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DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

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

Last Updated: 05/13/2025

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 VRd alone 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. At a median follow-up of 58.7 months (range, 0.1-64.7), the overall MRD-negativity (10-5 sensitivity with ≥CR) rate was significantly higher with D-VRd vs VRd (60.9% vs 39.4%; odds ratio [OR], 2.37; 95% CI, 1.58-3.55; P<0.0001). Similarly, the sustained MRD-negativity (10-5 sensitivity; ≥12 months) rate was significantly higher in the D-VRd vs VRd arm (48.7% vs 26.3%; OR, 2.63; 95% CI, 1.73-4; P<0.0001). The overall ≥CR rate was significantly higher with D-VRd vs VRd (81.2% vs 61.6%; OR, 2.73; 95% CI, 1.71-4.34; P<0.0001). Further, D-VRd significantly improved the PFS (HR, 0.57; 95% CI, 0.41-0.79; P=0.0005) with 43% reduction in the risk of progression or death vs VRd. The OS rate favored the D-VRd vs VRd arm (HR, 0.85; 95% CI, 0.58-1.24). Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%). The overall safety data were consistent with the established safety profile of each individual drug.
    • Zweegman et al (2024)4 presented an expanded analysis of MRD outcomes from the CEPHEUS study in patients with NDMM who were ineligible for a stem cell transplant (SCT) or were transplant deferred. D-VRd improved cumulative MRD-negativity rates (at both 10-5 and 10-6 sensitivities) vs VRd alone at all prespecified timepoints. At 54 months, among patients who achieved both MRD-negativity (10-6 sensitivity) and ≥CR with D-VRd, >85% were alive and progression free. Results of analyses of MRD-negativity (with ≥CR) rates for D-VRd vs VRd were generally consistent across prespecified subgroups.
  • PLEIADES is a phase 2 study evaluating the clinical benefit of DARZALEX FASPRO administered in combination with various treatment regimens in patients with MM, including D-VMP in NDMM.5
    • Moreau et al (2020)5 presented the updated safety and efficacy results of the PLEIADES study at a median follow-up of 25.2 months. Among patients with NDMM who received D-VMP, the ORR was 89.6%, and the MRD-negativity rate was 25.4%. Grade 3/4 TEAEs were reported in 78% of patients; the most common (≥20%) being thrombocytopenia (45%), neutropenia (37%), and lymphopenia (22%).
  • IFM2017-03 was a prospective, randomized, open-label, active-controlled, parallel-group, multicenter, phase 3 study assessing the safety and efficacy of DARZALEX FASPRO in combination with lenalidomide and dexamethasone (DR) vs Rd in elderly frail patients with NDMM who were not eligible for high-dose chemotherapy and ASCT.6 
    • Manier et al (2024)7 presented results from the IFM2017-03 study at a median follow-up of 46.3 months. The median PFS was 53.4 months (95% CI, 35.3-NR) vs 22.5 months (95% CI, 16.5-39) in the DR vs Rd arm, respectively (HR, 0.51; 95% CI, 0.37-0.70; P<0.0001). The ORR was 94% in the DR arm and 86% in the Rd arm. In the DR arm, the risk of disease progression or death was reduced by 49% and the risk of death was reduced by 48% compared with Rd (HR, 0.52; 95% CI, 0.35-0.77; P=0.0001). All grade ≥3 adverse events (AEs) were reported in 89% of patients (n=178) in the DR arm and 79% of patients (n=75) in the Rd arm.
  • Other relevant literature has been identified in addition to the data summarized above.8

PRODUCT LABELING

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.
  • 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.
    • 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.
  • 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.
  • 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 Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 global (EORTC QLQ-C30) health status domain score improved over time in both arms, with no negative impact from the addition of DARZALEX FASPRO.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:
      • 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.3 TEAEs in the safety population are summarized in Table: Most Common TEAEs in the Safety Population.
    • Overall, deaths were reported in 51 vs 60 patients from the D-VRd vs VRd arm, respectively and are summarized in Table: Summary of Deaths in the ITT Population.
      • The COVID-19 pandemic impacted OS with 24 (21.6%) of all deaths in the study attributed to COVID-19 (D-VRd, n=15 vs VRd, n=9).
      • Overall, 21 COVID-19 deaths occurred during the peak of the pandemic in 2020 and 2021, with 3 additional deaths in 2022 (post-vaccine availability), and none in 2023 or 2024.
      • Regional variations were observed in pandemic impact. Brazil reported 54.2% of COVID-19 deaths (17.5% of the study population), while Poland had 16.7% of deaths (18.7% of the study population).
      • Two sensitivity analyses of OS adjusting for COVID-19 deaths showed a stronger treatment effect for D-VRd vs VRd (censoring COVID-19 deaths [HR, 0.69; 95% CI, 0.45-1.05] and considering COVID-19 deaths as a competing risk [HR for non-COVID mortality, 0.67; 95% CI, 0.44-1.03]).
    • Grade 5 non-COVID-related TEAEs occurred in 10.7% vs 7.7% of patients from the D-VRd vs VRd arm, respectively.
    • Serious TEAEs occurred in 142 (72.1%) vs 131 (67.2%) of patients from the D-VRd vs VRd arm, respectively, with the most common serious TEAE being pneumonia (D-VRd, 13.7%; VRd, 12.8%). A summary of the serious TEAEs is presented in Table: Serious TEAEs (≥2%) in the Safety Population.
    • Most grade 5 TEAEs occurred after the discontinuation of bortezomib (cycle 8) in both arms (D-VRd, 13%; VRd, 9%). When adjusted for treatment exposure, the rate of grade 5 TEAEs was similar between the two arms (D-VRd, 0.39 per 100 patient-months; VRd, 0.31 per 100 patient-months).

Most Common TEAEs in the Safety Populationa,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
      Cholengiocellular carcinoma intrahepatic metastasis
-
1
      Renal failure, possibility of PD
-
1
Abbreviations: AE, adverse event; COVID-19, coronavirus disease 2019; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; PD, progressive disease; VRd, bortezomib + lenalidomide + dexamethasone.
aUntil the clinical cutoff.
bSubcategory terms are listed as originally entered in the database by the investigator.
cPatient died following admission and was outside AE reporting window.

Serious TEAEs (≥2%) in the Safety Populationa,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.

Expanded Analysis of MRD Outcomes - Results From the CEPHEUS Study

Zweegman et al (2024)4 presented (at the 66th ASH Annual Meeting) an expanded analysis of MRD outcomes from the CEPHEUS study in patients with NDMM who were ineligible for SCT or were transplant deferred.

Results

Patient Characteristics
  • A total of 395 patients were randomized into the D-VRd (n=197) and VRd (n=198) arms.4
Efficacy
  • A summary of cumulative and sustained MRD-negativity (≥CR) rates is presented in Table: Summary of Cumulative and Sustained MRD-Negativity (≥CR) Rates - CEPHEUS Expanded Analysis.
    • D-VRd improved the cumulative MRD-negativity rate (at both 10-5 and 10-6 sensitivities) vs VRd alone at all prespecified timepoints.4
    • D-VRd almost doubled the sustained MRD-negativity (≥CR) rate vs VRd alone at 12, 24, and 36 months.4
    • Among patients who achieved both MRD-negativity (10-6 sensitivity) and ≥CR with D-VRd, >85% were alive and progression free at 54 months.4
  • D-VRd vs VRd showed PFS benefit regardless of an MRD-negativity status (10-6 sensitivity).4
    • 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;4 the results are summarized in Table: MRD-Negativity (≥CR) Rates in Prespecified Subgroups.

Summary of Cumulative and Sustained MRD-Negativity (≥CR) Rates - CEPHEUS Expanded Analysis4
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 Subgroups4
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.5 Moreau et al (2020)5 presented updated safety and efficacy results of the D-VMP arm in the PLEIADES study.

Results

Patient Characteristics

Key Baseline Demographics and Patient Characteristicsa,5
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,5
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,5
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.
  • Response rates were similar to DARZALEX studies in ALCYONE.9
    • In the D-VMP cohort (n=67):
      • ORR was 89.6% versus 90.9% in the ALCYONE study.9
      • sCR was 31.3% versus 23.1%.
      • CR was 23.9% versus 22.6%.
      • VGPR was 22.4% versus 27.1%.
      • PR was 11.9% versus 18%.
  • MRD-negativity rates were evaluated via next-generation sequencing (NGS) at a sensitivity threshold of 10-5.
    • MRD-negativity rate was 25.4%.
    • MRD-negative ≥CR rate was 25.4%.
Safety
  • A summary of TEAEs reported in the D-VMP cohort is presented in Table: Summary of TEAEs in D-VMP arm.
  • Cardiac toxicities were infrequent (<5%).
  • Most patients with IRRs experienced them on the first administration (D-VMP, 83%).
  • IRRs were mild (grade 1/2); no patients reported grade 4 IRR.
  • Median (range) time to onset of IRRs was 411 (121-534) minutes.
  • Local injection site reactions occurred in 6% (11/198) of patients (all grade 1/2).

Summary of TEAEs in D-VMP Arma,5
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 DR vs Rd in elderly frail patients with NDMM who were not eligible for high-dose chemotherapy and ASCT.6 Manier et al (2024)7 presented results from the phase 3 IFM2017-03 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, Eastern Cooperative Oncology Group performance status [ECOG PS], Charlson index]).6,7
  • Eligible patients received DR or Rd until PD or unacceptable toxicity at the following dosage6,7:
    • DR arm:
      • DARZALEX FASPRO: 1800 mg SC QW for 8 weeks, Q2W for 16 weeks, and Q4W thereafter.
      • Lenalidomide: 25 mg 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.
  • Key secondary endpoints: ORR, ≥VGPR rate, MRD-negativity rate, OS, and safety.

Results

Patient Characteristics
  • A total of 295 patients were randomized 2:1 into the DR (n=200) or Rd (n=95) arm. Baseline characteristics of patients are presented in the Table: Baseline Characteristics.
  • At the data cutoff of November 06, 2024, the median follow-up was 46.3 months.
  • Treatment exposure of the patients in DR and Rd arms is shown in the Table: Treatment Exposure.

Baseline Characteristics7
Characteristic
DR Group
(n=200)
Rd Group
(n=95)
Median age (range), years
81 (68-92)
81 (68-90)
Age group, n (%)
   65 to <70 years
2 (1)
2 (2)
   70 to <75 years
30 (15)
13 (14)
   75 to <80 years
49 (24)
19 (20)
   ≥80 years
119 (60)
61 (64)
Sex, n (%)
   Female
102 (51)
49 (52)
   Male
98 (49)
46 (48)
ECOG performance status, n (%)
   0
21 (10)
9 (10)
   1
93 (46)
48 (50)
   2
86 (44)
38 (40)
   ≥3
11 (6)
3 (3)
Charlson index, n (%)
   ≤1
117 (58)
57 (60)
   >1
83 (42)
38 (40)
IFM frailty score, n (%)
   ≤1
0
0
   2
58 (29)
35 (37)
   3
80 (40)
26 (28)
   4
46 (23)
24 (25)
   5
16 (8)
9 (9)
ISS disease stage, n (%)
   I
33 (16)
19 (20)
   II
103 (52)
49 (52)
   III
64 (32)
27 (28)
Type of measurable disease, n (%)
   IgG
115 (57)
50 (53)
   IgA
36 (18)
20 (21)
   PBJ only
6 (3)
7 (7)
   SFLC only
26 (13)
10 (11)
Cytogenetics profile, n (%)
   Standard risk
146 (84)
56 (77)
   High riska
28 (16)
17 (23)
   del17p
16 (9)
11 (14)
   t(4;14)
9 (5)
5 (6)
   t(14;16)
5 (3)
2 (3)
Creatinine clearance, n (%)
   <30 mL/min
1 (1)
3 (3)
   30 to <60 mL/min
120 (59)
50 (53)
   ≥60 mL/min
79 (40)
41 (44)
Abbreviations: DR, DARZALEX FASPRO + lenalidomide; ECOG, Eastern Cooperative Oncology Group; IFM, Intergroupe Francophone du Myélome; Ig, immunoglobulin; ISS, International Staging System; NA, not applicable; PBJ, plasmacytoma/bone/joint; Rd, lenalidomide + dexamethasone, SFLC, serum free light chains.
aHigh risk defined as del17p and/or t(4;14) and/or t(14;16).

Treatment Exposure7
Parameter
DR Group
(n=200)
Rd Group
(n=95)
Median treatment duration, months (Q1-Q3)
31.6 (12-45.3)
14.3 (5.2-30.3)
Median total number of cycles received, (Q1-Q3)
33.5 (13.8-49)
16 (14-49)
Median relative dose intensity, % (Q1-Q3)
   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: DR, DARZALEX FASPRO + lenalidomide; Rd, lenalidomide + dexamethasone; Q, quartile.
Efficacy
  • At the median follow-up of 46.3 months, median PFS was 53.4 months (95% CI, 35.3-NR) vs 22.5 months (95% CI, 16.5-39) in the DR vs Rd arm, respectively (HR, 0.51; 95% CI, 0.37-0.70; P<0.0001). See Table: Efficacy Outcomes for additional details.
  • In the DR arm, the risk of disease progression or death was reduced by 49% and the risk of death was reduced by 48% (HR, 0.52; 95% CI, 0.35-0.77, P=0.0001).
  • The ≥VGPR rate was significantly higher with DR and deeper responses were reported with DR at all time points, including at early time points.
  • DR prolonged PFS across all subgroups. See Table: PFS by Subgroups for additional details.
  • DARZALEX FASPRO was well tolerated with high treatment exposure, while lenalidomide dose reductions were more frequent in the DR arm with longer treatment duration.

Efficacy Outcomes7 
Response
DR
(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
48
-
-
ORR, %
94
86
-
0.005
   CR
35
12
-
-
   ≥VGPR, %
71
51
-
-
      VGPR
36
39
-
-
   PR
23
35
-
-
Abbreviations: CI, confidence interval; CR, complete response; DR, 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.

PFS by Subgroups7
Subgroup
DR
(n=200)
Rd
(n=95)
HR (95% CI)
P value
Events/
Patients
Median PFS (95% CI)
Events/
Patients
Median PFS (95% CI)
Age (years)
   ≤75
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
23/44 (52)
37.7 (26.7-NR)
12/16 (75)
37.5 (20.2-NR)
0.71 (0.35-1.43)
   >80
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)
Cytogenetics
   Standard
   Risk
74/169 (44)
53.4 (37.4-NR)
55/78 (71)
30.6 (20-41.4)
0.52 (0.37-0.74)
0.66
   High Risk
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; DR, 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.
Safety
  • A summary of AEs at median treatment duration of 31.6 months for DR arm and 14.3 months for Rd arm is presented in Table: Summary of AEs.
  • Treatment discontinuation rate due to AEs was 30% (n=60) in the DR arm and 34% (n=32) in the Rd arm.

Summary of AEs7 
Event
DR
(n=200)
Rd
(n=95)
All grade 5 AEs, n (%)
23 (12)
12 (13)
All grade ≥3 AEs
178 (89)
75 (79)
   Hematologic, n (%)
123 (62)
32 (34)
      Neutropenia
110 (55)
23 (24)
      Anemia
24 (12)
3 (3)
      Thrombocytopenia
19 (10)
5 (5)
   Non-hematologic
132 (66)
68 (72)
      Infection, n (%)
38 (19)
20 (21)
         Pneumonia, n (%)
11 (6)
8 (8)
         Infection rate per patient per year, %
0.07
0.09
Abbreviations: AE, adverse event; DR, DARZALEX FASPRO + lenalidomide; Rd, lenalidomide + dexamethasone.
Health-Related Quality of Life
  • The quality of life improved and remained stable in DR arm.

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 24 April 2025.

 

References

Show
1 Zweegman S, Usmani S, Chastian K, et al. Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab in patients with newly diagnosed multiple myeloma for whom transplant is not planned as initial therapy: a multicenter, randomized, phase 3 study (CEPHEUS). Poster presented at: The Annual Meeting of the American Society of Clinical Oncology (ASCO). May 31-June 4, 2019; Chicago, IL.  
2 Janssen Research & Development, LLC. A study comparing daratumumab, velcade (bortezomib), lenalidomide, and dexamethasone (D-VRd) with velcade, lenalidomide, and dexamethasone (VRd) in participants with untreated multiple myeloma and for whom hematopoietic stem cell transplant is not planned as initial therapy. In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 April 17]. Available from: https://clinicaltrials.gov/ct2/show/NCT03652064 NML Identifier: NCT03652064.  
3 Usmani SZ, Facon T, Hungria V. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS study. doi.org/10.1038/s41591-024-03485-7. Nat Med. 2025.  
4 Zweegman S, Facon T, Hungria V, et al. Daratumumab + bortezomib, lenalidomide and dexamethasone (VRd) versus VRd alone in patients with newly diagnosed multiple myeloma ineligible for SCT or for whom SCT is not planned as initial therapy: analysis of minimal residual disease in the phase 3 CEPHEUS trial. Oral Presentation presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
5 Moreau P, Chari A, Haenel M, et al. Subcutaneous daratumumab (DARA SC) plus standard-of-care (SoC) regimens in multiple myeloma (MM) across lines of therapy in the phase 2 PLEIADES study: initial results of the DARA SC plus carfilzomib/dexamethasone (D-Kd) cohort, and updated results for the DARA SC plus bortezomib/melphalan/prednisone (D-VMP) and DARA SC plus lenalidomide/dexamethasone (D-Rd) cohorts. Poster presented at: The 62nd American Society of Hematology (ASH) Annual Meeting & Exposition; December 5-8, 2020; Virtual.  
6 Compare Lenalidomide and Subcutaneous Daratumumab vs Lenalidomide and Dexamethasone in Frail Subjects With Previously Untreated Multiple Myeloma Who Are Ineligible for High Dose Therapy (IFM2017_03). In: ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2000- [cited 2025 April 04]. Available from: https://clinicaltrials.gov/study/NCT03993912 NLM Identifier: NCT03993912. 2025 April 04. https://clinicaltrials.gov/study/NCT03993912?cond=NCT03993912&rank=1
7 Manier S, Lambert J, Hulin C, et al. A dexamethasone sparing-regimen with daratumumab and lenalidomide in frail patients with newly diagnosed multiple myeloma: the phase 3 IFM2017-03 trial. Oral Presentation presented at: The 66th American Society of Hematology (ASH) Annual Meeting and Exposition; December 7-10, 2024; San Diego, CA.  
8 Zweegman S, Usmani SZ, Hungria V, et al. The phase 3 CEPHEUS trial of daratumumab plus bortezomib, lenalidomide, and dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: frailty subgroup analysis. Oral Presentation presented at: The 6th European Myeloma Network (EMN) Meeting; April 10-12, 2025; Athens, Greece.  
9 Mateos MV, Cavo M, Blade J, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet. 2020;395(10218):132-141.