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DARZALEX®

(daratumumab)

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DARZALEX® (daratumumab)

Medical Information

DARZALEX – Use in High-Risk Multiple Myeloma in Clinical Trials

Last Updated: 02/09/2026

SUMMARY

  • Johnson & Johnson does not recommend the use of DARZALEX in a manner that is inconsistent with the approved labeling.
  • This response includes information on high-risk subgroups from studies that include patients with newly diagnosed multiple myeloma (NDMM) and relapsed/refractory multiple myeloma (RRMM).

Newly Diagnosed Multiple Myeloma

  • MAIA is a phase 3 study that evaluated the safety and efficacy of DARZALEX + lenalidomide and dexamethasone (D-Rd) compared to lenalidomide and dexamethasone (Rd) alone in transplant-ineligible NDMM patients.1
    • Kumar et al (2022)2 presented updated efficacy and safety results (median follow-up, 64.5 months), including updated overall survival (OS) results (median follow-up, 73.6 months) from MAIA. Among patients with a high-risk cytogenetic profile, median OS was 55.6 months vs 42.5 months in the D-Rd vs Rd arm, respectively (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.39-1.06). Grade 3/4 treatment-emergent adverse events (TEAEs) occurring in ≥20% of patients in the D-Rd vs Rd arm were neutropenia (54.1% vs 37%) and anemia (17% vs 21.6%).
    • Moreau et al (2025)3 reported the efficacy and safety results in clinically important subgroups of patients from the MAIA study, including International Staging System (ISS) stage III disease and cytogenetic risk. Median PFS was improved with D-Rd versus Rd across ISS stage III disease (42.4 vs 24.2 months; HR, 0.61; 95% CI, 0.43–0.86; P=0.0046) and high cytogenetic risk (45.3 vs 29.6 months; HR, 0.57; 95% CI, 0.34–0.96; P=0.0315). The most common (≥20%) grade 3/4 TEAEs among patients 75 years and older were neutropenia (D-Rd, 62.4%; Rd, 41.5%), lymphopenia (21.0%; 12.6%), anemia (20.4%; 25.2%), and pneumonia (20.4%; 14.5%).
  • ALCYONE is a phase 3 study which assessed the safety and efficacy of bortezomib, melphalan, and prednisone (VMP) alone and DARZALEX + VMP (D-VMP) in patients with NDMM who were ineligible for high-dose therapy (HDT) with autologous stem cell transplant (ASCT).4
    • Mateos et al (2025)5 reported the final efficacy and safety analysis results of the ALCYONE study at a median follow-up of 86.7 months. In the prespecified subgroup analysis of OS, there was a non-significant trend in favor of D-VMP vs VMP in subgroups with poor prognosis (ISS stage III disease, ≥75 years old, or renal impairment). The most common grade 3/4 TEAEs were neutropenia (D-VMP, 40%; VMP, 39%), thrombocytopenia (35%; 38%), and anemia (18%; 20%).
  • CASSIOPEIA is a 2-part, phase 3 study evaluating the safety and efficacy of DARZALEX + bortezomib, thalidomide, and dexamethasone (D-VTd) in transplant eligible patients with NDMM.6
    • Corre et al (2025)7 reported results on the long-term minimal residual disease (MRD) status and progression-free survival (PFS) outcomes analysis based on cytogenetic risk status and ISS stage disease from the CASSIOPEIA study.
  • GRIFFIN is a phase 2, 2-part study evaluating the safety and efficacy of DARZALEX when administered in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) in patients with NDMM eligible for HDT and ASCT.8
    • Chari et al (2024)9 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study, including ISS stage III disease and cytogenetic risk. MRD-negativity (10-5) rates in the ISS stage III subgroup were 71.4% versus 35.7% for D-VRd and VRd, respectively (odds ratio [OR], 4.50; 95% CI, 0.91-22.15). MRD-negativity (10-5) rates in the revised high cytogenetic risk subgroup were 54.8% versus 32.4% for D-VRd and VRd, respectively (OR, 2.52; 95% CI, 1.01-6.32).The most common (>20%) grade 3/4 TEAEs included neutropenia, (<65 years: D-VRd 50.0%, VRd 20.0%; ≥65 years: D-VRd 37.0%, VRd 29.6%), and lymphopenia (<65 years: D-VRd 22.2%, VRd 26.7%; ≥65 years: D-VRd 25.9%, VRd 11.1%).
  • MASTER evaluated the efficacy and safety of DARZALEX + carfilzomib + lenalidomide + dexamethasone (D-KRd) induction followed by autologous hematopoietic cell transplantation (AHCT) and MRD-adapted consolidation therapy in patients with NDMM.10
    • Costa et al (2023)10 reported the results from the final analysis of the MASTER study at a median follow-up of 42.2 months. The overall MRDnegative remission rate (next-generation sequencing [NGS]; <105 threshold) in MRD-evaluable patients at any point in treatment was 81%. The 3-year PFS rate was 88% for patients with standard-risk (0 high-risk cytogenic abnormalities [HRCAs]), 79% for patients with high-risk (1 HRCA), and 50% for patients with ultra high-risk (≥2 HRCAs) cytogenetic abnormalities. The 3-year OS rate was 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. Additional details on PFS and OS for different study populations and at different timepoints according to MRD status are also reported.
  • Jakubowiak et al (2022)11 conducted a pooled analysis of patient-level data from the MAIA and ALCYONE studies, analyzing progression-free survival (PFS) and best response in transplant-ineligible patients with NDMM and HRCAs. The median PFS was 21.2 months in the pooled DARZALEX cohort vs 19.3 months in the pooled control cohort (adjusted hazard ratio [HR], 0.59; 95% confidence interval [CI], 0.41-0.85; P=0.0046), representing a 41% reduction in risk of disease progression or death. Complete response (CR) or better (≥CR) was achieved in 41.6% (n=42) of patients in the pooled DARZALEX cohort vs 22.5% (n=20) of patients in the pooled control cohort (adjusted odds ratio [OR], 2.63; 95% CI, 1.34-5.16; P=0.0051).

Relapsed/Refractory Multiple Myeloma

  • CASTOR is a phase 3 study assessing the safety and efficacy of bortezomib and dexamethasone (Vd) alone and DARZALEX + Vd (D-Vd) in patients with RRMM.12
    • Sonneveld et al (2022)13 reported updated efficacy and safety results from CASTOR at a median follow-up of 72.6 months. Among patients in the high-risk cytogenetics prespecified subgroup, median OS was 38.4 months in the D-Vd arm and 28.8 months in the Vd arm (HR, 0.77; 95% CI, 0.41-1.46). The most common (≥10%) grade 3/4 TEAEs in the D-Vd vs Vd arm were thrombocytopenia (46.1% vs 32.9%), anemia (16% in both arms), neutropenia (13.6% vs 4.6%), lymphopenia (10.3% vs 2.5%), and pneumonia (10.7% vs 10.1%).
  • POLLUX is a phase 3 study assessing the safety and efficacy of D-Rd vs Rd in patients with RRMM.14
    • Dimopoulos et al (2022)15 presented updated efficacy and safety results from POLLUX at a median follow-up of 79.7 months. Among patients in the high-risk cytogenetic prespecified subgroup, median OS was 40.4 months in the D-Rd arm and 23.6 months in the Rd arm (HR, 0.70; 95% CI, 0.41-1.20). The most common (>10%) grade 3/4 TEAEs in the D-Rd vs Rd arm were neutropenia (57.6% vs 41.6%), anemia (19.8% vs 22.4%), pneumonia (17.3% vs 11%), thrombocytopenia (15.5% vs 15.7%), and diarrhea (10.2% vs 3.9%).
  • CANDOR is a phase 3 study evaluating the safety and efficacy of DARZALEX in combination with carfilzomib and dexamethasone (D-Kd) vs carfilzomib and dexamethasone (Kd) in patients with RRMM.16
    • Usmani et al (2023)17  reported the final efficacy and safety results of the CANDOR study after a median follow-up of approximately 50 months. Among patients in the high-risk cytogenetic prespecified subgroup, median OS was 34.3 months in the D-Kd arm and 17.1 months in the Kd arm (HR, 0.52; 95% CI, 0.29-0.94). The most common (≥15%) grade ≥3 TEAEs were thrombocytopenia (D-Kd, 24.7%; Kd, 16.3%), hypertension (D-Kd, 23.4%; Kd, 17.6%), pneumonia (D-Kd, 18.5%; Kd, 9.2%), and anemia (D-Kd, 17.5%; Kd, 16.3%).
  • Other relevant literature has been identified in addition to the data summarized above.18-22 

CLINICAL studies – newly Diagnosed Multiple Myeloma

DARZALEX in Combination with Lenalidomide and Dexamethasone

MAIA (MMY3008; NCT02252172) is an international, phase 3, randomized, open-label, active-controlled, multicenter study that evaluated the efficacy and safety of combination of D-Rd vs Rd in patients with NDMM not eligible for high-dose chemotherapy and ASCT (N=737).1

Study Design/Methods

  • Primary endpoint: PFS1
  • Secondary endpoints: complete response or better (≥CR) rate, very good partial response or better (≥VGPR) rate, duration of response (DOR), MRD-negativity rate    (10-5) via NGS, overall response rate (ORR), OS, PFS on subsequent line of therapy (PFS2), stringent complete response (sCR), time to next (2nd-line) treatment, time to response (TTR), time to progression (TTP), and safety.1

Updated Efficacy and Safety Analysis of the MAIA Study

Kumar et al (2022)2 presented the results of the updated efficacy and safety analysis (median follow-up, 64.5 months), including updated OS results (median follow-up, 73.6 months), of the MAIA study.

Study Design/Methods

  • Efficacy was assessed in the subgroup of patients with a high-risk cytogenic profile (defined by del17p, t[14;16], or t[4;14] abnormality [or a combination of these] on fluorescence in situ hybridization (FISH) or karyotype analysis).2 

Results

Efficacy
  • At a median follow-up of 73.6 months, the median OS in the D-Rd vs Rd arm was not reached (NR) vs 64.1 months (HR, 0.65; 95% CI, 0.52-0.80; P<0.0001).2 
    • The 60-month OS rate in the D-Rd vs Rd arm was 66.7% vs 53.7%. Among patients with high-risk cytogenetic profile, median OS was 55.6 months vs 42.5 months in the D-Rd vs Rd arm, respectively (HR, 0.65; 95% CI, 0.39-1.06). See Table: OS in ISS Staging and Cytogenetic Risk Subgroups (MAIA).

OS in ISS Staging and Cytogenetic Risk Subgroups (MAIA)2
Subgroup
D-Rda
Rda
HR (95% CI)a,b
n/N
Median OS, Months
n/N
Median OS, Months
ISS disease stage
   I
28/98
NE
36/103
NE
0.78 (0.48-1.28)
   II
64/163
NE
88/156
61.7
0.59 (0.43-0.81)
   III
58/107
65.2
78/110
47.3
0.66 (0.47-0.93)
Cytogenetic risk at study entry
   High riskc
28/48
55.6
36/44
42.5
0.65 (0.39-1.06)
   Standard risk
105/271
NE
147/279
65.5
0.64 (0.50-0.82)
Abbreviations: CI, confidence interval; D-Rd, daratumumab + lenalidomide + dexamethasone; HR, hazard ratio; ISS, International Staging System; NE, not estimable; OS, overall survival; Rd, lenalidomide + dexamethasone.
aData are based on a median follow-up of 73.6 months.
bHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR <1 indicates an advantage for D-Rd.
cPatients with high cytogenetic risk were positive by fluorescence in situ hybridization or karyotype testing for ≥1 of the following cytogenetic abnormalities: t(4;14), t(14;16), or del(17p).
Safety
  • No new safety concerns were reported with the longer follow-up.2
  • Grade 3/4 TEAEs occurring in ≥20% of patients in the D-Rd vs Rd arm were neutropenia (54.1% vs 37%) and anemia (17% vs 21.6%).2
  • The most common serious TEAE in both arms was pneumonia (D-Rd, 18.7%; Rd, 10.7%).2
  • The rate of treatment discontinuation due TEAEs in the D-Rd vs Rd arm was 14.6% vs 23.8%.2

Analysis of Clinically Important Subgroups from the MAIA Study

Moreau et al (2025)3 presented the efficacy and safety results in clinically important subgroups of patients from the MAIA study at a median follow-up of 64.5 months.

Study Design/Methods

  • Efficacy outcomes (PFS, ORR, and MRD-negativity) were analyzed in ISS stage III and cytogenetic risk based on the following patient characteristics3:
    • ISS stage III disease
    • Revised ISS stage III disease
    • Cytogenetic risk
      • Presence of HRCAs (t[4;14], t[14;16], and/or del[17p]) or a high serum lactate dehydrogenase level
      • Standard cytogenetic risk (0 of the following HRCAs: t[4;14], t[14;16], and del[17p])
      • High cytogenetic risk (≥1 of the following HRCAs: t[4;14], t[14;16], and del[17p])
      • Revised standard cytogenetic risk (0 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], and amp[1q21])
      • Revised high cytogenetic risk (≥1 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], and amp[1q21])
      • Gain(1q21) (3 copies of chromosome 1q21, with or without other HRCAs)
      • Amp(1q21) (≥4 copies of chromosome 1q21, with or without other HRCAs)
      • Gain(1q21) or amp(1q21) (3 or ≥4 copies of chromosome 1q21, with or without other HRCAs)
      • 1 HRCA (only 1 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], or amp[1q21])
      • Two or more HRCAs (≥2 of the following HRCAs: t[4;14], t[14;16], del[17p], t[14;20], gain[1q21], and amp[1q21])
      • Isolated gain(1q21) (3 copies of chromosome 1q21, without any other HRCAs)
      • Isolated amp(1q21) (≥4 copies of chromosome 1q21, without any other HRCAs)
      • Isolated gain(1q21) or amp(1q21) (3 or ≥4 copies of chromosome 1q21, without any other HRCAs)
      • Gain(1q21) or amp(1q21) plus ≥1 HRCA (3 or ≥4 copies of chromosome 1q21, plus ≥1 of the following HRCAs: t[4;14], t[14;16], del[17p], and t[14;20])

Results

Efficacy
  • Overall, 737 patients (D-Rd, 368; Rd, 369) were included in the intention-to-treat (ITT) population.3 
  • The PFS duration was longer in the D-Rd vs Rd arm in the patient subgroup of ISS stage III and cytogenetic risk. See Table: PFS in the ISS Stage III and Cytogenetic Risk Subgroups (ITT Population; MAIA).3
    • PFS was improved in the D-Rd vs Rd arm among patients with the following characteristics:
      • Revised standard cytogenetic risk (HR, 0.50; 95% CI, 0.37-0.66; P<0.0001)
      • 1 HRCA (HR, 0.55; 95% CI, 0.40-0.76; P=0.0003)
      • Isolated gain(1q21) (HR, 0.36; 95% CI, 0.19-0.67; P=0.0008)
      • Isolated amp(1q21) (HR, 0.78; 95% CI, 0.50-1.22; P=0.2764)
    • PFS was similar in the D-Rd and Rd arms among patients with ≥2 HRCAs (HR, 0.92 95% CI, 0.40-2.10; P=0.8477).

PFS in the ISS Stage III and Cytogenetic Risk Subgroups (ITT Population; MAIA)3 
Subgroup
D-Rd
Rd
HR (95% CI)a
n/N
Median PFS, Months
n/N
Median PFS, Months
ITT (overall)
176/368
61.9
228/369
34.4
0.55 (0.45-0.67)
Disease-related characteristics
   ISS stage III
61/107
42.4
73/110
24.2
0.61 (0.43-0.86)
   Revised ISS stage III
26/43
40.0
29/40
17.9
0.56 (0.33-0.97)
Cytogenetic risk
      Standard cytogenetic risk
126/271
63.8
174/279
34.4
0.51 (0.41-0.64)
      High cytogenetic risk
28/48
45.3
31/44
29.6
0.57 (0.34-0.96)
      Revised standard cytogenetic risk
78/176
NR
115/187
35.1
0.50 (0.37-0.66)
      Revised high cytogenetic risk
82/156
56
96/152
30.7
0.59 (0.44-0.80)
      Gain(1q21)
20/53
NR
28/44
37.8
0.43 (0.24-0.76)
      Amp(1q21)
48/74
40
45/76
26.1
0.81 (0.54-1.21)
      Gain(1q21) or amp(1q21)
68/127
53.2
73/120
32.3
0.63 (0.46-0.88)
      1 HRCA
68/137
61.4
86/137
31.2
0.55 (0.40-0.76)
      ≥2 HRCAs
14/19
24.9
10/15
24
0.92 (0.40-2.10)
      Isolated gain(1q21)
16/47
NR
27/42
37.8
0.36 (0.19-0.67)
      Isolated amp(1q21)
38/61
42.8
38/65
28.9
0.78 (0.50-1.22)
      Isolated gain(1q21) or amp(1q21)
54/108
61.4
65/107
37.1
0.58 (0.40-0.83)
      Gain(1q21) or amp(1q21) plus
      ≥1 HRCA
14/19
24.9
8/13
24
1.03 (0.42-2.48)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; NR, not reached; PFS, progression-free survival; Rd, lenalidomide + dexamethasone.
aHR <1 indicates an advantage for D-Rd.

ORR in the ISS Stage III and Cytogenetic Risk Subgroups (ITT Population; MAIA)3 
Subgroup
D-Rd
n/N (%)
Rd
n/N (%)
OR (95% CI)a
ITT (overall)
342/368 (92.9)
301/369 (81.6)
2.97 (1.84-4.79)
Disease-related characteristics
   ISS stage III
93/107 (86.9)
86/110 (78.2)
1.85 (0.90-3.81)
   Revised ISS stage III
36/43 (83.7)
28/40 (70.0)
2.20 (0.77-6.33)
Cytogenetic risk
      Standard cytogenetic risk
253/271 (93.4)
228/279 (81.7)
3.14 (1.78-5.54)
      High cytogenetic risk
44/48 (91.7)
33/44 (75)
3.67 (1.07-12.55)
      Revised standard cytogenetic risk
162/176 (92)
149/187 (79.7)
2.95 (1.54-5.66)
      Revised high cytogenetic risk
147/156 (94.2)
126/152 (82.9)
3.37 (1.52-7.46)
      Gain(1q21)
51/53 (96.2)
39/44 (88.6)
3.27 (0.60-17.75)
      Amp(1q21)
70/74 (94.6)
63/76 (82.9)
3.61 (1.12-11.65)
      Gain(1q21) or amp(1q21)
121/127 (95.3)
102/120 (85)
3.56 (1.36-9.30)
      1 HRCA
129/137 (94.2)
114/137 (83.2)
3.25 (1.40-7.56)
      ≥2 HRCAs
18/19 (94.7)
12/15 (80)
4.50 (0.42-48.53)
      Isolated gain(1q21)
46/47 (97.9)
37/42 (88.1)
6.22 (0.70-55.56)
      Isolated amp(1q21)
57/61 (93.4)
55/65 (84.6)
2.59 (0.77-8.75)
      Isolated gain(1q21) or amp(1q21)
103/108 (95.4)
92/107 (86)
3.36 (1.17-9.60)
      Gain(1q21) or amp(1q21) plus ≥1 HRCA
18/19 (94.7)
10/13 (76.9)
5.40 (0.49-59.02)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; OR, odds ratio; ORR, overall response rate; Rd, lenalidomide + dexamethasone.
aOR >1 indicates an advantage for D-Rd.

MRD-Negativity (10-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups (ITT Population; MAIA)3 
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)
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)
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)
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.

Sustained MRD-Negativity Rates in the ISS Stage and Cytogenetic Risk Subgroups Lasting ≥12 months (ITT Population; MAIA)3 
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)
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)
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.
Safety (Patients Aged ≥75 Years)
  • Among patients aged ≥75 years, grade 3/4 TEAEs were reported in 95.5% vs 95% patients in the D-Rd vs Rd arm.
  • Serious TEAEs were reported in 80.9% vs 79.2% of patients in the D-Rd vs Rd arm, the most common of which was pneumonia (D-Rd, 19.7%; Rd, 12.6%).
  • TEAEs led to treatment discontinuation in 15.3% vs 27.7% of patients in the D-Rd vs Rd arm.
  • TEAEs resulting in death were reported in 11.5% vs 13.2% of patients in the D-Rd vs Rd arm.

Most Common (≥10%) Grade 3/4 TEAEs Among Patients Aged ≥75 Years in the Safety Population (MAIA)3 
Grade 3/4 TEAE, n (%)
D-Rd
(n=157)
Rd
(n=159)
Neutropenia
98 (62.4)
66 (41.5)
Lymphopenia
33 (21.0)
20 (12.6)
Anemia
32 (20.4)
40 (25.2)
Pneumonia
32 (20.4)
23 (14.5)
Leukopenia
19 (12.1)
12 (7.5)
Hypokalemia
18 (11.5)
17 (10.7)
Hypertension
17 (10.8)
8 (5.0)
Thrombocytopenia
16 (10.2)
19 (11.9)
Diarrhea
16 (10.2)
8 (5.0)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event.

DARZALEX in Combination with Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007; NCT02195479) was a phase 3, multicenter, randomized, open-label, active-controlled study that assessed the safety and efficacy of VMP alone and D-VMP in patients with NDMM who were ineligible for HDT with ASCT.4

Study Design/Methods

  • Primary endpoint: PFS4
  • Key secondary endpoints: time to disease progression, CR rate, sCR rate, ≥VGPR, TTR, ORR, DOR, MRD-negativity rate, OS, time to subsequent antimyeloma therapy, PFS on next line of therapy, pharmacokinetics, immunogenicity, efficacy in high-risk cytogenetic subgroups, safety, and patient-reported outcomes.4

Final Efficacy and Safety Analysis of ALCYONE

Mateos et al (2025)5 reported the final efficacy and safety results at a median follow-up of 86.7 months. Results in the high-risk cytogenetic subgroup are summarized below.

Study Design/Methods

  • Cytogenetic risk was evaluated locally at the time of study entry using fluorescence in-situ hybridization or karyotype testing. Patients were classified as high risk if they had one or more of the following abnormalities: del(17p), t(4;14), or t(14;16).5

Results

Patient Characteristics

Baseline Characteristics Based on ISS Stage Disease and Cytogenetic Risk (ITT Population; ALCYONE)a, 5,23
Characteristic
D-VMP
(n=350)
VMP
(n=356)
Total
(N=706)
ISS disease stageb, n (%)
   I
69 (20)
67 (19)
136 (19)
   II
139 (40)
160 (45)
299 (42)
   III
142 (41)
129 (36)
271 (38)
Cytogenetic risk profilec, n/N (%)
   Standard risk
261/314 (83)
257/302 (85)
518/616 (84)
   High risk
53/314 (17)
45/302 (15)
98/616 (16)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ISS, International Staging System; ITT, intention-to-treat; VMP, bortezomib + melphalan + prednisone.
aThe ITT population was defined as all patients who were randomized.
bThe ISS 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 or karyotype testing; high risk was defined as the presence of t(4;14), t(14;16), or del(17p).
Efficacy
  • The median follow-up was 86.7 months (interquartile range [IQR], 28.5-85.2).5
  • The median OS in the D-VMP vs VMP group was 83.0 months (95% CI, 72.5-not estimable) vs 53.6 months (95% CI, 46.3-60.9), respectively (HR, 0.65; 95% CI, 0.53-0.80; P<0.0001).5
    • In the prespecified subgroup analysis of OS, there was a non-significant trend in favor of D-VMP versus VMP in subgroups with poor prognosis (ISS stage III disease, ≥75 years old, or renal impairment). See Table: OS in Prespecified Subgroups (ITT Population; ALCYONE).5

OS in Prespecified Subgroups (ITT Population; ALCYONE)5 
Subgroup
D-VMP
VMP
HR (95% CI)
Events/patients
n/N
Median
(95% CI), Months
Events/patients
n/N
Median
(95% CI), Months
ISS disease stagea
   I
19/69
94.4 (94.4-NE)
27/67
NE (67.0-NE)
0.53 (0.29-0.95)
   II
68/139
83.0 (59.5-NE)
96/160
61.3 (50.7-78.1)
0.70 (0.51-0.96)
   III
85/142
63.6 (52.9-79.2)
94/129
42.3 (36.0-46.9)
0.60 (0.45-0.81)
Cytogenetic risk at study entryb
   High risk
35/53
46.2 (26.7-72.5)
31/45
39.5 (31.6-54.1)
0.91 (0.56-1.47)
   Standard risk
122/261
85.9 (78.7-NE)
156/257
55.1 (48.1-66.4)
0.59 (0.47-0.75)
Abbreviations: CI, confidence interval; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; HR, hazard ratio; ISS, International Staging System; ITT, intention-to-treat; NE, not estimable; OS, overall survival; VMP, bortezomib + melphalan + prednisone.
aThe ISS disease stage is derived based on the combination of serum β2-microglobulin and albumin concentrations.
bHigh-risk cytogenetics are defined either by fluorescence in situ hybridization testing: t(4;14), t(14;16), or del(17p); or by karyotype testing: t(4;14) or del(17p).
Safety
  • No new safety concerns were identified with a longer follow-up.5
  • TEAEs were experienced by 98% of patients in the D-VMP group and 97% of patients in the VMP group. The most common TEAEs are summarized in Table: Summary of the Most Common TEAE (ALCYONE).5
    • Grade 3 or 4 TEAEs occurred in 83% of patients receiving D-VMP and 77% of patients receiving VMP.5
    • The most common grade 3 or 4 infection in both treatment groups was pneumonia (D-VMP, 16%; VMP, 5%).5
    • Infusion-related reactions (IRRs) of any grade were reported in 29% of patients in the D-VMP group, including a grade 3 reaction in 4% and a grade 4 reaction in 1% of patients.5
      • In the D-VMP group, IRR of any grade and grade 4 and serious TEAEs were reported in <1% of patients.23
      • No IRR of any grade was reported in the VMP group.23
    • The D-VMP group experienced a higher rate of serious TEAEs compared with the VMP group (21% vs 16%). The most common serious TEAE observed in the D-VMP vs VMP group was pneumonia (5% vs 2%, respectively).5
  • The rate of treatment discontinuation due to TEAEs was 9% in both D-VMP and VMP groups. One patient discontinued treatment in the VMP group due to grade 5 pneumonia.5
  • The incidence of second primary malignancies in the D-VMP vs VMP group was 8% vs 6%, respectively.5
    • The most frequently reported second primary malignancies in the D-VMP vs VMP group were basal cell carcinoma (1.2% vs 0.6%, respectively) and myelodysplastic syndrome (1.2% vs 0.6%, respectively).5,23
  • Deaths due to an AE considered related to at least one of the four study treatment components occurred in 5 (1%) of 346 patients in the D-VMP group (due to pneumonia, acute myocardial infarction, neuroendocrine tumor, tumor lysis syndrome, and acute respiratory failure [one each]) and in 3 (1%) of 354 patients in the VMP group (due to acute myeloid leukemia, pulmonary embolism, and bacterial pneumonia [one each]).5

Summary of the Most Common TEAEs (ALCYONE)5
Event, n (%)
D-VMP
(n=346)
VMP
(n=354)
Any Gradea
Grade 1-2
Grade
3
Grade
4
Grade
5
Any Gradea
Grade
1-2
Grade
3
Grade
4
Grade
5
Any TEAEs
338
(98)
47
(14)
184
(53)
77
(22)
30
(9)
342
(97)
65
(18)
180
(51)
77
(22)
20
(6)
Hematological AE
   Neutropenia
175
(51)
35
(10)
107
(31)
33
(10)
0
186
(53)
48
(14)
103
(29)
35
(10)
0
   Thrombocytopenia
173
(50)
53
(15)
83
(24)
37
(11)
0
190
(54)
56
(16)
83
(23)
51
(14)
0
   Anemia
112
(32)
49
(14)
61
(18)
2
(1)
0
131
(37)
61
(17)
68
(19)
2
(1)
0
Non-hematological AE
   Peripheral sensory
   neuropathy
100
(29)
95
(27)
4
(1)
1
(<1)
0
122
(34)
108
(31)
14
(4)
0
0
   Diarrhea
101
(29)
92
(27)
9
(3)
0
0
87
(25)
76
(21)
11
(3)
0
0
   Pyrexia
89
(26)
87
(25)
2
(1)
0
0
74
(21)
72
(20)
2
(1)
0
0
   Nausea
76
(22)
73
(21)
3
(1)
0
0
76
(21)
72
(20)
4
(1)
0
0
   Back pain
73
(21)
65
(19)
8
(2)
0
0
42
(12)
38
(11)
4
(1)
0
0
   Cough
71
(21)
70
(20)
1
(<1)
0
0
27
(8)
26
(7)
1
(<1)
0
0
   Upper respiratory
   tract infection
107
(31)
99
(29)
7
(2)
0
1
(<1)
50
(14)
44
(12)
6
(2)
0
0
   Bronchitis
77
(22)
66
(19)
11
(3)
0
0
27
(8)
24
(7)
3
(1)
0
0
   Pneumonia
78
(23)
19
(5)
53
(15)
4
(1)
2
(1)
 19
(5)
3
(1)
15
(4)
1
(<1)
0
Abbreviations: AE, adverse event; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; TEAE, treatment-emergent adverse event; VMP, bortezomib + melphalan + prednisone.
Terms are coded using the Medical Dictionary for Regulatory Activities, version 23.0.
Percentages were calculated with the number of patients in each group as the denominator.
aPreferred terms for any grade of TEAEs with an occurrence of ≥20% are reported.

DARZALEX in Combination with Bortezomib, Thalidomide and Dexamethasone

CASSIOPEIA (MMY3006; NCT02541383) was an open-label, 2-arm, multicenter, phase 3 study evaluating the safety and efficacy of D-VTd in patients with NDMM who are eligible for high dose chemotherapy and ASCT.6

Study Design/Methods

  • Primary endpoint: Proportion of patients who achieved sCR after consolidation for the induction/consolidation phase; PFS from second randomization for the maintenance phase.6 
  • Secondary endpoints: Overall MRD-negativity for the induction/consolidation and maintenance phase; MRD conversion for the maintenance phase.6

Long Term MRD and PFS Analysis of CASSIOPEIA Study

Corre et al (2025)7 reported results on the long-term MRD status and PFS outcomes analysis based on cytogenetic risk status and ISS stage disease from the CASSIOPEIA study after a median follow-up of 80.1 months.

Results

Efficacy

MRD-Negativity Rates Based on the Cytogenetic Risk Status (ITT Population; CASSIOPEIA)24
MRD-Negativity Status
Standard Risk
P Value
High-Risk
P Value
D-VTd
(n=460)
VTd
(n=454)
D-VTd
(n=82)a
VTd
(n=86)a
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 (Part 1).

MRD-Negativity Rates Based on the Revised ISS Stage (ITT Population; CASSIOPEIA)24
MRD-Negativity Status
ISS I
P Value
ISS II
P Value
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.

MRD-Negativity Rates Based on the Cytogenetic Risk Status (mITT Population; CASSIOPEIA)24
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 DARZALEX group and 34 (49%) patients in the Obs group had a t(4;14) abnormality only, 21 (37%) patients in the DARZALEX group and 29 (41%) patients in the Obs group had a del(17p) abnormality only, and 2 (3%) patients in the DARZALEX 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/DARZALEX group, 14 (42%) patients in the D-VTd/Obs group, 15 (58%) patients in the VTd/DARZALEX 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 Population; CASSIOPEIA)24
MRD-Negativity Sensitivity
Threshold
ISS I
P Value
ISS II
P Value
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.

PFS Analysis Based on the Cytogenetic Risk Status (ITT Population; CASSIOPEIA)24
Cytogenetic Risk Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
D-VTd standard risk
57.0
87.3
0.60 (0.5-0.72)
<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 (ITT Population; CASSIOPEIA)24
R-ISS Stage
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
D-VTd R-ISS I
65.0
Not reached
0.49 (0.33-0.72)
0.0002
VTd R-ISS I
36.9
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 Population; CASSIOPEIA)7 
Cytogenetic Risk Status
72-Month
PFS Rate, %
Median, Months
HR (95% CI)
P Value
DARZALEX standard riska
57.0
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
57.0
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 Population; CASSIOPEIA)24
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
35.5
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) was a 2-part, phase 2, 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.8

Study Design/Methods

  • Primary endpoint: sCR (by end of post-ASCT consolidation)8
  • Secondary endpoints: MRD (10-5 via NGS), CR, ORR, ≥VGPR8

Final Analysis of Clinically Relevant Subgroups from the GRIFFIN Study

Chari et al (2024)9 reported the final efficacy and safety analysis results of clinically relevant subgroups from the GRIFFIN study, including ISS stage III disease and cytogenetic risk (median follow-up, 49.6 months).

Study Design/Methods

  • This final analysis was conducted after all patients completed ≥1 year of follow-up after concluding study treatment, died, or withdrew.9
  • Cytogenetic risk was assessed by FISH; high-risk was defined as the presence of del17p, t(4;14), or t(14;16).9

Results

Efficacy

sCR in the ISS Stage III and Cytogenetic Subgroups (GRIFFIN)25
Subgroup
D-VRd, n/N (%)
VRd, n/N (%)
OR (95% CI)a
Response evaluable (overall)b
67/100 (67%)
47/98 (48%)
2.18 (1.22-3.89)
Baseline characteristic
   ISS stage III disease
9/14 (64.3)
8/13 (61.5)
1.13 (0.24-5.37)
   Cytogenetic risk
      High cytogenetic riskc
8/16 (50)
5/13 (38.5)
1.60 (0.36-7.07)
      Revised high cytogenetic riskd
23/41 (56.1)
20/36 (55.6)
1.02 (0.42-2.52)
      0 HRCAd
43/55 (78.2)
26/58 (44.8)
4.41 (1.94-10.04)
      1 HRCAd
18/31 (58.1)
17/28 (60.7)
0.90 (0.32-2.54)
      ≥2 HRCAsd
5/10 (50)
3/8 (37.5)
1.67 (0.25-11.07)
      Gain/amp(1q21)e
19/33 (57.6)
16/28 (57.1)
1.02 (0.37-2.82)
      Gain/amp(1q21) + 1 HRCAd
5/9 (55.6)
2/6 (33.3)
2.50 (0.29-21.40)
      Gain/amp(1q21) isolatedf
14/24 (58.3)
14/22 (63.6)
0.80 (0.24-2.63)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; MM, multiple myeloma; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR >1 indicates an advantage for D-VRd.
bThis analysis included patients from the response evaluable population, which included all randomized patients who had measurable disease (confirmed MM diagnosis), received ≥1 dose of study treatment, and had ≥ postbaseline disease assessment.
cHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16).
dRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21).
ePatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]).
fPatients with isolated gain/amp(1q21) did not have any other HRCAs.

MRD-Negativity (10-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN)9
Subgroup
D-VRd
n/N (%)
VRd
n/N (%)
OR (95% CI)a
ITT (overall)
67/104 (64.4)
31/103 (30.1)
4.23 (2.35-7.62)
Baseline characteristic
   ISS stage III disease
10/14 (71.4)
5/14 (35.7)
4.50 (0.91-22.15)
   Cytogenetic risk
      High cytogenetic riskb
7/16 (43.8)
4/14 (28.6)
1.94 (0.42-8.92)
      Revised high cytogenetic riskc
23/42 (54.8)
12/37 (32.4)
2.52 (1.01-6.32)
      0 HRCAc
42/56 (75)
19/60 (31.7)
6.47 (2.87-14.60)
      1 HRCAc
17/32 (53.1)
11/29 (37.9)
1.85 (0.67-5.15)
      ≥2 HRCAsc
6/10 (60)
1/8 (12.5)
10.50 (0.91-121.39)
      Gain/amp(1q21)d
21/34 (61.8)
8/28 (28.6)
4.04 (1.38-11.81)
      Gain/amp(1q21) + 1 HRCAc
6/9 (66.7)
0/6
NE (NE-NE)
      Gain/amp(1q21) isolatede
15/25 (60)
8/22 (36.4)
2.62 (0.81-8.55)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR >1 indicates an advantage for D-VRd.
bHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16).
cRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21).
dPatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]).
ePatients with isolated gain/amp(1q21) did not have any other HRCAs.

MRD-negativity (10-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups with a Best Response of ≥CR (GRIFFIN)9
Subgroup
D-VRd, n/N (%)
VRd, n/N (%)
OR (95% CI)a
Patients with best response of ≥CRb
64/83 (77.1)
28/59 (47.5)
3.70 (1.77-7.72)
Baseline characteristic
   ISS stage III disease
10/13 (76.9)
4/8 (50)
3.33 (0.50-22.14)
   Cytogenetic risk
      High cytogenetic riskc
6/10 (60)
4/7 (57.1)
1.13 (0.16-7.99)
      Revised high cytogenetic riskd
21/30 (70)
12/23 (52.2)
2.14 (0.69-6.63)
      0 HRCAd
41/49 (83.7)
16/35 (45.7)
6.09 (2.22-16.68)
      1 HRCAd
16/24 (66.7)
11/20 (55)
1.64 (0.48-5.56)
      ≥2 HRCAsd
5/6 (83.3)
1/3 (33.3)
10 (0.40-250.42)
      Gain/amp(1q21)e
19/25 (76)
8/17 (47.1)
3.56 (0.95-13.37)
      Gain/amp(1q21) + 1 HRCAd
5/6 (83.3)
0/2
NE (NE-NE)
      Gain/amp(1q21) isolatedf
14/19 (73.7)
8/15 (53.3)
2.45 (0.58-10.33)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; MM, multiple myeloma; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR >1 indicates an advantage for D-VRd.
bThis analysis included patients from the response evaluable population, which included all randomized patients who had measurable disease (confirmed MM diagnosis), received ≥1 dose of study treatment, and had ≥ postbaseline disease assessmentcHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16).
dRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21).
ePatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]).
fPatients with isolated gain/amp(1q21) did not have any other HRCAs.

Rates of Sustained MRD-negativity (10-5) lasting ≥12 months in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN)9
Subgroup
D-VRd, n/N (%)
VRd, n/N (%)
OR (95% CI)a
ITT (overall)
46/104 (44.2)
14/103(13.6)
5 (2.50-9.99)
Baseline characteristic
   Age ≥65 years
14/28 (50)
3/28 (10.7)
8.33 (2.04 (34.07)
   ISS stage III disease
6/14 (42.9)
2/14 (14.3)
4.50 (0.72-28.15)
   Cytogenetic risk
      High cytogenetic riskb
3/16 (18.8)
2/14 (14.3)
1.38 (0.20-9.77)
      Revised high cytogenetic riskc
14/42 (33.3)
6/37 (16.2)
2.58 (0.87-7.64)
      0 HRCAc
31/56 (55.4)
8/60 (13.3)
8.06 (3.24-20.06)
      1 HRCAc
12/32 (37.5)
5/29 (17.2)
2.88 (0.87-9.56)
      ≥2 HRCAsc
2/10 (20)
1/8 (12.5)
1.75 (0.13-23.70)
      Gain/amp(1q21)d
13/34 (38.2)
4/28 (14.3)
3.71 (1.05-13.15)
      Gain/amp(1q21) + 1 HRCAc
2/9 (22.2)
0/6
NE (NE-NE)
      Gain/amp(1q21) isolatede
11/25 (44)
4/22 (18.2)
3.54 (0.93-13.51)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NE, not evaluable; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aMantel-Haenszel estimate of the common OR for unstratified tables is used. An OR >1 indicates an advantage for D-VRd.
bHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16).
cRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21).
dPatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]).
ePatients with isolated gain/amp(1q21) did not have any other HRCAs.
  • Among MRD-evaluable patients who achieved MRD-negativity (10-5) at any time, 2 (both with ≥2 HRCAs) patients in the D-VRd arm and 5 (0 HRCA, n=2; 1 HRCA, n=3) patients in the VRd arm developed PD.9
    • Two patients from the D-VRd arm and 3 patients from the VRd arm, who initially achieved MRD-negativity, developed progressive disease (PD) after they became MRD-positive again. The remaining 2 patients from the VRd arm developed PD while they continued to be MRD-negative; however, MRD was not evaluated around the time of PD.
  • At a median follow-up of 49.6 months, the HR point estimates for PFS among ISS stage III disease and cytogenetic risk subgroups favored the D-VRd vs VRd arm, except for patients with ≥2 HRCAs. See Table: PFS in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN).9
    • Median PFS was not reached for either treatment group among patients with 0 HRCA, and the PFS HR was 0.39 (95% CI, 0.10-1.51) for D-VRd vs VRd.
    • Median PFS was not reached for D-VRd and was 47.9 months for VRd among patients with 1 HRCA, and the PFS HR was 0.19 (95% CI, 0.05-0.75) for D-VRd vs VRd.
    • Median PFS was 33.9 months for D-VRd and was not reached for VRd among patients with ≥2 HRCAs, (HR, 1.65; 95% CI, 0.30-9.18).
    • PFS was not reached for D-VRd and was 47.9 months for VRd among patients with gain/amp(1q21), with or without HRCAs, and the PFS HR was 0.42 (95% CI, 0.14-1.27) for D-VRd vs VRd.

PFS in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN)9
Subgroup
D-VRd
VRd
HR (95% CI)a
n/N
Median PFS, Months
n/N
Median PFS, Months
ITT (overall)
11/104
NR
18/103
NR
0.45 (0.21-0.95)
Baseline characteristic
   ISS stage III disease
2/14
NR
6/14
33.1
0.23 (0.05-1.13)
   Cytogenetic risk
      High cytogenetic riskb
5/16
NR
5/14
36.1
0.54 (0.15-1.88)
      Revised high cytogenetic riskc
7/42
NR
10/37
47.9
0.38 (0.14-1.01)
      0 HRCAc
3/56
NR
7/60
NR
0.39 (0.10-1.51)
      1 HRCAc
3/32
NR
8/29
47.9
0.19 (0.05-0.75)
      ≥2 HRCAsc
4/10
33.9
2/8
NR
1.65 (0.30-9.18)
      Gain/amp(1q21)d
6/34
NR
7/28
47.9
0.42 (0.14-1.27)
      Gain/amp(1q21) + 1 HRCAc
4/9
33.9
2/6
38.7
0.81 (0.15-4.47)
      Gain/amp(1q21) isolatede
2/25
NR
5/22
47.9
0.21 (0.04-1.09)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VRd, DARZALEX + bortezomib + lenalidomide + dexamethasone; FISH, fluorescence in situ hybridization; HR, hazard ratio; HRCA, high-risk cytogenetic abnormality; ISS, International Staging System; ITT, intent-to-treat; MRD, minimal residual disease; NR, not reached; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone.
aHR and 95% CI are from a Cox proportional hazards model with treatment as the sole explanatory variable. A HR <1 indicates an advantage for D-VRd.
bHigh-risk cytogenetics are defined based on FISH testing as ≥1 of the following: del17p, t(4;14), or t(14;16).
cRevised high-risk cytogenetics are defined based on FISH testing as ≥1 HRCA: del17p, t(4;14), t(14;16), t(14;20), or gain/amp(1q21) (≥3 copies of chromosome 1q21).
dPatients in this group had gain/amp(1q21) with or without other HRCAs (del17p, t[4;14], t[14;16], or t[14;20]).
ePatients with isolated gain/amp(1q21) did not have any other HRCAs.
  • Within the functionally high-risk subgroup of patients with a best response of <VGPR by the end of induction, more D-VRd vs VRd patients had revised high cytogenetic risk and 1 HRCA at baseline, and similar proportions had ≥2 HRCAs.9
    • Revised high risk: 48.3% (n=14/29) vs 32.6% (n=14/43), D-VRd vs VRd respectively.
    • 1 HRCA: 37.9% (n=11/29) vs 23.3% (n=10/43), D-VRd vs VRd respectively.
    • ≥2 HRCAs: 10.3% (n=3/29) vs 9.3% (n=4/43), D-VRD vs VRd respectively.
  • Among patients who did not achieve MRD-negativity (10-5)by the end of consolidation, the proportion of patients with revised high cytogenetic risk, 1 HRCA, and ≥2 HRCAs was higher for D-VRd vs VRd at baseline.9
    • Revised high risk: 52.1% (n=25/48) vs 34.2% (n=26/76), D-VRd vs VRd respectively.
    • 1 HRCA: 39.6% (n=19/48) vs 25% (n=19/76), D-VRd vs VRd respectively.
    • ≥2 HRCAs: 12.5% (n=6/48) vs 9.2% (n=7/76), D-VRd vs VRd respectively.
Safety

Most Common (>30%)a Any Grade TEAEs by Age (<65 years and ≥65 years)9
Most common TEAEs, n (%)
<65 years
≥65 years
D-VRd
(n=72)
VRd
(n=75)
D-VRd
(n=27)
VRd
(n=27)
Hematologic
   Neutropenia
47 (65.3)
29 (38.7)
16 (59.3)
12 (44.4)
   Thrombocytopenia
 30 (41.7)
24 (32)
14 (51.9)
12 (44.4)
   Leukopenia
29 (40.3)
21 (28)
10 (37)
9 (33.3)
   Anemia
25 (34.7)
25 (33.3)
12 (44.4)
8 (29.6)
   Lymphopenia
23 (31.9)
23 (30.7)
8 (29.6)
6 (22.2)
Nonhematologic
   Upper respiratory tract infection
51 (70.8)
37 (49.3)
16 (59.3)
14 (51.9)
Diarrhea
48 (66.7)
39 (52)
18 (66.7)
17 (63)
Fatigue
48 (66.7)
45 (60)
23 (85.2)
18 (66.7)
Peripheral neuropathyb
41 (56.9)
56 (74.7)
21 (77.8)
22 (81.5)
Nausea
38 (52.8)
37 (49.3)
14 (51.9)
14 (51.9)
Constipation
37 (51.4)
29 (38.7)
14 (51.9)
13 (48.1)
Insomnia
36 (50)
25 (33.3)
9 (33.3)
6 (22.2)
Cough
35 (48.6)
26 (34.7)
18 (66.7
5 (18.5)
Pyrexia
34 (47.2)
27 (36)
14 (51.9)
6 (22.2)
Back pain
30 (41.7)
29 (38.7)
11 (40.7)
7 (25.9)
Arthralgia
27 (37.5)
26 (34.7)
12 (44.4)
12 (44.4)
Headache
27 (37.5)
18 (24)
6 (22.2)
6 (22.2)
Muscle spasms
26 (36.1)
11 (14.7)
4 (14.8)
9 (33.3)
Vomiting
25 (34.7)
21 (28)
7 (25.9)
8 (29.6)
Peripheral edema
24 (33.3)
25 (33.3)
12 (44.4)
12 (44.4)
Hypokalemia
19 (26.4)
20 (26.7)
9 (33.3)
7 (25.9)
Pain in extremity
19 (26.4)
13 (17.3)
3 (11.1)
9 (33.3)
Dyspnea
14 (19.4)
24 (32)
10 (37)
7 (25.9)
Dizziness
15 (20.8)
16 (21.3)
8 (29.6)
9 (33.3)
Pneumonia
14 (19.4)
16 (21.3)
10 (37)
2 (7.4)
Dysgeusia
14 (19.4)
14 (18.7)
9 (33.3)
5 (18.5)
Abbreviations: D-VRd, daratumumab + lenalidomide + bortezomib + dexamethasone; TEAE, treatment-emergent adverse event; VRd, lenalidomide + bortezomib + dexamethasone.aIncludes TEAEs occurring in ≥30% of patients aged <65 years or ≥65 years in either treatment group from the safety analysis population (all randomized patients who received ≥1 dose of study treatment).bIncludes preferred terms neuropathy peripheral and peripheral sensory neuropathy.
  • Among patients aged <65 years (84.7% vs 80%) and ≥65 years (88.9% vs 77.8%), the rates of grade 3/4 TEAEs were slightly higher for D-VRd vs VRd.9
  • The incidence of serious TEAEs was lower in D-VRd vs VRd among patients <65 years, 41.7% vs 56% respectively.9
  • The incidence of serious TEAEs was higher in the D-VRd vs VRd among patients ≥65 years, 59.3% vs 40.7% respectively.9
  • The discontinuation of ≥1 therapeutic agent due to TEAEs were comparable between patients aged <65 years (D-VRd, 31.9% vs VRd, 33.3%) and higher for D-VRd vs VRd in patients ≥65 years (D-VRd, 37% vs 25.9%).9
    • The most common TEAE leading to discontinuation of ≥1 drug was peripheral neuropathy for patients <65 years (D-VRd, 11.1% vs VRd, 13.3%) and ≥65 years (D-VRd, 18.5% vs VRd, 11.1%).
  • The incidence of TEAEs leading to lenalidomide dose reduction was higher for D-VRd vs VRd (<65 years: D-VRd, 33.3% vs VRd, 28%; ≥65 years: D-VRd, 59.3% vs VRd, 33.3%) among patients aged <65 and ≥65 years.9
    • The most common TEAE leading to lenalidomide dose reduction was neutropenia for patients <65 years (D-VRd, 15.3% vs VRd, 5.3%) and ≥65 years (D-VRD, 22.2% vs VRd, 14.8%).
  • Two deaths due to a TEAE occurred and were considered unrelated to study treatment.9
    • <65 years (VRd, n=1; cause unknown)
    • ≥65 years (D-VRd, n=1; pneumonia)

DARZALEX in Combination with Carfilzomib, Lenalidomide, and Dexamethasone

MASTER (NCT03224507) evaluated the efficacy and safety of D-KRd induction followed by AHCT and MRD-adapted consolidation therapy in patients with NDMM.10

Study Design/Methods

  • Primary endpoint: Rate of MRD-negative responses (<10-5) by NGS (clonoSEQ®)10
  • Secondary endpoints: Toxicity of D-KRd, rates and kinetics of MRD resurgence upon treatment discontinuation, PFS, and OS10
  • Exploratory endpoints: PFS and OS for patients who transitioned to MRD-surveillance (MRD-SURE) and were monitored off therapy10

Final Analysis of the MASTER Study

Costa et al (2023)10 reported the results from the final analysis of the MASTER study at a median follow-up of 42.2 months.

Results

Patient Characteristics
  • A total of 123 patients were enrolled, of whom 118 (96%) patients with MRD were evaluable. See Table: Patient Demographics and Baseline Characteristics (MASTER).
  • The median follow-up was 42.2 months (IQR, 34.5-46) overall (0 HRCA, 43.7 months [IQR, 36.3-47.4]; 1 HRCA, 42.1 months [IQR, 32.9-45.8]; ≥2 HRCAs, 35.4 months [IQR, 26.1-43.4]).
  • The median duration of therapy was 11.6 months (IQR, 8-14.8) overall and 11.2 months (IQR, 8.412.4) for those who entered MRD-SURE.

Patient Demographics and Baseline Characteristics (MASTER)10
Characteristic
0 HRCA
(n=53)
1 HRCA
(n=46)
≥2 HRCAs
(n=24)
Total
(N=123)
Sex, n (%)
   Men
33 (62)
24 (52)
13 (54)
70 (57)
   Women
20 (38)
22 (48)
11 (46)
53 (43)
Age, years
   Median (IQR)
60 (50-69)
61 (57-68)
60 (56-66)
61 (55-68)
   ≥70 years, n (%)
12 (23)
10 (22)
2 (8)
24 (20)
Racial/ethnicity, n (%)
   Non-Hispanic White
42 (79)
33 (72)
19 (79)
94 (76)
   Non-Hispanic Black
10 (19)
11 (24)
4 (17)
25 (20)
   Other
1 (2)
2 (4)
1 (4)
4 (3)
ECOG PS, n (%)
   0-1
42 (79)
40 (87)
17 (71)
99 (80)
   2
11 (21)
6 (13)
7 (29)
24 (20)
LDH concentration, n (%)
   <240 U/L
45 (85)
34 (74)
18 (75)
97 (79)
   ≥240 U/L
8 (15)
12 (26)
6 (25)
26 (21)
β₂ microglobulin concentration, n (%)
   <3.5 g/L
36 (67)
22 (48)
7 (29)
65 (53)
   ≥3.5 to <5.5 g/L
12 (23)
12 (26)
6 (25)
29 (24)
   ≥5.5 g/L
5 (9)
12 (26)
11 (46)
29 (24)
Albumin concentration, n (%)
   <3.5 g/dL
15 (28)
20 (44)
12 (50)
47 (38)
   ≥3.5 g/dL
38 (72)
26 (57)
12 (50)
66 (54)
Cytogenetic abnormality, n (%)
   Hyperdiploidy
27 (51)
20 (44)
4 (17)
51 (41)
   del(13q)
19 (36)
20 (44)
18 (75)
57 (46)
   Gain/amp 1q
0 (0)
24 (52)
20 (83)
44 (36)
   del(1p)
3 (6)
4 (9)
5 (21)
12 (10)
   t(11;14)
14 (26)
7 (15)
0 (0)
21 (17)
   t(4;14)
0 (0)
8 (17)
13 (54)
21 (17)
   t(14;16)
0 (0)
2 (4)
4 (17)
6 (5)
   del(17p)
0 (0)
12 (26)
14 (58)
26 (21)
ISS, n (%)
   I
28 (53)
15 (33)
5 (21)
48 (39)
   II
20 (38)
19 (41)
8 (33)
46 (37)
   III
5 (9.4)
12 (26)
11 (46)
29 (24)
R-ISS, n (%)
   I
25 (47)
11 (24)
0 (0)
35 (28)
   II
27 (51)
23 (50)
13 (54)
63 (51)
   III
1 (2)
12 (26)
11 (46)
25 (20)
Multiple myeloma clinical manifestation, n (%)
   Bone disease
43 (81)
29 (63)
18 (75)
90 (73)
   Renal failure
2 (4)
8 (17)
6 (25)
16 (13)
   Anemia
22 (42)
30 (65)
20 (83)
72 (59)
   Hypercalcemia
8 (15)
7 (15)
7 (29)
22 (18)
Ig isotype, n (%)
   IgG
27 (51)
26 (57)
14 (58)
67 (54)
   IgA
12 (23)
15 (33)
8 (33)
35 (28)
   Light chain
14 (26)
5 (11)
2 (8)
21 (17)
Therapy before enrollment,a n (%)
   Yes
26 (49)
25 (54)
10 (42)
61 (50)
   No
27 (51)
21 (46)
14 (58)
62 (50)
MRD trackable by NGS (clonoSEQ®), n (%)
   Yes
50 (94)
44 (96)
24 (100)
118 (96)
   No
3 (6)
2 (4)
0 (0)
5 (4)
Abbreviations: 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; ECOG PS, Eastern Cooperative Oncology Group performance status; Ig, immunoglobulin; IQR, interquartile range; ISS, International Staging System; LDH, lactate dehydrogenase; MRD, minimal residual disease; NGS, next-generation sequencing; R-ISS, Revised International Staging System. aOne cycle of bortezomib with or without cyclophosphamide and with or without dexamethasone was allowed according to the protocol.
Efficacy
  • A total of 96 patients (81%; 95% CI, 73-88) reached MRD <10-5 at any point during treatment. See Table: MRD-Negative Response Rates (MASTER).
  • Of the 118 MRD-evaluable patients, 84 (71%) entered protocol-directed observation and MRD-SURE, 24 (20%) proceeded to lenalidomide maintenance, and 10 (8%) discontinued treatment (died, n=3; discontinued due to disease progression, n=5; patient’s choice, n=2).

MRD-Negative Response Rates (MASTER)a,10
0 HRCA
(n=50)
1 HRCA
(n=44)
≥2 HRCAs
(n=24)
Total
(N=118)
Rate of NGS MRD <10-5 (primary endpoint)
   At any point in treatment, n (%)
39 (78)
38 (86)
19 (79)
96 (81)
      95% CI
64-88
73-95
58-93
73-88
Rate of NGS MRD <10-6 (post hoc exploratory endpoint)
   At any point in treatment, n (%)
34 (68)
35 (80)
15 (63)
84 (71)
      95% CI
53-80
65-90
41-81
62-79
CR + MRD <10-5, n (%)
38 (76)
33 (75)
14 (58)
85 (72)
   95% CI
62-87
60-87
37-78
63-80
MRD <10-5 at 2 consecutive assessments and transitioned to MRD-SURE, n (%)
33 (66)
36 (82)
15 (63)
84 (71)
   95% CI
51-66
67-92
41-81
62-79
Sustained MRD <105, n (%)
32 (64)
32 (73)
11 (46)
-
   95% CI
49-77
57-85
26-67
-
Abbreviations: 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; CI, confidence interval; CR, complete response; MRD, minimal residual disease; MRD-SURE, MRD-surveillance; NGS, next-generation sequencing.
aHRCA included gain/amp 1q, t(4;14), t(14;16), t(14;20), or del(17p).

Final Analysis Survival Outcomes (MASTER)10
Characteristic
0 HRCA
(n=53)
1 HRCA
(n=46)
≥2 HRCAs
(n=24)
3-year PFS rate (N=123), %
88
79
50
   95% CI
78-95
67-88
30-70
3-year OS rate (N=123), %
94
92
75
   95% CI
88-98
86-96
63-85
3-year PFS rate for MRD-evaluable patients (n=118), %
88
80
50
   95% CI
78-94
68-90
30-70
3-year OS rate for MRD-evaluable patients (n=118), %
94
94
75
   95% CI
88-98
87-99
63-85
3-year PFS rate for patients reaching MRD-SURE (n=84), %
88
85
60
   95% CI
77-96
73-96
35-82
3-year OS rate for patients reaching MRD-SURE (n=84), %
97
93
100
   95% CI
91-100
84-100
NC-100
Cumulative incidence of progression rates for patients reaching MRD-SURE (n=84), %
9
9
47
   95% CI
1-19
1-18
23-72
2-year cumulative incidences of disease progression or MRD resurgence rates for patients reaching MRD-SURE (n=84), %
9
14
60
   95% CI
1-19
4-26
35-81
2-year PFS rate after cessation of therapy, %
88
85
53
   95% CI
77-95
73-94
28-78
2-year OS rate after cessation of therapy, %
97
93
100
   95% CI
91-100
85-99
NC-100
Abbreviations: 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; CI, confidence interval; MRD, minimal residual disease; MRD-SURE, MRD-surveillance; NC, not calculated; OS, overall survival; PFS, progression-free survival.
  • A total of 6 patients had disease progression while receiving protocol-directed therapy (induction phase, n=1; after AHCT and before consolidation, n=1; consolidation, n=4).
    • All 6 patients had gain/amp 1q, 5 had del(17p), and 5 had ≥2 HRCAs; all patients died from disease progression/complications of subsequent therapy within 1.3-10.8 months after initial progression.
  • Of the 118 MRD-evaluable patients, the 3-year PFS rate for those who reached sustained MRD-negativity (n=75 [64%]) vs those who did not reach sustained MRD-negativity (n=43 [36%]) was 89% (95% CI, 82-94) vs 55% (95% CI, 39-69), respectively. See Table: PFS and OS for Different Study Populations (MASTER).

PFS and OS for Different Study Populations (MASTER)10,26
Characteristic
1 HRCA vs 0 HRCA
≥2 HRCAs vs 0 HRCA
PFS for entire population
   HR (95% CI)
2.27 (0.91-5.68)
6.29 (2.49-15.89)
P value
0.81
<0.0001
OS for entire population
   HR (95% CI)
1.22 (0.30-4.88)
5.36 (1.53-18.75)
P value
0.78
0.0085
PFS for MRD-evaluable patients
   HR (95% CI)
2.03 (0.80-5.16)
5.98 (2.37-15.09)
P value
0.14
<0.0001
OS for MRD-evaluable patients
   HR (95% CI)
0.91 (0.20-4.08)
5.12 (1.46-17.97)
P value
0.90
0.011
PFS for MRD-SURE
   HR (95% CI)
1.84 (0.62-5.51)
4.37 (1.38-13.82)
P value
0.27
0.012
OS for MRD-SURE
   HR (95% CI)
1.24 (0.17-8.87)
1.74 (0.15-20.16)
P value
0.83
0.66
Abbreviations: 0 HRCA, standard risk cytogenetic abnormalities; 1 HRCA, high-risk cytogenetic abnormalities; ≥2 HRCAs, ultra high-risk cytogenetic abnormalities; CI, confidence interval; HR, hazard ratio; MRD, minimal residual disease; MRD-SURE, MRD-surveillance; OS, overall survival; PFS, progression-free survival.
  • Of the 106 patients without disease progression at 18 months from enrollment, the 3year PFS rate for those who reached sustained MRD-negativity vs those who did not reach sustained MRD-negativity was 89% (n=75; 95% CI, 82-94) vs 70% (n=31; 95% CI, 5483), respectively.
  • Of the 84 patients who transitioned to MRD-SURE, 23 (27%) resumed therapy, of whom 16 resumed due to disease progression without MRD resurgence and 7 due to MRD resurgence without progression.
Safety
  • All patients had ≥1 TEAE.
  • DARZALEX doses were neither reduced nor discontinued in any patient due to toxicity.
    • Carfilzomib and lenalidomide was discontinued in 2 patients each due to toxicity.
  • The most common TEAEs reported in the MASTER study are presented in Table: Most Common TEAEs (MASTER).
  • The most common serious TEAEs were pneumonia (n=8) and thromboembolic events (n=3).
  • No patient developed a secondary malignancy due to protocol-directed therapy.
  • A total of 15 patients died among 123 included patients.
    • Three patients died during protocol-directed therapy (not judged to be treatment related), of whom 2 had sudden death and 1 died from metapneumovirus pneumonia.
    • Three patients died after therapy and while on MRD-SURE without disease progression due to sudden death, COVID-19 pneumonia, and an accidental fall (n=1 each).
    • Nine patients died from progression of MM while receiving protocoldirected therapy (n=6) and after the completion of therapy (n=3).
  • A total of 4 patients died among 118 MRD-evaluable patients.

Most Common TEAEs (MASTER)10
Event, n (%)
Grade 1/2
Grade 3
Grade 4
Grade 5
All events
123 (100)
69 (56)
22 (18)
3 (2)
Hematologic
   Neutropenia
8 (7)
36 (29)
7 (6)
0 (0)
   Lymphopenia
6 (5)
18 (15)
10 (8)
0 (0)
   Anemia
13 (11)
11 (9)
2 (2)
0 (0)
   Thrombocytopenia
11 (9)
9 (7)
3 (2)
0 (0)
   Leukopenia
10 (8)
6 (5)
6 (5)
0 (0)
Non-hematologic
   Fatigue
58 (47)
11 (9)
0 (0)
0 (0)
   Bone pain
61 (50)
7 (6)
0 (0)
0 (0)
   Maculopapular rash
45 (37)
5 (4)
0 (0)
0 (0)
   Nausea
49 (40)
0 (0)
0 (0)
0 (0)
   Constipation
48 (39)
0 (0)
0 (0)
0 (0)
   Upper respiratory tract infection
44 (36)
1 (1)
0 (0)
0 (0)
   Diarrhea
38 (31)
5 (4)
0 (0)
0 (0)
   Insomnia
32 (26)
3 (2)
0 (0)
0 (0)
   Dyspnea
32 (26)
2 (2)
0 (0)
0 (0)
   Cough
33 (27)
0 (0)
0 (0)
0 (0)
   Hypertension
19 (15)
13 (11)
0 (0)
0 (0)
   Dizziness
29 (24)
1 (1)
0 (0)
0 (0)
   Peripheral sensory neuropathy
24 (20)
2 (2)
0 (0)
0 (0)
   Dysgeusia
25 (20)
0 (0)
0 (0)
0 (0)
   Hyperglycemia
18 (15)
5 (4)
1 (1)
0 (0)
   Headache
22 (18)
2 (2)
0 (0)
0 (0)
   Fever
23 (19)
0 (0)
0 (0)
0 (0)
   Edema in limbs
21 (17)
1 (1)
0 (0)
0 (0)
   Increased ALT concentration
19 (15)
2 (2)
0 (0)
0 (0)
   Weight loss
17 (14)
1 (1)
0 (0)
0 (0)
   Hypophosphatemia
7 (6)
9 (7)
0 (0)
0 (0)
   Weight gain
13 (11)
1 (1)
0 (0)
0 (0)
   Increased ASP concentration
12 (10)
1 (1)
0 (0)
0 (0)
   Hypocalcemia
11 (9)
1 (1)
1 (1)
0 (0)
   Thromboembolic event
8 (7)
3 (2)
2 (2)
0 (0)
   Lung infection
4 (3)
3 (2)
2 (2)
1 (1)
   Acute kidney injury
8 (7)
1 (1)
0 (0)
0 (0)
   Sudden death
0 (0)
0 (0)
0 (0)
2 (2)
   Hemolytic uremic syndrome
0 (0)
0 (0)
1 (1)
0 (0)
   Heart failure
1 (1)
0 (0)
0 (0)
0 (0)
IRR
32 (26)
2 (2)
0 (0)
0 (0)
Abbreviations: AE, adverse event; ALT, alanine transaminase; ASP, aspartate aminotransferase; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event.

CLINICAL STUDIES – RELAPSED/REFRACTORY MULTIPLE MYELOMA

DARZALEX in Combination with Bortezomib and Dexamethasone

CASTOR (MMY3004; NCT02136134) was a phase 3, open-label, randomized, multicenter, active-controlled study that assessed the safety and efficacy of Vd alone and D-Vd in patients with RRMM.12

Study Design/Methods

  • Primary endpoint: PFS12
  • Secondary endpoints: time to disease progression; percentage of patients with overall response; DOR; TTR, percentage of patients with a ≥VGPR; percentage of patients with OS; MRD12

Updated Results of the CASTOR Study

Sonneveld et al (2022)13 reported updated results of the CASTOR study, including OS, at a median follow-up of 72.6 months. Results in the high-risk cytogenetic subgroup are summarized below.

Results


Key Baseline Characteristics (ITT Population; CASTOR)13
Characteristic
D-Vd
(n=251)
Vd
(n=247)
ISS staginga, n (%)
   I
98 (39)
96 (39)
   II
94 (37)
100 (40)
   III
59 (24)
51 (21)
Cytogenetic profileb, n/N (%)
   Standard risk
140/181 (77)
137/174 (79)
   High risk
41/181 (23)
37/174 (21)
Abbreviations: D-Vd, DARZALEX + bortezomib + dexamethasone; ISS, International Staging System; Vd, bortezomib + dexamethasone.
aISS staging is derived based on the combination of serum β2-microglobulin and albumin.
bCytogenetic risk was assessed locally by fluorescence in situ hybridization or karyotype testing; high risk was defined as the presence of t(4;14), t(14;16), or del17p.
Efficacy

OS in ISS Staging and Cytogenetic Risk Pre-Specified Subgroups (ITT Population; CASTOR)13
Subgroup
D-Vd
Vd
Hazard Ratio (95% CI)
n/N
Median
n/N
Median
ISS disease stagea
   I
49/98
72.7
59/96
49.8
0.70 (0.47-1.03)
   II
57/94
48.5
70/100
40.3
0.73 (0.50-1.05)
   III
42/59
21.6
42/51
12.9
0.77 (0.48-1.24)
Cytogenetic risk at study entryb
   High risk
30/40
38.4
27/35
28.8
0.77 (0.41-1.46)
   Low risk
78/141
55.8
93/140
41.8
0.71 (0.52-0.98)
Abbreviations: CI, confidence interval; D-Vd, DARZALEX + bortezomib + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; OS, overall survival; Vd, bortezomib + dexamethasone.
aISS disease stage was derived based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more severe disease.bCytogenetic risk was assessed locally by fluorescence in situ hybridization or karyotype testing. High risk was defined as the presence of t(4;14), t(14;16), or del17p.
Safety
  • Grade 3/4 TEAEs occurring in ≥10% of patients in the D-Vd vs Vd arm were thrombocytopenia (46.1% vs 32.9%), anemia (16% in both arms), neutropenia (13.6% vs 4.6%), lymphopenia (10.3% vs 2.5%), and pneumonia (10.7% vs 10.1%).13
  • Serious TEAEs were reported in 134 (55.1%) patients vs 81 (34.2%) patients in the D-Vd vs Vd arms, respectively.13
    • The most common serious TEAE was pneumonia (D-Vd, 10.7%; Vd, 10.1%).
  • Treatment discontinuations due to TEAEs was 10.7% vs 9.3% in the D-Vd vs Vd arms, respectively.13
  • Deaths due to TEAEs were reported in 17 (7%) patients vs 14 (5.9%) patients in the D-Vd vs Vd arms, respectively.13
    • The most frequent TEAEs leading to death were pneumonia (0.8% in both arms) and general physical health (D-Vd, 0.4%; Vd, 1.3%).

DARZALEX in Combination with Lenalidomide and Dexamethasone

POLLUX (MMY3003; NCT02076009) was a phase 3, randomized, open-label, multicenter study assessed the safety and efficacy of Rd vs D-Rd in patients with RRMM.14

Study Design/Methods

  • Primary endpoint: PFS14
  • Secondary endpoints: TTP, ORR, rate of ≥VGPR, ≥CR, OS, DOR, safety, and MRD14

Updated Results of the POLLUX Study

Dimopoulos et al (2022)15 presented updated results of the POLLUX study, including OS, at a median follow-up of 79.7 months. Results in the high-risk cytogenetic subgroup are summarized below.

Results


Key Baseline Characteristics (ITT Population; POLLUX)15
Characteristic
D-Rd
(N=286)
Rd
(N=283)
ISS staginga, n (%)
   I
137 (47.9)
140 (49.5)
   II
93 (32.5)
86 (30.4)
   III
56 (19.6)
57 (20.1)
Cytogenetic profileb, n/N (%)
   Standard risk
193/228 (84.6)
176/211 (83.4)
   High risk
35/228 (15.4)
35/211 (16.6)
Abbreviations: aISS staging was based on the combination of serum β2-microglobulin and albumin.bCytogenetic risk was assessed locally by fluorescence in situ hybridization or karyotype testing; high risk was defined as the presence of t(4;14), t(14;16), or del17p.
Efficacy

OS in ISS Staging and Cytogenetic Risk Pre-Specified Subgroups (ITT Population; POLLUX)15
Subgroup
D-Rd
Rd
Hazard Ratio (95% CI)
n/N
Median
n/N
Median
ISS disease stagea
   I
54/137
NE
70/140
71.9
0.76 (0.53-1.08)
   II
61/93
50.4
65/86
38.5
0.71 (0.50-1.01)
   III
38/56
39
40/57
20.3
0.74 (0.47-1.15)
Cytogenetic risk at study entryb
   High risk
25/35
40
28/35
23.6
0.70 (0.41-1.20)
   Low risk
104/193
67.6
107/176
51.8
0.80 (0.61-1.05)
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; ISS, International Staging System; ITT, intent-to-treat; OS, overall survival; Rd, lenalidomide + dexamethasone.
aISS disease stage was derived based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more severe disease.
bCytogenetic risk was assessed locally by fluorescence in situ hybridization or karyotype testing. High risk was defined as the presence of t(4;14), t(14;16), or del17p.
Safety
  • Grade 3/4 TEAEs occurring in ≥10% of patients in the D-Rd vs Rd arm were neutropenia (57.6% vs 41.6%), anemia (19.8% vs 22.4%), pneumonia (17.3% vs 11%), thrombocytopenia (15.5% vs 15.7%), and diarrhea (10.2% vs 3.9%).15
  • Treatment discontinuations due to TEAEs was 19.1% vs 16% in the DRd vs Rd arms, respectively.15
  • Deaths due to TEAEs were reported in 35 (12.4%) patients vs 24 (8.5%) patients in the DRd vs Rd arms, respectively.15

DARZALEX in Combination with Carfilzomib and Dexamethasone

CANDOR (NCT03158688) was a randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-Kd vs Kd in patients with RRMM.16

Study Design/Methods

  • High-risk cytogenetic status was assessed by FISH and included those who had ≥1 of the following abnormalities: t(4;14), t(14;16), or del17p.16
  • Primary endpoint: PFS16
  • Key secondary endpoints: ORR, MRD (10-5 sensitivity), and OS16

Final Efficacy and Safety Results of the CANDOR Study

Usmani et al (2023)17 reported the final efficacy and safety results of the CANDOR study after a median follow-up of approximately 50 months. Results in high-risk patients are summarized below.

Results

Patient Characteristics

Key Baseline Patient and Disease Characteristics (CANDOR)17 
Characteristic 
D-Kd (n=312)
Kd (n=154)
ISS stage, n (%)
   I
147 (47)
79 (51)
   II
103 (33)
48 (31)
   III
61 (20)
27 (18)
   Unknown
1 (<1)
0 (0)
Cytogenetic risk group by FISH, n (%)
   High-riska
48 (15)
26 (17)
   Standard-risk
107 (34)
56 (36)
   Unknownb
156 (50)
72 (47)
Abbreviations: D-Kd, DARZALEX + carfilzomib + dexamethasone; FISH, fluorescence in situ hybridization; ISS, International Staging System; Kd, carfilzomib + dexamethasone.
aConsists of genetic subtypes t(4;14), t(14;16), or del(17p).
bIncludes samples that failed or were cancelled.
Efficacy

OS in Pre-specified ISS Staging and Cytogenetic Risk Subgroups (CANDOR)17 
Events/Patients
Median OS, months (95% CI)
HR for D-Kd vs Kd (95% CI)
D-Kd
Kd
D-Kd
Kd
Overall
148/312
80/154
50.8 (44.7-NE)
43.6 (35.3-NE)
0.784 (0.595-1.033)
ISS stage at screening
   I or II
104/252
58/127
NE (50.8-NE)
51.8 (41.9-NE)
0.870 (0.630-1.200)
   III
44/60
22/27
26.5 (21.4-38.3)
12 (4.9-17.8)
0.584 (0.345-0.989)
Cytogenetic risk group
   High risk
32/48
20/26
34.3 (22-46.5)
17.1 (8.5-35.3)
0.521 (0.288-0.942)
   Standard risk
44/108
30/56
NE (48.8-NE)
38.2 (32.9-NE)
0.621 (0.382-1.009)
   Unknown
72/156
30/72
NE (43.2-NE)
NE (42.9-NE)
1.062 (0.690-1.635)
Abbreviations: CI, confidence interval; D-Kd, DARZALEX + carfilzomib + dexamethasone; HR, hazard ratio; ISS, International Staging System; Kd, carfilzomib + dexamethasone; NE, not estimable; PFS, progression-free survival.
Safety
  • No new safety signals were identified with the longer follow-up.17 
  • In the safety population (D-Kd, n=308; Kd, n=153), any grade TEAEs occurred in 99.4% and 97.4% of patients in the D-Kd and Kd arm, respectively.17 
  • Grade ≥3 TEAEs occurred in 88.6% and 78.4% of patients in the D-Kd and Kd arm, respectively. The most common (≥15%) grade ≥3 TEAEs were thrombocytopenia (D-Kd, 24.7%; Kd, 16.3%), hypertension (D-Kd, 23.4%; Kd, 17.6%), pneumonia (D-Kd, 18.5%; Kd, 9.2%), and anemia (D-Kd, 17.5%; Kd, 16.3%).17 
  • Treatment-related fatal adverse events occurred in 2% of patients in the D-Kd arm and none in the Kd arm.17 

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 16 June 2025.

 

References

Show
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2 Kumar SK, Moreau P, Bahlis N, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): updated analysis of the phase 3 MAIA study. Poster presented at: The 64th American Society of Hematology (ASH) Annual Meeting & Exposition; December 10-13, 2022; New Orleans, LA.  
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8 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.  
9 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).  
10 Costa LJ, Chhabra S, Medvedova E, et al. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol. 2023;10(11):e890-e901.  
11 Jakubowiak AJ, Kumar S, Medhekar R, et al. Daratumumab Improves Depth of Response and Progression-free Survival in Transplant-ineligible, High-risk, Newly Diagnosed Multiple Myeloma. Oncol. 2022;27(7):oyac067-.  
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16 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.  
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18 Fu W, Bang SM, Huang H, et al. Bortezomib, melphalan, and prednisone with or without daratumumab in transplant-ineligible Asian patients with newly diagnosed multiple myeloma: the phase 3 OCTANS study. Clin Lymphoma Myeloma Leuk. 2023;23:446-455 e4.  
19 Hou J, Fu W, Bang SM, et al. Daratumumab, bortezomib, melphalan, and prednisone versus bortezomib, melphalan, and prednisone in transplant-ineligible patients with newly diagnosed multiple myeloma: pooled analysis of OCTANS and ALCYONE. Poster presented at: 63rd American Society of Hematology (ASH) Annual Meeting & Exposition; December 11-14, 2021; Atlanta, GA/Virtual.  
20 Fu W, Bang SM, Huang H, et al. Subgroup analyses of progression-free survival from the phase 3 OCTANS and ALCYONE studies in transplant-ineligible patients with newly diagnosed multiple myeloma treated with bortezomib, melphalan, and prednisone with or without daratumumab. Poster presented at: 65th American Society of Hematology (ASH) Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA.  
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