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DARZALEX FASPRO®

(daratumumab and hyaluronidase-fihj)

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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

Medical Information

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

Last Updated: 10/10/2025

Summary

  • Janssen does not recommend the use of DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • CEPHEUS is an ongoing phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO + bortezomib, lenalidomide, and dexamethasone (D-VRd) vs bortezomib, lenalidomide, and dexamethasone (VRd) alone in patients with newly diagnosed multiple myeloma (NDMM) who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred).1-3
    • Usmani et al (2025)3 reported results from the phase 3 CEPHEUS study. At a median follow-up of 58.7 months, the overall minimal residual disease (MRD)-negativity (10-5 sensitivity with complete response or better [≥CR]) rate was significantly higher with D-VRd vs VRd (60.9% vs 39.4%; odds ratio [OR], 2.37; 95% confidence interval [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 progression-free survival (PFS; hazard ratio [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 overall survival (OS) rate favored the D-VRd vs VRd arm (HR, 0.85; 95% CI, 0.58-1.24). Serious treatment-emergent adverse events (TEAEs) occurred in 72.1% vs 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.
    • Mian et al (2025)4 presented the results of a post hoc analysis assessing outcomes based on dynamic frailty of TIE patients in the CEPHEUS and MAIA studies. Frailty in patients with TIE NDMM changed in 34% of CEPHEUS and 26% of MAIA patients with data over 4 years. Deterioration of frailty level was due to increases in both Eastern Cooperative Oncology Group Performance Status (ECOG PS) and age. Incidence of related serious TEAEs and TEAEs leading to treatment discontinuation was generally similar or lower in patients receiving D-VRd vs VRd, regardless of changes in frailty.4 
    • Zweegman et al (2024)5 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 multiple myeloma (MM), including DARZALEX FASPRO + bortezomib, melphalan, and prednisone (D-VMP) in NDMM.6
    • Moreau et al (2020)6 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 overall response rate (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 (D-R) vs lenalidomide and dexamethasone (Rd) in elderly frail patients with NDMM who were not eligible for high-dose chemotherapy and autologous stem cell transplant (ASCT).7 
    • Manier et al (2025)8 reported results of the IFM2017-03 study. At a median follow-up of 46.3 months, disease progression or death occurred in 162 patients (D-R, 46%; Rd, 73%). The median PFS in the D-R vs Rd group was 53.4 months (95% CI, 35.3-not reached [NR]) vs 22.5 months (95% CI, 16.5-39), respectively (HR, 0.51; 95% CI, 0.37-0.7; P<0.0001). In the D-R vs Rd group, the ORR was 91% vs 86%, respectively. Grade ≥3 adverse events (AEs) were reported in 178 patients (89%) in the D-R group and 75 patients (79%) in the Rd group. Hematological AEs reported in the D-R vs Rd group, respectively, were neutropenia (55% vs 24%), anemia (12% vs 3%), and thrombocytopenia (10% vs 5%). Grade ≥3 pneumonia in the D-R vs Rd group was observed in 6% vs 8% of patients, respectively.
  • Other relevant literature has been identified in addition to the data summarized above.9

CLINICAL DATA

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).1-3 Usmani et al (2025)3 reported results from the phase 3 CEPHEUS study.

Results

Patient Characteristics


Baseline Demographics and Clinical Characteristics of the ITT Populationa,3
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.3 
  • 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.3
  • 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.3 
    • 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%).3
    • 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%).3
    • 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.3 
  • 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.3
  • 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).3
  • 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).3
  • The treatment effect on PFS remained consistent across the predefined subgroups and is summarized in Table: PFS in Prespecified Subgroups.3 
  • 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).3
  • 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).3
    • OS data were immature, and follow-up is ongoing.3
  • 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%]).3
  • The European Organisation 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.3

Duration of Treatment and Relative Dose Intensities in the Safety Populationa,b,3
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 Population3
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 Rates3
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 Subgroups3
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.3
    • Reasons for treatment discontinuation in the D-VRd vs VRd arm, respectively, included:
      • Progressive disease (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. TEAEs in the safety population are summarized in Table: Most Common TEAEs in the Safety Population.3
    • 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,3
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,3
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
      Cholangiocellular 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,3
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.

Post Hoc Analysis of Outcomes Based on Dynamic Frailty in CEPHEUS TIE Patients

Mian et al (2025)4 presented the results of a post hoc analysis assessing outcomes based on dynamic frailty of transplant ineligible patients in the CEPHEUS and MAIA studies. Results specific to the CEPHEUS study are summarized below.

Study Design/Methods

  • Patients were randomized 1:1 to receive D-VRd vs VRd (CEPHEUS; TIE patients only) or D-Rd vs Rd (MAIA).4
  • Frailty was assessed using IFM simplified frailty score (nonfrail, score 0/1; frail score ≥2; ultrafrail score ≥3) at baseline and 12, 24, 36, and 48 months.4
  • PFS and overall MRD negativity (10-5 sensitivity with ≥CR) were assessed across dynamic frailty subgroups.4

Results

Efficacy

  • Across both treatment arms, 88 patients (48%) remained nonfrail from baseline to 48 months. Additionally, 52 patients (28%) switched from nonfrail to frail, 33 patients (18%) remained frail, and 10 patients (6%) shifted from frail to nonfrail. Changes in frailty level are summarized in Table: Change in Frailty Levels Yearly Across Both Treatment Arms.4
  • MRD-negativity rates and PFS were consistently increased in the D-VRd arm across frailty groups and timepoints.4
    • For patients with worsening frailty, the 48-month PFS rate for D-VRd vs VRd was 82.6% (95% CI, 60.1-93.1) vs 73.2% (95% CI, 51.8-86.2), respectively.
    • For patients with stable frailty, the 48-month PFS rate for D-VRd vs VRd was 95.5% (95% CI, 71.9-99.3) vs 60.0% (95% CI, 25.3-82.7), respectively.

Change in Frailty Levels Yearly Across Both Treatment Arms4
Baseline
12 Months
24 Months
36 Months
48 Months
Frailty Category, %
   Nonfrail
71.3
57.1
50.2
42.6
33.9
   Frail
28.7
26.3
28.7
28.4
29.4
   Death
0
8.3
14.5
19.7
24.2
   Study Discontinuation
0
3.8
4.2
4.8
5.5
   Othera
0
4.5
2.4
4.5
6.9
Reasons for deterioration, %b
   Increase in both age and ECOG
-
1.5
3.4
7.3
9.7
   Increase in age
-
2.4
6.8
9.2
11.7
   Increase in ECOG
-
10.02
9.7
4.9
3.9
Abbreviations: ECOG, Eastern Cooperative Oncology Group
aIncludes those for whom data for frailty score calculation were not available within the correct time window.bIn 206 patients who were nonfrail at baseline.

Safety


Safety Summary Based on Frailty Change at 4 Years4
Parameter
D-VRd
VRd
Frail at baseline, nonfrail at 48 months (improving)
   N
6
4
   At least 1 related serious TEAE, %a
33.3
75
   TEAE leading to treatment discontinuation, %
16.7
25
Nonfrail at baseline, frail at 48 months (worsening)
   N
23
29
   At least 1 related serious TEAE, %a
30.4
51.7
   TEAE leading to treatment discontinuation, %
8.7
27.6
Nonfrail at baseline and at 48 months (stable nonfrail)
   N
47
41
   At least 1 related serious TEAE, %a
34
34.1
   TEAE leading to treatment discontinuation, %
2.1
14.6
Frail at baseline and at 48 months (stable frail)
   N
22
11
   At least 1 related serious TEAE, %a
50
45.5
   TEAE leading to treatment discontinuation, %
13.6
18.2
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; TEAE, treatment-emergent adverse event; VRd, bortezomib + lenalidomide + dexamethasone.aTEAEs related to at least 1 of the 4 components of study treatment.

Expanded Analysis of MRD Outcomes - Results From the CEPHEUS Study

Zweegman et al (2024)5 presented 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.5
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.5
    • D-VRd improved the cumulative MRD-negativity rate (at both 10-5 and 10-6 sensitivities) vs VRd alone at all prespecified timepoints.
    • D-VRd almost doubled the sustained MRD-negativity (≥CR) rate vs VRd alone at 12, 24, and 36 months.
    • Among patients who achieved both MRD-negativity (10-6 sensitivity) and ≥CR with D-VRd, >85% were alive and progression free at 54 months.
  • D-VRd vs VRd showed PFS benefit regardless of an MRD-negativity status (10-6 sensitivity).5
    • 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; the results are summarized in Table: MRD-Negativity (≥CR) Rates in Prespecified Subgroups.5

Summary of Cumulative and Sustained MRD-Negativity (≥CR) Rates - CEPHEUS Expanded Analysis5
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 Subgroups5
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.6 Moreau et al (2020)6 presented updated safety and efficacy results of the D-VMP arm in the PLEIADES study.

Results

Patient Characteristics

Key Baseline Demographics and Patient Characteristicsa,6
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,6
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,6
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 FASPRO
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.6 
  • Response rates were similar to DARZALEX studies in ALCYONE.10
    • In the D-VMP cohort (n=67):
      • ORR was 89.6% versus 90.9% in the ALCYONE study.10
      • Stringent complete response (sCR) was 31.3% versus 23.1%.
      • CR was 23.9% versus 22.6%.
      • Very good partial response (VGPR) was 22.4% versus 27.1%.
      • Partial response (PR) was 11.9% versus 18%.
  • MRD-negativity rates were evaluated via next-generation sequencing (NGS) at a sensitivity threshold of 10-5.6 
    • 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%).6 
  • Most patients with IRRs experienced them on the first administration (D-VMP, 83%).6 
  • IRRs were mild (grade 1/2); no patients reported grade 4 IRR.6 
  • Median time to onset of IRRs was 411 (range, 121-534) minutes.6 
  • Local injection site reactions occurred in 6% (11/198) of patients (all grade 1/2).6 

Summary of TEAEs in D-VMP Arma,6
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).

DARZALEX FASPRO in Combination With Lenalidomide

IFM2017-03 (NCT03993912) is a prospective, randomized, open-label, active-controlled, parallel-group, multicenter, phase 3 study assessing the safety and efficacy of D-R vs Rd in elderly frail patients with NDMM who were not eligible for high-dose chemotherapy and ASCT.7 Manier et al (2025)8 reported results study at a median follow-up of 46.3 months.

Study Design/Methods

  • This study included patients aged ≥65 years who were diagnosed with NDMM and IFM frailty score ≥2 (age, ECOG PS, Charlson index).7 
  • Eligible patients received DR or Rd until PD or unacceptable toxicity at the following dosage:7,11
    • D-R arm:
      • DARZALEX FASPRO: 1800 mg subcutaneously (SC) weekly (QW) for 8 weeks, every 2 weeks (Q2W) for 16 weeks, and every 4 weeks (Q4W) thereafter.
      • Lenalidomide: 25 mg orally (PO) on days 1 through 21 of each 28-day cycle, until progression.
      • Dexamethasone: 20 mg PO on days 1, 8, 15, and 22 of each 28-day cycle, until progression for the first 2 cycles, then discontinued.
    • Rd arm:
      • Lenalidomide: 25 mg PO on days 1 through 21 of each 28-day cycle, until progression.
      • Dexamethasone: 20 mg PO on days 1 through 21 of each 28-day cycle, until progression.
  • Primary endpoint: PFS.7 
  • Key secondary endpoints: ORR, ≥VGPR rate, MRD-negativity rate, OS, and safety.7

Results

Patient Characteristics and Disposition
  • A total of 295 patients were enrolled and randomized 2:1 into the D-R (n=200) and Rd (n=95) groups.8 Demographic and baseline characteristics of patients are presented in Table: Demographic and Disease Characteristics at Baseline (ITT Population).
  • At the data cutoff of November 6, 2024, a total of 119 patients (60%) in the D-R group and 84 patients (88%) in the Rd group had discontinued treatment, most commonly because of progressive disease (D-R vs Rd, respectively; 22% vs 41%) or AEs (18% vs 24%).8
  • Treatment exposures of patients in D-R and Rd groups are summarized in Table: Treatment Exposure.
    • A total of 27 patients in the D-R group discontinued lenalidomide but continued to receive DARZALEX FASPRO as monotherapy.8
    • The median duration of DARZALEX FASPRO monotherapy was 17.2 months (range, 1.9-41.6).8

Demographic and Disease Characteristics at Baseline (ITT Population)8
Characteristic
D-R
(n=200)
Rd
(n=95)
Total
(N=295)
Median age (range), years
81 (68-92)
81 (68-90)
81 (68-92)
Age group, n (%)
   65 to <75 years
32 (16)
15 (16)
47 (16)
   75 to <80 years
49 (24)
19 (20)
 68 (23)
   ≥80 years
119 (60)
61 (64)
180 (61)
Sex, n (%)
   Female
102 (51)
49 (52)
151 (51)
   Male
98 (49)
46 (48)
144 (49)
ECOG performance status, n (%)
   0
21 (10)
9 (9)
30 (10)
   1
92 (46)
48 (51)
140 (47)
   2
76 (38)
35 (37)
111 (38)
   ≥3
11 (6)
3 (3)
14 (5)
Charlson Comorbidity index, n (%)
   ≤1
117 (58)
57 (60)
174 (59)
   >1
83 (42)
38 (40)
121 (41)
IFM frailty score, n (%)
   2
58 (29)
35 (37)
93 (32)
   3
80 (40)
27 (28)
107 (36)
   4
46 (23)
24 (25)
70 (24)
   5
16 (8)
9 (9)
25 (8)
ISS disease stage, n (%)
   I
33 (16)
19 (20)
52 (18)
   II
103 (52)
49 (52)
152 (52)
   III
64 (32)
27 (28)
91 (31)
Type of measurable disease, n (%)
   IgG
115 (57)
50 (53)
165 (56)
   IgA
36 (18)
20 (21)
56 (19)
   BJP
6 (3)
7 (7)
13 (4)
   SFLC
26 (13)
10 (11)
36 (12)
Cytogenetics profilea, n (%)
   Standard risk
146 (84)
56 (77)
202 (82)
   High risk
28 (16)
17 (23)
45 (18)
      del17p
16 (9)
11 (14)
27 (11)
      t(4;14)
9 (5)
5 (6)
14 (5)
      t(14;16)
5 (3)
2 (3)
7(3)
   NA
26
22
48
Creatinine clearance, n (%)
   <30 mL/min
0
3 (3)
3 (1)
   30 to <60 mL/min
121 (60)
50 (53)
171 (58)
   ≥60 mL/min
79 (40)
42 (44)
121 (41)
Abbreviations: BJP, Bence-Jones protein; D-R, DARZALEX FASPRO + lenalidomide; ECOG, Eastern Cooperative Oncology Group; IFM, Intergroupe Francophone Myeloma; Ig, immunoglobulin; ISS, International Staging System; ITT, intention-to-treat; NA, not applicable; Rd, lenalidomide + dexamethasone; SFLC, serum free light chanin.
adel17p, t(4;14), t(14;16).

Treatment Exposure8
Parameter
D-R
(n=200)
Rd
(n=95)
Median treatment duration, months (IQR)
31.6 (12-45.3)
14.3 (5.2-30.3)
Median number of treatment cycles received (IQR)
33.5 (13.8-49.0)
16 (6.0-30.5)
Median relative dose intensity, % (IQR)
   DARZALEX FASPRO
95.2 (84.6-98.4)
-
   Lenalidomide
34.8 (22.3-57.1)
47.1 (29-75.8)
   Dexamethasone
-
53.1 (23.2-90.2)
Abbreviations: D-R, DARZALEX FASPRO + lenalidomide; IQR, interquartile range; Rd, lenalidomide + dexamethasone.
Efficacy
  • At a median follow-up of 46.3 months (95% CI, 44.9-47.6), disease progression or death occurred in 162 patients (D-R, 93 of 200 patients [46%]; Rd, 69 of 95 patients [73%]).7 Efficacy outcomes are detailed in Table: Efficacy Outcomes.
  • Higher ≥VGPR rates observed as early as cycle 4 in the D-R vs /Rd group were 32% vs 20%, respectively (P=0.044).8
  • The MRD-negativity rate (10-5 sensitivity) in the D-R vs Rd group was 10% vs 4% and did not reach significance (P=0.11).8
  • The prespecified analysis of PFS confirmed the superiority of D-R over Rd across all subgroups.8 See Table: Prespecified Subgroup Analysis of PFS for details.

Efficacy Outcomes8
Parameter
D-R
(n=200)
Rd
(n=95)
HR (95% CI)
P Value
Median PFSa, months (95% CI)
53.4 (35.3-NR)
22.5 (16.5-39)
0.51 (0.37-0.7)
<0.0001
Median OS, months
NR
47.2
 0.52 (0.35-0.77)
0.0001
4-year OS rate, %
68
47.8
-
-
ORR, %
91
86
-
0.005
   CR
34
12
-
-
   ≥VGPR
69
51
-
-
   VGPR
35
39
-
-
   PR
22
35
-
-
Abbreviations: CI, confidence interval; CR, complete response; D-R, DARZALEX FASPRO + lenalidomide; HR, hazard ratio; NR, not reached; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PR, partial response; Rd, lenalidomide + dexamethasone; VGPR, very good partial response.
aA total of 93 and 63 events were reported in the DR and Rd arms, respectively.

Prespecified Subgroup Analysis of PFS8
Subgroup
D-R
(n=200)
Rd
(n=95)
HR (95% CI)
P Value
Events/
Patients
Median PFS (95% CI)
Events/
Patients
Median PFS (95% CI)
Age group
   ≤75 years
14/37 (38)
NR (42.1-NR)
12/18 (67)
24.6 (16.5-NR)
0.44 (0.20-0.95)
0.67
   76-80 years
23/44 (52)
37.7 (26.7-NR)
12/16 (75)
37.5 (20.2-NR)
0.71 (0.35-1.43)
   >80 years
51/108 (47)
48.6 (32.1-NR)
37/53 (70)
22.5 (14.3-42.9)
0.52 (0.34-0.79)
Sex
   Male
49/98 (50)
46.2 (33.2-NR)
37/46 (80)
18 (13.2-30.7)
0.44 (0.29-0.68)
0.48
   Female
44/102 (43)
54.2 (34.2-NR)
32/49 (65)
39 (20.1-47.8)
0.57 (0.36-0.89)
ECOG performance status
   0
9/21 (43)
53.6 (32.1-NR)
5/9 (56)
47.3 (19.4-NR)
0.75 (0.25-2.24)
0.17
   1
46/92 (50)
48.5 (30.9-NR)
34/48 (71)
36.2 (18.4-46.5)
0.63 (0.40-0.98)
   ≥2
38/87 (44)
53.4 (34.6-NR)
30/38 (79)
16.5 (10.3-28.5)
0.35 (0.22-0.58)
Charlson index
   ≤1
54/117 (46)
48.5 (31.6-NR)
43/57 (75)
22.8 (14.3-41.1)
0.49 (0.33-0.73)
0.82
   >1
39/83 (47)
53.6 (34.2-NR)
26/38 (68)
21.5 (16.2-47.8)
0.55 (0.34-0.91)
IFM frailty score
   2
23/58 (40)
NR (37.6-NR)
24/35 (69)
30.6 (20-47.3)
0.46 (0.26-0.82)
0.75
   3
39/80 (49)
46.2 (30.9-NR)
20/27 (74)
32.6 (16-53.1)
0.58 (0.34-0.99)
   4/5
31/62 (50)
35.3 (28.4-NR)
25/33 (76)
14.3 (8.4-36.2)
0.44 (0.25-0.75)
ISS stage
   I
12/33 (36)
NR (35.3-NR)
12/19 (63)
39 (16.5-NR)
0.46 (0.21-1.03)
0.97
   II
43/103 (42)
53.6 (46.2-NR)
35/49 (71)
26.2 (18.4-46.7)
0.48 (0.31-0.75)
   III
38/64 (59)
31.6 (26.7-NR)
22/27 (81)
14.3 (10.3-36.7)
0.53 (0.31-0.90)
Cytogenetic risk
   Standard
74/169 (44)
53.4 (37.4-NR)
55/78 (71)
30.6 (20-41.4)
0.52 (0.37-0.74)
0.66
   Higha
19/31 (61)
33.3 (20.3-NR)
14/17 (82)
13.7 (8.2-42.8)
0.42 (0.20-0.86)
Creatinine clearance
   ≤60 mL/min
56/121 (46)
53.4 (33.1-NR)
40/53 (75)
23.1 (19.4-42.8)
0.50 (0.33-0.76)
0.95
   >60 mL/min
37/79 (47)
48.6 (35.2-NR)
29/42 (69)
20.1 (13.2-41.4)
0.50 (0.31-0.82)
Abbreviations: CI, confidence interval; D-R, DARZALEX FASPRO + lenalidomide; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; IFM, Intergroupe Francophone du Myélome; ISS, International Staging System; NR, not reached; PFS, progression-free survival; Rd, lenalidomide + dexamethasone.
aA high-risk cytogenetic profile was defined by the detection of a del17p, t(14;16), or t(4;14) on fluorescence in situ hybridization or next-generation sequencing.
Safety

Most Common AEs and Secondary Primary Cancers Reported During Treatment in the Safety Population8
Parameter
D-R
(n=200)
Rd
(n=95)
Median treatment duration (months)
31.6
14.3
All AEs, n (%)
197 (98)
93 (98)
AEs of grade ≥3
178 (89)
75 (79)
   SAEs
126 (63)
66 (69)
   All grade 5
23 (12)
12 (13)
Hematologic, grade ≥3, n (%)
123 (62)
32 (34)
      Neutropenia
110 (55)
23 (24)
      Anemia
24 (12)
3 (3)
      Thrombocytopenia
19 (10)
5 (5)
Nonhematologic AEs, grade ≥3, n (%)
132 (66)
68 (72)
      Infection
38 (19)
20 (21)
         Pneumonia
11 (6)
8 (8)
         COVID-19
11 (6)
4 (4)
   Fatigue
8 (4)
8 (8)
   Gastrointestinal disorder
14 (7)
5 (5)
   Second primary malignancies
14 (7)
10 (11)
      Noncutaneous
12 (6)
6 (6)
      Cutaneous
2 (1)
4 (4)
Infection rate per patient per year, %
0.07
0.09
Treatment discontinuation due to AEs, n (%)
36 (18)
23 (24)
Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-R, DARZALEX FASPRO + lenalidomide; Rd, lenalidomide + dexamethasone; SAE, serious adverse event.
  • Deaths were reported in 104 patients: 59 (30%) in the D-R group and 45 (47%) in the Rd group.8
Health-Related Quality of Life
  • The EORTC QLQ-C30 and EuroQol 5-Dimension 3-Level (EQ-5D-3L) scores improved and remained stable in the D-R and Rd arms.8

LITERATURE SEARCH

A literature search of MEDLINE®, Embase®, BIOSIS Previews®, and Derwent Drug File databases (and/or other resources, including internal/external databases) was conducted on 18 September 2025.

 

References

Show
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