0% vs 4.9% of patients in the D-VRd vs VRd group, respectively.
  • Serious adverse events (SAEs) in the safety population are summarized in Table: SAEs in the Safety Population.
  • A second primary malignancy was observed in 37 patients (10.5%) in the D-VRd group and 25 patients (7.2%) in the VRd group.
  • The number of deaths recorded due to coronavirus disease 2019 (COVID-19) in the D-VRd vs VRd group was 4 (1.1%) vs 1 (0.3%) patients, respectively.
  • A total of 25.9% vs 54.2% of patients in the D-VRd vs VRd group discontinued treatment, respectively.
    • The most common reasons for treatment discontinuation over all phases of the study were AEs (D-VRd, 9.1%; VRd, 22.5%) and PD (D-VRd, 8.3%; VRd, 20.7%).
  • A total of 34 vs 44 patients died in the D-VRd vs VRd group, respectively.
    • A total of 7 patients died due to COVID-19 (D-VRd, n=4; VRd, n=3).

Most Common AEs During Treatment in the Safety Populationa,1
Event, n (%)
D-VRd (n=351)
VRd (n=347)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Any AE
349 (99.4)
321 (91.5)
344 (99.1)
297 (85.6)
Hematologic AEs
   Neutropenia
243 (69.2)
218 (62.1)
204 (58.8)
177 (51.0)
   Thrombocytopenia
170 (48.4)
102 (29.1)
119 (34.3)
60 (17.3)
   Anemia
78 (22.2)
21 (6.0)
72 (20.7)
22 (6.3)
   Febrile neutropenia
34 (9.7)
33 (9.4)
38 (11.0)
35 (10.1)
Nonhematologic AEs
   Diarrhea
214 (61.0)
37 (10.5)
188 (54.2)
27 (7.8)
   Peripheral sensory neuropathy
188 (53.6)
15 (4.3)
179 (51.6)
14 (4.0)
   Constipation
119 (33.9)
8 (2.3)
118 (34.0)
6 (1.7)
   Pyrexia
111 (31.6)
8 (2.3)
109 (31.4)
9 (2.6)
   Insomnia
95 (27.1)
8 (2.3)
61 (17.6)
6 (1.7)
   Asthenia
94 (26.8)
12 (3.4)
89 (25.6)
9 (2.6)
   Cough
85 (24.2)
1 (0.3)
51 (14.7)
0
   Fatigue
84 (23.9)
10 (2.8)
92 (26.5)
18 (5.2)
   Rash
82 (23.4)
9 (2.6)
94 (27.1)
17 (4.9)
   Back pain
80 (22.8)
2 (0.6)
66 (19.0)
1 (0.3)
   Peripheral edema
72 (20.5)
4 (1.1)
74 (21.3)
1 (0.3)
   Nausea
71 (20.2)
2 (0.6)
58 (16.7)
2 (0.6)
   Infections
305 (86.9)
124 (35.3)
266 (76.7)
95 (27.4)
      COVID-19
123 (35.0)
12 (3.4)
83 (23.9)
4 (1.2)
      Upper respiratory tract
      infection
111 (31.6)
2 (0.6)
87 (25.1)
6 (1.7)
      Pneumonia
64 (18.2)
37 (10.5)
38 (11.0)
21 (6.1)
Second primary malignancy
37 (10.5)
NA
25 (7.2)
NA
Any IRR
21 (6.0)
3 (0.9)
NA
NA
Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; IRR, infusion-related reaction; NA, not applicable;
VRd, bortezomib + lenalidomide + dexamethasone.
aThe safety population included patients who received ≥1 dose of the study treatment. AEs of any grade that were reported in ≥20% of patients in either treatment group and grade 3/4 AEs that were reported in ≥10% of patients in either treatment group are listed.

SAEs in the Safety Populationa,23
n (%)
D-VRd (n=351)
VRd (n=347)
Total no. of patients with SAEs
200 (57.0)
171 (49.3)
SAEs occurring in ≥2% of patients in either treatment group
   Infections
123 (35.0)
95 (27.4)
      Pneumonia
40 (11.4)
21 (6.1)
      COVID-19
13 (3.7)
6 (1.7)
      COVID-19 pneumonia
11 (3.1)
5 (1.4)
      Lower respiratory tract infection
9 (2.6)
3 (0.9)
      Sepsis
7 (2.0)
9 (2.6)
      Upper respiratory tract infection
7 (2.0)
8 (2.3)
   Febrile neutropenia
16 (4.6)
16 (4.6)
   Pyrexia
13 (3.7)
16 (4.6)
   Pulmonary embolism
9 (2.6)
5 (1.4)
   Atrial fibrillation
9 (2.6)
2 (0.6)
   Diarrhea
7 (2.0)
9 (2.6)
Abbreviations: COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; SAE, serious adverse event; VRd, bortezomib + lenalidomide + dexamethasone.
aThe safety population included patients who received ≥1 dose of the study treatment.
  • Median cluster of differentiation 34+ (CD34+) cell yield in the D-VRd vs VRd group was 5.5x106/kg vs 7.4x106/kg, respectively.
  • The proportion of patients proceeding to ASCT in the D-VRd vs VRd group was 89.7% vs 87.0%, respectively.
  • The median time to complete hematopoietic reconstitution in the D-VRd vs VRd group was 14 days each.

DARZALEX in Combination with Bortezomib, Thalidomide, and Dexamethasone

CASSIOPEIA (MMY3006; NCT02541383) is an ongoing, open-label, 2-group, multicenter, randomized, phase 3 study evaluating the safety and efficacy of D-VTd in patients with previously untreated MM who are eligible for HDT and ASCT.3,4 Corre et al (2025)5 reported results on the long-term MRD status and PFS outcomes from the CASSIOPEIA study in transplant-eligible patients with NDMM following DARZALEX addition in the induction/consolidation and maintenance vs observation phases.

Study Design/Methods

  • At clinical cutoff (September 1, 2023), the median follow-up was 80.1 months (range, 0.0-94.6) from the first randomization and 70.6 months (range, 1.7-86.3) from the second randomization.
  • Patients were randomly assigned (1:1) to receive D-VTd or VTd for induction/consolidation. Patients were rerandomized to the maintenance phase to undergo DARZALEX maintenance or observation for upto 2 years. The MRD status was assessed at predefined timepoints during each study phase.5
  • During maintenance, MRD analyses were conducted in patients who achieved VGPR or ≥VGPR at 6, 12, and 24 months of maintenance or observation.5
  • During follow-up, MRD analyses were performed at 1, 2, and 3 years in patients who did not progress and were MRD-negative after 24 months of maintenance vs observation or at their last assessment since day 100 post-ASCT.5
  • The sustained MRD-negativity rate was determined by a consistent result of MRD-negativity (with no MRD-positive result between measurements) for a given length of time (minimum of 12 months, with measurements up to ≥36 months), as observed at any timepoint between postinduction and the end of follow-up; it was compared across treatment groups, stratified by the depth of response.5
  • The accumulative MRD-negativity rate was calculated as the proportion of patients achieving MRD-negativity before a set timepoint; it was compared within the mITT population, stratified by the study site, ISS disease stage, and cytogenetic risk status.5

Results

Baseline Characteristics

Demographic and Clinical Characteristics in the Intent-to-Treat Population3
Characteristic
D-VTd
(n=543)
VTd
(n=542)
Median (range) age, years
59 (22-65)
58 (26-65)
Sex, n (%)
   Male
316 (58.2)
319 (58.9)
   Female
227 (41.8)
223 (41.1)
ECOG PS, n(%)
   0
265 (49)
257 (47)
   1
225 (41)
230 (42)
   2
53 (10)
55 (10)
Type of measurable disease, n(%)
   IgG
331 (61)
314 (58)
   IgA
80 (15)
99 (18)
   Othera
3 (2)
22 (4)
   Detected in urine only
70 (13)
67 (12)
   Detected in serum FLCs only
48 (9)
40 (7)
   Unknown
1 (<1)b
0
ISS disease stagec, n(%)
   I
204 (38)
228 (42)
   II
255 (47)
233 (43)
   III
84 (15)
81 (15)
Cytogenetic profile, n/total (%)d
   Standard risk
460/542 (85)
454/540 (84)
   High riske
82/542 (15)
86/540 (16)
Median (range) time since MM diagnosis, months
0.92 (0.2-9.4)
0.92 (0.2-22.9)
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; Ig, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; VTd, bortezomib + thalidomide + dexamethasone.
aIncludes IgD, IgM, IgE, and biclonal.
bOne patient was assessed as having light-chain disease only, despite a monoclonal peak in the serum and urine.
cBaseline disease stage based on the revised ISS criteria.
dCytogenetic risk was assessed by fluorescence in situ hybridization. Patients for whom cytogenetic testing failed were considered to have a standard risk (D-VTd, 7.6%; VTd, 7.4%).
eThese patients had at least 1 high-risk abnormality: del17p (≥50% abnormal cells) or t(4;14) (≥30% abnormal cells).

Baseline Demographics and Disease Characteristics After Second Randomization4
Characteristic
DARZALEX Monotherapy
(n=442)
Observation
(n=444)
Median (IQR) age, years
59 (53-63)
59 (53-63)
Male, n (%)
261 (59)
254 (57)
ECOG PS, n (%)
   0
252 (57)
260 (59)
   1
174 (39)
172 (39)
   ≥2
16 (4)
12 (3)
ISS disease stagea, n (%)
   I
189 (43)
171 (39)
   II
181 (41)
214 (48)
   III
72 (16)
59 (13)
Cytogenetic profilea, n/total (%)
   Standard risk
383/440 (87)
374/444 (84)
   High risk
57/440 (13)
70/444 (16)
Type of induction/consolidation, n (%)
   D-VTd
229 (52)
229 (52)
   VTd
213 (48)
215 (48)
Depth of responseb, n (%)
   MRD-negative, ≥VGPR
337 (76)
337 (76)
   MRD-positive, ≥VGPR
68 (15)
69 (16)
   MRD-positive, PRc
37 (8)
38 (9)
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; IQR, interquartile range; ISS, International Staging System; MRD, minimal residual disease; PR, partial response; VGPR, very good partial response; VTd, bortezomib + thalidomide + dexamethasone.
aPre-induction.
bAs determined based on MRD measured by multiparametric flow cytometry at 10-4 and the post-consolidation response per investigator assessment used for stratification.
cSix patients (3 who received previous D-VTd and 3 who received previous VTd) were MRD-negative with a PR at post-consolidation and were categorized as MRD-positive with PR due to the lack of a specific stratum defined in the protocol for such patients.
Efficacy

MRD-Negativity Rates at Any Time During Maintenance and Follow-up in the mITT Population5,6
MRD-Negativity Sensitivity Threshold
D-VTd
OR
P Value
VTd
OR
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
Overall MRD-negativitya, %
   10-5
77.3
70.7
1.76
0.0417
70.9
51.2
3.16
<0.0001
   10-6
60.7
52
1.55
0.0365
48.4
30.7
2.41
<0.0001
At 6 monthsb, %
   10-5
59.4
53.3
1.27
0.2132
48.8
34.4
1.78
0.0043
   10-6
38.4
36.7
1.06
0.7662
27.2
19.5
1.58
0.0550
At 12 monthsb, %
   10-5
61.6
55.9
1.23
0.2667
48.8
33.0
1.92
0.0012
   10-6
39.3
34.9
1.17
0.4372
31.9
18.1
2.09
0.0013
At 24 monthsb, %
   10-5
62.9
50.7
1.62
0.0121
49.3
21.4
3.47
<0.0001
   10-6
46.3
31.4
1.81
0.0024
32.9
13.0
3.49
<0.0001
MRD-negativity conversion ratec, %
   10-5
36.7
25.0
1.74
0.1540
47.4
9.9
8.22
<0.0001
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.
aPost-consolidation after the second randomization.
bmITT population.
cPercentages were calculated with the number of patients with a post-consolidation MRD-positive status in each treatment group as the denominator (D-VTd/DARZALEX, n=60; D-VTd/Obs, n=68; VTd/DARZALEX, n=97; VTd/Obs, n=91).

MRD-Negativity With ≥CR Rates at Defined Time Points During Maintenance in the mITT Population5
MRD-Negativity Sensitivity Threshold
D-VTd
OR
P Value
VTd
OR
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
At 6 months, %
   10-5
57.2
50.2
1.30
0.1750
44.1
29.8
1.85
0.0027
   10-6
37.6
35.8
1.06
0.7848
25.8
18.1
1.59
0.0541
At 12 months, %
   10-5
59.4
52.0
1.31
0.1541
47.4
30.2
2.08
0.0004
   10-6
38.9
34.5
1.18
0.4178
31.5
16.7
2.25
0.0005
At 24 months, %
   10-5
60.3
47.2
1.66
0.0081
47.4
20.5
3.41
<0.0001
   10-6
45.9
31.0
1.83
0.0021
31.9
12.6
3.47
<0.0001
Abbreviations: CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.


Accumulative MRD-Negativity Rates in the mITT Population Over Time5
MRD-Negativity Sensitivity Threshold
D-VTd
VTd
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
MRD-negativity rate, %
   At day 28
      10-5
31.0
28.8
23.9
16.3
      10-6
8.7
9.2
8.5
4.7
   At day 100a
      10-5
68.1
64.2
47.4
51.2
      10-6
32.8
31.0
19.7
18.6
   At week 25
      10-5
74.2
68.6
61.5
55.3
      10-6
46.7
44.5
32.9
26.5
   At week 52
      10-5
75.1
71.6
66.7
57.7
      10-6
52.8
48.5
41.3
28.8
   At week 105
      10-5
77.7
73.8
71.4
58.1
      10-6
58.5
51.5
47.4
29.8
   At 12 monthsb
      10-5
79.0
74.2
73.2
58.1
      10-6
59.4
53.3
47.4
31.6
   At 24 monthsb
      10-5
79.0
74.2
73.2
58.1
      10-6
60.3
53.3
48.8
32.1
   At 36 monthsb
      10-5
79.0
74.2
73.2
58.1
      10-6
60.7
53.3
48.8
32.1
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; VTd, bortezomib + thalidomide + dexamethasone.
aPost autologous stem cell transplantation.
bPreprogressive disease follow-up.

Accumulative MRD-Negativity With ≥CR Rates in the mITT Population Over Time5
MRD-Negativity Sensitivity Threshold
D-VTd
VTd
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
MRD-negativity with ≥CR, %
   At day 28
      10-5
28.4
27.9
22.1
12.6
      10-6
8.3
9.2
7.5
4.2
   At day 100a
      10-5
63.8
60.3
42.7
40.9
      10-6
31.9
30.6
17.8
17.2
   At week 25
      10-5
68.6
63.8
54.0
42.8
      10-6
45.9
43.2
31.0
23.7
   At week 52
      10-5
69.4
65.1
58.7
45.1
      10-6
52.0
46.7
39.0
25.1
   At week 105
      10-5
71.6
66.4
63.4
45.6
      10-6
57.6
49.8
44.6
26.0
   At 12 monthsb
      10-5
72.1
66.4
63.8
45.6
      10-6
58.5
51.1
44.6
27.9
   At 24 monthsb
      10-5
72.1
66.4
63.8
45.6
      10-6
59.4
51.1
46.0
28.4
   At 36 monthsb
      10-5
72.1
66.4
63.8
45.6
      10-6
59.8
51.1
46.0
28.4
Abbreviations: CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; VTd, bortezomib + thalidomide + dexamethasone.
aPost autologous stem cell transplantation.
bPreprogressive disease follow-up.

Sustained MRD-Negativity Rates at Any Time During the Study - mITT Population5
Sustained MRD-Negativity Sensitivity Threshold
D-VTd
OR
P Value
VTd
OR
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
At ≥12 months, %
   10-5
65.5
57.2
1.59
0.0369
50.7
32.1
2.53
<0.0001
   10-6
49.3
37.1
1.75
0.0053
32.4
15.3
2.89
<0.0001
At ≥24 months, %
   10-5
58.5
46.7
1.78
0.0056
43.7
20.9
3.50
<0.0001
   10-6
41.9
28.4
1.91
0.0017
25.4
10.2
3.20
<0.0001
At ≥36 months, %
   10-5
43.7
32.3
1.70
0.0088
31.9
12.1
3.79
<0.0001
   10-6
29.7
22.7
1.46
0.0821
19.7
6.5
3.74
<0.0001
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.

Sustained MRD-Negativity With ≥CR Rates at Any Time During the Study - mITT Population5
Sustained MRD-Negativity Sensitivity Threshold
D-VTd
OR
P Value
VTd
OR
P Value
DARZALEX
(n=229)
Obs
(n=229)
DARZALEX
(n=213)
Obs
(n=215)
At ≥12 months, %
   10-5
63.3
53.7
1.66
0.0191
48.8
29.3
2.64
<0.0001
   10-6
47.6
36.2
1.68
0.0096
31.9
14.9
2.92
<0.0001
At ≥24 months, %
   10-5
57.6
44.5
1.88
0.0022
42.7
20.0
3.54
<0.0001
   10-6
41.0
27.9
1.87
0.0023
24.9
10.2
3.11
<0.0001
At ≥36 months, %
   10-5
43.2
31.0
1.78
0.0047
31.5
11.6
3.87
<0.0001
   10-6
29.3
22.3
1.47
0.0807
19.7
6.5
3.74
<0.0001
Abbreviations: CR, complete response; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation; OR, odds ratio; VTd, bortezomib + thalidomide + dexamethasone.

MRD-Negativity Rates Based on the Cytogenetic Risk Status - ITT Population6
MRD-Negativity Sensitivity Thresholda
Standard Risk
P Value
High Risk
P Value
D-VTd
(n=460)
VTd
(n=454)
D-VTd
(n=82)b
VTd
(n=86)b
10-5, %
66.1
45.8
<0.0001
62.2
47.7
0.0595
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ITT, intent-to-treat; MRD, minimal residual disease; VTd, bortezomib + thalidomide + dexamethasone.
aAmong patients with high cytogenetic risk, 40 (49%) patients in the D-VTd group and 47 (55%) patients in the VTd group had a t(4;14) abnormality only, 31 (38%) patients in the D-VTd group and 33 (38%) patients in the VTd group had a del(17p) abnormality only, and 11 (13%) patients in the D-VTd group and 6 (7%) patients in the VTd group had both t(4;14) and del(17p) abnormalities. High cytogenetic risk was a stratification factor for the induction/consolidation phase.
bMRD-negativity in the ITT population during the induction/consolidation phase.

MRD-Negativity Rates Based on the Revised ISS Stage - ITT Population6
MRD-Negativity Sensitivity Thresholda
Revised ISS I
P Value
Revised ISS II
P Value
Revised ISS III
P Value
D-VTd
(n=103)
VTd
(n=146)
D-VTd
(n=383)
VTd
(n=344)
D-VTd
(n=49)
VTd
(n=50)
10-5, %
69.9
42.5
<0.0001
64.2
47.7
<0.0001
63.3
48.0
0.1284
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; VTd, bortezomib + thalidomide + dexamethasone.
aMRD-negativity in the ITT population during the induction/consolidation phase.

MRD-Negativity Rates Based on the Cytogenetic Risk Status - mITT Population6
MRD-Negativity Sensitivity Threshold
Standard Risk
P Value
High Risk
P Value
DARZALEX
(n=383)
Obs
(n=374)
DARZALEX
(n=57)a
Obs
(n=70)a
Overall MRD-negativityb, %
   10-5
73.4
61.8
0.0007
78.9
58.6
0.0150
   10-6
52
42
0.0060
73.7
40
0.0002
≥12 months of sustained MRD-negativityc, %
   10-5
56.4
46.0
0.0042
70.2
40.0
0.0007
   10-6
38.6
28.9
0.0045
57.9
14.3
<0.0001
Abbreviations: mITT, maintenance intent-to-treat; MRD, minimal residual disease; Obs, observation.
aAmong patients with high cytogenetic risk, 34 (60%) patients in the DARA group and 34 (49%) patients in the OBS group had a t(4;14) abnormality only, 21 (37%) patients in the DARA group and 29 (41%) patients in the OBS group had a del(17p) abnormality only, and 2 (3%) patients in the DARA group and 7 (10%) patients in the OBS group had both t(4;14) and del(17p) abnormalities. High cytogenetic risk was not a stratification factor for the maintenance phase (Part 2). When broken down by induction treatment arm, among patients with high cytogenetic risk, 19 (61%) patients in the D-VTd/DARA group, 14 (42%) patients in the D-VTd/OBS group, 15 (58%) patients in the VTd/DARA group, and 20 (54%) patients in the D-VTd/OBS group had a t(4;14) abnormality only; 11 (36%), 15 (46%), 10 (38%), and 14 (38%) patients, respectively, had a del(17p) abnormality only, and 1 (3%), 4 (12%), 1 (4%), and 3 (8%) patients, respectively, had both t(4;14) and del(17p) abnormalities.
bMRD-negativity in the maintenance ITT population during maintenance and follow-up.
cMRD-negativity in the maintenance ITT population from post-induction up to the end of follow-up.

MRD-Negativity Rates Based on the Revised ISS Stage - mITT Population6
MRD-Negativity Sensitivity
Threshold
Revised ISS I
P Value
Revised ISS II
P Value
Revised ISS III
P Value
D-VTd
(n=105)
VTd
(n=102)
D-VTd
(n=287)
VTd
(n=310)
D-VTd
(n=44)
VTd
(n=29)
Overall MRD-negativitya, %
   10-5
74.3
65.7
0.1779
73.9
59.7
0.0002
75.0
65.5
0.3844
   10-6
48.6
42.2
0.3552
56.4
40.6
0.0001
61.4
51.7
0.4181
≥12 months of sustained MRD-negativityb, %
   10-5
59.0
45.1
0.0451
58.2
44.8
0.0011
56.8
48.3
0.4771
   10-6
41.9
30.4
0.0857
41.8
25.5
<0.0001
36.4
24.1
0.2745
Abbreviations: D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; ISS, International Staging System; mITT, maintenance intent-to-treat; MRD, minimal residual disease; VTd, bortezomib + thalidomide + dexamethasone.
aMRD-negativity in the maintenance ITT population during maintenance and follow-up.bMRD-negativity in the maintenance ITT population from post-induction up to the end of follow-up.
  • During post-induction, patients with MRD-negativity (at 10-5 threshold sensitivity) achieved a longer PFS as compared with patients with MRD-positivity, regardless of induction/consolidation treatment (HR, 0.40; 95% CI, 0.32-0.49; P<0.0001).5
    • The median PFS was not reached in patients with MRD-negativity in the D-VTd group. PFS analysis results by the post-induction MRD status and the induction/consolidation group are presented in Table: PFS Analysis by the Post-induction MRD Status and Induction/Consolidation Group - ITT Population.5
    • A longer PFS was achieved by patients who were MRD-negative post-induction than  that achieved by patients who were not MRD-negative until post-consolidation, regardless of induction/consolidation or a second randomization (HR, 0.54; 95% CI, 0.42-0.70; P<0.0001).5,6
    • PFS improved with DARZALEX maintenance (HR, 0.63; 95% CI, 0.42-0.96; P=0.0294) vs observation (HR, 0.40; 95% CI, 0.28-0.59; P<0.0001) irrespective of whether MRD-negativity was achieved post-induction/consolidation.6
  • Maintenance with DARZALEX improved PFS irrespective of induction/consolidation treatment and the post-consolidation MRD status.5
    • Post-consolidation, patients with MRD-negativity achieved a longer PFS vs patients with MRD-positivity (DARZALEX MRD-negative vs DARZALEX MRD-positive: HR, 0.48 [95% CI, 0.34-0.67] [P<0.0001]; observed MRD-negative vs observed MRD-positive: HR, 0.47 [95% CI, 0.36-0.60] [P<0.0001]).5
    • PFS analysis results from the second randomization by induction treatment, regardless of the post-consolidation MRD status, are summarized in Table: PFS Analysis From Second Randomization by the Post-consolidation MRD Status - mITT Population.5
  • DARZALEX induction/consolidation improved PFS regardless of the cytogenetic risk status and revised ISS disease stage in the ITT population.5,6
  • DARZALEX maintenance improved PFS regardless of the cytogenetic risk status and revised ISS disease stage.5,6

PFS Analysis by the Post-induction MRD Status and Induction/Consolidation Group - ITT Population5
MRD Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
D-VTd MRD-negative
76.9
Not reached
0.40 (0.27-0.59)
<0.0001
VTd MRD-negative
52.9
77
D-VTd MRD-positive
39.7
54.1
0.74 (0.61-0.89)
0.0018
VTd MRD-positive
30.8
45.3
D-VTd MRD-negative
76.9
Not reached
0.30 (0.22-0.41)
<0.0001
D-VTd MRD-positive
39.7
54.1
VTd MRD-negative
52.9
77
0.57 (0.43-0.75)
<0.0001
VTd MRD-positive
30.8
45.3
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; MRD, minimal residual disease; PFS, progression-free survival; VTd, bortezomib + thalidomide + dexamethasone.

PFS Analysis From Second Randomization by the Post-consolidation MRD Status - mITT Population5
MRD Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
DARZALEX MRD-negative
72.1
Not reached
0.54 (0.38-0.78)
0.0007
Obs MRD-negative
47.3
78.1
DARZALEX MRD-positive
52
66.2
0.48 (0.39-0.60)
<0.0001
Obs MRD-positive
26.2
36.6
Abbreviations: CI, confidence interval; HR, hazard ratio; MRD, minimal residual disease; Obs, observation; PFS, progression-free survival.

PFS Analysis Based on the Cytogenetic Risk Status - ITT Population5,6
Cytogenetic Risk Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
D-VTd standard risk
57.0
87.3
0.60 (0.50-0.72)
<0.0001
VTd standard risk
39.7
57.8
D-VTd high risk
36.1
48.5
0.68 (0.47-0.99)
0.0410
VTd high risk
22.9
34.2
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival; VTd, bortezomib + thalidomide + dexamethasone.

PFS Analysis Based on the R-ISS Stage in the ITT Population6
R-ISS Stage
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
ITT population
   D-VTd R-ISS I
65.0
Not reached
0.49 (0.33-0.72)
0.0002
   VTd R-ISS I
39.6
60.8
   D-VTd R-ISS II
52.1
75.4
0.64 (0.52-0.77)
<0.0001
   VTd R-ISS II
37.2
51.1
   D-VTd R-ISS III
41.4
56.8
0.63 (0.39-1.02)
0.0600
   VTd R-ISS III
25.1
36.7
Abbreviations: CI, confidence interval; D-VTd, DARZALEX + bortezomib + thalidomide + dexamethasone; HR, hazard ratio; ITT, intent-to-treat; PFS, progression-free survival; R-ISS, revised International Staging System;  VTd, bortezomib + thalidomide + dexamethasone.

PFS Analysis Based on the Cytogenetic Risk Status - mITT Population5
Cytogenetic Risk Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
DARZALEX standard riska
57.3
Not reached
0.58 (0.48-0.71)
<0.0001
Obs standard risk
39.8
49
DARZALEX high riska
54.2
Not reached
0.39 (0.25-0.63)
<0.0001
Obs high risk
19.6
27.2
DARZALEX standard riska
57.3
Not reached
0.83 (0.55-1.25)
0.3696
DARZALEX high riska
54.2
Not reached
Abbreviations: CI, confidence interval; HR, hazard ratio; mITT, maintenance intent-to-treat; Obs, observation; PFS, progression-free survival.
aDARZALEX standard risk vs DARZALEX high risk: HR, 0.83; P=0.3696.

PFS Analysis Based on the R-ISS Stage - mITT Population6
R-ISS Stage
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
DARZALEX R-ISS I
58.4
Not reached
0.55 (0.37-0.82)
0.0032
Obs R-ISS I
41.9
49.1
DARZALEX R-ISS II
57.9
Not reached
0.52 (0.41-0.65)
<0.0001
Obs R-ISS II
35.4
45.2
DARZALEX R-ISS III
50.0
Not reached
0.54 (0.30-0.97)
0.0359
Obs R-ISS III
24.1
33.1
Abbreviations: CI, confidence interval; HR, hazard ratio; mITT, maintenance intent-to-treat; Obs, observation; PFS, progression-free survival; R-ISS, revised International Staging System.

DARZALEX in Combination with Bortezomib, Lenalidomide, and Dexamethasone

GRIFFIN (MMY2004; NCT02874742) is an open-label, multicenter, 2-Part, randomized, active-controlled, phase 2 United States study evaluating the safety and efficacy of D-VRd in patients with NDMM eligible for HDT and ASCT.7-9

Study Design/Methods

  • Of note, the data presented utilized the abbreviation “RVd”, which has been replaced with “VRd” in the summary below to remain consistent throughout this scientific response.
  • 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 NGS), CR, ORR, ≥VGPR

Part 1: Safety Run-in Phase Final Analysis

Voorhees et al (2021)10 reported the final analysis of the safety run-in cohort of the GRIFFIN study.

Results

Baseline Characteristics
  • Demographics and baseline characteristics are presented in table: Baseline Characteristics (GRIFFIN Part 1).
  • Median follow-up was 40.8 months (range, 20.6-43.0) after patients completed D-VRd treatment and 24 months of D-R maintenance therapy.
  • 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 PD (n=1) or AE (n=1; neuralgia or thrombocytopenia) during maintenance therapy.
  • Stem cell collection and neutrophil and platelet engraftment are present in table: Stem Cell Collection and Transplantation (GRIFFIN Part 1).

Baseline Characteristics (GRIFFIN Part 1)10
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 multiple myeloma, months
1.6 (0-5)
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System.
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.

Stem Cell Collection and Transplantation (GRIFFIN Part 1)10
D-VRd
(n=16)
CD34+ yield, median (range) (x 106 cells/kg)
8.05 (3.5-17.6)
CD34+ cells transplanted, median (range) (x 106 cells/kg)
4.72 (2.2-6.0)
Patients receiving plerixafor for mobilization, n (%)
9 (56.3)
Patients receiving cyclophosphamide, n (%)
0
Days to neutrophil (0.5 x 109/L) engraftmenta median (maximum)
14
Days to platelet (20 x 109/L) engraftmentb median (maximum)
13.5
Abbreviation: CD, cluster of differentiation; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone.
aFor neutrophil engraftment, there were 15 evaluable patients.bFor platelet engraftment, there were 16 evaluable patients.
Safety
  • During cycle 1, 3/16 patients developed 4 dose-limiting toxicities (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 (87.5%) patients experienced any grade infections, and 5 (31.3%) patients experienced grade 3/4 infections.
    • During the maintenance phase 31.3% (n=5) of patients 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% (n=5) of patients.
    • IRRs included pruritus, chills, flushing, maculo-papular rash, and vascular access site swelling; all occurred during cycle 1 except vascular access site swelling.
  • A SAE occurred in 11 (68.6%) patients.
  • Eleven patients (68%) experienced a SAE. For the incidences of Grade 3/4 TEAEs, please see Table: Most Common Grade 3/4 TEAEs (GRIFFIN Part 1).

Most Common Grade 3/4 TEAEs (GRIFFIN Part 1)10
Patients, 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 duration of response was NE.
  • Median time to ≥CR was 7.36 months (range, 2.8-18.5), and median duration of ≥CR was NE.
  • 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 vs 10-6 sensitivity threshold:
    • 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 was sustained for ≥12 months in 8 (50.0%) patients.
  • Response rates are presented in Table: Updated Response Rates Over Time for the Safety Run-in Cohort (GRIFFIN Part 1).

Updated Response Rates Over Time for the Safety Run-in Cohort (GRIFFIN Part 1)a,10
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 or better; CR, complete response; 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.

Part 2: Randomized Phase

Voorhees et al (2020)7,8,24 presented the primary analysis and updated analysis of the randomized portion of this study. Kaufman et al (2020)25 presented a 1-year update of safety and efficacy results at the 62nd American Society of Hematology Annual Meeting & Exposition in December 2020. Laubach et al (2021)26 presented updated efficacy and safety results after 2 years of maintenance therapy in the GRIFFIN Study. Voorhees et al (2023)11 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

Baseline Characteristics
  • A total of 207 patients were randomized (D-VRd, n=104; VRd, n=103).
  • The median follow-up was 13.5 months in the primary analysis and 22.1 months in the updated analysis.
  • Ninety percent of patients in the D-VRd group underwent ASCT compared to 76% in the VRd group (ASCT rate lower due to early discontinuations).

Patient Demographics in the Randomized Phase (ITT; GRIFFIN Part 2)7
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 creatinine clearance, 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: 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 (22.1-Month Follow-Up)
  • Primary endpoint 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 D-VRd vs VRd group (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 group was 19.2%, 27.3%, 51.5%, and 79.8%, respectively, vs 13.4%, 19.6%, 42.3%, and 60.8% in the VRd group.
  • In the ITT population, 51% of patients in the D-VRd group achieved post-ASCT MRD-negativity vs 20.4% of patients in the VRd group, regardless of response (OR, 4.07; 95% CI, 2.18-7.59; P<0.0001). Additional MRD results are in Table: Post-Consolidation MRD-Negativity (GRIFFIN Part 2).
  • Median stem cell yield (D-VRd vs VRd): 8.2 vs 9.4 x 106 cells.

Post-Consolidation MRD-Negativity (GRIFFIN Part 2)7
MRD-Negative Status (10-5),a n(%); ITT
D-VRd (n=104)
VRd (n=103)
Odds Ratio (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; 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 next-generation sequencing in accordance with International Myeloma Working Group criteria. MRD assessments occurred in patients who had both baseline (with clone identified/calibrated) and post-baseline 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 odds ratio 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 odds ratio >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 NR in the D-VRd and VRd groups. In the D-VRd vs VRd groups (Kaplan-Meier estimates):
    • 12-month PFS rates were 96.9% vs 95.3%.
    • 24-month PFS rates were 95.8% vs 89.8%.
    • 12-month OS rates were 99.0% vs 97.9%.
    • 24-month OS rates were 95.8% vs 93.4%.
  • DARZALEX did not impact time to engraftment and hematopoietic reconstitution. See Table: Stem Cell Collection and Transplantation (GRIFFIN Part 2).

Stem Cell Collection and Transplantation (GRIFFIN Part 2)24
D-VRd
VRd
Median (range) stem cell yield, x 106 CD34+ cells/kga, b
8.2 (3-33)
9.4 (4-29)
Median stem cells transplanted, x 106 CD34+ cells/kgc
4.2
4.8
Patients receiving plerixafor for mobilization, n(%)d
66 (70)
45 (56)
Patients receiving cyclophosphamide, n (%)d
5 (5)
4 (5)
Median (max) days to neutrophil engraftment (0.5 x 109/L)
12 (31)
12 (23)
Median (max) days to platelet engraftment (20 x 109/L)
13 (31)
12 (23)
Abbreviations: CD, cluster of differentiation; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; G-CSF, granulocyte colony-stimulating factor; max, maximum; VRd, bortezomib + lenalidomide + dexamethasone.aAmong patients who underwent peripheral blood stem cell apheresis (D-VRd, n=93; VRd, n=80).
bOne patient in the D-VRd group had a stem cell yield <3 x 106 cells/kg; no patients in either group had a stem cell yield <2 x 106 cells/kg.
cAmong patients receiving transplant (D-VRd, n=94; VRd, n=78).
dAmong patients who underwent mobilization (D-VRd, n=95; VRd, n=80). Patients underwent stem cell mobilization with G-CSF with or without plerixafor, according to institutional standards; if unsuccessful, cyclophosphamide-based mobilization was permitted.
Safety
  • In the updated safety and efficacy analysis, any grade infections occurred in 91% of patients in the D-VRd group vs 62% of patients in the VRd group, 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 group vs 22% of patients in the VRd group.7,24 See Table: Most Common TEAEs (GRIFFIN Part 2).
    • Pneumonia was reported in 13% of patients in the D-VRd group vs 15% of patients in the VRd group.

Most Common TEAEs (GRIFFIN Part 2)a,7,24
Event, 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)
Infusion-related reactions
42 (42.4)
6 (6)c
-
-
Abbreviations: D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone.
aAny grade TEAEs are listed that occurred in ≥30% of patients in either group. 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 infusion-related reactions were reported.

Final Efficacy and Safety Analysis of Maintenance Therapy

Voorhees et al (2023)11 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 duration of follow-up was 49.6 months (IQR, 47.4-52.1).
  • By the final analysis, 25% of patients in the D-VRd group and 51% in the VRd group discontinued treatment. See Table: Patient Disposition.
  • The median duration of treatment in the D-VRd and VRd groups was 32.5 months (IQR, 31.1-33.4) and 27.5 months (IQR, 2.9-32.7), respectively.
    • In the D-VRd group, 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 Disposition11
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) group, 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.11,27

Summary of Response Over Time11
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: ≥CR, complete response or better; ASCT, autologous stem cell transplant; CR, complete response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; IQR, interquartile range; NE, not estimable; 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 Group11
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: ≥CR, complete response or better; ≥VGPR, very good partial response or better; CI, confidence interval; DOR, duration of response; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; NR, not reached; ORR, overall response rate; sCR, stringent complete response; VRd, bortezomib + lenalidomide + dexamethasone.

Final Analysis of Best Response and MRD-Negativity Rates at the End of Maintenance11,27
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: ≥CR, complete response or better; ≥VGPR, very good partial response or better; CI, confidence interval; CR, complete response; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; MM, multiple myeloma; MRD, minimal residual disease; 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 groups, 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 group. See Table: Summary of MRD-Negativity Rates Over Time (ITT Population).

Summary of MRD-Negativity Rates Over Time (ITT Population)a,11,27
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; 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 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 group 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 group 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)11,27
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, intent-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) groups, grade 3/4 TEAEs occurred in 86% (n=85) vs 79% (n=81), respectively.
  • In the D-VRd vs VRd group, 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 groups (D-VRd, 33% [n=33]; VRd, 31% [n=32]). One patient in each group died due to TEAEs unrelated to study treatment.
  • Any-grade infections were more common in the D-VRd vs VRd group (93% [n=92] vs 66% [n=67]). Similar incidence rates were reported across treatment groups 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 group, 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 group, COVID-19 infections were reported in 5% (n=5) vs 2% (n=2) of patients, respectively. Of these, 1 patient in each group had a grade 3 COVID-19-related event (including 1 serious event in the D-VRd group).
  • TEAEs occurring in the safety population are summarized in Table: Most Common TEAEs in the Safety Population.
  • During maintenance therapy, second primary malignancies with first onset after the start of maintenance therapy were reported in 4 of 89 (4%) evaluable patients in the D-VRd group and 3 of 71 (4%) evaluable patients in the VRd group.
  • 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 [39%] IRRs reported at the initial infusion, 2 [2%] IRRs at the second infusion, and 14 [14%] IRRs at the subsequent infusions.27

Most Common TEAEs in the Safety Populationa,11,27
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 group (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 group.

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 11 June 2025.

 

References

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20 Bertamini L, Fokkema C, Rodriguez-Otero P, et al. Circulating tumor cells as a biomarker to identify high-risk transplant-eligible myeloma patients treated with bortezomib, lenalidomide, and dexamethasone with or without daratumumab during induction/consolidation, and lenalidomide with or without daratumumab during maintenance: results from the PERSEUS study. Oral Presentation presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
21 Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant, measurable residual disease (MRD)-based, response-adapted Dara-KRd consolidation in patients with newly diagnosed multiple myeloma (NDMM). Oral Presentation presented at: 61st Annual Meeting of the American Society of Hematology (ASH); Dec 7-10, 2019; Orlando, FL.  
22 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.  
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24 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.  
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