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Use of DARZALEX + DARZALEX FASPRO in Combination with Lenalidomide and Dexamethasone in Multiple Myeloma

Last Updated: 03/26/2025

SUMMARY

  • MAIA is a phase 3 study evaluating the safety and efficacy of DARZALEX for intravenous (IV) use in combination with lenalidomide and dexamethasone (D-Rd) compared to lenalidomide plus dexamethasone (Rd) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients.1,2
    • Facon et al (2019)1 reported the prespecified interim results of this ongoing study.
    • Facon et al (2025)3 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 progression-free survival (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 overall survival (OS) was not reached 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) minimal residual disease (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 treatment-emergent adverse events (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)4 presented (at the European Hematology Association [EHA] Hybrid Congress) 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.
    • Other relevant subgroup analyses from MAIA Study have been referenced below.5-16
  • POLLUX was a phase 3 study evaluating the safety and efficacy of Rd and D-Rd in patients with relapsed or refractory multiple myeloma (RRMM).17
    • Dimopoulos et al (2023)18 reported updated efficacy and safety results from POLLUX at a median follow-up of 79.7 months. Median OS in the intention-to-treat (ITT) population with D-Rd was 67.6 months (95% CI, 53.1-80.5) with D-Rd and
      51.8 months (95% CI, 44.0-60.0) with Rd (HR, 0.73; 95% CI, 0.58-0.91; P=0.0044). The most common grade 3/4 (≥10%) TEAEs were neutropenia (D-Rd, 57.6%; Rd, 41.6%), anemia (D-Rd, 19.8%; Rd, 22.4%), pneumonia (D-Rd, 17.3%; Rd, 11%), thrombocytopenia (D-Rd, 15.5%; Rd, 15.7%), and diarrhea (D-Rd, 10.2%; Rd, 3.9%).
    • Other relevant subgroup analyses from POLLUX Study have been referenced below.19-24
  • AURIGA is a phase 3 study evaluating the conversion rate to MRD-negativity after maintenance treatment with DARZALEX FASPRO in combination with lenalidomide (D-R) vs lenalidomide (R) alone in patients with NDMM who are anti-cluster of differentiation (CD) 38 naïve, have ≥VGPR, and are MRD-positive following ASCT after standard-of-care induction/consolidation.25,26
    • Badros et al (2025)26-28 reported primary results from the phase 3 AURIGA study. The MRD-negativity (10-5) conversion rate by 12 months from initiation of maintenance (primary endpoint), was significantly higher for D-R vs R (50.5% vs 18.8%; odds ratio [OR], 4.51; 95% CI, 2.37-8.57; P<0.0001). Similarly, the MRD-negativity (10-6) conversion rate by 12 months from initiation of maintenance was higher with D-R vs R (23.2% vs 5.0%; OR, 5.97; 95% CI, 2.15-16.58; P=0.0002). At a median follow-up of 32.3 months, the D-R vs R arm showed a higher overall MRD-negativity conversion rate (10-5 sensitivity, 60.6% vs 27.7%; 10-6 sensitivity, 36.4% vs 12.9%) and a higher ≥CR rate (75.8% vs 61.4%). PFS favored D-R vs R with 47% reduction in the risk of disease progression or death (HR, 0.53; 95% CI, 0.29-0.97). At 30 months, the estimated PFS was 82.7% vs 66.4% and the estimated OS for the ITT population was 94.6% vs 91.0% in the D-R vs R arm, respectively. Slightly higher occurrence rates of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were observed with D-R vs R. Serious adverse events (AEs) were reported in 30.2% vs 22.4% of patients in the D-R vs R arm, respectively.
    • Other relevant subgroup analysis from AURIGA Study have been referenced below.29
  • PLEIADES is an ongoing, phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with 4 standard-of-care treatment regimens in patients with multiple myeloma (MM).30-34 Results from patients in the D-Rd arm are summarized below.
  • Other relevant literature that has been identified has been referenced below.35,36

PRODUCT LABELING

Clinical studies

DARZALEX in Combination with Lenalidomide and Dexamethasone in Patients with NDMM

MAIA (MMY3008; NCT02252172) is an international, phase 3, randomized, open-label, active-controlled, multicenter study in patients with NDMM not eligible for high dose chemotherapy and ASCT (N=737).1,2 Facon et al (2021)37 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)3 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)4 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 PD or unacceptable toxicity at the following dosage1,2:
    • D-Rd arm:
      • DARZALEX: 16 mg/kg IV weekly during cycles 1-2, every 2 weeks during cycles 3-6, then every 4 weeks during cycle 7+
      • Lenalidomide: 25 mg 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)3 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 Population38
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 Subgroups38
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 Population38
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)3,38
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).3
  • 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%).3
  • 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).3
    • 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.3
    • 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.3
    • 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,38
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,38
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 Population3
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 Subgroups3
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 Subgroups3
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.3
    • 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.3
    • 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,3
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,38
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)4 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,4
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,4
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.
    • Progressive disease 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,4
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 Lenalidomide and Dexamethasone in Patients with RRMM

POLLUX (MMY3003; NCT02076009) is a phase 3, randomized, open-label, multicenter study to evaluate the safety and efficacy of D-Rd and Rd in patients with RRMM (N=569).17 Dimopoulos et al (2023)18 reported updated results of the POLLUX study, including OS, at a median follow-up of 79.7 months.

Results

Patients and Treatments

Baseline Demographics and Clinical Characteristics (POLLUX; ITT Population)18
Characteristic
D-Rd
(n=286)
Rd
(n=283)
Age, years
   Median (range)
65 (34-89)
65 (42-87)
   ≥75, n (%)
29 (10.1)
35 (12.4)
ISS staginga, n (%)
   I
137 (47.9)
140 (49.5)
   II
93 (32.5)
86 (30.4)
   III
56 (19.6)
57 (20.1)
Median (range) time from diagnosis, years
3.48 (0.4-27.0)
3.95 (0.4-21.7)
Prior lines of therapy, n (%)
   Median (range)
1 (1-11)
1 (1-8)
   1
149 (52.1)
146 (51.6)
   2
85 (29.7)
80 (28.3)
   3
38 (13.3)
38 (13.4)
   >3
14 (4.9)
19 (6.7)
Prior IMiD, n (%)
158 (55.2)
156 (55.1)
   Prior thalidomide
122 (42.7)
125 (44.2)
   Prior lenalidomide
50 (17.5)
50 (17.7)
Prior PI, n (%)
245 (85.7)
242 (85.5)
   Prior bortezomib
241 (84.3)
238 (84.1)
Prior PI+ IMiD, n (%)
125 (43.7)
125 (44.2)
Refractory to bortezomib, n (%)
59 (20.6)
58 (20.5)
Refractory to last line of prior therapy, n (%)
80 (28)
76 (26.9)
Cytogenetic risk profileb, n/N (%)
   Standard risk
193/228 (84.6)
176/211 (83.4)
   High risk
35/228 (15.4)
35/211 (16.6)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; IMiD, immunomodulatory drug; ISS, International Staging System; ITT, intention-to-treat; PI, proteasome inhibitor; Rd, lenalidomide + dexamethasone.
aISS staging was based on the combination of serum β2-microglobulin and albumin.
bCytogenetic risk was assessed locally by fluorescence in situ hybridization or karyotype testing; high risk was defined as the presence of t(4;14), t(14;16), or del17p abnormality.
Efficacy
  • At a median follow-up of 79.7 months, D-Rd arm provided a 27% reduction in the risk of death compared to Rd arm (HR, 0.73; 95% CI, 0.58-0.91; P=0.0044).
    • Median OS in the ITT population with D-Rd was 67.6 months (95% CI, 53.1-80.5) vs 51.8 months (95% CI, 44.0-60.0) with Rd.
  • MRD-negativity rate at a 10-5 sensitivity threshold was 33.2% vs 6.7% in the D-Rd vs Rd arms, respectively (P<0.0001).
  • In the ITT population, median disease progression on the next line of therapy or death (PFS2) was significantly prolonged in D-Rd vs Rd arms, respectively, at 57.9 months vs 32.0 months (HR, 0.54; 95% CI, 0.43-0.67; P<0.0001).
  • OS benefit of D-Rd vs Rd was generally consistent across prespecified patient subgroups as presented in Table: OS in Prespecified Patient Subgroups in the ITT Population (POLLUX).
  • In total, 44.9% (127 of 283) of patients vs 74.7% (210 of 281) of patients in the D-Rd vs Rd arms, respectively, received subsequent therapy. See Table: Most Common Subsequent Anticancer Therapies in the D-Rd and Rd arms.
    • Of the patients in the Rd arm who received subsequent therapy, 122 (58.1%) patients received DARZALEX in any subsequent line of therapy.
    • Median number of subsequent lines of therapy was 2 (range, 1-13) vs 2 (range, 1-12) in the D-Rd vs Rd arms, respectively.
  • Median time to subsequent treatment was significantly increased with D-Rd vs Rd (69.3 vs 23.1 months; HR, 0.40; 95% CI, 0.32-0.50; P<0.0001).
  • The most common first line subsequent anticancer therapy was pomalidomide and dexamethasone (12.5%) or bortezomib and dexamethasone (10.2%) in the D-Rd arm and DARZALEX monotherapy (22.4%) in the Rd arm.

OS in Prespecified Patient Subgroups in the ITT Population (POLLUX)18
D-Rd
Rd
Hazard Ratio (95% CI)
n/N
Median
n/N
Median
Age
   <65
57/133
NE
79/140
58.7
0.66 (0.47-0.93)
   ≥65
96/153
53.1
96/143
49.9
0.85 (0.64-1.13)
Sex
   Male
100/173
56.7
106/164
51.5
0.85 (0.65-1.12)
   Female
53/113
NE
69/119
51.8
0.65 (0.46-0.93)
Race
   White
109/207
74.3
114/186
57.7
0.76 (0.58-0.99)
   Asian
29/54
58.6
31/46
35.7
0.65 (0.39-1.08)
   Other
15/25
53.1
30/51
58.4
1.01 (0.54-1.87)
ISS disease stagea
   I
54/137
NE
70/140
71.9
0.76 (0.53-1.08)
   II
61/93
50.4
65/86
38.5
0.71 (0.50-1.01)
   III
38/56
39.0
40/57
20.3
0.74 (0.47-1.15)
Cytogenetic risk at study entryb
   High risk
25/35
40.0
28/35
23.6
0.70 (0.41-1.20)
   Standard risk
104/193
67.6
107/176
51.8
0.80 (0.61-1.05)
Number of prior lines of therapy
   1
76/149
77.8
89/146
57.7
0.75 (0.56-1.02)
   2
47/85
53.1
51/80
45.4
0.75 (0.50-1.11)
   3
21/38
59.0
25/38
52.0
0.74 (0.41-1.32)
   >3
9/14
51.9
10/19
49.0
1.14 (0.46-2.80)
Prior lenalidomide treatment
   Yes
31/50
49.5
26/50
68.3
1.27 (0.75-2.14)
   No
122/236
75.6
149/233
50.4
0.70 (0.55-0.89)
Prior PI
   Yes
136/245
65.0
152/242
51.3
0.79 (0.63-0.99)
   No
17/41
NE
23/41
63.3
0.65 (0.35-1.22)
Refractory to PI
   Yes
41/64
47.7
40/60
33.0
0.85 (0.55-1.31)
   No
95/181
72.0
112/182
58.4
0.76 (0.58-1.00)
Refractory to last line of therapy
   Yes
52/80
47.7
55/76
33.0
0.74 (0.50-1.08)
   No
101/206
79.3
120/207
61.9
0.77 (0.59-1.00)
Type of measurable MMc
   IgG
70/151
NE
89/158
56.0
0.70 (0.51-0.96)
   Non-IgG
36/54
48.8
37/53
44.0
0.86 (0.55-1.37)
Baseline renal function (CrCl)
   >60 mL/min
98/199
79.3
124/216
59.6
0.80 (0.61-1.04)
   ≤60 mL/min
53/80
52.0
51/65
28.4
0.60 (0.41-0.89)
ECOG PS score
   0
67/139
77.5
86/150
59.9
0.79 (0.57-1.09)
   ≥1
86/147
58.5
89/133
39.4
0.72 (0.54-0.97)
Abbreviations: CI, confidence interval; CrCl, creatinine clearance; D-Rd, DARZALEX + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; IgG, immunoglobulin G; ISS, International Staging System; ITT, intention-to-treat; MM, multiple myeloma; NE, not estimable; OS, overall survival; PI, proteosome inhibitor; Rd, lenalidomide + dexamethasone.
aISS disease stage was derived based on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more severe disease.
bCytogenetic risk was assessed locally by fluorescence in situ hybridization or karyotype testing. High risk was defined as the presence of t(4;14), t(14;16), or del17p.
cIncludes patients who had measurable disease in serum.

Most Common Subsequent Anticancer Therapies in the D-Rd and Rd arms18
Drug, %
D-Rd
Rd
Dexamethasone
39.2
63.0
Daratumumab
-
43.4
Pomalidomide
23.7
37.0
Bortezomib
19.8
33.8
Cyclophosphamide
17.7
38.1
Carfilzomib
16.6
23.5
Lenalidomide
-
18.5
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone.
Safety

Most common (>15% of Patients) and Grade 3/4 (>5% of Patients) TEAEs in the Safety Population18
TEAE, n (%)
All Grades
Grade 3/4
D-Rd
(n=283)
Rd
(n=281)
D-Rd
(n=283)
Rd
(n=281)
Hematologic
   Neutropenia
185 (65.4)
136 (48.4)
163 (57.6)
117 (41.6)
   Anemia
121 (42.8)
117 (41.6)
56 (19.8)
63 (22.4)
   Thrombocytopenia
93 (32.9)
90 (32.0)
44 (15.5)
44 (15.7)
   Lymphopenia
20 (7.1)
17 (6.0)
17 (6.0)
12 (4.3)
   Febrile neutropenia
18 (6.4)
8 (2.8)
18 (6.4)
8 (2.8)
Nonhematologic
   Diarrhea
170 (60.1)
108 (38.4)
29 (10.2)
11 (3.9)
   URIT
125 (44.2)
79 (28.1)
6 (2.1)
5 (1.8)
   Fatigue
119 (42.0)
87 (31.0)
20 (7.1)
12 (4.3)
   Cough
107 (37.8)
43 (15.3)
1 (0.4)
0 (0.0)
   Nasopharyngitis
100 (35.3)
62 (22.1)
0 (0.0)
0 (0.0)
   Constipation
95 (33.6)
77 (27.4)
4 (1.4)
2 (0.7)
   Muscle spasms
87 (30.7)
61 (21.7)
3 (1.1)
5 (1.8)
   Nausea
87 (30.7)
53 (18.9)
6 (2.1)
2 (0.7)
   Insomnia
80 (28.3)
65 (23.1)
6 (2.1)
6 (2.1)
   Pneumonia
80 (28.3)
49 (17.4)
49 (17.3)
31 (11)
   Back pain
77 (27.2)
59 (21.0)
10 (3.5)
5 (1.8)
   Pyrexia
77 (27.2)
41 (14.6)
9 (3.2)
7 (2.5)
   Arthralgia
75 (26.5)
56 (19.9)
4 (1.4)
4 (1.4)
   Peripheral edema
72 (25.4)
50 (17.8)
3 (1.1)
4 (1.4)
   Dyspnea
67 (23.7)
39 (13.9)
15 (5.3)
2 (0.7)
   Vomiting
66 (23.3)
20 (7.1)
3 (1.1)
4 (1.4)
   Bronchitis
63 (22.3)
50 (17.8)
9 (3.2)
9 (3.2)
   Cataract
61 (21.6)
35 (12.5)
21 (7.4)
13 (4.6)
   Asthenia
59 (20.8)
47 (16.7)
10 (3.5)
9 (3.2)
   Hypokalemia
58 (20.5)
35 (12.5)
19 (6.7)
12 (4.3)
   Headache
57 (20.1)
23 (8.2)
0 (0.0)
0 (0.0)
   Rash
51 (18.0)
36 (12.8)
1 (0.4)
0 (0.0)
   Decreased appetite
50 (17.7)
37 (13.2)
6 (2.1)
1 (0.4)
   Pain in extremity
48 (17.0)
42 (14.9)
0 (0.0)
1 (0.4)
   Influenza
46 (16.3)
24 (8.5)
11 (3.9)
3 (1.1)
   Hypophosphatemia
22 (7.8)
14 (5.0)
16 (5.7)
8 (2.8)
   Syncope
16 (5.7)
4 (1.4)
15 (5.3)
4 (1.4)
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; URTI, Upper respiratory tract infection.

TEAEs Leading to Treatment Discontinuation or Deaths (POLLUX)18
TEAEs
D-Rd
(n=283)
Rd
(n=281)
Serious TEAEs, %
72.4
52.7
   Pneumonia
17.0
11.4
TEAEs leading to treatment discontinuation, %
19.1
16.0
   Infections, n (%)
13 (4.6)
11 (3.9)
TEAEs leading to death, n (%)
35 (12.4)
24 (8.5)
   Septic shock, %
1.4
0.4
   Cardiac arrest, %
1.1
0.4
   Sudden death, %
1.1
0.4
   Pneumonia, %
0.7
1.1
   Acute kidney injury, %
0.4
1.1
   Sepsis, %
0
1.1
Abbreviations: D-Rd, DARZALEX + lenalidomide + dexamethasone; Rd, lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event.

AURIGA (MMY3021; NCT03901963) is a phase 3 study evaluating the conversion rate to MRDnegativity after maintenance treatment with DR vs lenalidomide alone in patients with NDMM who are MRD-positive after ASCT.25-27 Badros et al (2025)26,27 reported primary results from the phase 3 AURIGA study.

Study Design/Methods

  • The trial enrolled 200 patients from the United States and Canada.26

Primary Results from the AURIGA Study

Results

Patient Characteristics
  • A total of 200 patients were randomized into the D-R maintenance (n=99) and R alone maintenance (n=101) arms.26
  • The median duration of treatment was 30.7 (range, 0.7-37.5) months vs 20.6
    (range, 0-37.7) months in the D-R vs R arm, respectively.26
  • The baseline demographics and disease characteristics of the ITT population are presented in Table: Baseline Demographics and Disease Characteristics of the ITT Population.26
  • The median follow-up was 32.3 months.26
  • Patients in the D-R vs R arm received a median of 33.0 (range, 1-36) vs 21.5
    (range, 1-36) maintenance cycles, respectively.26
  • Overall, 85 of 96 (88.5%) vs 77 of 98 (78.6%) patients in the D-R vs R arm completed ≥12 maintenance cycles, respectively.26

Baseline Demographics and Disease Characteristics of the ITT Population26
D-R (n=99)
R (n=101)
Median age (range), years
63 (35-77)
62 (35-78)
   <65 years, n (%)
61 (61.6)
61 (60.4)
   65-70 years, n (%)
23 (23.2)
21 (20.8)
   ≥70 years, n (%)
15 (15.2)
19 (18.8)
Sex, n (%)
   Male
61 (61.6)
58 (57.4)
   Female
38 (38.4)
43 (42.6)
Race, n (%)
   White
67 (67.7)
68 (67.3)
   Black or African American
20 (20.2)
24 (23.8)
   Asian
5 (5.1)
1 (1.0)
   American Indian or Alaska Native
0
1 (1.0)
   Othera
5 (5.1)
5 (5.0)
   NR
2 (2.0)
2 (2.0)
ECOG PS, n (%)
   0
45 (45.5)
55 (54.5)
   1
52 (52.5)
44 (43.6)
   2
2 (2.0)
2 (2.0)
ISS disease stage, n (%)b
   I
40 (44.0)
38 (38.8)
   II
28 (30.8)
37 (37.8)
   III
23 (25.3)
23 (23.5)
Median induction cycles (range), nc
5.0 (4.0-8.0)
5.0 (4.0-8.0)
Cytogenetic risk at diagnosis, n (%)d
   Standard risk
63 (68.5)
66 (74.2)
   High riske
22 (23.9)
15 (16.9)
      del(17p)
13 (14.1)
3 (3.4)
      t(4;14)
10 (10.9)
12 (13.5)
      t(14;16)
6 (6.5)
7 (7.9)
   Unknown
7 (7.6)
8 (9.0)
Revised cytogenetic risk at diagnosis, n (%)f
   Standard risk
52 (55.9)
53 (59.6)
   High riskg
32 (34.4)
30 (33.7)
      del(17p)
13 (14.0)
3 (3.4)
      t(4;14)
10 (10.8)
12 (13.5)
      t(14;16)
6 (6.5)
7 (7.9)
      t(14;20)
1 (1.1)
2 (2.2)
      gain/amp(1q21)
16 (17.2)
22 (24.7)
   Unknown
9 (9.7)
6 (6.7)
Abbreviations: D-R, DARZALEX FASPRO + lenalidomide; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intention-to-treat; NR, not reported; R, lenalidomide.
aPatients reporting multiple races.
bD-R vs R: n=91 vs n=98, respectively.
cD-R vs R: n=98 vs n=99, respectively.
dD-R vs R: n=92 vs n=89, respectively.
eHigh risk is defined as positive for any of del(17p), t(14;16), or t(4;14).
fD-R vs R: n=93 vs n=89, respectively.
gRevised high-risk cytogenetics is defined as ≥1 abnormality from del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21).
Efficacy
  • The MRD status and response rates in the ITT population are summarized in Table: Summary of MRD Status and Response Rates in the ITT Population.26,27
    • The MRD-negativity (10-5) conversion rate by 12 months from initiation of maintenance (primary endpoint), was significantly higher for D-R vs R (50.5% vs 18.8%; OR, 4.51; 95% CI, 2.37-8.57; P<0.0001).
    • The D-R arm yielded ~2.5 times greater sustained MRD-negativity (10-5) rates at ≥6 months (35.4% vs 13.9%) and relatively higher sustained MRD-negativity (10-5 sensitivity) rates at ≥12 months (17.2% vs 5.0%) than the R arm.
  • Subgroup analyses of MRD-negativity (10-5 sensitivity) conversion rates at 12 months appeared to consistently favor D-R over R across most clinically relevant subgroups, including patients with a standard or high cytogenetic risk and older patients; the results are summarized in Table: Subgroup Analysis of MRD-Negativity (10-5) Conversion Rate From Baseline to 12 Months of Maintenance Treatment in the ITT Population.26
  • At a median follow-up of 32.3 months, treatment with D-R vs R maintenance yielded a greater improvement in PFS, with 47% reduction in the risk of disease progression or death (HR, 0.53; 95% CI, 0.29-0.97; nominal P=0.0361).26,27
  • At 30 months, the estimated PFS rate in the D-R vs R arm was 82.7%
    (95% CI, 72.8-89.3) vs 66.4% (95% CI, 54.0-76.2), respectively.26
  • At 30 months, the estimated OS in the D-R vs R arm of the ITT population was
    94.6% vs 91.0% (HR, 0.50; 95% CI, 0.17-1.50; P=0.2081), respectively.26,28

Summary of MRD Status and Response Rates in the ITT Population26,27
Parameter
D-R (n=99)
R (n=101)
ORa (95% CI)
P-Valueb
Overall MRD-negativity conversion rate, n (%)c
   10-5 sensitivity
60 (60.6)
28 (27.7)
4.12 (2.26-7.52)
<0.0001
   10-6 sensitivity
36 (36.4)
13 (12.9)
3.91 (1.91-7.99)
0.0001
MRD-negativity conversion rate at 12 months from start of maintenance, n (%)
   10-5 sensitivity
50 (50.5)
19 (18.8)
4.51 (2.37-8.57)
<0.0001
   10-6 sensitivity
23 (23.2)
5 (5.0)
5.97 (2.15-16.58)
0.0002
Sustained MRD-negativity (10-5), n (%)
   ≥6 monthsd
35 (35.4)
14 (13.9)
3.40 (1.69-6.83)
0.0005
   ≥12 monthsd
17 (17.2)
5 (5.0)
4.08 (1.43-11.62)
0.0065
Overall response, n (%)
   ≥CR
75 (75.8)
62 (61.4)
2.00 (1.08-3.69)
0.0255
      sCR
50 (50.5)
36 (35.6)
-
-
      CR
25 (25.3)
26 (25.7)
-
-
   VGPR
24 (24.2)
39 (38.6)
-
-
Abbreviations: CI, confidence interval; CR, complete response; D-R, DARZALEX FASPRO + lenalidomide; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; R, lenalidomide; sCR, stringent complete response; VGPR, very good partial response.
aMantel-Haenszel estimate of the common OR for stratified tables was used. The stratification factor was the baseline cytogenetic risk per investigator assessment (high vs standard/unknown) as used for randomization. An OR of >1 indicates an advantage for the D-R arm.
bAll parameters, except ≥CR were assessed using Fisher’s exact test. ≥CR rates were accessed using Cochran-Mantel-Haenszel chi-squared test.
cAt a median follow-up of 32.3 months.dSustained MRD-negativity at ≥6 months and ≥12 months is defined as an MRD-negative status (at 10-5 sensitivity threshold) in 2 bone marrow aspirate assessments spaced a minimum of 6 months and 12 months apart, respectively, without any assessment showing an MRD-positive status in between the assessments.

Subgroup Analysis of MRD-Negativity (10-5) Conversion Rate From Baseline to 12 Months of Maintenance Treatment in the ITT Population26
Subgroup, n/N (%)
D-R (n=99)
R (n=101)
OR (95% CI)
ITT (overall)
50/99 (50.5)
19/101 (18.8)
4.51 (2.37-8.57)
Sex
   Male
32/61 (52.5)
11/58 (19.0)
4.71 (2.06-10.78)
   Female
18/38 (47.4)
8/43 (18.6)
3.94 (1.45-10.68)
Age
   <65 years
30/61 (49.2)
12/61 (19.7)
3.95 (1.76-8.85)
   ≥65 years
20/38 (52.6)
7/40 (17.5)
5.24 (1.86-14.74)
Race
   White
31/67 (46.3)
14/68 (20.6)
3.32 (1.55-7.10)
   Black
12/20 (60.0)
4/24 (16.7)
7.50 (1.85-30.34)
   Other
7/12 (58.3)
1/9 (11.1)
11.20 (1.04-120.36)
Weight
   ≤70 kg
12/23 (52.2)
4/18 (22.2)
3.82 (0.96-15.18)
   >70 kg
38/76 (50.0)
15/81 (18.5)
4.40 (2.14-9.03)
Baseline ECOG PS score
   0
20/45 (44.4)
9/55 (16.4)
4.09 (1.62-10.31)
   ≥1
30/54 (55.6)
10/46 (21.7)
4.50 (1.86-10.88)
ISS staging at diagnosis
   I
19/40 (47.5)
8/38 (21.1)
3.39 (1.25-9.19)
   II
13/28 (46.4)
7/37 (18.9)
3.71 (1.23-11.25)
   III
15/23 (65.2)
3/23 (13.0)
12.50 (2.83-55.25
Cytogenetic risk at diagnosis
   High riska
7/22 (31.8)
1/15 (6.7)
6.53 (0.71-60.05)
   Standard risk
35/63 (55.6)
14/66 (21.2)
4.64 (2.15-10.04)
Revised cytogenetic risk at diagnosis
   High riskb
14/32 (43.8)
4/30 (13.3)
5.06 (1.43-17.88)
   Standard risk
28/52 (53.8)
12/53 (22.6)
3.99 (1.72-9.26)
Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO + lenalidomide; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; ITT, intention-to-treat; MRD, minimal residual disease; OR, odds ratio; R, lenalidomide.
aHigh risk is defined as positive for any of the following abnormalities: del(17p), t(14;16), or t(4;14).
bRevised high-risk cytogenetics is defined as ≥1 abnormality from del(17p), t(4;14), t(14;16), t(14;20), and gain/amp(1q21).
Safety
  • The most common AEs in the safety population are summarized in Table: Most Common AEs in the Safety Population.26
    • Slightly higher occurrence rates of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were observed with D-R vs R.
    • Serious AEs were reported in 30.2% vs 22.4% of patients in the D-R vs R arm, respectively.
    • Any TEAEs occurred in 99.0% of patients in both the D-R and R arms.
      • Grade 3/4 TEAEs occurred in 74.0% and 67.3% of patients in the D-R and R arms, respectively.
  • During the analysis, 32 of 96 (33.3%) vs 47 of 98 (48.0%) patients in the D-R vs R arm, respectively, discontinued ≥1 component of the study treatment. The reasons for treatment discontinuation are summarized in Table: Reasons for Treatment Discontinuation During Analysis.26

Most Commona AEs in the Safety Population26
AE, n (%)
D-R (n=96)
R (n=98)
Any Grade
Grade 3/4
Any Grade
Grade 3/4
Hematologic
   Neutropenia
62 (64.6)
45 (46.9)
60 (61.2)
41 (41.8)
   Leukopenia
25 (26.0)
9 (9.4)
29 (29.6)
6 (6.1)
   Thrombocytopenia
23 (24.0)
3 (3.1)
28 (28.6)
2 (2.0)
   Lymphopenia
23 (24.0)
10 (10.4)
13 (13.3)
5 (5.1)
   Anemia
22 (22.9)
4 (4.2)
17 (17.3)
3 (3.1)
Nonhematologic
   Diarrhea
59 (61.5)
3 (3.1)
54 (55.1)
5 (5.1)
   Fatigue
44 (45.8)
2 (2.1)
46 (46.9)
3 (3.1)
   Upper respiratory tract infection
40 (41.7)
0 (0)
26 (26.5)
0 (0)
   Cough
37 (38.5)
0 (0)
36 (36.7)
0 (0)
   Hypokalemia
33 (34.4)
7 (7.3)
36 (36.7)
6 (6.1)
   Arthralgia
32 (33.3)
1 (1.0)
36 (36.7)
1 (1.0)
   Back pain
31 (32.3)
0 (0)
20 (20.4)
1 (1.0)
   COVID-19
28 (29.2)
1 (1.0)
29 (29.6)
3 (3.1)
   Nausea
26 (27.1)
0 (0)
26 (26.5)
0 (0)
   Nasal congestion
25 (26.0)
0 (0)
19 (19.4)
0 (0)
   Headache
24 (25.0)
1 (1.0)
17 (17.3)
0 (0)
   Constipation
22 (22.9)
0 (0)
26 (26.5)
0 (0)
   Muscle spasms
22 (22.9)
0 (0)
21 (21.4)
0 (0)
   Pain in extremity
22 (22.9)
1 (1.0)
17 (17.3)
0 (0)
   Rash maculopapular
21 (21.9)
1 (1.0)
17 (17.3)
2 (2.0)
   Hypertension
14 (14.6)
7 (7.3)
10 (10.2)
4 (4.1)
   Pneumonia
10 (10.4)
5 (5.2)
14 (14.3)
4 (4.1)
Infusion-related reactions
13 (13.5)
0 (0)
-
-
Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-R, DARZALEX FASPRO + lenalidomide; R, lenalidomide.
aAEs of any grade that occurred in ≥20% of patients and grade 3/4 AEs that occurred in ≥5% of patients in either treatment group.

Reasons for Treatment Discontinuation During Analysis26
Reasons for Discontinuation, n
D-R (n=96)a
R (n=98)b
Discontinuation of R
32
47
   Progressive disease
11
23
   AE
12
8
   Patient withdrawal
3
4
   Death
2
1
   Physician decision
2
4
   Patient refused further study treatment
1
5
   Protocol deviation
-
1
   Other
1
1
Discontinuation of D
27
-
   Progressive disease
13
-
   AE
6
-
   Patient withdrawal
3
-
   Death
2
-
   Physician decision
2
-
   Patient refused further study treatment
1
-
Abbreviations: AE, adverse event; D, DARZALEX FASPRO; D-R, DARZALEX FASPRO + lenalidomide; R, lenalidomide.aOf the patients randomized to the D-R (n=99) arm, 3 patients were not treated due to physician decision, study schedule being too intense, and protocol deviation (n=1 each).
bOf the patients randomized to the R arm (n=101), 3 patients were not treated due to study tests being too hard, patient not wanting to be on the lenalidomide only treatment arm, and patient withdrawal of consent (n=1 each).

DARZALEX FASPRO in Combination with 4 Standard-of-Care Regimens

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. Chari et al (2021)33 presented updated safety and efficacy results for DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd), DARZALEX FASPRO in combination with bortezomib, melphalan, and prednisone (D-VMP), and D-Rd arms of the PLEIADES study. Results specific to the D-Rd arm at a median follow-up of 14.7 months are summarized below. Moreau et al (2020)34 presented updated safety and efficacy results for DARZALEX FASPRO in combination with carfilzomib and dexamethasone D-Kd (primary analysis), D-Rd, and D-VMP arms of the PLEIADES study. Results specific to the D-Rd arm at a median follow up of 25.7 months are summarized below.

Results: D-Rd Cohort at a Median Follow-up of 14.7 Months


Baseline Demographics and Patient Characteristics - D-Rd Cohort (PLEIADES)a,33
RRMM with ≥ 1 prior line of therapy
D-Rd (n=65)
Age, years
   Median (range)
69 (33-82)
   18 to <65, n (%)
22 (33.8)
   65 to <75, n (%)
29 (44.6)
   ≥75, n (%)
14 (21.5)
Male, n (%)
45 (69.2)
Median (range) body weight, kg
80.6 (54-143)
Race, n (%)
   White
45 (69.2)
   Black or African American
2 (3.1)
   Asian
0 (0.0)
ECOG PS score, n (%)
   0
36 (55.4)
   1
29 (44.6)
   2
0 (0.0)
Median (range) number of prior lines of therapy, n
1 (1-5)
ISS stagingb, n (%)
   I
27 (41.5)
   II
19 (29.2)
   III
18 (27.7)
Cytogenic riskc, d, n (%)
n=31
   Standard risk
20 (64.5)
   High risk
11 (35.5)
   t(4;14)
6 (19.4)
   t(14;16)
3 (9.7)
   del17p
4 (12.9)
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, international staging system; RRMM, relapsed or refractory multiple myeloma.
aAll-treated population, defined as patients who received ≥1 dose of study treatment.
bBased on the combination of serum β2-microglobulin and albumin at screening.
cBased on fluorescence in situ hybridization or karyotyping testing conducted locally.
dHigh cytogenetic risk was defined as having ≥1 of t(4;14), t(14;16) or del17p abnormalities.

Patient Disposition and Exposure - D-Rd Cohort (PLEIADES)a, 33
RRMM with ≥ 1 prior line of therapy
D-Rd (n=65)
Median (range) number of treatment cycles
16 (1-19)
Median (range) duration of treatment, months
14.9 (0-17)
Relative dose intensity, median %
   DARZALEX FASPRO
100
   Bortezomib
-
   Melphalan
-
   Prednisone
-
   Lenalidomide
82
   Dexamethasone
65.6
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; RRMM, relapsed or refractory multiple myeloma.
aThe all-treatedpopulation included all patients who received ≥1 dose of study treatment.
Efficacy
  • Median follow-up was 14.7 months for D-Rd cohort.
  • Primary endpoints were met for the D-Rd cohort with available data and response rates similar to the DARZALEX study, POLLUX.39
    • In the D-Rd cohort:
      • ORR was 93.8% vs 92.9% in the POLLUX study.
      • VGPR was 40% vs 32.7%.
      • PR was 15.4% vs 17.1%.
      • CR was 20% vs 24.9%.
      • stringent complete response (sCR) was 18.5% vs 18.1%.
  • MRD-negativity rates were evaluated via NGS at a sensitivity threshold of 10-5.
    • MRD-negativity rate was 15.4% (90% CI, 8.6-24.7) in the D-Rd cohort.  
Pharmacokinetics
  • Overall, serum trough concentrations (Ctrough) and immunogenicity values were consistent with historical daratumumab IV data.
  • Cmax after the 1st dose was 108 ± 49.9 µg/mL in the D-Rd cohort.
  • Sixteen patients developed rHuPh20 antibodies (all were non-neutralizing).
  • No patients developed anti-daratumumab antibodies.
Safety
  • Treatment discontinuation due to TEAEs were 8% in the D-Rd cohort.
  • A summary of TEAEs in each cohort is presented in Table: Safety Summary - D-Rd Cohort (PLEIADES).
  • Any-grade IRRs occurred in 8% of patient across all cohorts.

Safety Summary - D-Rd Cohort (PLEIADES)33
n (%)
RRMM with ≥ 1 prior line of therapy
D-Rd (n=65)
Any TEAE
65 (100)
Serious TEAE
34 (52.3)
Grade 3/4 TEAE
58 (89.2)
Grade 5
2 (3.1)
TEAEs leading to treatment discontinuation
5 (7.7)
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; RRMM, relapsed or refractory multiple myeloma; TEAE, treatment-emergent adverse event.
  • Across all 3 cohorts with available data any grade IRRs occurred in 8% (15/199) of patients.
    • IRRs were mild (grade 1/2), one patient had grade 3 IRR and no patients reported grade 4 IRR.
  • Median time to onset of IRRs was 5.5 hours in the D-Rd cohorts.
  • Local injection site reactions occurred in 8% of patients in all cohorts (all grade 1/2).
  • A summary of most common TEAEs is presented in Table: Most Common TEAEs in D-Rd Cohort (≥ 5%; PLEIADES).

Most Common TEAEs in D-Rd Cohort (≥5%)33
Event, n (%)
RRMM with ≥ 1 prior line of therapy
D-Rd (n=65)
Hematologic
   Neutropenia
32 (49.2)
   Lymphopenia
7 (10.8)
   Thrombocytopenia
9 (13.8)
   Leukopenia
6 (9.2)
   Anemia
6 (9.2)
Nonhematologic
   Pneumonia
8 (12.3)
   Hypertension
1 (1.5)
   Hyperglycemia
6 (9.2)
   Hypokalemia
4 (6.2)
Any-grade IRR
3 (4.6)
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; IRR, infusion-related reaction; RRMM, relapsed or refractory multiple myeloma; TEAE, treatment-emergent adverse event.

Results: D-Rd Cohort at a Median Follow-up of 25.7 Months

Patient Characteristics

Baseline Demographics and Patient Characteristics - D-Rd Cohort (PLEIADES)a, 34
RRMM with ≥1 prior line of therapy
D-Rd (n=65)
Time since initial diagnosis, median (range), months
35.0 (3.6-384.5)
Prior ASCT, n (%)
34 (52)
   Last prior line of therapy
20 (31)
   PI and IMiD
1 (2)
   Lenalidomide
-
Bone marrow % plasma cells, n (%)
   N
65
      <10
15 (23)
      10-30
28 (43)
      >30
22 (34)
Abbreviations: ASCT, autologous stem cell transplantation; D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; IMiD, immunomodulatory drug; ISS, International Staging System; PI, proteasome inhibitor; RRMM, relapsed or refractory multiple myeloma.
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 Disposition - D-Rd Cohort (PLEIADES)a,34
n (%)
RRMM with ≥1 prior line of therapy
D-Rd (n=65)
Patients who are still on treatment
41 (63)
Patients who discontinued treatment
24 (37)
Reason for discontinuation
   Progressive disease
13 (20)
   Patient withdrawal
2 (3)
   Death
1 (2)
   Adverse event
7 (11)
   Other
0 (0)
   Protocol deviation
1 (2)
   Physician decision
0 (0)
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; RRMM, relapsed or refractory multiple myeloma.
aAll-treated population, defined as patients who received ≥1 dose of study treatment.

Patient Drug Exposure - D-Rd Cohort (PLEIADES)a,34
RRMM with ≥1 prior line of therapy
D-Rd (n=65)
Median (range) number of treatment cycles
27.0 (1-31)
Median (range) duration of treatment, months
25.6 (0-28)
Relative dose intensity, median %
   Daratumumab
100.0
   Carfilzomib
-
   Dexamethasoneb
59.7
   Lenalidomide
77.8
   Bortezomib
-
   Melphalan
-
   Prednisone
-
Abbreviations: COVID-19, coronavirus disease 2019; D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; RRMM, relapsed or refractory multiple myeloma.
aAll-treated population, defined as patients who received ≥1 dose of study treatment.
bDexamethasone dose intensity was affected by dose modifications due to the COVID-19 pandemic.
Efficacy
  • Median duration of follow-up was 25.7 months for D-Rd cohort.
  • Response rates were similar to DARZALEX studies in POLLUX.39
    • In the D-Rd cohort (n=65):
      • ORR was 93.8% vs 92.9% in the POLLUX study.39
      • sCR was 23.1% vs 29.5%.
      • CR was 26.2% vs 28.1%.
      • VGPR was 30.8% vs 23.5%.
      • PR was 13.8% vs 11.7%.
  • MRD-negativity rates were evaluated via NGS at a sensitivity threshold of 10-5.
    • MRD-negativity rate was 20.0% in the D-Rd cohort.
    • MRD-negative ≥CR rate was 20.0% in the D-Rd cohort.
Safety
  • A summary of TEAEs reported is presented in Table: Summary of TEAEs in D-Rd Cohort (PLEIADES).
  • Cardiac toxicities were infrequent (<5%) in D-Rd cohort.
  • Most patients with IRRs experienced them on the first administration (D-Rd, 100%).
  • IRRs were mild (grade 1/2).
  • Median (range) time to onset of IRRs was 330 (254-330) minutes in the D-Rd cohort.
  • Local injection site reactions occurred in 6% (11/198) of patients (all grade 1/2).

Summary of TEAEs in D-Rd Cohort (PLEIADES)a,34
n (%)
RRMM with ≥1 prior line of therapy
D-Rd (n=65)
Any-grade TEAE
65 (100)
Grade 3/4 TEAE
61 (94)
   Most common hematologic TEAEs (≥5% in any cohort)
      Thrombocytopenia
9 (14)
      Lymphopenia
7 (11)
      Anemia
6 (9)
      Neutropenia
36 (55)
      Leukopenia
6 (9)
   Most common nonhematologic TEAEs (≥5% in any cohort)
      Hypertension
8 (12)
      Insomnia
3 (5)
      Pneumonia
10 (15)
      Hyperglycemia
6 (9)
      Hypokalemia
4 (6)
      Diarrhea
4 (6)
      Lower respiratory tract infection
4 (6)
Grade 5 TEAE
2 (3)
Serious TEAEs
36 (55)
TEAEs leading to treatment discontinuationb
6 (9)
Any-grade IRR
3 (5)
Abbreviations: D-Rd, DARZALEX FASPRO + lenalidomide + dexamethasone; IRR, infusion-related reaction; RRMM, relapsed or refractory multiple myeloma; TEAE, treatment-emergent adverse event.
aAll-treated population, defined as patients who received ≥1 dose of study treatment.
bPneumonia (n=2), diverticulitis (n=1), enterobacter infection (n=1), myocardial infarction (n=1), and face edema (n=1).

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 21 March 2025. For purposes of streamlining, this scientific response has been limited to phase 2/3 clinical studies.

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

References

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1 Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380:2104-2115.  
2 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.  
3 Facon T, Moreau P, Weisel K, et al. Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes. [published online ahead of print February 27, 2025]. 2025. doi:10.1038/s41375-024-02505-2.  
4 Facon T, Kumar SK, Orlowski R, et al. Final survival analysis of daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: MAIA study. Poster presented at: The European Hematology Association (EHA) Hybrid Congress; June 13-16, 2024; Madrid, Spain.  
5 Facon T, Kumar S, Weisel K, et al. Daratumumab plus lenalidomide and dexamethasone in patients with transplant-ineligible newly diagnosed multiple myeloma: MAIA age subgroup analysis. 2022;(Poster).  
6 Moreau P, Facon T, Usmani S, et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): clinical assessment of key subgroups of the phase 3 MAIA study. 2022;(Poster).  
7 Facon T, Kumar S, Plesner T, et al. Time to response, duration of response, and patient-reported outcomes (PROs) with daratumumab (DARA) plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): subgroup analysis of the phase 3 MAIA study. Poster presented at: American Society of Clinical Oncology (ASCO) Annual Meeting; June 3-7, 2022; Chicago, IL/Virtual Meeting.  
8 Facon T, Cook G, Usmani SZ, et al. Daratumumab plus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA. Leukemia. 2022;36(4):1066-1077.  
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