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DARZALEX® (daratumumab)

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

Last Updated: 04/15/2025

Summary

  • DARZALEX for intravenous (IV) use + DARZALEX FASPRO for subcutaneous (SC) use are not approved by the regulatory agencies for use in combination with bortezomib, cyclophosphamide, and dexamethasone (VCd) or for use in combination with carfilzomib, lenalidomide, and dexamethasone (KRd) for the treatment of multiple myeloma (MM). Also, DARZALEX for IV use is not approved by the regulatory agencies for use in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of MM. Janssen does not recommend the use of DARZALEX or DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • ALCYONE is a phase 3 study evaluating the safety and efficacy of bortezomib, melphalan, and prednisone (VMP) alone and DARZALEX + VMP (D-VMP) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for high-dose chemotherapy with autologous stem cell transplant (ASCT).1
    • Mateos et al (2022)2 presented an updated efficacy and safety analysis of the ALCYONE study (median follow-up, 78.8 months). In the D-VMP vs VMP arm, the median progression-free survival (PFS) was 37.3 vs 19.7 months, and the median overall survival (OS) was 82.7 vs 53.6 months. The rate of minimal residual disease (MRD)-negativity and sustained MRD-negativity lasting both for ≥12 and ≥18 months were higher in the D-VMP vs VMP arm. Grade 3/4 treatment-emergent adverse events (TEAEs) in the D-VMP vs VMP arm were reported in 82.9% vs 77.4% of patients. The most common serious TEAE in both treatment arms was pneumonia (D-VMP, 14.7%; VMP, 3.7%).
  • MAIA is a phase 3 study evaluating the safety and efficacy of lenalidomide and dexamethasone (Rd) and DARZALEX in combination with Rd (D-Rd) in transplant-ineligible patients with NDMM.3
    • Facon et al (2019)3 reported the prespecified interim results of this ongoing study.
    • Facon et al (2025)4 reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months. As of the clinical cutoff date of October 21, 2021, the median PFS was 61.9 months vs 34.4 months in the D-Rd vs Rd arm, respectively (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.45-0.67; P<0.0001). The median OS was not reached (NR) in the D-Rd arm and was 65.5 months in the Rd arm (HR, 0.66; 95% CI, 0.53-0.83; P=0.0003). The D-Rd vs Rd arm showed a significantly higher (all P<0.0001) overall response rate (ORR) (92.9% vs 81.6%), complete response (CR) or better (≥CR) rate (51.1% vs 30.1%), and very good partial response (VGPR) or better (≥VGPR) rate (81.5% vs 56.9%). Similarly, the D-Rd vs Rd arm showed a significantly higher (all P<0.0001) MRD-negativity (10-5 sensitivity) rate (32.1% [n=118] vs 11.1% [n=41]) and sustained MRD-negativity rate (≥12 months: 18.8% [n=69] vs 4.1% [n=15]; ≥18 months: 16.8% [n=62] vs 3.3% [n=12]). No new safety concerns were observed with a longer follow-up. Grade 3/4 TEAEs occurred in 95.9% vs 88.8% of patients from the D-Rd vs Rd arm, respectively. The most common (≥20%) grade 3/4 TEAEs with D-Rd vs Rd were neutropenia (54.1% vs 37.0%, respectively) and anemia (17.0% vs 21.6%, respectively). Grade 3/4 infections occurred in 42.6% vs 29.6% of patients from the D-Rd vs Rd arm, respectively. Serious TEAEs occurred in 78.8% vs 71.0% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (18.7% vs 10.7%, respectively). The overall discontinuation rate due to TEAEs was lower in the D-Rd vs Rd arm (14.6% vs 23.8%). TEAEs leading to death were reported in 9.9% vs 9.3% of patients from the D-Rd vs Rd arm, respectively.
    • Facon et al (2024)5 presented the results of the updated efficacy and safety analysis of the MAIA study. At a median follow-up of 89.3 months (range, 0-102.2), a 33% reduction in the risk of death was observed with the D-Rd vs Rd arms. Median OS was reached for the D-Rd arm and was prolonged for patients in the D-Rd vs Rd arms (90.3 vs 64.1 months [HR, 0.67; 95% CI, 0.55-0.82; nominal P<0.0001]). The median time to subsequent antimyeloma therapy was 42.4 months in the Rd arm and NR in the D-Rd arm (HR, 0.51; 95% CI, 0.41-0.63; nominal P<0.0001). Deaths were reported for 47.5% (n=173) of patients in the D-Rd arm and 59.7% (n=218) of patients in the Rd arm, mostly due to disease progression.
  • LYRA is a phase 2 study evaluating the safety and efficacy of DARZALEX when administered in combination VCd for the treatment of MM in patients who have not received previous treatment or have relapsed after receiving only 1 line of treatment.6-8
    • Yimer et al (2022)8 reported the end-of-study analysis of LYRA. At the end of cycle 4, ≥VGPR was achieved by 57.1% patients in the relapsed multiple myeloma (RMM) arm and 44.2% patients in the NDMM arm. The median PFS was 21.7 months in the RMM arm and NR in the NDMM arm (both in patients who received and did not receive transplant). The ORR was 86% in the RMM arm, 97% in the NDMM transplant arm, and 83% in the NDMM non-transplant arm. The most frequent any-grade TEAE was fatigue (68.6%). Grade 3/4 TEAEs occurred in 62.8% of patients with the most frequent being neutropenia (12.8%).
  • EQUULEUS is a phase 1b multicenter study evaluating the safety and efficacy of DARZALEX when administered in combination with various treatment regimens, including KRd, for the treatment of NDMM for transplant eligible and non-eligible patients.9,10
  • CEPHEUS is an ongoing phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO + bortezomib, lenalidomide, and dexamethasone (D-VRd) vs VRd alone in patients with NDMM who are transplant ineligible or for whom transplant is not planned as initial therapy (transplant deferred).11-13
    • Usmani et al (2025)13 reported results from the phase 3 CEPHEUS study. At a median follow-up of 58.7 months (range, 0.1-64.7), the overall MRD-negativity (10-5 sensitivity with ≥CR) rate was significantly higher with D-VRd vs VRd (60.9% vs 39.4%; odds ratio [OR], 2.37; 95% CI, 1.58-3.55; P<0.0001). Similarly, the sustained MRD-negativity (10-5 sensitivity; ≥12 months) rate was significantly higher in the D-VRd vs VRd arm (48.7% vs 26.3%; OR, 2.63; 95% CI, 1.73-4; P<0.0001). The overall ≥CR rate was significantly higher with D-VRd vs VRd (81.2% vs 61.6%; OR, 2.73; 95% CI, 1.71-4.34; P<0.0001). Further, D-VRd significantly improved the PFS (HR, 0.57; 95% CI, 0.41-0.79; P=0.0005) with 43% reduction in the risk of progression or death vs VRd. The OS rate favored the D-VRd vs VRd arm (HR, 0.85; 95% CI, 0.58-1.24). Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%). The overall safety data were consistent with the established safety profile of each individual drug.
    • Zweegman et al (2024)14 presented an expanded analysis of MRD outcomes from the CEPHEUS study in patients with NDMM who were ineligible for a stem cell transplant (SCT) or were transplant deferred. D-VRd improved cumulative MRD-negativity rates (at both 10-5 and 10-6 sensitivities) vs VRd alone at all prespecified timepoints. At 54 months, among patients who achieved both MRD-negativity (10-6 sensitivity) and ≥CR with D-VRd, >85% were alive and progression free. Results of analyses of MRD-negativity (with ≥CR) rates for D-VRd vs VRd were generally consistent across prespecified subgroups.
  • PLEIADES is a phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM, including D-VMP in NDMM.15
    • Moreau et al (2020)15 presented the updated safety and efficacy results of the PLEIADES study at a median follow-up of 25.2 months. Among patients with NDMM who received D-VMP, the ORR was 89.6%, and the MRD-negativity rate was 25.4%. Grade 3/4 TEAEs were reported in 78% of patients; the most common (≥20%) being thrombocytopenia (45%), neutropenia (37%), and lymphopenia (22%).
  • IFM2017-03 was a prospective, randomized, open-label, active-controlled, parallel-group, multicenter, phase 3 study assessing the safety and efficacy of DARZALEX FASPRO in combination with lenalidomide and dexamethasone (DR) vs Rd in elderly frail patients with NDMM who were not eligible for high-dose chemotherapy and ASCT.16 
    • Manier et al (2024)17 presented results from the IFM2017-03 study. The median PFS was prolonged for patients in the DR vs Rd arm (48.5 vs 21.5 months [HR, 0.52; 95% CI, 0.35-0.77; P=0.0001]). The median OS was not reached in the DR arm and was 36.0 months in the Rd arm (HR, 0.46; 95% CI, 0.31-0.69; P=0.0001). At least 1 adverse event (AE) of grade ≥3 occurred in 88% of patients in DR arm and 77% of patients in the Rd arm. 
  • Other relevant literature has been identified in addition to the data summarized above.18-27

PRODUCT LABELING

CLINICAL DATA

DARZALEX in Combination With Bortezomib, Melphalan, and Prednisone

ALCYONE (MMY3007; NCT02195479) is a multicenter, randomized, open-label, active-controlled, phase 3 study evaluating the safety and efficacy of D-VMP compared with VMP alone for the treatment of NDMM in patients (N=706) who were ineligible for high-dose chemotherapy with ASCT.1 Mateos et al (2018)1reported results of a planned interim analysis from the ongoing ALCYONE study with a median follow-up of 16.5 months. Mateos et al (2022)2 presented an 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 of the updated analysis is summarized below.

Results

Patient Characteristics
  • A total of 706 patients were randomized (D-VMP, n=350; VMP, n=356) in the ALCYONE study.
  • The median duration of follow-up was 78.8 months.
  • At data cutoff, all patients had either discontinued or completed 9 cycles of VMP therapy.
  • Patient characteristics in the intention-to-treat (ITT) population is summarized in Table: Summary of Patient Characteristics (ALCYONE).

Summary of Patient Characteristics (ALCYONE)2
Parameter
D-VMP (n=350)
VMP (n=356)
Patients treateda, n (%)
346 (98.9)
354 (99.4)
Patients still on treatmentb, n (%)
86 (24.9)
0 (0.0)
Patients who discontinued treatmentb, n (%)
260 (75.1)
118 (33.3)
Reason for discontinuation, n (%)
   Progressive disease
164 (47.4)
47 (13.3)
   Adverse event
32 (9.2)
34 (9.6)
   Death
26 (7.5)
8 (2.3)
   Noncompliance with study drug
16 (4.6)
15 (4.2)
   Patient withdrawal
10 (2.9)
6 (1.7)
   Physician decision
4 (1.2)
7 (2)
   Lost to follow-up
2 (0.6)
0 (0.0)
   Other
6 (1.7)
1 (0.3)
Abbreviations: D-VMP, daratumumab + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone.
aPercentages are based on the number of patients randomized.
bPercentages are based on the number of patients treated.
Efficacy
  • In the D-VMP vs VMP arm, the median PFS was 37.3 vs 19.7 months (HR, 0.43; 95% CI, 0.36-0.52; P<0.0001) and the 72-month PFS rate was 31.9% vs 7%.
  • 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 Prespecified Subgroups (ALCYONE)2
Subgroup
D-VMP
VMP
HR (95% CI)a
n/N
Median OS (months)
n/N
Median OS (months)
Sex
   Male
78/160
72.7
94/167
50.7
0.70 (0.52-0.95)
   Female
82/190
83
113/189
55.1
0.60 (0.45-0.79)
Age
   <75 years
105/246
85.5
137/249
56.6
0.62 (0.48-0.80)
   ≥75 years
55/104
59.1
70/107
49.7
0.71 (0.50-1.01)
Race
   White
142/297
81
182/304
52.9
0.66 (0.53-0.82)
   Other
18/53
NE
25/52
78.1
0.55 (0.30-1.01)
Region
   Europe
137/289
82.2
177/295
53.6
0.66 (0.53-0.83)
   Other
23/61
NE
30/61
57.9
0.57 (0.33-0.98)
Baseline renal function (CrCl)
   >60 mL/min
92/200
83
113/211
57.9
0.71 (0.54-0.94)
   ≤60 mL/min
68/150
79.2
94/145
48.1
0.55 (0.40-0.76)
Baseline hepatic function
   Normal
140/301
82.2
173/303
55.7
0.68 (0.54-0.85)
   Impaired
20/46
NE
34/52
40.7
0.51 (0.29-0.89)
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)
Type of MM
   IgG
98/207
81
124/218
58.2
0.71 (0.54-0.92)
   Non-IgG
43/82
72.5
51/83
46.2
0.67 (0.45-1.01)
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)
ECOG PS score
   0
22/78
NE
55/99
53.7
0.35 (0.21-0.57)
   1-2
138/272
72.5
152/257
52.9
0.73 (0.58-0.92)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-VMP, daratumumab + bortezomib + melphalan + prednisone; del, deletion; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IgG, immunoglobulin G; ISS, International Staging System; MM, multiple myeloma; 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).

Summary of MRD-Negativity Rates and Sustained MRD-Negativity Rates in ITT Population (ALCYONE)2
Parameter
D-VMP (n=350)
VMP (n=356)
P Value
MRD-negative, n (%)
99 (28.3)
25 (7)
<0.0001
Sustained MRD-negativity, n (%)
   Lasting ≥12 months
49 (14)
10 (2.8)
<0.0001
   Lasting ≥18 months
31 (8.9)
6 (1.7)
<0.0001
Abbreviations: D-VMP, daratumumab + bortezomib + melphalan + prednisone; ITT, intention to treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone.
  • A total of 139 patients in the D-VMP arm, and 235 patients in the VMP arm received subsequent treatment.
    • In the D-VMP vs VMP arm, 5.8% vs 35.3% of patients received DARZALEX-containing treatment in a subsequent line of therapy.

Safety

  • The most common TEAEs are summarized in the Table: Summary of Any Grade (≥15%) and Grade 3/4 (≥5%) TEAEs in the Safety Population (ALCYONE).
  • 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.
  • 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%.

Summary of Any Grade (≥15%) and Grade 3/4 (≥5%) TEAEs in the Safety Population (ALCYONE)2
Event, n (%)
D-VMP (n=346)
VMP (n=354)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
175 (50.6)
140 (40.5)
186 (52.5)
138 (39)
   Thrombocytopenia
173 (50)
120 (34.7)
190 (53.7)
134 (37.9)
   Anemia
112 (32.4)
63 (18.2)
131 (37)
70 (19.8)
   Leukopenia
47 (13.6)
28 (8.1)
53 (15)
30 (8.5)
   Lymphopenia
39 (11.3)
27 (7.8)
36 (10.2)
22 (6.2)
Nonhematologic
   Upper respiratory tract infection
107 (30.9)
8 (2.3)
50 (14.1)
6 (1.7)
   Diarrhea
101 (29.2)
9 (2.6)
87 (24.6)
11 (3.1)
   Peripheral sensory neuropathy
100 (28.9)
5 (1.4)
122 (34.5)
14 (4)
   Pyrexia
89 (25.7)
2 (0.6)
74 (20.9)
2 (0.6)
   Bronchitis
76 (22)
11 (3.2)
27 (7.6)
3 (0.8)
   Nausea
75 (21.7)
3 (0.9)
76 (21.5)
4 (1.1)
   Pneumonia
74 (21.4)
56 (16.2)
19 (5.4)
16 (4.5)
   Back pain
71 (20.5)
8 (2.3)
42 (11.9)
4 (1.1)
   Cough
71 (20.5)
1 (0.3)
27 (7.6)
1 (0.3)
   Constipation
64 (18.5)
3 (0.9)
65 (18.4)
1 (0.3)
   Peripheral edema
68 (19.7)
3 (0.9)
39 (11)
1 (0.3)
   Vomiting
62 (17.9)
5 (1.4)
55 (15.5)
6 (1.7)
   Fatigue
61 (17.6)
12 (3.5)
51 (14.4)
9 (2.5)
   Hypertension
52 (15)
23 (6.6)
11 (3.1)
6 (1.7)
Abbreviations: D-VMP, daratumumab + bortezomib + melphalan + prednisone; VMP, bortezomib + melphalan + prednisone.

Predictive and Prognostic Role of MRD-Negativity and Durability - Analysis of ALCYONE

San-Miguel et al (2021)25 evaluated the predictive and prognostic role of MRD-negativity and durability in patients with NDMM ineligible for transplant.

Results

Patient Characteristics

Demographics and Baseline Characteristics by MRD Durability25
Characteristic
D-VMP
VMP
ITT (n=350)
MRD-negative patients
ITT (n=356)
MRD-negative patients
At any time
(n=94)
≥12 months
(n=49)
Not ≥12 months
(n=45)
At any time (n=25)
≥12 months (n=10)
Not ≥12 months (n=15)
Age, years
   Median (range)
71
(40-93)
71
(40-93)
71
(40-87)
71
(56-93)
71
(50-91)
73
(52-82)
72
(52-82)
74
(67-82)
   Distribution, n (%)
      <75
246 (70.3)
68 (72.3)
36 (73.5)
32 (71.1)
249 (69.9)
15 (60)
6 (60)
9 (60)
      ≥75
104 (29.7)
26 (27.7)
13 (26.5)
13 (28.9)
107 (30.1)
10 (40)
4 (40)
6 (40)
ISS disease stagea, n (%)
   I
69 (19.7)
16 (17)
9 (18.4)
7 (15.6)
67 (18.8)
5 (20)
2 (20)
3 (20)
   II
139 (39.7)
39 (41.5)
23 (46.9)
16 (35.6)
160 (44.9)
10 (40)
5 (50)
5 (33.3)
   III
142 (40.6)
39 (41.5)
17 (34.7)
22 (48.9)
129 (36.2)
10 (40)
3 (30)
7 (46.7)
Cytogenetic profileb
   Patients evaluated, n
314
88
46
42
302
23
9
14
   Standard-risk
   cytogenetic
   abnormality, n (%)
261 (83.1)
74 (84.1)
40 (87)
34 (81)
257 (85.1)
19 (82.6)
7 (77.8)
12 (85.7)
   High-risk cytogenetic
   abnormalityc, n (%)
53 (16.9)
14 (15.9)
6 (13)
8 (19)
45 (14.9)
4 (17.4)
2 (22.2)
2 (14.3)
      del(17p), n (%)
29 (9.2)
8 (9.1)
4 (8.7)
4 (9.5)
27 (8.9)
3 (13)
1 (11.1)
2 (14.3)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; del, deletion; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone.
All data are n (%) unless otherwise indicated.
aISS staging is derived based on the combination of serum β2-microglobulin and albumin.
bCytogenetic risk status was determined by fluorescence in situ hybridization or karyotype testing.
cHigh risk is defined as having a positive test for any of the del17p, t(14;16), or t(4;14) molecular abnormalities.
Efficacy
  • In the ITT population and among patients with ≥CR, patients receiving the D-VMP regimen achieved higher rates of MRD-negativity and durability compared with VMP. Please see Table: Rates of Sustained MRD-negativity Status in Transplant-ineligible NDMM.
  • In the ITT population, MRD-negative patients had improved PFS compared with MRD-positive patients.
  • Durable MRD-negativity lasting ≥6 months or ≥12 months improved PFS compared with MRD-negative patients who did not maintain MRD-negativity for ≥6 months or ≥12 months.
  • Estimated 36-month rates of time to subsequent anticancer therapy were mostly higher for patients who achieved MRD-negativity at any time vs MRD-positive patients, and for patients with sustained MRD-negativity lasting ≥6 months or ≥12 months compared with those who did not have durable MRD-negativity. Please see Table: Estimated Rates of Patients Without Subsequent Therapy at 36 Months (ITT Population).
  • Estimated 36-month PFS on next line of therapy (PFS2) rate (ITT; D-VMP, n=350; VMP, n=356)28:
    • MRD-negative (10-5) at ≥1 time point: D-VMP: 87% (n=94); VMP: 92% (n=25)
    • MRD-positive: D-VMP: 67.9% (n=256); VMP: 51.9% (n=331)

Rates of Sustained MRD-negativity Status in Transplant-ineligible NDMM25
MRD-negativity (10-5)
(N=706)
D-VMP
VMP
P Valuea
ITT
n=350
n=356
   MRD-negative status, n (%)
94 (26.9)
25 (7)
<0.0001
      ≥6 months sustained
55 (15.7)
16 (4.5)
<0.0001
      ≥12 months sustained
49 (14)
10 (2.8)
<0.0001
≥CR
n=160
n=90
   MRD-negative status, n (%)
94 (58.8)
25 (27.8)
<0.0001
      ≥6 months sustained
55 (34.4)
16 (17.8)
0.0055
      ≥12 months sustained
49 (30.6)
10 (11.1)
0.0006
Abbreviations: CR, complete response ; D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intention-to-treat; MRD, minimal residual disease; NDMM, newly diagnosed multiple myeloma; VMP, bortezomib + melphalan + prednisone.
aP value was calculated using Fisher’s exact test.

Estimated Rates of Patients Without Subsequent Therapy at 36 Months (ITT Population)25
Estimated 36-month time to subsequent anticancer therapy rate, %
D-VMP (n=350)
VMP
(n=356)
MRD-negative (10-5) at ≥1 time point, n (%)
94 (88.7)
25 (75.3)
MRD-positive, n (%)
256 (54.9)
331 (33.2)
Achieved and remained MRD-negative (10-5) for ≥6 months, n (%)
55 (96.3)
16 (93.8)
MRD-negativity not ≥6 months, n (%)
39 (77.2)
9 (38.9)
Achieved and remained MRD-negative (10-5) for ≥12 months, n (%)
49 (95.8)
10 (100)
MRD-negativity not ≥12 months, n (%)
45 (80.5)
15 (57.8)
Abbreviations: D-VMP, DARZALEX + bortezomib + melphalan + prednisone; ITT, intention-to-treat; MRD, minimal residual disease; VMP, bortezomib + melphalan + prednisone.

DARZALEX in Combination With Lenalidomide and Dexamethasone

MAIA (MMY3008; NCT02252172) is an international,  randomized, open-label, active-controlled, multicenter, phase 3 study in patients with NDMM not eligible for high dose chemotherapy and ASCT (N=737).3 Facon et al (2021)29 reported the updated safety and efficacy results in the MAIA study at the prespecified interim OS analysis with a median follow-up of 56.2 months. Facon et al (2025)4 reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months. Facon et al (2024)5 presented updated efficacy and safety results at a median follow-up of 89.3 months.


Study Design/Methods

  • Eligible patients were randomized 1:1 to receive 28-day cycles of D-Rd or Rd until progressive disease (PD) or unacceptable toxicity at the following dosage3,30:
    • D-Rd arm:
      • DARZALEX: 16 mg/kg IV weekly (QW) during cycles 1-2, every 2 weeks (Q2W) during cycles 3-6, then every 4 weeks (Q4W) during cycle 7+
      • Lenalidomide: 25 mg orally (PO) daily on days 1-21
      • Dexamethasone: 40 mg PO on days 1, 8, 15, and 22
    • Rd arm:
      • Lenalidomide and dexamethasone at the same dosage as the D-Rd arm.

Long-term Efficacy and Safety Analysis of the MAIA Study

Facon et al (2025)4 reported the updated efficacy and safety results from the MAIA study at a long-term median follow-up of 64.5 months.

Results

Patient Characteristics

Demographic and Baseline Disease Characteristics of the ITT Population31
Characteristic
D-Rd
(n=368)
Rd
(n=369)
Age
   Median (range), years
73.0 (50-90)
74.0 (45-89)
ECOG PSa, n (%)
   0
127 (34.5)
123 (33.3)
   1
178 (48.4)
187 (50.7)
   ≥2
63 (17.1)
59 (16.0)
ISS disease stageb, n (%)
   I
98 (26.6)
103 (27.9)
   II
163 (44.3)
156 (42.3)
   III
107 (29.1)
110 (29.8)
Type of measurable disease, n (%)
   IgG
225 (61.1)
231 (62.6)
   IgA
65 (17.7)
66 (17.9)
   Otherc
9 (2.4)
10 (2.7)
   Detected in urine only
40 (10.9)
34 (9.2)
   Detected in serum FLC only
29 (7.9)
28 (7.6)
Cytogenetic riskd
   N
319
323
   Standard risk, n (%)
271 (85.0)
279 (86.4)
   High risk, n (%)
48 (15.0)
44 (13.6)
Median (range) time since initial diagnosis of MM, months
0.95 (0.1-13.3)
0.89 (0-14.5)
Abbreviations: del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; Ig, immunoglobulin; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; Rd, lenalidomide + dexamethasone; t, translocation.
aECOG PS is scored on a scale of 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bISS disease stage was based on the combination of serum β2-microglobulin and albumin.
cIncludes IgD, IgE, IgM, and biclonal disease.
dCytogenetic 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).

Demographic and Baseline Disease Characteristics Based on Age Subgroups31
Characteristic
<70 Years
≥70 to <75 Years
≥75 Years
≥80 Years
D-Rd
(n=78)
Rd
(n=77)
D-Rd
(n=130)
Rd
(n=131)
D-Rd
(n=160)
Rd
(n=161)
D-Rd
(n=66)
Rd
(n=71)
Age
   Median (range), years
68
(50-69)
68
(45-69)
72
(70-74)
72
(70-74)
78
(75-90)
79
(75-89)
82
(79-90)
82
(80-89)
ECOG PSa, n (%)
   0
34 (43.6)
28 (36.4)
42 (32.3)
48 (36.6)
51 (31.9)
47 (29.2)
21 (31.8)
18 (25.4)
   1
31 (39.7)
37 (48.1)
69 (53.1)
67 (51.1)
78 (48.8)
83 (51.6)
32 (48.5)
37 (52.1)
   ≥2
13 (16.7)
12 (15.6)
19 (14.6)
16 (12.2)
31 (19.4)
31 (19.3)
13 (19.7)
16 (22.5)
ISS disease stageb, n (%)
   I
31 (39.7)
25 (32.5)
34 (26.2)
41 (31.3)
33 (20.6)
37 (23.0)
13 (19.7)
13 (18.3)
   II
21 (26.9)
32 (41.6)
67 (51.5)
54 (41.2)
75 (46.9)
70 (43.5)
27 (40.9)
28 (39.4)
   III
26 (33.3)
20 (26.0)
29 (22.3)
36 (27.5)
52 (32.5)
54 (33.5)
26 (39.4)
30 (42.3)
Type of measurable disease, n (%)
   IgG
44 (56.4)
45 (58.4)
79 (60.8)
82 (62.6)
102 (63.8)
104 (64.6)
41 (62.1)
41 (57.7)
   IgA
13 (16.7)
18 (23.4)
26 (20.0)
21 (16.0)
26 (16.3)
27 (16.8)
13 (19.7)
10 (14.1)
   Otherc
2 (2.6)
1 (1.3)
2 (1.5)
4 (3.1)
5 (3.1)
5 (3.1)
2 (3.0)
4 (5.6)
   Detected in urine only
12 (15.4)
9 (11.7)
12 (9.2)
12 (9.2)
16 (10.0)
13 (8.1)
4 (6.1)
8 (11.3)
   Detected in serum FLC only
7 (9.0)
4 (5.2)
11 (8.5)
12 (9.2)
11 (6.9)
12 (7.5)
6 (9.1)
8 (11.3)
Cytogenetic riskd, n (%)
   N
66
66
112
119
141
138
57
60
   Standard risk
56 (84.8)
58 (87.9)
98 (87.5)
103 (86.6)
117 (83.0)
118 (85.5)
47 (82.5)
52 (86.7)
   High risk
10 (15.2)
8 (12.1)
14 (12.5)
16 (13.4)
24 (17.0)
20 (14.5)
10 (17.5)
8 (13.3)
Median (range) time since initial diagnosis of MM, months
0.85 (0.2-6.2)
0.82 (0.3-14.5)
0.90 (0.1-8.7)
0.95 (0.2-9.2)
0.95 (0.2-13.3)
0.92 (0.0-9.2)
1.02 (0.2-13.3)
0.95 (0.0-9.2)
Abbreviations: del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; Ig, immunoglobulin; ISS, International Staging System; MM, multiple myeloma; Rd, lenalidomide+dexamethasone; t, translocation.
aECOG PS is scored on a scale of 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bISS disease stage was based on the combination of serum β2-microglobulin and albumin.
cIncludes IgD, IgE, IgM, and biclonal disease.
dCytogenetic 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).

Treatment Exposure in the Overall Safety Population31
Parameter
D-Rd
(n=364)
Rd
(n=365)
Median (range) number of treatment cycles
51 (1-83)
24 (1-82)
Relative dose intensity
DARZALEX
      n
364
0
      Median (range), %
98.0 (3.2-107.0)
-
Lenalidomide
      n
326
338
      Median (range), %
65.0 (7.9-202.1)
83.4 (4.8-239.3)
Dexamethasone
      n
364
365
      Median (range), %
76.5 (21.9-110.7)
84.8 (18.9-154.5)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone.

Patient Disposition and Treatment Discontinuation According to Age Group (MAIA - Long-term Follow-up)4,31
Parameter
<70 Years
≥70 to <75 Years
≥75 Years
≥80 Years
D-Rd (n=78)
Rd (n=77)
D-Rd (n=130)
Rd (n=131)
D-Rd (n=160)
Rd (n=161)
D-Rd (n=66)
Rd (n=71)
Patients treateda, n (%)
78
(100)
76
(98.7)
129
(99.2)
130
(99.2)
157
(98.1)
159
(98.8)
65
(98.5)
70
(98.6)
Patients who discontinued treatmentb, n (%)
37
(47.4)
64
(84.2)
79
(61.2)
106
(81.5)
117
(74.5)
141
(88.7)
44
(67.7)
64
(91.4)
   Reasons for discontinuation, n (%)
      PD
17 (21.8)
34 (44.7)
42 (32.6)
47 (36.2)
48 (30.6)
50 (31.4)
20 (30.8)
22 (31.4)
      AE
9 (11.5)
12 (15.8)
20 (15.5)
33 (25.4)
28 (17.8)
44 (27.7)
6 (9.2)
21 (30.0)
      Noncompliance with study drug
5 (6.4)
5 (6.6)
7 (5.4)
7 (5.4)
9 (5.7)
18 (11.3)
5 (7.7)
7 (10.0)
      Death
5 (6.4)
2 (2.6)
5 (3.9)
7 (5.4)
14 (8.9)
16 (10.1)
6 (9.2)
6 (8.6)
      Physician’s decision
1 (1.3)
9 (11.8)
3 (2.3)
7 (5.4)
12 (7.6)
8 (5.0)
3 (4.6)
6 (8.6)
      Patient withdrawal
0 (0)
2 (2.6)
1 (0.8)
3 (2.3)
1 (0.6)
3 (1.9)
0 (0)
0 (0)
      Lost to follow-up
0 (0)
0 (0)
0 (0)
0 (0)
1 (0.6)
2 (1.3)
1 (1.5)
2 (2.9)
      Other
0 (0)
0 (0)
1 (0.8)
2 (1.5)
4 (2.5)
0 (0)
3 (4.6)
0 (0)
Abbreviations: AE, adverse event; D-Rd, DARZALEX + lenalidomide + dexamethasone; PD, progressive disease; Rd, lenalidomide + dexamethasone.
aPercentages are based on the number of patients randomized.
bPercentages are based on the number of patients treated.
Efficacy
  • The median PFS was 61.9 months vs 34.4 months in the D-Rd vs Rd arm, respectively (HR, 0.55; 95% CI, 0.45-0.67; P<0.0001).4
  • The most common reasons for confirmed PD in each group were biochemical (D-Rd, 76.2%; Rd, 83.6%), bone lesions (D-Rd, 16.4%; Rd, 13.6%), plasmacytomas (D-Rd, 8.2%; Rd, 4.5%), and other causes (D-Rd, 1.6%; Rd, 2.3%).4
  • The median OS was NR in the D-Rd arm and was 65.5 months in the Rd arm (HR, 0.66; 95% CI, 0.53-0.83; P=0.0003).4
    • The estimated 60-month OS rate was 66.6% vs 53.6% in the D-Rd vs Rd arm, respectively.
    • OS improved with D-Rd vs Rd across subgroups of patients based on age as summarized in Table: PFS and OS Based on Age Subgroups:
    • The OS benefit with D-Rd vs Rd was consistent across prespecified patient subgroups based on baseline characteristics as presented in Table: Analysis of OS in Prespecified Patient Subgroups.
  • The D-Rd vs Rd arm showed a significantly higher (all P<0.0001) ORR (92.9% vs 81.6%), ≥CR rate (51.1% vs 30.1%), and ≥VGPR rate (81.5% vs 56.9%) as presented in Table: Response Rates in the ITT Population.
    • The ORR, ≥CR rate, and ≥VGPR rate were higher for the D-Rd vs Rd arm across all age subgroups and are summarized in Table: Response Rates Based on Age Subgroups.
    • The cumulative best response rate improved with continuous D-Rd treatment in patients who achieved ≥CR and ≥VGPR.
    • Continued D-Rd treatment markedly deepened the best response rate over time, with the ≥CR rate increasing from 8.2% by 6 months to 28.0% by 12 months, 40.8% by 18 months, 45.4% by 24 months, 48.1% by 30 months, and 51.1% by 48 months.
    • For patients who achieved ≥CR:
      • The median PFS was NR in either treatment arm (HR, 0.52; 95% CI, 0.35-0.76; P=0.0007).
      • The estimated 60-month PFS rate was 73.7% vs 53.8% in the D-Rd vs Rd arm, respectively.
      • The median OS was NR in either treatment arm (HR, 0.58; 95% CI, 0.37-0.91; P=0.0164).
      • The estimated 60-month OS rate was 81.7% vs 69.1% in the D-Rd vs Rd arm, respectively.
    • For patients who achieved VGPR:
      • The median PFS was 42.7 months vs 36.2 months in the D-Rd vs Rd, respectively (HR, 0.71; 95% CI, 0.51-0.99; P=0.0401).
      • The estimated 60-month PFS rate was 37.1% vs 23.2% in the D-Rd vs Rd arm, respectively.
      • The median OS was NR in the D-Rd arm and was 63.1 months in the Rd arm (HR, 0.78; 95% CI, 0.53-1.16; P=0.2256).
      • The estimated 60-month OS rate was 61.5% vs 53.0% in the D-Rd vs Rd arm, respectively.
  • The D-Rd vs Rd arm showed a significantly higher (all P<0.0001) MRD-negativity rate (10-5 sensitivity; 32.1% vs 11.1%) and sustained MRD-negativity rate (10-5 sensitivity; ≥12 months, 18.8% vs 4.1%; ≥18 months, 16.8% vs 3.3%) as summarized in Table: Response Rates in the ITT Population.4
    • The MRD-negativity response rate deepened over time, increasing from 12.8% at 12 months to 20.4% at 18 months, 24.2% at 24 months, 27.4% at 30 months, 29.3% at 36 months, 31.5% at 48 months, and 31.8% at 60 months.
    • The D-Rd vs Rd arm was associated with an increased MRD-negativity rate across all age subgroups as summarized in Table: Response Rates Based on Age Subgroups.
    • PFS and OS improved in patients who achieved MRD-negativity vs those who were MRD-positive in both treatment arms, with more patients in the D-Rd arm achieving MRD-negativity.
  • A total of 128 (35.2%) vs 194 (53.2%) patients from the D-Rd vs Rd arm, respectively, received subsequent therapy.4
    • In the D-Rd vs Rd arm, 9.4% vs 23.2% of patients received DARZALEX-containing treatment as their first subsequent therapy, respectively.
    • In the D-Rd vs Rd arm, 14.1% vs 48.5% of patients received DARZALEX-containing treatment as any subsequent line of therapy, respectively.
    • PFS on next line of therapy was 73.7 months vs 48.9 months in the D-Rd vs Rd arm, respectively (HR, 0.61; 95% CI, 0.49-0.76; P<0.0001).

Analysis of PFS in Prespecified Patient Subgroupsa,31
Subgroup
D-Rd
Rd
HR (95% CI)b
n/N
Median PFS, Months
n/N
Median PFS, Months
Sex
   Male
91/189
61.9
120/195
32.3
0.57 (0.44-0.76)
   Female
85/179
62.1
108/174
35.4
0.54 (0.40-0.71)
Age
   <75 years
89/208
NE
122/208
37.5
0.52 (0.39-0.68)
   ≥75 years
87/160
54.3
106/161
31.4
0.59 (0.44-0.79)
Race
   White
161/336
61.9
208/339
34.5
0.55 (0.45-0.67)
   Other
15/32
62.1
20/30
30.4
0.59 (0.30-1.16)
Region
   North America
49/101
58.2
60/102
30.4
0.57 (0.39-0.83)
   Other
127/267
61.9
168/267
36.9
0.55 (0.43-0.69)
Baseline renal function (CrCl)
   >60 mL/min
94/206
73.7
136/227
37.4
0.54 (0.41-0.70)
   ≤60 mL/min
82/162
56.7
92/142
29.7
0.55 (0.41-0.75)
Baseline hepatic function
   Normal
157/335
62.8
211/340
33.8
0.52 (0.43-0.65)
   Impaired
19/31
29.2
17/29
35.1
0.99 (0.51-1.91)
ISS disease stage
   I
38/98
NE
48/103
52.5
0.65 (0.42-1.00)
   II
77/163
63.8
107/156
29.7
0.46 (0.34-0.62)
   III
61/107
42.4
73/110
24.2
0.61 (0.43-0.86)
Type of MM
   IgG
112/225
60.7
135/231
38.7
0.69 (0.53-0.88)
   Non-IgG
34/74
63.8
53/76
23.5
0.39 (0.25-0.60)
Cytogenetic risk at study entry
   High riskc
28/48
45.3
31/44
29.6
0.57 (0.34-0.96)
   Standard risk
126/271
63.8
174/279
34.4
0.51 (0.41-0.64)
ECOG PS
   0
54/127
NE
74/123
39.6
0.51 (0.36-0.72)
   1
90/178
58.2
113/187
35.1
0.58 (0.44-0.77)
   ≥2
32/63
48.4
41/59
23.5
0.56 (0.35-0.89)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IgG, immunoglobulin G; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; NE, not estimable; PFS, progression-free survival; Rd, lenalidomide + dexamethasone; t, translocation.
aAnalysis of PFS in subgroups of the ITT population, which were defined according to baseline characteristics.
bHRs and 95% CIs from a Cox proportional hazards model with treatment as the sole explanatory variable. HR <1 indicates an advantage for D-Rd.
cPatients at a high cytogenetic risk tested positive for ≥1 of the following cytogenetic abnormalities on fluorescence in situ hybridization or karyotype testing: del(17p), t(14;16), or t(4;14).

Analysis of OS in Prespecified Patient Subgroupsa,31
Subgroup
D-Rd
Rd
HR (95% CI)b
n/N
Median OS, Months
n/N
Median OS, Months
Sex
   Male
76/189
NE
101/195
61.0
0.71 (0.53-0.96)
   Female
56/179
73.7
75/174
68.6
0.63 (0.45-0.89)
Age
   <75 years
59/208
NE
90/208
NE
0.59 (0.43-0.83)
   ≥75 years
73/160
73.7
86/161
54.8
0.75 (0.55-1.02)
Race
   White
120/336
NE
158/339
66.4
0.69 (0.54-0.87)
   Other
12/32
NE
18/30
49.1
0.52 (0.25-1.07)
Region
   North America
36/101
NE
52/102
54.8
0.60 (0.39-0.92)
   Other
96/267
NE
124/267
66.9
0.70 (0.54-0.91)
Baseline renal function (CrCl)
   >60 mL/min
70/206
NE
102/227
68.6
0.67 (0.49-0.90)
   ≤60 mL/min
62/162
NE
74/142
54.8
0.65 (0.46-0.90)
Baseline hepatic function
   Normal
117/335
NE
164/340
65.4
0.63 (0.50-0.80)
   Impaired
15/31
66.1
12/29
NE
1.23 (0.57-2.63)
ISS disease stage
   I
21/98
NE
29/103
NE
0.71 (0.40-1.24)
   II
60/163
73.7
79/156
61.7
0.62 (0.44-0.87)
   III
51/107
66.1
68/110
47.3
0.69 (0.48-1.00)
Type of MM
   IgG
83/225
NE
102/231
68.6
0.78 (0.58-1.04)
   Non-IgG
26/74
NE
40/76
53.7
0.54 (0.33-0.88)
Cytogenetic risk at study entry
   High riskc
27/48
55.6
28/44
42.5
0.81 (0.48-1.38)
   Standard risk
90/271
NE
131/279
65.5
0.62 (0.48-0.81)
ECOG PS
   0
28/127
NE
41/123
NE
0.62 (0.38-1.01)
   1
73/178
73.7
96/187
58.3
0.70 (0.51-0.95)
   ≥2
31/63
61.9
39/59
39.0
0.61 (0.38-0.97)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IgG, immunoglobulin G; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; NE, not estimable; OS, overall survival; Rd, lenalidomide + dexamethasone; t, translocation.
aAnalysis of OS in subgroups of the ITT population, which were defined according to baseline characteristics.
bHRs and 95% CIs from a Cox proportional hazards model with treatment as the sole explanatory variable. HR <1 indicates an advantage for D-Rd.
cPatients at a high cytogenetic risk tested positive for ≥1 of the following cytogenetic abnormalities on fluorescence in situ hybridization or karyotype testing: del(17p), t(14;16), or t(4;14).

Response Rates in the ITT Population4
Response, n (%)
D-Rd
(n=368)
Rd
(n=369)
P Value
ORR
342 (92.9)
301 (81.6)
<0.0001a
   ≥CR
188 (51.1)
111 (30.1)
<0.0001a
      sCR
131 (35.6)
58 (15.7)
<0.0001a
      CR
57 (15.5)
53 (14.4)
-
  ≥VGPR
300 (81.5)
210 (56.9)
<0.0001a
      VGPR
112 (30.4)
99 (26.8)
-
   PR
42 (11.4)
91 (24.7)
-
SD
11 (3.0)
55 (14.9)
-
PD
1 (0.3)
0 (0)
-
NE
14 (3.8)
13 (3.5)
-
MRD-negativity response rate (10-5 sensitivity), n (%)
118 (32.1)
41 (11.1)
<0.0001b
Sustained MRD-negativity response rate (10-5 sensitivity), n (%)
≥12 months
69 (18.8)
15 (4.1)
<0.0001b
≥18 months
62 (16.8)
12 (3.3)
<0.0001b
Abbreviations: CR, complete response; D-Rd, DARZALEX + lenalidomide + dexamethasone; ITT, intention-to-treat; NE, not estimable; ORR, overall response rate; PD, progressive disease; PR, partial response; Rd, lenalidomide + dexamethasone; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.
aP value was calculated using the Cochran-Mantel-Haenszel chi-square test.
bP value was calculated using the Fisher’s exact test.

Response Rates Based on Age Subgroups4
Response, n (%)
Age <70 Years
Age ≥70 to <75 Years
Age ≥75 Years
Age ≥80 Years
D-Rd
(n=78)
Rd
(n=77)
P Value
D-Rd
(n=130)
Rd
(n=131)
P Value
D-Rd
(n=160)
Rd
(n=161)
P Value
D-Rd
(n=66)
Rd
(n=71)
P Value
ORR
73 (93.6)
62 (80.5)
0.0156a
125 (96.2)
108 (82.4)
0.0004a
144 (90.0)
131 (81.4)
0.0275a
59 (89.4)
55 (77.5)
0.0629a
   ≥CR
44 (56.4)
24 (31.2)
0.0016a
73 (56.2)
41 (31.3)
<0.0001a
71 (44.4)
46 (28.6)
0.0033a
29 (43.9)
15 (21.1)
0.0044a
      sCR
31 (39.7)
11 (14.3)
0.0004a
50 (38.5)
23 (17.6)
0.0002a
50 (31.3)
24 (14.9)
0.0005
23 (34.8)
8 (11.3)
0.0010a
      CR
13 (16.7)
13 (16.9)
-
23 (17.7)
18 (13.7)
-
21 (13.1)
22 (13.7)
-
6 (9.1)
7 (9.9)
-
   ≥VGPR
64 (82.1)
45 (58.4)
0.0013a
111 (85.4)
76 (58.0)
<0.0001a
125 (78.1)
89 (55.3)
<0.0001a
50 (75.8)
31 (43.7)
0.0001a
      VGPR
20 (25.6)
21 (27.3)
-
38 (29.2)
35 (26.7)
-
54 (33.8)
43 (26.7)
-
21 (31.8)
16 (22.5)
-
   PR
9 (11.5)
17 (22.1)
-
14 (10.8)
32 (24.4)
-
19 (11.9)
42 (26.1)
-
9 (13.6)
24 (33.8)
-
SD
1 (1.3)
14 (18.2)
-
3 (2.3)
20 (15.3)
-
7 (4.4)
21 (13.0)
-
3 (4.5)
11 (15.5)
-
PD
0 (0)
0 (0)
-
0 (0)
0 (0)
-
1 (0.6)
0 (0)
-
0 (0)
0 (0)
-
NE
4 (5.1)
1 (1.3)
-
2 (1.5)
3 (2.3)
-
8 (5.0)
9 (5.6)
-
4 (6.1)
5 (7.0)
-
MRD-negativity response rate, n (%)
28 (35.9)
9 (11.7)
0.0006
47 (36.2)
16 (12.2)
0.0001
43 (26.9)
16 (9.9)
0.0001
17 (25.8)
4 (5.6)
0.0016
Abbreviations: CR, complete response; D-Rd, DARZALEX + lenalidomide + dexamethasone; MRD, minimal residual disease; NE, not estimable; ORR, overall response rate; PD, progressive disease; PR, partial response; Rd, lenalidomide + dexamethasone; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response.
aP value was calculated using the Cochran-Mantel-Haenszel chi-square test.

PFS and OS Based on Age Subgroups4
Parameter
Age <70 Years
Age ≥70 to <75 Years
Age ≥75 Years
Age ≥80 Years
D-Rd
(n=78)
Rd
(n=77)
HR (95% CI)
P Value
D-Rd
(n=130)
Rd
(n=131)
HR (95% CI)
P Value
D-Rd
(n=160)
Rd
(n=161)
HR (95% CI)
P Value
D-Rd
(n=66)
Rd
(n=71)
HR (95% CI)
P Value
PFS
Median,  months
NR
39.2
0.35 (0.21-0.56)
<0.0001
61.9
37.5
0.64 (0.45-0.89)
0.0079
54.3
31.4
0.59 (0.44-0.79)
0.0003
52.2
30.4
0.48 (0.31-0.76)
0.0011
OS
   Median, months
-
-
0.50 (0.27-0.90)
0.0179
-
-
0.64 (0.43-0.96)
0.0274
-
-
0.75 (0.55-1.02)
0.0671
-
-
0.71 (0.44-1.14)
0.1574
Abbreviations: CI, confidence interval; D-Rd, DARZALEX + lenalidomide + dexamethasone; HR, hazard ratio; NR, not reachable; OS, overall survival; Rd, lenalidomide + dexamethasone.
Safety
  • At clinical cutoff, 52 patients from the D-Rd arm discontinued lenalidomide ± dexamethasone but remained on the rest of the study treatment; 46 (88.5%) of these patients discontinued due to AEs.4
    • The median time to lenalidomide discontinuation was 37.8 months (range, 1-70).
    • The median duration of DARZALEX treatment was 66.2 months (range, 56-77).
    • The estimated 60-month PFS and OS rates were 98.1% and 100.0%, respectively.
    • Of the aforementioned 52 patients, 13 (25.0%) discontinued lenalidomide but continued DARZALEX + dexamethasone and 39 (75.0%) discontinued lenalidomide + dexamethasone and continued DARZALEX monotherapy.
      • In the 39 patients who discontinued lenalidomide + dexamethasone and continued DARZALEX monotherapy, the median time to discontinuation was 39.1 months (range, 3-67) and the median DARZALEX treatment duration was 65.6 months (range, 56-73). The estimated 60-month PFS and OS rates were 97.4% and 100.0%, respectively.
      • One patient in the D-Rd arm stopped DARZALEX after 15 days due to AEs but continued lenalidomide treatment without progression at the clinical cutoff.
  • No new safety concerns were observed with a longer follow-up.4
    • Grade 3/4 TEAEs occurred in 95.9% vs 88.8% of patients from the D-Rd vs Rd arm, respectively.
    • Grade 3/4 infections occurred in 42.6% vs 29.6% of patients from the D-Rd vs Rd arm, respectively.
    • Serious TEAEs occurred in 78.8% vs 71.0% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (18.7% vs 10.7%, respectively).
      • Among patients aged ≥75 years, serious TEAEs occurred in 80.9% vs 79.2% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (19.7% vs 12.6%, respectively).
      • Among patients aged ≥80 years, serious TEAEs occurred in 81.5% vs 82.9% of patients from the D-Rd vs Rd arm, respectively, with pneumonia being the most common serious TEAE (24.6% vs 8.6%, respectively).
    • The overall discontinuation rate due to TEAEs was lower in the D-Rd vs Rd arm (14.6% vs 23.8%).
      • Discontinuation of lenalidomide due to TEAEs was reported in 36.8% vs 24.4% of patients from the D-Rd vs Rd arm, respectively.
      • Discontinuation of dexamethasone due to TEAEs was reported in 39.8% vs 36.2% of patients from the D-Rd vs Rd arm, respectively.
      • Discontinuation of DARZALEX due to TEAEs was reported in 14.6% of patients.
      • Among patients aged ≥75 years, treatment discontinuation due to TEAEs was reported in 15.3% vs 27.7% of patients from the D-Rd vs Rd arm, respectively.
      • Among patients aged ≥80 years, treatment discontinuation due to TEAEs was reported in 6.2% vs 20.0% of patients from the D-Rd vs Rd arm, respectively.
    • TEAEs leading to death were reported in 9.9% vs 9.3% of patients from the D-Rd vs Rd arm, respectively.
      • Among patients aged ≥75 years, TEAEs leading to death were reported in 11.5% vs 13.2% of patients from the D-Rd vs Rd arm, respectively.
      • Among patients aged ≥80 years, TEAEs leading to death were reported in 12.3% vs 11.4% of patients from the D-Rd vs Rd arm, respectively.

Most Common Any-Grade or Grade 3/4 TEAEs in the Safety Populationa,4
TEAE, n (%)
D-Rd (n=364)
Rd (n=365)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
224 (61.5)
197 (54.1)
166 (45.5)
135 (37.0)
   Anemia
154 (42.3)
62 (17.0)
150 (41.1)
79 (21.6)
Nonhematologic
   Diarrhea
240 (65.9)
33 (9.1)
188 (51.5)
22 (6.0)
   Fatigue
164 (45.1)
33 (9.1)
114 (31.2)
17 (4.7)
   Constipation
157 (43.1)
6 (1.6)
137 (37.5)
2 (0.5)
   Peripheral edema
155 (42.6)
10 (2.7)
117 (32.1)
3 (0.8)
   Back pain
155 (42.6)
14 (3.8)
109 (29.9)
14 (3.8)
   Asthenia
136 (37.4)
19 (5.2)
101 (27.7)
18 (4.9)
   Nausea
133 (36.5)
7 (1.9)
88 (24.1)
2 (0.5)
   Insomnia
125 (34.3)
11 (3.0)
116 (31.8)
14 (3.8)
   Bronchitis
124 (34.1)
12 (3.3)
87 (23.8)
7 (1.9)
   Cough
123 (33.8)
2 (0.5)
65 (17.8)
0 (0.0)
   Dyspnea
119 (32.7)
12 (3.3)
63 (17.3)
4 (1.1)
   Pneumonia
113 (31.0)
71 (19.5)
66 (18.1)
39 (10.7)
   Weight decreased
112 (30.8)
10 (2.7)
69 (18.9)
11 (3.0)
   Peripheral sensory neuropathy
111 (30.5)
9 (2.5)
66 (18.1)
2 (0.5)
   Muscle spasms
111 (30.5)
2 (0.5)
86 (23.6)
5 (1.4)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event.
aAny-grade TEAEs that are listed are those that occurred in ≥30% of patients in either group.

Most Common Any-Grade or Grade 3/4 TEAEs Among Patients Aged ≥75 Years and ≥80 Years in the Safety Populationa,31
TEAE, n (%)
Patients Aged ≥75 years
Patients Aged ≥80 years
D-Rd (n=157)
Rd (n=159)
D-Rd (n=65)
Rd (n=70)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
109 (69.4)
98
(62.4)
81
(50.9)
66
(41.5)
45
(69.2)
37
(56.9)
34
(48.6)
26
(37.1)
   Anemia
71 (45.2)
32 (20.4)
73 (45.9)
40 (25.2)
31 (47.7)
12 (18.5)
35 (50.0)
19 (27.1)
   Thrombocytopenia
39 (24.8)
16 (10.2)
43 (27.0)
19 (11.9)
21 (32.3)
7 (10.8)
20 (28.6)
8 (11.4)
   Lymphopenia
37 (23.6)
33 (21.0)
25 (15.7)
20 (12.6)
10 (15.4)
8 (12.3)
13 (18.6)
10 (14.3)
Nonhematologic
   Diarrhea
98 (62.4)
16 (10.2)
80 (50.3)
8 (5.0)
37 (56.9)
5 (7.7)
35 (50.0)
3 (4.3)
   Peripheral edema
76 (48.4)
6 (3.8)
53 (33.3)
2 (1.3)
31 (47.7)
0 (0.0)
24 (34.3)
2 (2.9)
   Constipation
75 (47.8)
2 (1.3)
61 (38.4)
1 (0.6)
27 (41.5)
0 (0.0)
27 (38.6)
1 (1.4)
   Fatigue
73 (46.5)
15 (9.6)
48 (30.2)
8 (5.0)
26 (40.0)
7 (10.8)
19 (27.1)
3 (4.3)
   Back pain
65 (41.4)
7 (4.5)
53 (33.3)
6 (3.8)
24 (36.9)
2 (3.1)
21 (30.0)
2 (2.9)
   Asthenia
58 (36.9)
8 (5.1)
43 (27.0)
10 (6.3)
25 (38.5)
3 (4.6)
26 (37.1)
8 (11.4)
   Weight decreased
49 (31.2)
6 (3.8)
31 (19.5)
5 (3.1)
19 (29.2)
2 (3.1)
16 (22.9)
2 (2.9)
   Bronchitis
48 (30.6)
7 (4.5)
31 (19.5)
4 (2.5)
18 (27.7)
2 (3.1)
15 (21.4)
1 (1.4)
   Nausea
48 (30.6)
2 (1.3)
40 (25.2)
0 (0.0)
21 (32.3)
1 (1.5)
20 (28.6)
0 (0.0)
   Pneumonia
44 (28.0)
32 (20.4)
33 (20.8)
23 (14.5)
22 (33.8)
17 (26.2)
13 (18.6)
8 (11.4)
   Pyrexia
44 (28.0)
6 (3.8)
22 (13.8)
3 (1.9)
20 (30.8)
4 (6.2)
7 (10.0)
0 (0.0)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event.
aAny-grade TEAEs that are listed are those that occurred in ≥30% of patients in either group.

Final Survival Analysis of the MAIA Study

Facon et al (2024)5 presented the updated OS results for the D-Rd vs Rd arm at a long-term median follow-up of around 7.5 years.

Results

Patient Characteristics
Efficacy
  • At a median follow-up of 89.3 months (range, 0-102.2), the 7-year OS rate was 53.1% for the D-Rd arm and 39.3% for the Rd arm.
  • Median OS was reached for the D-Rd group and was prolonged for patients in the D-Rd vs Rd arm (90.3 vs 64.1 months [HR, 0.67; 95% CI, 0.55-0.82; nominal P<0.0001]). See Table: Analysis of OS in PreSpecified Patient Subgroups.
  • Median time to subsequent antimyeloma therapy was 42.4 months in the Rd arm and NR in the D-Rd arm (HR, 0.51; 95% CI, 0.41-0.63; nominal P<0.0001). See Table: Summary of First Subsequent Antimyeloma Therapy in the Safety Population.
    • In the D-Rd vs Rd arm, 10.7% (15/140) vs 24.4% (49/201) of patients received DARZALEX-containing regimens as their first subsequent therapy.
    • Among treated patients, 38.5% (140/364) vs 55.1% (201/365) of patients in the D-Rd vs Rd arm received ≥1 subsequent antimyeloma therapy.
    • Across subsequent therapy lines, the most common antineoplastic agents in the D-Rd vs Rd arms were bortezomib (27.7% vs 41.9%), DARZALEX (6.3% vs 28.8%), and carfilzomib (7.7% vs 12.3%).
    • In patients evaluable for best response to first subsequent antimyeloma therapy, ≥CR was achieved by 4.6% (6/130) vs 4.1% (8/193) in the D-Rd vs Rd arm, and ≥VGPR was achieved by 13.8% (18/130) vs 23.8% (46/193) of patients in the D-Rd vs Rd arm.
    • No patient in either group reported the use of B-cell maturation antigen (BCMA)- or G protein-coupled receptor class C group 5 member D (GPRC5D)-targeted therapy.
    • Investigational drug was given to 2 patients in the D-Rd group and 2 patients in the Rd group in subsequent therapy lines.

Analysis of OS in PreSpecified Patient Subgroupsa,5
Subgroup
D-Rd
Rd
HR (95% CI)b
n/N
Median OS, Months
n/N
Median OS, Months
Sex
   Male
95/189
82.5
120/195
60.6
0.72 (0.55-0.94)
   Female
80/179
NE
98/174
67.8
0.66 (0.49-0.89)
Age
   <75 years
84/208
NE
107/208
79.6
0.69 (0.52-0.92)
   ≥75 years
91/160
72.3
111/161
54.8
0.67 (0.51-0.88)
Race
   White
161/336
92.7
197/339
65.5
0.71 (0.57-0.87)
   Other
14/32
90.3
21/30
49.1
0.50 (0.25-0.99)
Region
   North America
46/101
92.7
64/102
54.8
0.57 (0.39-0.83)
   Other
129/267
90.3
154/267
66.8
0.74 (0.58-0.93)
Baseline renal function (CrCl)
   >60 mL/min
99/206
92.7
123/227
69.9
0.78 (0.60-1.01)
   ≤60 mL/min
76/162
90.3
95/142
54.4
0.57 (0.42-0.77)
Baseline hepatic function
   Normal
156/335
NE
203/340
63.8
0.65 (0.53-0.80)
   Impaired
19/31
63.5
15/29
87.4
1.31 (0.66-2.58)
ISS disease stage
   I
34/98
NE
42/103
NE
0.79 (0.50-1.24)
   II
77/163
92.7
95/156
61.7
0.63 (0.46-0.85)
   III
64/107
65.2
81/110
47.3
0.68 (0.49-0.95)
Type of MM
   IgG
111/225
87.2
132/231
69.3
0.78 (0.60-1.00)
   Non-IgG
35/74
86.4
49/76
53.7
0.58 (0.37-0.89)
Cytogenetic risk at study entryc
   High risk
31/48
55.6
36/44
42.5
0.65 (0.40-1.06)
   Standard risk
122/271
NE
160/279
65.5
0.66 (0.52-0.84)
ECOG PS
   0
48/127
NE
56/123
NE
0.76 (0.52-1.12)
   1
86/178
92.7
118/187
58.3
0.64 (0.48-0.84)
   ≥2
41/63
62.8
44/59
39.0
0.68 (0.44-1.04)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; del, deletion; D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; IgG, immunoglobulin G; ISS, International Staging System; MM, multiple myeloma; NE, not estimable; OS, overall survival; Rd, lenalidomide + dexamethasone; t, translocation.
aIn the ITT population, which included all randomized patients.
bHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable. HR <1 indicates an advantage for D-Rd.
cCytogenetic risk was based on fluorescence in situ hybridization or karyotype analysis; patients who had a high-risk cytogenetic profile had ≥1 of the following high-risk abnormalities: del(17p), t(14;16), or t(4;14).

Summary of First Subsequent Antimyeloma Therapy in the Safety Populationa,5
n (%)
D-Rd
(n=140)
Rd
(n=201)
First subsequent therapy classb,c
   PI only
69 (49.3)
101 (50.2)
   IMiD only
22 (15.7)
25 (12.4)
   PI + IMiD
25 (17.9)
16 (8.0)
   DARZALEX monotherapy or combination
15 (10.7)
49 (24.4)
   Other
9 (6.4)
10 (5.0)
Most common first subsequent therapy regimensb,d
   Bortezomib/cyclophosphamide/dexamethasone
19 (13.6)
29 (14.4)
   Bortezomib/dexamethasone
20 (14.3)
28 (13.9)
   Bortezomib/melphalan/prednisone
14 (10.0)
28 (13.9)
   DARZALEX/bortezomib/dexamethasone
4 (2.9)
27 (13.4)
   Lenalidomide/dexamethasone
13 (9.3)
16 (8.0)
   Bortezomib/pomalidomide/dexamethasone
9 (6.4)
3 (1.5)
   Bortezomib/lenalidomide/dexamethasone
8 (5.7)
3 (1.5)
   DARZALEX/lenalidomide/dexamethasone
4 (2.9)
6 (3.0)
   Pomalidomide/dexamethasone
2 (1.4)
6 (3.0)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; IMiD, immunomodulatory drugs; PI, proteasome inhibitor; Rd, lenalidomide + dexamethasone.
aThe safety population included all randomized patients who received ≥1 dose of study treatment.
bPercentages were calculated with the number of patients who received subsequent therapy in each treatment group as the denominator.
cTherapy classes are mutually exclusive. Patients in any therapy class subgroup may have received additional agents (other than PI, IMiD, or DARZALEX), such as dexamethasone.
dRegimens received by ≥3% of patients in either treatment group.
Safety and Tolerability
  • Among the safety population, 78.3% (n=285) of patients in the D-Rd arm and 94.5% (n=345) in the Rd arm discontinued study treatment.
    • PD was the primary reason for discontinuation in both the D-Rd (32.7%) and Rd arms (38.6%).
    • A lower proportion of patients in the D-Rd (16.5%) and Rd arms (25.8%) discontinued study treatment due to AEs.
  • In the D-Rd vs Rd arm, 33% reduction in the risk of death was reported.

Summary of Death and Causes of Death in the Safety Populationa,5
n (%)
D-Rd
(n=364)
Rd
(n=365)
Total number of patients who died during the study
173 (47.5)
218 (59.7)
   Primary cause of death
      Disease progression
76 (20.9)
88 (24.1)
      Adverse events
44 (12.1)
40 (11.0)
         Related to study treatmentb
14 (3.8)
10 (2.7)
         Unrelated to study treatment
28 (7.7)
29 (7.9)
         Othersc
53 (14.6)
90 (24.7)
         Infections/infestations
9 (2.5)
30 (8.2)
         General disorders/administration site conditionsd
11 (3.0)
5 (1.4)
         Neoplasms (benign, malignant, or unspecified)
11 (3.0)
4 (1.1)
         Cardiac disorders
1 (0.3)
8 (2.2)
         Nervous system disorders
3 (0.8)
5 (1.4)
         Unknown
13 (3.6)
27 (7.4)
Deaths within 30 days of last study treatment dose
31 (8.5)
35 (9.6)
   Primary cause of death
      Disease progression
1 (0.3)
1 (0.3)
      Adverse events
29 (8.0)
32 (8.8)
         Related to study treatmentb
11 (3.0)
10 (2.7)
         Unrelated to study treatment
18 (4.9)
22 (6.0)
         Othere
1 (0.3)
2 (0.5)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone.
aThe safety population included all randomized patients who received ≥1 dose of study treatment.
bAdverse events were related to ≥1 of the 3 components of study treatment: DARZALEX, lenalidomide, and dexamethasone.
cOther reasons were reported in ≥1% of patients in either treatment group.
dAll events were related to the general health condition of the patient.
eIncludes a nervous system disorder in 1 patient in the D-Rd group and a blood and lymphatic system disorder and general disorder/administration site condition in 1 patient each in the Rd group.

DARZALEX in Combination With Bortezomib, Cyclophosphamide and Dexamethasone

LYRA (MMY2012; NCT02951819) is a phase 2 study evaluating the safety and efficacy of DARZALEX when administered in combination with VCd for the treatment of MM in patients who have not received previous treatment or have relapsed after receiving only 1 line of treatment.6-8 Rifkin et al (2019)32 presented updated safety and efficacy results with a median follow-up of 25.8 months for NDMM and 26.6 months for RMM. Yimer et al (2022)8 reported end-of-study analysis results of the LYRA study.

Results

Patient Characteristics
  • Overall, 101 patients were included (RMM, n=14; NDMM, n=87), of whom 100 received ≥1 dose of study treatment (RMM, n=14; NDMM, n=86).8
  • The median follow-up duration was 35.3 months for the RMM arm and 35.7 months for the NDMM arm.8
  • In total, 1 patient with RMM and 39 patients with NDMM received ASCT.8
  • Demographic and baseline characteristics are summarized in Table: Patient Characteristics (LYRA).

Patient Characteristics (LYRA)8
Characteristic
RMM
NDMM
All
(n=14)
All
(n=87)
Transplant
(n=39)
Non-transplant
(n=48)
Median age (range), years
68 (48-78)
63 (41-82)
60 (41-74)
66.5 (41-82)
   <65 years, n (%)
6 (42.9)
46 (52.9)
29 (74.4)
17 (35.4)
   65-74 years, n (%)
4 (28.6)
31 (35.6)
10 (25.6)
21 (43.8)
   ≥75 years, n (%)
4 (28.6)
10 (11.5)
0 (0)
10 (20.8)
Male, n (%)
10 (71.4)
55 (63.2)
22 (56.4)
33 (68.8)
ECOG PS score, n (%)
   0
6 (42.9)
40 (46)
18 (46.2)
22 (45.8)
   1
7 (50)
42 (48.3)
20 (51.3)
22 (45.8)
   2
1 (7.1)
5 (5.7)
1 (2.6)
4 (8.3)
ISS disease stagea, n (%)
   I
2 (14.3)
30 (34.5)
14 (35.9)
16 (33.3)
   II
3 (21.4)
31 (35.6)
15 (38.5)
16 (33.3)
   III
9 (64.3)
26 (29.9)
10 (25.6)
16 (33.3)
Type of measurable diseaseb, n (%)
   IgG
4 (28.6)
47 (54)
22 (56.4)
25 (52.1)
   IgA
1 (7.1)
14 (16.1)
5 (12.8)
9 (18.8)
   Otherc
1 (7.1)
0
0
0
   Urine only
4 (28.6)
17 (19.5)
8 (20.5)
9 (18.8)
   Serum free light chain
4 (28.6)
9 (10.3)
4 (10.3)
5 (10.4)
Median time from MM diagnosis to enrollment (range), months
2.22 (0.4-5.8)
0.08 (0-3.1)
0.08 (0-0.3)
0.08 (0-3.1)
Cytogenetic profiled, n
14
84
37
47
   Standard risk, n (%)
10 (71.4)
53 (63.1)
26 (70.3)
27 (57.4)
   High risk, n (%)
4 (28.6)
31 (36.9)
11 (29.7)
20 (42.6)
      del17p
0 (0)
7 (8.3)
3 (8.1)
4 (8.5)
      t(4;14)
3 (21.4)
20 (23.8)
8 (21.6)
12 (25.5)
      t(14;16)
3 (21.4)
27 (32.1)
10 (27)
17 (36.2)
Abbreviations: del, deletion; ECOG PS, Eastern Cooperative Oncology Group performance status; IgA, immunoglobulin A; IgD, immunoglobulin D; IgE, immunoglobulin E; IgG, immunoglobulin G; IgM, immunoglobulin M; ISS, International Staging System; MM, multiple myeloma; NDMM, newly diagnosed multiple myeloma; RMM, relapsed multiple myeloma; t, translocation.
aBased on the combination of serum ß2-microglobulin and albumin levels.
bIncludes patients without measurable disease in serum and urine.
cIncludes IgD, IgM, IgE, and biclonal antibodies.
dCytogenetic risk was based on local fluorescence in situ hybridization or karyotype analysis. Patients with high-risk cytogenetics had a del17p, t(4;14), or t(14;16) abnormality. Patients with standard-risk cytogenetic abnormalities had no high-risk cytogenetic abnormalities.
Efficacy

Summary of Response Rates Over Time in Patients With RMM (LYRA)8
Patients, %
End of Cycle 4
(n=14)
End of Induction
(n=14)
End of Study
(n=14)
ORR
71
79
86
≥VGPR
57.1
71.4
71.4
   ≥CR
-
28.6
64.3
      sCR
-
14.3
28.6
      CR
14.3
14.3
35.7
   VGPR
42.9
42.9
7.1
PR
14.3
7.1
14.3
Abbreviations: ≥CR, complete response or better; CR, complete response; ORR, overall response rate; PR, partial response; RMM, relapsed multiple myeloma; sCR, stringent complete response; VGPR, very good partial response.

Summary of Response Rates Over Time in Transplant Patients With NDMM (LYRA)8
Patients, %
End of Cycle 4
(All NDMM, n=86)
End of Induction
(n=39)
End of Study
(n=39)
ORR
79
92
97
≥VGPR
44.2
64.1
82.1
   ≥CR
-
-
48.7
      sCR
-
-
23.1
      CR
4.7
5.1
25.6
   VGPR
39.5
59
33.3
PR
34.9
28.2
15.4
Abbreviations: ≥CR, complete response or better; CR, complete response; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.

Summary of Response Rates Over Time in Non-transplant Patients With NDMM (LYRA)8
Patients, %
End of Cycle 4
(All NDMM, n=86)
End of Induction
(n=47)
End of Study
(n=47)
ORR
79
83
83
≥VGPR
44.2
63.8
70.2
   ≥CR
-
17
29.8
      sCR
-
10.6
17
      CR
4.7
6.4
12.8
   VGPR
39.5
46.8
40.4
PR
34.9
19.1
12.8
Abbreviations: ≥CR, complete response or better; CR, complete response; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
  • In patients with NDMM achieving ≥CR vs those achieving ≤VGPR, estimated 36-month PFS rates were higher in both transplant (87.5% vs 51.2%) and non-transplant arms (100% vs 57.7%).8
  • Among evaluable patients with NDMM and standard (n=52) vs high (n=31) cytogenetic risk8:
    • After induction, the rate of ≥VGPR was 61.5% vs 67.7% and the rate of ≥CR was 9.6% vs 16.1% for standard vs high risk, respectively.
    • By the end of the study, the rate of ≥VGPR was 75% vs 77.4% and the rate of ≥CR was 42.3% vs 29% for standard vs high risk, respectively.
  • Among evaluable patients with NDMM and standard (n=53) vs high (n=31) cytogenetic risk8:
    • The median PFS was NR vs 33.1 months for standard vs high risk, respectively.
    • The estimated 36-month PFS rate was 87.5% vs 45.2% for standard vs high risk, respectively.
Safety
  • In the RMM vs NDMM (both transplant and non-transplant) arm, grade 3/4 TEAEs occurred in 57.1% vs 62.8% of patients, serious TEAEs occurred in 35.7% vs 32.6% of patients, and cardiac TEAEs occurred in 0% vs 16.3% of patients.8 See Table: Most Common TEAEs of Any Grade (≥25%) and Grade 3/4 (≥10%) in the Safety Analysis Set (LYRA).
  • TEAEs leading to treatment discontinuation occurred in 1 patient in the RMM arm and 7 patients in the NDMM arm.8
    • TEAEs leading to treatment discontinuation in the NDMM arm were anemia (n=2), atrial fibrillation, hip fracture, nephrotic syndrome, laryngeal edema, and rash (n=1 each).
    • In the NDMM arm, TEAEs leading to treatment discontinuation occurred in 5.6% (n=2) of patients who received transplant and 2.6% (n=1) of those who did not receive transplant.
  • TEAEs leading to death were reported in 1 patient each in both the RMM and NDMM arms, all of which were unrelated to study treatment.8
  • In the NDMM arm, serious TEAEs occurred in 16.7% (n=6) of patients who received transplant and 23.1% (n=9) of patients who did not receive transplant.8
  • The incidence of IRRs was 57.1% in the RMM arm and 55.8% in the NDMM arm.8
    • In the RMM arm, all IRRs occurred during the induction phase and were grade 1/2. No patient discontinued study treatment due to an IRR.
    • In the NDMM arm:
      • Grade 3 IRRs included anaphylactic reaction, chest discomfort, and hypertension (n=1 each). One patient reported laryngeal edema as a grade 4 IRR.
      • The majority of IRRs occurred during the first cycle of treatment.
      • Among patients who received transplants, 9 (25%) patients reported ≥1 IRR during the first maintenance cycle, with the majority being grade 1/2. Grade 3 (chest discomfort) and grade 4 (laryngeal edema) IRRs were reported in 1 patient each.
      • No IRRs were reported during maintenance treatment in patients who did not receive transplant.
      • One patient discontinued study treatment due to an IRR.
  • TEAEs occurring in the maintenance phase are summarized in Tables: Most Common TEAEs of Any Grade (≥20%) and Grade 3/4 (≥5%) Occurring During the Maintenance Phase in the Safety Analysis Set (LYRA, RMM Arm) and Most Common TEAEs of Any Grade (≥20%) and Grade 3/4 (≥5%) Occurring During the Maintenance Phase in the Safety Analysis Set (LYRA, NDMM Arm).

Most Common TEAEs of Any Grade (≥25%) and Grade 3/4 (≥10%) in the Safety Analysis Set (LYRA)a,8
Patients With ≥1 TEAE, n (%)
RMM (n=14)
NDMM (n=86)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
3 (21.4)
3 (21.4)
12 (14)
11 (12.8)
   Leukopenia
2 (14.3)
2 (14.3)
8 (9.3)
5 (5.8)
Nonhematologic
   Fatigue
7 (50)
0 (0)
59 (68.6)
6 (7)
   Nausea
3 (21.4)
0 (0)
43 (50)
1 (1.2)
   Cough
6 (42.9)
0 (0)
42 (48.8)
0 (0)
   Diarrhea
6 (42.9)
1 (7.1)
38 (44.2)
4 (4.7)
   Upper respiratory tract infection
7 (50)
0 (0)
30 (34.9)
0 (0)
   Insomnia
2 (14.3)
0 (0)
28 (32.6)
0 (0)
   Back pain
6 (42.9)
1 (7.1)
27 (31.4)
1 (1.2)
   Dyspnea
3 (21.4)
0 (0)
27 (31.4)
1 (1.2)
   Constipation
0 (0)
0 (0)
27 (31.4)
0 (0)
   Vomiting
5 (35.7)
0 (0)
26 (30.2)
3 (3.5)
   Headache
3 (21.4)
0 (0)
24 (27.9)
0 (0)
   Pain in extremity
4 (28.6)
1 (7.1)
15 (17.4)
1 (1.2)
   Oropharyngeal pain
4 (28.6)
0 (0)
12 (14)
0 (0)
   Nasopharyngitis
5 (35.7)
0 (0)
11 (12.8)
0 (0)
   Productive cough
4 (28.6)
0 (0)
8 (9.3)
0 (0)
   Pneumonia
4 (28.6)
2 (14.3)
8 (9.3)
3 (3.5)
   Abdominal pain
4 (28.6)
0 (0)
8 (9.3)
0 (0)
   Myalgia
4 (28.6)
0 (0)
8 (9.3)
0 (0)
   Sinusitis
4 (28.6)
0 (0)
7 (8.1)
1 (1.2)
IRRs
8 (57.1)
0 (0)
48 (55.8)
4 (4.7)
Abbreviations: IRR, infusion-related reaction; NDMM, newly diagnosed multiple myeloma; RMM, relapsed multiple myeloma; TEAE, treatment-emergent adverse event.
aThe safety analysis set includes all patients who received ≥1 dose of study treatment.

Most Common TEAEs of Any Grade (≥20%) and Grade 3/4 (≥5%) Occurring During the Maintenance Phase in the Safety Analysis Set (LYRA, RMM Arm)a,8
Patients With ≥1 TEAE, n (%)
RMM (n=10)
Any Grade
Grade 3/4
Total TEAEs
9 (90)
3 (30)
Pneumonia
4 (40)
2 (20)
Fatigue
4 (40)
0 (0)
Upper respiratory tract infection
3 (30)
0 (0)
Cough
3 (30)
0 (0)
Productive cough
3 (30)
0 (0)
Nasopharyngitis
2 (20)
0 (0)
Nasal congestion
2 (20)
0 (0)
Back pain
2 (20)
0 (0)
Pain in extremity
2 (20)
1 (10)
Bronchiectasis
1 (10)
1 (10)
Abbreviations: RMM, relapsed multiple myeloma; TEAE, treatment-emergent adverse event.
aThe safety analysis set includes all patients who received ≥1 dose of study treatment.

Most Common TEAEs of Any Grade (≥20%) and Grade 3/4 (≥5%) Occurring During the Maintenance Phase in the Safety Analysis Set (LYRA, NDMM Arm)a,b,8
Patients With ≥1 TEAE, n (%)
NDMM (n=86)
Transplant (n=36)
Non-transplant (n=39)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Total TEAEs
36 (100)
13 (36.1)
34 (87.2)
10 (25.6)
Cough
16 (44.4)
0 (0)
10 (25.6)
0 (0)
Upper respiratory tract infection
11 (30.6)
0 (0)
8 (20.5)
0 (0)
Fatigue
9 (25)
0 (0)
7 (17.9)
1 (2.6)
Dyspnea
9 (25)
1 (2.8)
1 (2.6)
0 (0)
Nausea
8 (22.2)
0
4 (10.3)
0 (0)
Diarrhea
8 (22.2)
1 (2.8)
3 (7.7)
0 (0)
Pruritus
8 (22.2)
0 (0)
1 (2.6)
0 (0)
Cataract
0 (0)
0 (0)
4 (10.3)
2 (5.1)
Atrial fibrillation
0 (0)
0 (0)
2 (5.1)
2 (5.1)
Abbreviations: NDMM, newly diagnosed multiple myeloma; TEAE, treatment-emergent adverse event.
aThe safety analysis set includes all patients who received ≥1 dose of study treatment.
bNo patient died due to a TEAE during the maintenance phase.

DARZALEX Phase 1b Study in Combination With Various Treatment Regimens

EQUULEUS (MMY1001; clincialtrials.gov identifier: NCT01998971) is an ongoing study evaluating the safety and efficacy of DARZALEX when administered in combination with various treatment regimens, including KRd, for the treatment of NDMM.10 Chari et al (2019)9 presented updated safety and efficacy results from the final analysis of the MMY1001 study.

Study Design/Methods

  • The trial includes 6 arms, one of which is D-KRd (N=22 patients).
  • Eligibility criteria for the D-KRd arm: NDMM; transplant eligible and non-eligible; treatment duration: ≤13 cycles or until elective discontinuation for ASCT; no clinically significant cardiac disease.

Results

  • At a median follow-up of 23.7 months, a total of 50 (59%) patients discontinued study treatment.
    • A total of 36 (42%) patients discontinued treatment due to PD, 6 (7%) due to withdrawal of consent, 5 (6%) due to AEs, 2 (2%) due to physician decision, and 1 (1%) due to death.
  • Patients received a median (range) of 21 (1-37) cycles of treatment.
  • The median relative dose intensity was 100% (range, 49-108) for DARZALEX, 95% (22-105) for carfilzomib, and 98% (50-101) for dexamethasone.
  • No patients were positive for anti-daratumumab antibodies.
Efficacy
  • Among patients who received the D-Kd regimen (N=85):
    • Median follow-up: 23.7 months.
    • Response rates were (n=82): sCR: 22%, ≥CR: 37%, ≥VGPR: 71%, and ORR: 84%.
    • Response rates in lenalidomide-refractory patients (n=48) were: sCR: 19%, ≥CR: 33%, ≥VGPR: 69%, and ORR: 79%.
    • Optional MRD testing was conducted in 30 patients with CR/sCR. MRD-negative rates (10-5) were:
      • All treated patients (n=30): 47%.
      • Lenalidomide-refractory patients (n=19): 32%.
    • Median DOR among all response-evaluable patients who responded to treatment (time to at least partial response [≥PR]): 27.5 months (95% CI, 20.5-NR).
  • All treated patients:
    • Median PFS: 25.7 months (95% CI, 14.8-NR); 24-month PFS: 52.7% months (95% CI, 40.9-63.2).
    • Median OS: NR; 24-month OS: 71.2% (95% CI, 59.9-79.9)
  • Lenalidomide refractory patients:
    • Median PFS: 22.3 months (95% CI, 12-NR); 24-month PFS: 46.9% months (95% CI, 31.5-60.9).
  • A total of 32 (38%) patients received subsequent anticancer therapy, with a median time to subsequent therapy of 29.2 (95% CI, 19.5-NR) months.
    • The most common (>5%) subsequent therapies included dexamethasone (26 [31%] patients), pomalidomide (18 [21%] patients), cyclophosphamide (12 [14%] patients), melphalan (9 [11%] patients), doxorubicin, bortezomib, and other neoplastic agents (7 [8%] patients each).
    • Four (5%) patients received subsequent therapy with DARZALEX.
  • Median PFS2 in all treated patients: NR; 24-month PFS2: 60.8% (95% CI, 48.6-71.1).
Safety
  • The most common any-grade (>20%) and grade 3/4 (>10%) TEAEs are presented in Table: Most Common Any-Grade (>20%) and Grade 3/4 (>10%) TEAEs.
    • Grade 3/4 infections occurred in 18 (21%) patients; the most common was pneumonia, with 4 (5%) patients experiencing a grade 3/4 event.
  • SAEs occurred in 41 (48%) patients, and 31 (37%) patients experienced a grade 3/4 SAE.
    • The most common grade 3/4 SAE was pneumonia (4 [5%] patients).
    • Among patients with SAEs, 8 (9%) events were related to DARZALEX, 16 (19%) to carfilzomib, and 12 (14%) to dexamethasone.
  • Five (6%) patients discontinued all study treatment due to TEAEs, including 1 patient each due to thrombocytopenia, asthenia, hydrocephalus, prostate cancer, and back pain.
  • Two deaths due to TEAEs occurred. One TEAE (general physical health deterioration) was not related to study treatment, and 1 TEAE (multiple organ dysfunction syndrome) was possibly related to study treatment.
  • Grade 3/4 cardiac AEs of interest occurred in 7 (8%) patients and included cardiac failure (2 [2%] patients), sinus tachycardia (2 [2%] patients), and acute pulmonary edema, left ventricular failure, atrial fibrillation, and myocardial ischemia (1 [1%] patient each).
  • Median left ventricular ejection fraction (LVEF) did not notably change over time (Table: Echocardiogram Assessment).

Most Common Any-Grade (>20%) and Grade 3/4 (>10%) TEAEs9
Event, n (%)
D-Kd (N=85)
Any Grade
Grade 3/4
Total TEAEs
85 (100)
67 (79)
Thrombocytopenia
58 (68)
27 (32)
Anemia
44 (52)
18 (21)
Upper respiratory tract infection
38 (45)
3 (4)
Asthenia
36 (42)
13 (15)
Nausea
36 (42)
1 (1)
Vomiting
34 (40)
1 (1)
Diarrhea
32 (38)
2 (2)
Pyrexia
31 (37)
1 (1)
Dyspnea
30 (35)
3 (4)
Hypertension
28 (33)
17 (20)
Insomnia
28 (33)
4 (5)
Neutropenia
26 (31)
18 (21)
Lymphopenia
25 (29)
21 (25)
Cough
24 (28)
0 (0)
Headache
23 (27)
1 (1)
Back pain
21 (25)
0 (0)
Abbreviations: D-Kd, DARZALEX + carfilzomib + dexamethasone; TEAE, treatment emergent adverse event.

Echocardiogram Assessmenta,9
Time point
LVEF, median % (range)
Baseline (n=84)
64 (44-83)
Cycle 6 (n=54)
62 (46-77)
Cycle 12 (n=47)
61 (32-76)
Cycle 18 (n=22)
59 (50-74)
Cycle 24 (n=10)
63 (53-76)
Abbreviation: LVEF, left ventricular ejection fraction.
aSafety population, defined as patients who received ≥1 dose of study treatment.

DARZALEX FASPRO in Combination With Bortezomib, Lenalidomide, and Dexamethasone

CEPHEUS (MMY3019; NCT03652064) is an ongoing, randomized, open-label, multicenter, phase 3 study evaluating the efficacy and safety of
D-VRd vs VRd in patients with NDMM who are transplant ineligible or for whom transplant is not planned as initial therapy (transplant deferred).11-13 Usmani et al (2025)13 reported results from the phase 3 CEPHEUS study.

Study Design/Methods

  • The trial has enrolled 395 patients from 13 different countries including the US.12

Results

Patient Characteristics


Baseline Demographics and Clinical Characteristics of the ITT Populationa,13
Characteristic
D-VRd (n=197)
VRd (n=198)
Median age (range), years
70 (42-79)
70 (31-80)
   <65 years, n (%)
36 (18.3)
35 (17.7)
   65 to <70 years, n (%)
52 (26.4)
53 (26.8)
   ≥70 years, n (%)
109 (55.3)
110 (55.6)
Age or transplant eligibility, n (%)
   <70 years and transplant ineligible
35 (17.8)
35 (17.7)
   <70 years and transplant deferred
53 (26.9)
53 (26.8)
   ≥70 years
109 (55.3)
110 (55.6)
Maleb, n (%)
87 (44.2)
111 (56.1)
Raceb, n (%)
   White
162 (82.2)
156 (78.8)
   Black or African American
10 (5.1)
9 (4.5)
   Asian
11 (5.6)
14 (7.1)
   Native Hawaiian or other Pacific Islander
0 (0)
1 (0.5)
   Other
1 (0.5)
2 (1)
   Not reported
13 (6.6)
16 (8.1)
ECOG PSc, n (%)
   0
71 (36)
84 (42.4)
   1
103 (52.3)
100 (50.5)
   2
23 (11.7)
14 (7.1)
Frailty scored, n (%)
   0 (fit)
124 (62.9)
132 (66.7)
   1 (intermediate fitness)
73 (37.1)
66 (33.3)
Type of measurable disease, n (%)
   Detected in serum only
120 (60.9)
108 (54.5)
      IgG
89 (45.2)
76 (38.4)
      IgA
27 (13.7)
31 (15.7)
      Othere
4 (2)
1 (0.5)
   Detected in serum and urine
41 (20.8)
45 (22.7)
   Detected in urine only
20 (10.2)
24 (12.1)
   Detected in serum FLCs only
16 (8.1)
21 (10.6)
ISS disease stagef, n (%)
   I
68 (34.5)
68 (34.3)
   II
73 (37.1)
75 (37.9)
   III
56 (28.4)
55 (27.8)
Cytogenetic risk profileg, n (%)
   Standard risk
149 (75.6)
149 (75.3)
   High risk
25 (12.7)
27 (13.6)
   Indeterminateh
23 (11.7)
22 (11.1)
Median time since diagnosis of MM (range), months
1.2 (0.4-5.8)
1.3 (0.3-8)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; FLC, free light chain; Ig, immunoglobulin; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; VRd, bortezomib + lenalidomide + dexamethasone.
aThe ITT population was defined as all patients who underwent randomization.
bSex and race were reported by the patient.
cECOG PS is scored on a scale of 0-5, with 0 indicating no symptoms and higher scores indicating increasing disability.
dTotal additive frailty is scored on a scale of 0-5 based on age, comorbidities, and cognitive and physical conditions, with 0 indicating fit, 1 indicating intermediate fitness, and ≥2 indicating frail, per the Myeloma Geriatric Assessment score (http://www.myelomafrailtyscorecalculator.net/).
eIncludes IgD, IgM, IgE, and biclonal.fBased on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.
gAssessed by fluorescence in situ hybridization; high risk was defined as the presence of del(17p), t(4;14), and/or t(14;16).
hIndeterminate includes patients with missing or unevaluable samples.

Efficacy

  • The duration of treatment and relative dose intensities are summarized in Table: Duration of Treatment and Relative Dose Intensities in the Safety Population.
  • As of the clinical cutoff date of May 7, 2024, 102 (51.8%) vs 67 (34.4%) patients from the D-VRd vs VRd arm, respectively, continued their treatment.13
  • A summary of the MRD status and response rates in the ITT population is presented in Table: Summary of MRD Status and Response Rates in the ITT Population.
    • D-VRd vs VRd significantly increased the overall MRD-negativity rate (10-5 sensitivity with ≥CR; 60.9% vs 39.4%) and ≥CR rate (81.2% vs 61.6%).13
    • Patients in the D-VRd vs VRd arm showed a higher MRD-negativity rate at 10-6 sensitivity (46.2% vs 27.3%) and a significantly higher sustained (≥12 months) MRD-negativity rate at 10-5 sensitivity (48.7% vs 26.3%).13
    • The treatment effect on the overall MRD-negativity rate remained consistent across the predefined subgroups and is summarized in Table: Prespecified Subgroup Analysis of Overall MRD-Negativity Rates.
  • At a median follow-up duration of 58.7 months, the median PFS was NR in the D-VRd arm, while it was 52.6 months in the VRd arm.13
  • D-VRd significantly improved PFS with a 43% reduction in the risk of progression or death (HR, 0.57; 95% CI, 0.41-0.79; P=0.0005).13
  • At 54 months, the estimated PFS for D-VRd vs VRd was 68.1% (95% CI, 60.8-74.3) vs 49.5% (95% CI, 41.8-56.8).13
  • The treatment effect on PFS remained consistent across the predefined subgroups and is summarized in Table: PFS in Prespecified Subgroups.
  • Data for PFS on the subsequent line of therapy are still immature. However, HR favored D-VRd over VRd (HR, 0.78; 95% CI, 0.54-1.14) and further improved when censoring for death due to COVID-19 (HR, 0.60; 95% CI, 0.40-0.93).13
  • OS for ITT population favored the D-VRd vs VRd arm (HR, 0.85; 95% CI, 0.58-1.24) and further improved when censoring for death due to COVID-19 (HR, 0.69; 95% CI, 0.45-1.05).13
  • OS data were immature, and follow-up is ongoing.13
  • A lower proportion of patients who received subsequent therapy received an anti-CD38-based therapy in the D-VRd arm (3 of 22 patients [13.6%]) vs the VRd arm (39 of 65 patients [60%]).13
  • The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 global (EORTC QLQ-C30) health status domain score improved over time in both arms, with no negative impact from the addition of DARZALEX FASPRO.13

Duration of Treatment and Relative Dose Intensities in the Safety Populationa,b,13
Parameter
D-VRd (n=197)
VRd (n=195)
Median duration of treatment (range), months
56.3 (0.1-64.6)
34.3 (0.5-63.8)
Median number of treatment cycles (range)
59 (1-71)
(1-70)
Median relative dose intensity (range)
   Bortezomib
84.5 (12.7-104.3)
81.6 (22.4-102.1)
   Lenalidomide
80.6 (2.5-248.2)
83.8 (25.7-246)
   Dexamethasone
81.5 (19.6-177)
77.9 (23.4-173.4)
DARZALEX FASPRO
      Cycles 1 and 2 (n=197)
100 (33.3-105.6)
-
      Cycles 3 to 8 (n=191)
100 (33.3-101.1)
-
      Cycle 9+ (n=175)
100 (10-100.4)
-
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; VRd, bortezomib + lenalidomide + dexamethasone.
aDose intensity was defined as the ratio of total administered dose to total planned dose.
bThe safety population included all patients who received ≥1 dose of study treatment.

Summary of MRD Status and Response Rates in the ITT Population13
Parameter
D-VRd (n=197)
VRd (n=198)
OR (95% CI)
P Value
Overall MRD-negativitya, %
   10-5 sensitivity
60.9
39.4
2.37 (1.58-3.55)
<0.0001
   10-6 sensitivity
46.2
27.3
2.24 (1.48-3.40)
0.0001
Sustained MRD-negativity
(10‒5) for ≥12 months, %
48.7
26.3
2.63 (1.73-4)
<0.0001
Responseb, n
191
184
-
-
   ORR, % (95% CI)
97 (93.5-98.9)
92.9 (88.4-96.1)
-
0.0698
      sCR, n (%)
128 (65)
88 (44.4)
-
<0.0001
      CR, n (%)
32 (16.2)
34 (17.2)
-
-
      VGPR, n (%)
23 (11.7)
50 (25.3)
-
-
      PR, n (%)
8 (4.1)
12 (6.1)
-
-
   ≥CR, n (%)
160 (81.2)
122 (61.6)
2.73 (1.71-4.34)
<0.0001
   ≥VGPR, n (%)
183 (92.9)
172 (86.9)
-
0.0495
   SD, n (%)
5 (2.5)
7 (3.5)
-
-
   PD, n (%)
0 (0)
0 (0)
-
-
   Response could not be evaluated, n (%)
1 (0.5)
7 (3.5)
-
-
Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; IMWG, International Myeloma Working Group; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; ORR, overall response rate; PD, progressive disease; PR, partial response; sCR, stringent complete response; SD, stable disease; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
aMRD-negativity rate was defined as the proportion of patients who achieved both MRD-negativity (10-5 threshold) and ≥CR.
bResponse rates at any time during the study. Response was assessed based on IMWG response criteria. P values were calculated using the stratified Cochran-Mantel-Haenszel chi-squared test.

Prespecified Subgroup Analysis of Overall MRD-Negativity Rates13
Subgroup
D-VRd
VRd
OR (95% CI)
Number of Patients With MRD-Negativity/
Total Number of Patients (%)
Sex
   Male
54/87 (62.1)
39/111 (35.1)
3.02 (1.69-5.41)
   Female
66/110 (60)
39/87 (44.8)
1.85 (1.04-3.26)
Age
   <70 years
59/88 (67)
36/88 (40.9)
2.94 (1.59-5.44)
   ≥70 years
61/109 (56)
42/110 (38.2)
2.06 (1.20-3.53)
Region
   Europe
69/120 (57.5)
46/116 (39.7)
2.06 (1.23-3.46)
   North America
21/37 (56.8)
13/31 (41.9)
1.82 (0.69-4.77)
   Other
30/40 (75)
19/51 (37.3)
5.05 (2.03-12.60)
Weight
   ≤65 kg
40/58 (69)
22/63 (34.9)
4.14 (1.94-8.86)
   >65-85 kg
58/101 (57.4)
31/88 (35.2)
2.48 (1.38-4.47)
   >85 kg
22/38 (57.9)
25/47 (53.2)
1.21 (0.51-2.87)
ISS staging
   I
45/68 (66.2)
30/68 (44.1)
2.48 (1.24-4.96)
   II
47/73 (64.4)
29/75 (38.7)
2.87 (1.47-5.59)
   III
28/56 (50)
19/55 (34.5)
1.89 (0.88-4.07)
Cytogenetic risk
   High risk
12/25 (48)
15/27 (55.6)
0.74 (0.25-2.20)
   Standard risk
95/149 (63.8)
57/149 (38.3)
2.84 (1.78-4.54)
   Indeterminate
13/23 (56.5)
6/22 (27.3)
3.47 (0.99-12.09)
ECOG PS score
   0
41/71 (57.7)
36/84 (42.9)
1.82 (0.96-3.45)
   ≥1
79/126 (62.7)
42/114 (36.8)
2.88 (1.71-4.87)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.

PFS in Prespecified Subgroups13
Subgroups
D-VRd
VRd
D-VRd
VRd
HR (95% CI)
Number of Disease Progression Events or Deaths/Total Number of Patients
Median PFS, months
Sex
   Male
24/87
53/111
NE
49.2
0.46 (0.29-0.75)
   Female
39/110
38/87
NE
NE
0.73 (0.47-1.15)
Age
   <70 years
30/88
38/88
NE
NE
0.72 (0.44-1.16)
   ≥70 years
33/109
53/110
NE
49.4
0.50 (0.33-0.78)
Region
   Europe
37/120
54/116
NE
51.1
0.54 (0.36-0.82)
   North America
10/37
13/31
NE
50.2
0.51 (0.22-1.17)
   Other
16/40
24/51
NE
NE
0.87 (0.46-1.64)
Weight
   ≤65 kg
17/58
24/63
NE
NE
0.62 (0.34-1.16)
   >65-85 kg
34/101
40/88
NE
51.1
0.65 (0.41-1.02)
   >85 kg
12/38
27/47
NE
41.9
0.46 (0.23-0.91)
ISS staging
   I
21/68
28/68
NE
60.6
0.66 (0.37-1.16)
   II
18/73
37/75
NE
45.6
0.36 (0.21-0.64)
   III
24/56
26/55
NE
49.2
0.84 (0.48-1.46)
Cytogenetic risk
   High risk
13/25
17/27
39.8
31.7
0.88 (0.42-1.84)
   Standard risk
43/149
60/149
NE
60.6
0.61 (0.41-0.91)
   Indeterminate
7/22
14/22
NE
47.9
0.33 (0.13-0.82)
ECOG PS score
   0
16/71
30/84
NE
NE
0.53 (0.29-0.97)
   ≥1
47/126
61/114
NE
43.8
0.59 (0.40-0.86)
Abbreviations: CI, confidence interval; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ISS, International Staging System; NE, not estimated; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone.

Safety

  • A total of 95 vs 128 patients from the D-VRd vs VRd arm, respectively, discontinued treatment.13
    • Reasons for treatment discontinuation in the D-VRd vs VRd arm, respectively, included:
      • PD: 27 (13.7%) vs 51 (26.2%) patients.
      • AEs: 16 vs 32 patients.
      • Deaths: 34 vs 24 patients.
        • COVID-19-related deaths: 12 (6.1%) vs 6 (3.1%) patients.
      • Refused further treatment: 15 vs 8 patients.
      • Physician decision: 3 vs 12 patients.
      • Received concurrent treatment for MM prior to disease progression: 0 vs 1 patient.
    • Treatment discontinuation due to TEAEs was observed in 7.6% vs 15.9% of patients from the D-VRd vs VRd arm, respectively.
  • The safety data were consistent with the established safety profile of each individual drug.13 TEAEs in the safety population are summarized in Table: Most Common TEAEs in the Safety Population.
    • Overall, deaths were reported in 51 vs 60 patients from the D-VRd vs VRd arm, respectively and are summarized in Table: Summary of Deaths in the ITT Population.
      • The COVID-19 pandemic impacted OS with 24 (21.6%) of all deaths in the study attributed to COVID-19 (D-VRd, n=15 vs VRd, n=9).
      • Overall, 21 COVID-19 deaths occurred during the peak of the pandemic in 2020 and 2021, with 3 additional deaths in 2022 (post-vaccine availability), and none in 2023 or 2024.
      • Regional variations were observed in pandemic impact. Brazil reported 54.2% of COVID-19 deaths (17.5% of the study population), while Poland had 16.7% of deaths (18.7% of the study population).
      • Two sensitivity analyses of OS adjusting for COVID-19 deaths showed a stronger treatment effect for D-VRd vs VRd (censoring COVID-19 deaths [HR, 0.69; 95% CI, 0.45-1.05] and considering COVID-19 deaths as a competing risk [HR for non-COVID mortality, 0.67; 95% CI, 0.44-1.03]).
    • Grade 5 non-COVID-related TEAEs occurred in 10.7% vs 7.7% of patients from the D-VRd vs VRd arm, respectively.
    • Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%). A summary of the serious TEAEs is presented in Table: Serious TEAEs (≥2%) in the Safety Population.
    • Most grade 5 TEAEs occurred after the discontinuation of bortezomib (cycle 8) in both arms (D-VRd, 13%; VRd, 9%). When adjusted for treatment exposure, the rate of grade 5 TEAEs was similar between the two arms (D-VRd, 0.39 per 100 patient-months; VRd, 0.31 per 100 patient-months).

Most Common TEAEs in the Safety Populationa,13
TEAE, n (%)
D-VRd (n=197)
VRd (n=195)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
110 (55.8)
87 (44.2)
76 (39)
58 (29.7)
   Thrombocytopenia
92 (46.7)
56 (28.4)
66 (33.8)
39 (20)
   Anemia
73 (37.1)
26 (13.2)
62 (31.8)
23 (11.8)
   Lymphopenia
36 (18.3)
24 (12.2)
34 (17.4)
20 (10.3)
Nonhematologic
   Diarrhea
112 (56.9)
24 (12.2)
115 (59)
18 (9.2)
   Peripheral sensory neuropathy
110 (55.8)
16 (8.1)
119 (61)
16 (8.2)
   Peripheral edema
83 (42.1)
4 (2)
76 (39)
1 (0.5)
   Constipation
75 (38.1)
4 (2)
82 (42.1)
5 (2.6)
   Insomnia
63 (32)
4 (2)
63 (32.3)
2 (1)
   Fatigue
63 (32)
18 (9.1)
60 (30.8)
16 (8.2)
   Hypokalemia
58 (29.4)
24 (12.2)
25 (12.8)
12 (6.2)
   Cataract
55 (27.9)
17 (8.6)
51 (26.2)
17 (8.7)
   Back pain
55 (27.9)
6 (3)
43 (22.1)
6 (3.1)
   Cough
53 (26.9)
1 (0.5)
38 (19.5)
2 (1)
   Asthenia
51 (25.9)
7 (3.6)
40 (20.5)
5 (2.6)
   Rash
50 (25.4)
5 (2.5)
48 (24.6)
3 (1.5)
   Nausea
49 (24.9)
0 (0)
48 (24.6)
4 (2.1)
   Pyrexia
46 (23.4)
2 (1)
30 (15.4)
1 (0.5)
   Arthralgia
45 (22.8)
3 (1.5)
39 (20)
0 (0)
   Decreased appetite
42 (21.3)
2 (1)
39 (20)
5 (2.6)
   Dizziness
41 (20.8)
1 (0.5)
41 (21)
2 (1)
   Infections
181 (91.9)
79 (40.1)
167 (85.6)
62 (31.8)
      Upper respiratory tract infection
78 (39.6)
1 (0.5)
64 (32.8)
1 (0.5)
      COVID-19
75 (38.1)
22 (11.2)
48 (24.6)
9 (4.6)
      Pneumonia
48 (24.4)
28 (14.2)
39 (20)
25 (12.8)
      Urinary tract
41 (20.8)
7 (3.6)
29 (14.9)
5 (2.6)
Second primary malignancyb
15 (7.6)
-
18 (9.2)
-
Any injection-related reaction
7 (3.6)
1 (0.5)c
-
-
Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone.
aThe safety population included patients who received ≥1 dose of study treatment. AEs of any grade that were reported in ≥20% of patients in either treatment arm and grade 3/4 AEs that were reported in ≥10% of patients in either treatment arm are listed.
bOf all second primary malignancies, cutaneous malignancies were reported in 7 (3.6%) vs 7 (3.6%) patients from the D-VRd vs VRd arm, respectively.
cGrade 3.

Summary of Deaths in the ITT Populationa,13
Parameter, n
D-VRd (n=197)
VRd (n=195)
Overall deaths
51
60
   PD
8
16
   AEb
37
25
      COVID-19
7
5
      COVID-19 pneumonia
5
1
      Pneumonia
3
4
      Death/sudden death
3
1
      Cardiac arrest
2
1
      General physical health deterioration
2
-
      Drug induced liver injury
1
-
      COVID-19, multiple organ dysfunction syndrome, and pulmonary embolism
1
-
      Colitis
1
-
      Sudden cardiac death
1
-
      Respiratory failure
1
-
      Acute kidney injury/failure
1
1
      Dyspnea
1
-
      Pulmonary embolism
1
-
      Pulmonary fibrosis
-
1
      Myocardial infarction
1
1
      Acute myocardial infarction, cardiogenic shock
-
1
      Multiple organ dysfunction syndrome
-
1
      Lung neoplasm malignant
-
1
      Completed suicide
-
1
      Hypovolemic shock
-
1
      Septic shock
1
1
      Sepsis
-
2
      Urinary tract infection
-
1
      Cerebrovascular accident
1
-
      Cardiopulmonary failure
1
-
      Hepatic failure
-
1
      Febrile neutropenia
1
-
      Abdominal pain
1
-
      Esophageal adenocarcinoma
1
-
   Otherb
6
19
      Unknown
3
10
      COVID-19 or COVID-19 positive/infection
1
2
      Acute hypoxic respiratory failure due to COVID-19
1
-
      COVID-19 bronchopneumonia bilat.
-
1
      Severe acute hepatitis
1
-
      No more information available
-
1
      Pneumocystosis infection
-
1
      Ischemic bowel stroke
-
1
      Acute kidney injuryc
-
1
      Cholengiocellular carcinoma intrahepatic metastasis
-
1
      Renal failure, possibility of PD
-
1
Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; PD, progressive disease; VRd, bortezomib + lenalidomide + dexamethasone.
aUntil the clinical cutoff.
bSubcategory terms are listed as originally entered in the database by the investigator.
cPatient died following admission and was outside AE reporting window.

Serious TEAEs (≥2%) in the Safety Populationa,13
TEAE, n (%)
D-VRd (n=197)
VRd (n=195)
Serious TEAEs
142 (72.1)
131 (67.2)
   Infections
78 (39.6)
69 (35.4)
      Pneumonia
27 (13.7)
25 (12.8)
      COVID-19
22 (11.2)
16 (8.2)
      COVID-19 pneumonia
8 (4.1)
4 (2.1)
      Sepsis
7 (3.6)
4 (2.1)
      Urinary tract infection
7 (3.6)
4 (2.1)
      Septic shock
6 (3 )
1 (0.5)
      Gastroenteritis
4 (2)
4 (2.1)
      Influenza
4 (2)
1 (0.5)
   Pulmonary embolism
11 (5.6)
5 (2.6)
   Diarrhea
10 (5.1)
6 (3.1)
   Atrial fibrillation
7 (3.6)
7 (3.6)
   Acute kidney injury
6 (3)
3 (1.5)
   Asthenia
6 (3)
2 (1)
   Anemia
6 (3)
2 (1)
   Cataract
5 (2.5)
4 (2.1)
   Pvrexia
5 (2.5)
3 (1.5)
   Hypokalemia
5 (2.5)
3 (1.5)
   Hyponatremia
5 (2.5)
1 (0.5)
   Febrile neutropenia
4 (2)
4 (2.1)
   Thrombocytopenia
4 (2)
2 (1)
   Deep vein thrombosis
4 (2)
2 (1)
   Syncope
3 (1.5)
6 (3.1)
   Hypotension
3 (1.5)
4 (2.1)
   Orthostatic hypotension
2 (1)
5 (2.6)
   Dehydration
0 (0)
5 (2.6)
Abbreviations: COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone.
aThe safety population included patients who received ≥1 dose of study treatment.

Expanded Analysis of MRD Outcomes - Results From the CEPHEUS Study

Zweegman et al (2024)14 presented (at the 66th ASH Annual Meeting) an expanded analysis of MRD outcomes from the CEPHEUS study in patients with NDMM who were ineligible for SCT or were transplant deferred.

Results

Patient Characteristics
  • A total of 395 patients were randomized into the D-VRd (n=197) and VRd (n=198) arms.14
Efficacy
  • A summary of cumulative and sustained MRD-negativity (≥CR) rates is presented in Table: Summary of Cumulative and Sustained MRD-Negativity (≥CR) Rates - CEPHEUS Expanded Analysis.
    • D-VRd improved the cumulative MRD-negativity rate (at both 10-5 and 10-6 sensitivities) vs VRd alone at all prespecified timepoints.14
    • D-VRd almost doubled the sustained MRD-negativity (≥CR) rate vs VRd alone at 12, 24, and 36 months.14
    • Among patients who achieved both MRD-negativity (10-6 sensitivity) and ≥CR with D-VRd, >85% were alive and progression free at 54 months.14
  • D-VRd vs VRd showed PFS benefit regardless of an MRD-negativity status (10-6 sensitivity).14
    • For D-VRd vs VRd, the overall MRD-negativity rate (10-6 sensitivity) was 46.2% vs 27.3%, respectively, and the overall MRD-positivity rate (10-6 sensitivity) was 53.8% vs 72.7%, respectively.
    • At 54 months, the estimated PFS by an MRD-negativity status (10-6 sensitivity) was 86.2% vs 79% and by an MRD-positivity status was 51% vs 36.5% for D-VRd vs VRd, respectively.
  • Analyses of MRD-negativity (with ≥CR) rates in prespecified subgroups appeared to consistently favor D-VRd over VRd across these subgroups;14 the results are summarized in Table: MRD-Negativity (≥CR) Rates in Prespecified Subgroups.

Summary of Cumulative and Sustained MRD-Negativity (≥CR) Rates - CEPHEUS Expanded Analysis14
Parameter
D-VRd
(n=197)
VRd
(n=198)
OR (95% CI)
P Value
Cumulative MRD-negativity (10-5 sensitivity; ≥CR), %
   12 months
43.1
28.3
-
-
   24 months
56.9
35.9
-
-
   36 months
59.9
37.4
-
-
   48 months
60.9
38.4
-
-
Cumulative MRD-negativity (10-6 sensitivity; ≥CR), %
   12 months
22.8
11.1
-
-
   24 months
38.1
22.2
-
-
   36 months
40.6
25.3
-
-
   48 months
45.2
27.3
-
-
Sustained MRD-negativity (10-5 sensitivity; ≥CR)a, %
   ≥12 monthsb
49.2
27.3
2.56 (NR)
<0.0001
   ≥24 monthsc
42.1
22.7
2.47 (NR)
<0.0001
   ≥36 monthsd
29.9
15.2
2.37 (NR)
0.0005
Sustained MRD-negativity (10-6 sensitivity; ≥CR)a, %
   ≥12 monthsb
34
16.2
NR
NR
   ≥24 monthsc
27.9
13.6
NR
NR
   ≥36 monthsd
18.8
8.6
NR
NR
Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; MRD, minimal residual disease; NR, not reported; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aAt any time during the study.
bProportion of patients who achieved ≥CR and achieved an MRD-negative status at 2 bone marrow assessments that were 12 months apart with an allotted window of ±1 month, without an MRD-positive status in between.
cAchieving an MRD-negative status at 2 bone marrow assessments that were 24 months apart with an allotted window of ±3 months, without an MRD-positive status in between.
dAchieving an MRD-negative status at 2 bone marrow assessments that were 36 months apart with an allotted window of ±3 months, without an MRD-positive status in between.

MRD-Negativity (≥CR) Rates in Prespecified Subgroups14
Subgroups,
n/N (%)
D-VRd
VRd
OR
(95% CI)
D-VRd
VRd
OR
(95% CI)
10-5 Sensitivity
10-6 Sensitivity
Sex
   Male
54/87
(62.1)
39/111 (35.1)
3.02
(1.69-5.41)
42/87
(48.3)
28/111 (25.2)
2.77
(1.52-5.04)
   Female
66/110 (60)
39/87
(44.8)
1.85
(1.04-3.26)
49/110 (44.5)
26/87
(29.9)
1.88
(1.04-3.41)
Age
   <70 years
59/88
(67)
36/88
(40.9)
2.94
(1.59-5.44)
44/88
(50)
25/88
(28.4)
2.52
(1.35-4.70)
   ≥70 years
61/109 (56)
42/110
(38.2)
2.06
(1.20-3.53)
47/109 (43.1)
29/110 (26.4)
2.12
(1.20-3.74)
Region
   Europe
69/120 (57.5)
46/116
(39.7)
2.06
(1.23-3.46)
57/120 (47.5)
34/116 (29.3)
2.18
(1.28-3.73)
   North America
21/37
(56.8)
13/31
(41.9)
1.82
(0.69-4.77)
14/37
(37.8)
9/31
(29)
1.49
(0.54-4.13)
   Other
30/40
(75)
19/51
(37.3)
5.05
(2.03-12.6)
20/40
(50)
11/51
(21.6)
3.64
(1.46-9.04)
Weight
   ≤65 kg
40/58
(69)
22/63
(34.9)
4.14
(1.94-8.86)
31/58
(53.4)
18/63
(28.6)
2.87
(1.35-6.09)
   >65-85 kg
58/101
(57.4)
31/88
(35.2)
2.48
(1.38-4.47)
45/101 (44.6)
19/88
(21.6)
2.92
(1.54-5.54)
   >85 kg
22/38
(57.9)
25/47
(53.2)
1.21
(0.51-2.87)
15/38
(39.5)
17/47
(36.2)
1.15
(0.48-2.78)
ISS staging
   I
45/68
(66.2)
30/68
(44.1)
2.48
(1.24-4.96)
32/68
(47.1)
22/68
(32.4)
1.86
(0.93-3.73)
   II
47/73
(64.4)
29/75
(38.7)
2.87
(1.47-5.59)
37/73
(50.7)
17/75
(22.7)
3.51
(1.73-7.13)
   III
28/56
(50)
19/55
(34.5)
1.89
(0.88-4.07)
22/56
(39.3)
15/55
(27.3)
1.73
(0.78-3.84)
Cytogenetic risk
   High risk
12/25
(48)
15/27
(55.6)
0.74
(0.25-2.20)
8/25
(32)
12/27
(44.4)
0.59
(0.19-1.83)
   Standard risk
95/149
(63.8)
57/149
(38.3)
2.84
(1.78-4.54)
71/149 (47.7)
37/149 (24.8)
2.76
(1.69-4.50)
ECOG PS score
   0
41/71
(57.7)
36/84
(42.9)
1.82
(0.96-3.45)
28/71
(39.4)
27/84
(32.1)
1.37
(0.71-2.66)
   ≥1
79/126
(62.7)
42/114
(36.8)
2.88
(1.71-4.87)
63/126 (50)
27/114 (23.7)
3.22
(1.85-5.61)
Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.

DARZALEX FASPRO in Combination With Bortezomib, Melphalan, and Prednisone

PLEIADES (MMY2040; NCT03412565) is an ongoing, phase 2, non-randomized, open-label, multicenter study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM, including D-VMP in NDMM.15 Moreau et al (2020)15 presented updated safety and efficacy results of the D-VMP arm in the PLEIADES study.

Results

Patient Characteristics

Key Baseline Demographics and Patient Characteristicsa,15
Characteristic
D-VMP
(n=67)
Age, years
   Median (range)
75 (66-86)
   18 to <65, n (%)
0 (0)
   65 to <75, n (%)
33 (49)
   ≥75, n (%)
34 (51)
Race, n (%)
   White
46 (69)
ECOG PS score, n (%)
   0
25 (37)
   1
38 (57)
   2
4 (6)
ISS disease stage, n (%)
   N
67
      I
22 (33)
      II
30 (45)
      III
15 (22)
Time since initial diagnosis, median (range), months
1.2 (0.5-5.3)
Bone marrow % plasma cells, n (%)
   N
67
      <10
3 (5)
      10-30
31 (46)
      >30
33 (49)
Cytogenetic profilec
   N
41
      Standard risk, n (%)
33 (81)
      High risk, n (%)
8 (20)
         t(4;14)
2 (5)
         t(14;16)
2 (5)
         del17p
4 (10)
Abbreviations: D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; del, deletion; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System.
aAll-treated population, defined as patients who received ≥1 dose of study treatment.
bBased on the combination of serum β2-microglobulin and albumin.
cBased on fluorescence in situ hybridization/karyotype testing.

Patient Dispositiona,15
D-VMP
(n=67)
Patients who are still on treatment, n (%)
42 (63)
Patients who discontinued treatment, n (%)
25 (37)
Reason for discontinuation, n (%)
   Progressive disease
16 (24)
   Patient withdrawal
2 (3)
   Death
2 (3)
   Adverse event
4 (6)
   Other
0 (0)
   Protocol deviation
0 (0)
   Physician decision
1 (1)
Abbreviation: D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone.
aAll-treated population, defined as patients who received ≥1 dose of study treatment.

Patient Drug Exposurea,15
D-VMP
(n=67)
Median (range) number of treatment cycles
23 (1-26)
Median (range) duration of treatment, months
24.9 (0-28)
Relative dose intensity, median %
   DARZALEX
100
   Bortezomib
95.2
   Melphalan
97.5
   Prednisone
98
Abbreviations: D-Kd, DARZALEX FASPRO + carfilzomib + dexamethasone; D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone.
aAll-treated population, defined as patients who received ≥1 dose of study treatment.
Efficacy
  • Median duration of follow-up was 25.2 months for D-VMP arm.
  • Response rates were similar to DARZALEX studies in ALCYONE.33
    • In the D-VMP cohort (n=67):
      • ORR was 89.6% versus 90.9% in the ALCYONE study.33
      • sCR was 31.3% versus 23.1%.
      • CR was 23.9% versus 22.6%.
      • VGPR was 22.4% versus 27.1%.
      • PR was 11.9% versus 18%.
  • MRD-negativity rates were evaluated via next-generation sequencing (NGS) at a sensitivity threshold of 10-5.
    • MRD-negativity rate was 25.4%.
    • MRD-negative ≥CR rate was 25.4%.
Safety
  • A summary of TEAEs reported in the D-VMP cohort is presented in Table: Summary of TEAEs in D-VMP arm.
  • Cardiac toxicities were infrequent (<5%).
  • Most patients with IRRs experienced them on the first administration (D-VMP, 83%).
  • IRRs were mild (grade 1/2); no patients reported grade 4 IRR.
  • Median (range) time to onset of IRRs was 411 (121-534) minutes.
  • Local injection site reactions occurred in 6% (11/198) of patients (all grade 1/2).

Summary of TEAEs in D-VMP Arma,15
D-VMP
(n=67)
Any-grade TEAE, n (%)
67 (100)
Grade 3/4 TEAE, n (%)
52 (78)
   Most common (≥5% in any cohort)
      Hypertension
6 (9)
      Thrombocytopenia
30 (45)
      Lymphopenia
15 (22)
      Anemia
13 (19)
      Neutropenia
25 (37)
      Insomnia
2 (3)
      Pneumonia
5 (7)
      Leukopenia
4 (6)
      Hyperglycemia
1 (1)
      Hypokalemia
2 (3)
      Diarrhea
2 (3)
      Lower respiratory tract infection
0
Grade 5 TEAEs, n (%)
3 (4)
Serious TEAEs, n (%)
30 (45)
TEAEs leading to treatment discontinuationb, n (%)
4 (6)
Any grade IRR, n (%)
6 (9)
Abbreviations: D-VMP, DARZALEX FASPRO + bortezomib + melphalan + prednisone; IRR, infusion-related reaction; TEAE, treatment-emergent adverse event.
aAll-treated population, defined as patients who received ≥1 dose of study treatment.
bD-VMP arm: neutropenic sepsis (n=1), hepatic neoplasm (n=1), cognitive disorder (n=1), and pneumonitis (n=1).

IFM2017-03 (NCT03993912) is a prospective, randomized, open-label, active-controlled, parallel-group, multicenter, phase 3 study assessing the safety and efficacy of DR vs Rd in elderly frail patients with NDMM who were not eligible for high-dose chemotherapy and ASCT.16 Manier et al (2024)17 presented results from the phase 3 IFM2017-03 study.

Study Design/Methods

  • This study included patients aged ≥65 years who were diagnosed with NDMM and an Eastern Cooperative Oncology Group (ECOG) proxy frailty score of ≥2 and were enrolled from 90 different centers.
  • Eligible patients received 28-day cycles of DR or Rd until PD or unacceptable toxicity at the following dosage16,17:
    • DR arm:
      • DARZALEX FASPRO: 1800 mg SC QW for 8 weeks, Q2W for 16 weeks, and Q4W thereafter
      • Lenalidomide: 25 mg PO daily on days 1 to 21
      • Dexamethasone: 20 mg PO on days 1, 8, 15, and 22 for the first 2 cycles, then discontinued
    • Rd arm:
      • Lenalidomide and dexamethasone (continued throughout) at the same dosage as that in the DR arm
  • Primary endpoint: PFS.
  • Key secondary endpoints: ≥VGPR rate, ORR, OS, and safety.

Results

Patient Characteristics
  • A total of 295 patients were randomized 2:1 into the DR (n=200) or Rd (n=95) arm.
  • The median age of the patients was 81 years (range, 68-92); 84% of patients were >75 years old, and 61% of patients were >80 years old.
  • At data cutoff, the median follow-up was 40 months (95% CI, 38.5-41.7).
  • Overall, 79 patients (42%) in the DR arm and 16 patients (17%) in the Rd arm remained on treatment.
  • The median treatment duration was 34.5 months (95% CI, 28.3-40.9) in the DR arm and 14.3 months (95% CI, 10.8-20.6) in the Rd arm.
Efficacy
  • A summary of the PFS, OS, and best response rate is presented in Table: Summary of PFS, OS, and Best Response Rate.
  • DR therapy prolonged the PFS across all subgroups, including those defined by age, ECOG proxy frailty score, Charlson Comorbidity Index, International Staging System (ISS), cytogenetics, and creatinine clearance.

Summary of PFS, OS, and Best Response Rate17 
Parameter
DR
(n=200)
Rd
(n=95)
HR (95% CI)
P Value
Median PFS, months
48.5
21.5
0.51 (0.37-0.7)
<0.0001
Median OS, months
NR
36
0.46 (0.31-0.69)
0.0001
Best response rate, %
92
85
-
0.025
Abbreviations: CI, confidence interval; DR, DARZALEX + lenalidomide; HR, hazard ratio; NR, not reached; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide + dexamethasone.
Safety
  • A summary of AEs is presented in Table: Most Common Grade ≥3 AEs.
  • Treatment discontinuation rate due to AEs was higher in the Rd arm (34%) than in the DR arm (28%).

Most Common Grade ≥3 AEs17 
Event, %
DR
(n=200)
Rd
(n=95)
At least 1 AE
88
77
   Hematologic
      Neutropenia
62
33
   Nonhematologic
      Infection
18
19
         Pneumonia
5
7
Abbreviations: AE, adverse event; DR, DARZALEX + lenalidomide; Rd, lenalidomide + dexamethasone.
Health-Related Quality of Life
  • The baseline health-related quality of life was similar in both groups. However, compared with the Rd group, the DR arm showed a faster improvement in all EORTC QLQ-C30 domains.

LITERATURE SEARCH

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 15 April 2025.

 

References

Show
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29 Facon T, Kumar S, Plesner T, et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(11):1582-1596.  
30 Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed multiple myeloma (NDMM) ineligible for transplant (MAIA). Oral presentation presented at: 60th American Society of Hematology (ASH) Annual Meeting & Exposition; December 1-4, 2018; San Diego, CA.  
31 Facon T, Moreau P, Weisel K, et al. Supplement to: Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. Leukemia. 2025;39(4):942-950.  
32 Rifkin R, Melear J, Faber E, et al. Daratumumab (DARA) maintenance therapy improves depth of response and results in durable progression-free survival (PFS) following DARA plus cyclophosphamide, bortezomib, and dexamethasone (CyBorD) induction therapy in multiple myeloma (MM): update of the LYRA study. presented at: 61st American Society of Hematology (ASH) Annual Meeting & Exposition; December 7-10, 2019; Orlando, FL.  
33 Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141.