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DARZALEX® (daratumumab)

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

Last Updated: 04/30/2025

SUMMARY

  • Janssen 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 Rd alone in transplant-ineligible NDMM patients.1
  • 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 ASCT.4
  • Jakubowiak et al (2022)6 conducted a pooled analysis of patient-level data from the MAIA and ALCYONE studies, analyzing 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 HR, 0.59; 95% CI, 0.41-0.85; P=0.0046), representing a 41% reduction in risk of disease progression or death. Complete response 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).
  • 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.7
  • GRIFFIN is a phase 2, 2-part study evaluating the safety and efficacy of DARZALEX when administered in combination with VRd (D-VRd) in patients with NDMM eligible for HDT and ASCT.9-11
  • 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.14
    • Costa et al (2023)14 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 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.
    • Costa et al (2023)15 reported additional details on PFS and OS for different study populations and at difference timepoints according to MRD status.
  • Callander et al (2024)16 reported the results of a post hoc analysis evaluating the clinical efficacy of DARZALEX-based quadruplet therapies, including 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 (105) was reported in 80%, 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.

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.17
  • POLLUX is a phase 3 study assessing the safety and efficacy of Rd vs D-Rd in patients with RRMM.20
    • Dimopoulos et al (2022)21 presented updated efficacy and safety results from POLLUX at a median follow-up of 79.7 months. Efficacy data by key subgroups is noted in Table: OS in ISS Staging and Cytogenetic Risk Pre-Specified Subgroups (ITT Population; POLLUX).
    • Kaufman et al (2020)22 presented updated efficacy and safety data based cytogenetic risk status of D-Rd from POLLUX in patients with RRMM. Among patients with high cytogenetic risk, PFS was prolonged with D-Rd vs Rd in MRD-positive patients (median, 20.3 months vs 8.3 months; HR, 0.49; 95% CI, 0.23-1.03; P=0.0567); median PFS with D-Rd in MRD-negative patients was not estimable (NE). MRD-negativity rates were higher with D-Rd vs Rd, regardless of cytogenetic risk.
  • Mateos et al (2022)23 presented the results of a post hoc subgroup analysis of the phase 3 CASTOR and POLLUX studies, evaluating the efficacy of D-Vd vs Vd alone (CASTOR) and D-Rd vs Rd alone (POLLUX) in patients with RRMM. In the pooled intent-to-treat (ITT) population of CASTOR and POLLUX, PFS benefit of the DARZALEX (median, 20.3 months) vs control (median, 7.3 months) arm was observed (HR, 0.45; 95% CI, 0.31-0.65) and OS benefit of the DARZALEX (median, 40 months) vs control (median, 23.6 months) arm was observed (HR, 0.68; 95% CI, 0.47-1) in patients with high cytogenetic risk.
  • CANDOR is a phase 3 study evaluating the safety and efficacy of D-Kd vs carfilzomib and dexamethasone in patients with RRMM.24,25
  • Other relevant literature has been identified in addition to the data summarized above.27-32 

PRODUCT LABELING

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 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 in patients with NDMM who were ineligible for high-dose chemotherapy and ASCT. Results in the high-risk cytogenetic subgroup are summarized below. Moreau et al (2025)3 presented the efficacy and safety results in clinically important subgroups of patients from the MAIA study.

Study Design/Methods

  • Primary endpoint: PFS
  • Secondary endpoints: ≥CR rate, ≥VGPR rate, duration of response (DOR), MRD-negativity rate (10-5) via NGS, ORR, OS, PFS on subsequent line of therapy (PFS2), sCR, time to next (2nd-line) treatment, time to response (TTR), time to progression (TTP), and safety
  • Cytogenetic analysis: efficacy 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 FISH or karyotype analysis)

Results

Efficacy
  • At a median follow-up of 73.6 months, the median OS in the D-Rd vs Rd arm was NR vs 64.1 months (HR, 0.65; 95% CI, 0.52-0.80; P<0.0001).
    • 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; IgG, immunoglobulin G; 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.
  • 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%).
  • The most common serious TEAE in both arms was pneumonia (D-Rd, 18.7%; Rd, 10.7%).
  • The rate of treatment discontinuation due TEAEs in the D-Rd vs Rd arm was 14.6% vs 23.8%.

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.

Study Design/Methods

  • Efficacy outcomes (PFS, ORR, and MRD-negativity) were analyzed in ISS stage III and cytogenetic risk based on the following patient characteristics:
    • 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

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

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, Month
n/N
Median PFS, Month
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 Population3 
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) 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 Mateos et al (2022)5 presented updated analysis of the ALCYONE study that evaluated the efficacy and safety of D-VMP vs VMP in patients with NDMM who were ineligible for high-dose chemotherapy and ASCT. Results in the high-risk cytogenetic subgroup are summarized below.

Study Design/Methods

  • Primary endpoint: PFS
  • Key secondary endpoints: CR rate, ORR, OS, safety
  • Cytogenetic analysis: efficacy 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 FISH or karyotype analysis)

Results

Patient Characteristics
  • A total of 98 patients (D-VMP, n=53; VMP, n=45) were classified as high cytogenetic risk and 518 patients (D-VMP, n=261; VMP, n=257) were classified as standard cytogenetic risk.
Efficacy
  • Median duration of follow-up was 78.8 months.
  • In the D-VMP vs VMP arm, the median OS was 82.7 vs 53.6 months (HR, 0.64; 95% CI, 0.52-0.79; P<0.0001) and the 72-month OS rate was 55.7% vs 39.7%.

OS in ISS Staging and Cytogenetic Risk Subgroups (ALCYONE)5
Subgroup
D-VMP
VMP
HR (95% CI)a
n/N
Median OS (months)
n/N
Median OS (months)
ISS disease stage
   I
18/69
NE
26/67
NE
0.52 (0.29-0.96)
   II
63/139
83
88/160
61.3
0.72 (0.52-1)
   III
79/142
63
93/129
42.3
0.57 (0.42-0.78)
Cytogenetic risk at study entry
   High riskb
33/53
46.2
31/45
39.5
0.85 (0.52-1.38)
   Standard risk
113/261
83
149/257
55.1
0.58 (0.45-0.74)
Abbreviations: CI, confidence interval; D-VMP, daratumumab + bortezomib + melphalan + prednisone; HR, hazard ratio; ISS, International Staging System; NE, not estimable; OS, overall survival; VMP, bortezomib + melphalan + prednisone.
aHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable. An HR <1 indicates an advantage for D-VMP.
bPatients 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
  • In the D-VMP vs VMP arm, grade 3/4 TEAEs were reported in 82.9% vs 77.4% of patients, and grade 3/4 infections were reported in 30.3% vs 15% of patients.
  • Grade 3/4 TEAEs occurring in ≥20% of patients in the D-VMP vs VMP arm were neutropenia (40.5% vs 39%) and thrombocytopenia (34.7% vs 37.9%).
  • The most common serious TEAE in both treatment arms was pneumonia (D-VMP, 14.7%; VMP, 3.7%).
  • The rate of treatment discontinuation due to TEAEs in the D-VMP vs VMP arm was 9% vs 9.3%.

DARZALEX in Combination with Bortezomib, Thalidomide and Dexamethasone

CASSIOPEIA (MMY3006) is an ongoing, 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.7 Moreau et al (2021)8 reported the results from Part 2 of the CASSIOPEIA study (maintenance treatment). Results in the high-risk cytogenetic subgroup are summarized below.

Study Design/Methods

  • Part 2: Responders (patients who completed consolidation and achieved partial response or better [≥PR]) were rerandomized to 1 of 2 treatment groups:
    • Arm A: DARZALEX 16 mg/kg maintenance therapy every 8 weeks for 2 years
    • Arm B: Observation
  • Primary endpoint: Part 2: PFS after second randomization
  • Secondary endpoints: Part 2: TTP from second randomization, rates of ≥CR, MRD-negativity rates (in patients with ≥CR at a threshold of 10-5 by NGS), PFS2, ORR, and OS from second randomization

Results

Baseline Characteristics

Key Baseline Demographics and Disease Characteristics after Second Randomization (CASSIOPEIA Part 2)8
Characteristics, n (%)
DARZALEX monotherapy
(n=442)
Observation
(n=444)
ISS disease stagea
   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)
Abbreviation: ISS, International Staging System.
aPre-induction.
Efficacy
  • After a median follow-up of 35.4 months (interquartile range [IQR], 30.2-39.9), median PFS from second randomization was NR (95% CI, not evaluable) in the DARZALEX monotherapy group vs 46.7 months (95% CI, 40-NE) in the observation group (HR, 0.53; 95% CI, 0.42-0.68; P<0.0001).
    • The DARZALEX monotherapy group experienced 108 PFS events, while the observation group experienced 173 events.
    • The PFS benefit of the DARZALEX monotherapy group vs the observation group was consistent across most prespecified subgroups, except for patients with ISS stage III disease, patients with creatinine clearance ≤90 mL/min, and those who received VTd as a part of induction, ASCT, and consolidation treatment group, as presented in Table: PFS in the Prespecified ISS and Cytogenetic Risk Subgroups (CASSIOPEIA Part 2).
  • After a median follow-up of 44.5 months (IQR, 38.9-49.1), an updated analysis was performed from first randomization (Part 1 CASSIOPEIA study) of patients in the D-VTd group vs VTd group.
    • The median PFS was NR (95% CI, NE-NE) in the D-VTd group vs 51.5 months (95% CI, 46.3-NE) in the VTd group (HR, 0.58; 95% CI, 0.47-0.72; P<0.0001).
    • The median OS was NR for patients in the D-VTd group vs VTd group (41 [8%] deaths of patients in D-VTd group vs 73 [13%] deaths in VTd group; HR, 0.54; 95% CI, 0.37-0.79).

PFS in the Prespecified ISS and Cytogenetic Risk Subgroups (CASSIOPEIA Part 2)8
Hazard Ratio (95% CI)
ISS disease staging
   I
0.50 (0.32-0.78)
   II
0.56 (0.40-0.79)
   III
0.75 (0.44-1.29)
Cytogenetic risk
   High-risk
0.43 (0.25-0.73)
   Standard-risk
0.62 (0.48-0.82)
Abbreviations: CI, confidence interval; ISS, International Staging System; PFS, progression-free survival.
Safety
  • Any TEAEs occurred in 95% (n=420) of patients in the DARZALEX monotherapy group vs 89% (n=394) in the observation group.
  • Grade ≥3 TEAEs occurred in 28% (n=122) of patients in the DARZALEX monotherapy group (who received at least 1 dose) vs 24% (n=108) in the observation group.
  • Serious AEs that occurred in >1% of patients in the DARZALEX monotherapy vs observation groups were pneumonia (n=11 [3%] vs n=7 [2%]) and lung infection (n=6 [1%] vs n=7 [2%], respectively.
  • Two AEs led to death in the DARZALEX monotherapy group (septic shock and natural killer-cell lymphoblastic lymphoma, n=1 each); both were treatment-related.

DARZALEX with Bortezomib, Lenalidomide, and Dexamethasone

Final Subgroup Analysis From GRIFFIN

GRIFFIN (MMY2004; NCT02874742) is 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.9-11 Chari et al (2024)12,13 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

  • 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.
  • This final analysis was conducted after all patients completed ≥1 year of follow-up after concluding study treatment, died, or withdrew.
  • Primary endpoint: sCR (by end of post-ASCT consolidation)
  • Secondary endpoints: MRD (10-5 via NGS), CR, ORR, ≥VGPR
  • Cytogenetic risk was assessed by FISH; high-risk was defined as the presence of del17p, t(4;14), or t(14;16)

Results

Efficacy
  • MRD-negativity (10-5) rates favored the D-VRd vs VRd arm in the patient subgroup of ISS stage III and cytogenetic risk. See Table: Final Analysis of MRD-Negativity (10-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN).
  • A final analysis of sCR rates were higher for D-VRd vs VRd for most subgroups, including the patient subgroup of ISS stage III and cytogenetic risk. See Table: Final Analysis of sCR in the ISS Stage III and Cytogenetic Subgroups (GRIFFIN).
  • MRD-negativity (10-5) rates favored the D-VRd vs VRd arm in the patient subgroup of ISS stage III and cytogenetic risk among patients who achieved a best response ≥CR by the end of the study. See Table: Final Analysis of MRD-negativity (10-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups with a Best Response of ≥CR (GRIFFIN).  
  • D-VRd was associated with higher rates of sustained MRD-negativity (10-5) lasting ≥12 in the patient subgroup of ISS stage III and cytogenetic risk. See Table: Final Analysis of Rates of Sustained MRD-negativity (10-5) lasting ≥12 months in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN).
    • No patients who achieved sustained MRD-negativity (10-5) lasting ≥12 months developed PD.
  • 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.
    • Two patients from the D-VRd arm and 3 patients from the VRd arm, who initially achieved MRD-negativity, developed 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: Final Analysis of PFS in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN).
    • 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.
  • 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.
    • 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.
    • 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.

Final Analysis of MRD-Negativity (10-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN)12
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.

Final Analysis of sCR in the ISS Stage III and Cytogenetic Subgroups (GRIFFIN)13
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 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.

Final Analysis of MRD-negativity (10-5) Rates in the ISS Stage III and Cytogenetic Risk Subgroups with a Best Response of ≥CR (GRIFFIN)12
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.

Final Analysis of Rates of Sustained MRD-negativity (10-5) lasting ≥12 months in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN)12
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.

Final Analysis of PFS in the ISS Stage III and Cytogenetic Risk Subgroups (GRIFFIN)12
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.
Safety
  • A summary of the most common (>30%) TEAEs in the safety analysis population separated by age <65 years and ≥65 years is provided in Table: Most Common (>30%) and grade TEAEs by Age (<60 years and ≥65 years).
  • 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.
  • The incidence of serious TEAEs was lower in D-VRd vs VRd among patients <65 years, 41.7% vs 56% respectively.
  • The incidence of serious TEAEs was higher in the D-VRd vs VRd among patients ≥65 years, 59.3% vs 40.7% respectively.
  • 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%).
    • 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.
    • 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.
    • <65 years (VRd, n=1; cause unknown)
    • ≥65 years (D-VRd, n=1; pneumonia)

Most Common (>30%)a any grade TEAEs by Age (<65 years and ≥65 years)12
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.

DARZALEX in Combination with KRd

MASTER (NCT03224507) evaluated the efficacy and safety of D-KRd induction followed by AHCT and MRD-adapted consolidation therapy in patients with NDMM.14 Costa et al (2023)14 reported the results from the final analysis of the MASTER study at a median follow-up of 42.2 months. Results from the final analysis are reported below.

Study Design/Methods

  • Key eligibility criteria: Patients of any age group with NDMM with measurable disease; with Eastern Cooperative Oncology Group performance status (ECOG PS) of ≤2; who had measurable renal function (creatinine clearance ≥40 mL/min); and who were either untreated or had received up to 1 cycle of bortezomib, cyclophosphamide, and dexamethasone (VCd) were included. Patients with a concomitant or recent malignancy, or significant cardiopulmonary disease were excluded.
  • Primary endpoint: Rate of MRD-negative responses (<10-5) by NGS (clonoSEQ®)
  • Secondary endpoints: Toxicity of D-KRd, rates and kinetics of MRD resurgence upon treatment discontinuation, PFS, and OS
  • Exploratory endpoints: PFS and OS for patients who transitioned to MRD-surveillance (MRD-SURE) and were monitored off therapy
  • Enrichment for patients with HRCA was planned during recruitment.

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 duration of 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)14
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,14
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).
  • A total of 33 PFS events were recorded among 123 included patients and 32 PFS events were recorded among 118 MRD-evaluable patients. See Table: Final Analysis Survival Outcomes (MASTER).
  • 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 (MASTERS).
  • 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.
  • At the last MRD-SURE observation timepoint, 61 patients (MRD-evaluable patients, 52%; transitioned to MRDSURE, 73%) remained free of therapy with sustained MRDnegativity, including 3 patients who died of unrelated causes without previous disease progression. See Table: Landmark PFS and OS According to MRD Status at Different Timepoints (MASTER).
  • 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.

Final Analysis Survival Outcomes (MASTER)14
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.

PFS and OS for Different Study Populations (MASTER)14,15
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.

Landmark PFS and OS According to MRD Status at Different Timepoints (MASTER)15
Characteristic
Landmark PFS according to MRD status (<10-5) at end of induction
HR (95% CI)
1.06 (0.50-2.12)
   Log-rank P value
0.94
Landmark OS according to MRD status (<10-5) at end of induction
   HR (95% CI)
0.33 (0.07-1.49)
   Log-rank P value
0.11
Landmark PFS according to MRD status (<10-5) post-AHCT
   HR (95% CI)
0.95 (0.43-2.08)
   Log-rank P value
0.90
Landmark OS according to MRD status (<10-5) post-AHCT
   HR (95% CI)
0.63 (0.28-2.27)
   Log-rank P value
0.48
Exploratory landmark PFS according to MRD status (<10-6) at end of induction
   HR (95% CI)
0.85 (0.37-2)
   Log-rank P value
0.72
Exploratory landmark OS according to MRD status (<10-6) at end of induction
   HR (95% CI)
0.28 (0.04-2.17)
   Log-rank P value
0.15
Exploratory landmark PFS according to MRD status (<10-6) post-AHCT
   HR (95% CI)
1 (0.48-2.10)
   Log-rank P value
0.99
Exploratory landmark OS according to MRD status (<10-6) post-AHCT
   HR (95% CI)
0.26 (0.05-1.22)
   Log-rank P value
0.065
Abbreviations: AHCT, autologous hematopoietic cell transplantation; CI, confidence interval; HR, hazard ratio; MRD, minimal residual disease; OS, overall survival; PFS, progression free survival.
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)14
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) is 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.17 Sonneveld et al (2022)18 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.

Study Design/Methods

  • Primary endpoint: PFS
  • 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; MRD

Results


Key Baseline Characteristics (ITT Population; CASTOR)18
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)18
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%).
  • Serious TEAEs were reported in 134 (55.1%) patients vs 81 (34.2%) patients in the D-Vd vs Vd arms, respectively.
    • 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.
  • Deaths due to TEAEs were reported in 17 (7%) patients vs 14 (5.9%) patients in the D-Vd vs Vd arms, respectively.
    • 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%).

Subgroup Analysis from CASTOR

Weisel et al (2020)19 reported updated efficacy and safety data based on cytogenetic risk status of D-Vd from CASTOR in patients with RRMM.

Study Design/Methods

  • Cytogenetic risk was evaluated using local FISH or karyotyping.
  • Patients in the ITT population who had ≥1 FISH or karyotyping assessment were included in the analysis.
  • Patients with high-risk cytogenetics included those who had ≥1 of the following abnormalities: t(4;14), t(14;16), or del17p.

Results


Key Patient Baseline Disease and Clinical Characteristics (CASTOR)19
Characteristic
Standard Cytogenetic Riska
High Cytogenetic Riska,b
D-Vd
(n=141)
Vd
(n=140)
D-Vd
(n=40)
Vd
(n=35)
ISS stagingc, n (%)
   I
48 (34)
55 (39)
22 (55)
14 (40)
   II
57 (40)
56 (40)
11 (28)
16 (46)
   III
36 (26)
29 (21)
7 (18)
5 (14)
Cytogenetic profilea, n (%)
   t(4;14)
-
-
13 (33)
15 (43)
   t(14;16)
-
-
4 (10)
5 (14)
   del17p
-
-
27 (68)
20 (57)
   ≥2 risk factorsd
-
-
4 (10)
4 (11)
Abbreviations: D-Vd, DARZALEX + bortezomib + dexamethasone; FISH, fluorescence in situ hybridization;
ISS, International Staging System; Vd, bortezomib + dexamethasone.
Note: percentages may not equal 100% due to rounding.
aBased on FISH/karyotype testing.
bPatients with high cytogenetic risk had a t(4;14), t(14;16), or del17p abnormality.
cISS staging is derived based on the combination of serum β2-microglobulin and albumin.
dPatients with ≥2 of the t(4;14), t(14;16), or del17p risk factors.
Efficacy
  • After a median follow-up of 40 months (ITT population), treatment with D-Vd significantly prolonged PFS compared with Vd in patients with standard cytogenetic risk (median: 16.6 months vs 6.6 months; HR, 0.26; 95% CI, 0.19-0.37; P<0.0001) and high cytogenetic risk (median: 12.6 vs 6.2 months; HR, 0.41; 95% CI, 0.21-0.83; P=0.0106).
    • Among patients who had received 1 prior line of therapy, treatment with D-Vd significantly prolonged PFS compared with Vd in patients with standard cytogenetic risk (median: 29.8 vs 7.5 months; HR, 0.25; 95% CI, 0.15-0.42; P<0.0001) and high cytogenetic risk (median: 20.1 months vs 8.4 months; HR, 0.20; 95% CI, 0.06-0.62; P=0.0026).
  • ORR and rates of ≥VGPR and ≥CR were higher with D-Vd vs Vd, regardless of cytogenetic risk status; Please see Table: Response and MRD-negative Rates in Patients with Standard and High Cytogenetic Risk (CASTOR).
    • Time to ≥VGPR was decreased with D-Vd vs Vd in patients with standard cytogenetic risk (median: 3.5 months vs NE; HR, 2.16; 95% CI, 1.46-3.20; P<0.0001) and high cytogenetic risk (median: 3.5 months vs 6.2 months; HR, 1.96; 95% CI, 0.86-4.45; P=0.1004).
  • Rates of MRD-negativity were higher with D-Vd vs Vd, regardless of cytogenetic risk status as shown in Table: Response and MRD-negative Rates in Patients with Standard and High Cytogenetic Risk (CASTOR).
  • PFS was prolonged with D-Vd vs Vd in MRD-positive (median: 13.5 months vs 6.5 months; HR, 0.28; 95% CI, 0.20-0.40; P<0.0001) and MRD-negative (median, NE vs 37.6 months; HR, NE; P=0.4142) patients with standard cytogenetic risk.
  • Among patients with high cytogenetic risk, PFS was prolonged with D-Vd vs Vd in MRD-positive patients (median: 10.5 months vs 6.2 months; HR, 0.49; 95% CI, 0.25-0.97; P=0.0383); median PFS with D-Vd in MRD-negative patients was NE.
  • PFS2 was prolonged with D-Vd vs Vd in the standard cytogenetic risk (median: 34.2 months vs 18.5 months; HR, 0.41; 95% CI, 0.30-0.58; P<0.0001) and high cytogenetic risk (median: 28.1 months vs 19.7 months; HR, 0.58; 95% CI, 0.30-1.10; P=0.0915) subgroups.
  • At the time of analysis, OS data were immature and follow-up for OS was ongoing.

Response and MRD-negative Rates in Patients with Standard and High Cytogenetic Risk (CASTOR)19
Responsea, n (%)
Standard-Risk
High-Riskb
D-Vd
(n=135)
Vd
(n=134)
P value
D-Vd
(n=39)
Vd
(n=34)
P value
ORR
113 (84)
83 (62)
<0.0001
33 (85)
19 (56)
0.0512
≥CR
38 (28)
13 (10)
2 (6)
2 (6)
sCR
12 (9)
3 (2)
4 (10)
0
CR
26 (19)
10 (8)
7 (18)
2 (6)
≥VGPR
83 (62)
38 (28)
<0.0001
23 (59)
11 (32)
0.1259
VGPR
45 (33)
25 (19)
12 (31)
9 (27)
PR
30 (22)
45 (34)
10 (26)
8 (24)
MRD-negative (10-5)c
n=141
n=140
n=40
n=35
n (%)
16 (11)
4 (3)
0.0091
6 (15)
0
0.0271
Sustained MRD negativity (≥6 months), n (%)
9 (6)
3 (2)
0.1374
5 (13)
0
0.0569
Sustained MRD negativity (≥12 months), n (%)
2 (1)
0
0.4982
3 (8)
0
0.2432
Abbreviations: CR, complete response; D, DARZALEX; ITT, intent-to-treat; MRD, minimal residual disease; ORR, overall response rate; PR, partial response; sCR, stringent complete response; Vd, bortezomib + dexamethasone; VGPR, very good partial response.
aResponse-evaluable population.bPatients with high cytogenetic risk had a t(4;14), t(14;16), or del17p abnormality.
cITT population.
Safety
  • The most frequent any grade (≥25% of patients) TEAEs and most frequent grade 3/4 (≥5% of patients) TEAEs are summarized in Table: Most Common Any-grade (≥25% of Patients) and Grade 3/4 (≥5% of Patients) TEAEs (CASTOR).
  • Treatment discontinuation rates due to TEAEs were similar between treatment groups for patients with standard cytogenetic risk (D-Vd, n=11 [8%]; Vd, n=14 [10%]).
  • Among patients with high cytogenetic risk, a similar proportion discontinued treatment due to TEAEs (D-Vd, n=4 [10%]; Vd, n=3 [9%]).

Most Common Any-grade (≥25% of Patients) and Grade 3/4 (≥5% of Patients) TEAEs (CASTOR)19
TEAE, n (%)
Any-Grade
Grade 3/4
Standard-Risk
High-Riska
Standard-Risk
High-Riska
D-Vd
(n=137)
Vd
(n=136)
D-Vd
(n=40)
Vd
(n=34)
D-Vd
(n=137)
Vd
(n=136)
D-Vd
(n=40)
Vd
(n=34)
Hematologic
   Thrombocytopenia
85 (62)
58 (43)
24 (60)
16 (47)
65 (47)
45 (33)
19 (48)
12 (35)
   Anemia
45 (33)
41 (30)
7 (18)
14 (41)
25 (18)
23 (17)
4 (10)
6 (18)
   Neutropenia
29 (21)
16 (12)
9 (23)
3 (9)
21 (15)
6 (4)
6 (15)
2 (6)
   Lymphopenia
18 (13)
5 (4)
4 (10)
4 (12)
14 (10)
3 (2)
3 (8)
3 (9)
   Leukopenia
15 (11)
5 (4)
3 (8)
3 (9)
5 (4)
1 (1)
1 (3)
2 (6)
Nonhematologic
   Peripheral sensory
   neuropathy
67 (49)
50 (37)
22 (55)
13 (38)
4 (3)
8 (6)
2 (5)
4 (12)
   Upper respiratory tract
   infection
43 (31)
20 (15)
15 (38)
8 (24)
1 (1)
0 (0)
3 (8)
1 (3)
   Diarrhea
42 (31)
35 (26)
11 (28)
6 (18)
6 (4)
2 (2)
1 (3)
0 (0)
   Cough
40 (29)
19 (14)
9 (23)
4 (12)
0 (0)
0 (0)
0 (0)
0 (0)
   Fatigue
25 (18)
40 (29)
17 (43)
8 (24)
6 (4)
5 (4)
2 (5)
1 (3)
   Back pain
24 (18)
15 (11)
13 (33)
1 (3)
3 (2)
0 (0)
1 (3)
0 (0)
   Insomnia
22 (16)
20 (15)
11 (28)
5 (15)
2 (2)
0 (0)
0 (0)
1 (3)
   Pneumonia
22 (16)
20 (15)
5 (13)
4 (12)
15 (11)
14 (10)
2 (5)
3 (9)
   Asthenia
15 (11)
19 (14)
4 (10)
9 (27)
1 (1)
3 (2)
0 (0)
1 (3)
   Hypertension
15 (11)
5 (4)
4 (10)
1 (3)
9 (7)
1 (1)
2 (5)
0 (0)
   Decreased appetite
14 (10)
8 (6)
10 (25)
1 (3)
0 (0)
1 (1)
1 (3)
0 (0)
   Spinal pain
4 (3)
3 (2)
2 (5)
0 (0)
1 (1)
0 (0)
2 (5)
0 (0)
   Gastroenteritis
2 (2)
3 (2)
2 (5)
1 (3)
0 (0)
2 (2)
2 (5)
1 (3)
   Squamous cell carcinoma
   of skin
0 (0)
0 (0)
2 (5)
0 (0)
0 (0)
0 (0)
2 (5)
0 (0)
Abbreviations: D-Vd, DARZALEX + bortezomib + dexamethasone; TEAE, treatment-emergent adverse event; Vd, bortezomib + dexamethasone.
aPatients with high cytogenetic risk had a t(4;14), t(14;16), or del17p abnormality.

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.20 Dimopoulos et al (2022)21 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.

Study Design/Methods

  • Primary endpoint: PFS
  • Secondary endpoints: TTP, ORR, rate of ≥VGPR, rate of CR or better, OS, DOR, safety, and MRD

Results


Key Baseline Characteristics (ITT Population; POLLUX)21
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)21
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%).
  • Treatment discontinuations due to TEAEs was 19.1% vs 16% in the DRd vs Rd arms, respectively.
  • Deaths due to TEAEs were reported in 35 (12.4%) patients vs 24 (8.5%) patients in the DRd vs Rd arms, respectively.

DARZALEX in Combination with Carfilzomib and Dexamethasone

CANDOR (NCT03158688) is a randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of D-Kd vs Kd in patients with RRMM.24,25 Usmani et al (2023)26 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.

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.
  • Primary endpoint: PFS
  • Key secondary endpoints: ORR, MRD (10-5), and OS

Results

Patient Characteristics

Key Baseline Patient and Disease Characteristics (CANDOR)26
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
157 (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)26
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.
  • 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.
  • 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%).
  • Treatment-related fatal adverse events occurred in 2% of patients in the D-Kd arm and none in the Kd arm.

Literature Search

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 17 April 2025.

 

References

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