J&J Medical Connect
DARZALEX FASPRO®

(daratumumab and hyaluronidase-fihj)

Medical inquiries

Connect with my medical science liaison

Connect with my medical science liaison

Chat live

Chat live

Available Monday - Friday 9AM - 4:30PM ET

Call me now

Call me now

Available Monday - Friday 9AM - 7:30PM ET

Email your inquiry

Email your inquiry

Call 1-800-526-7736

Call 1-800-526-7736

Available Monday - Friday 9AM - 8PM ET

Live video

Live video

Available Monday - Friday 9AM - 4:30PM ET

This information is intended for US healthcare professionals to access current scientific information about J&J Innovative Medicine products. It is prepared by Medical Information and is not intended for promotional purposes, nor to provide medical advice.

DARZALEX FASPRO® (daratumumab and hyaluronidase-fihj)

Medical Information

+ Save link

DARZALEX FASPRO - MMY3019 (CEPHEUS) Study

Last Updated: 04/17/2025

SUMMARY

  • DARZALEX FASPRO for subcutaneous (SC) use is not approved by the regulatory agencies for use in combination with bortezomib, lenalidomide, and dexamethasone (VRd) for the treatment of multiple myeloma (MM) in newly diagnosed multiple myeloma (NDMM) patients for whom transplant is not intended as initial therapy. Janssen does not recommend the use of DARZALEX FASPRO in a manner that is inconsistent with the approved labeling.
  • CEPHEUS (MMY3019) is a phase 3 study evaluating the efficacy and safety of DARZALEX FASPRO in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) or VRd in patients with NDMM who are transplant ineligible (TIE) or for whom transplant is not planned as initial therapy (transplant deferred). The trial has enrolled 395 patients in 13 countries.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 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 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 CEPHEUS study in NDMM patients who were ineligible for stem cell transplant (SCT) or transplant deferred. The addition of DARZALEX FASPRO to VRd improved cumulative MRD-negativity rates (both 10-5 and 10-6 sensitivity) vs VRd alone at all prespecified timepoints. At 54 months, among patients who achieved both MRD negativity (10-6) and ≥CR, >85% were alive and progression free. D-VRd vs VRd analyses of MRD-negativity (with ≥CR) rates in prespecified subgroups were generally consistent  across prespecified subgroups.
  • Zweegman et al (2025)5presented a subgroup analysis to assess efficacy and safety outcomes from the CEPHEUS study based on frailty status in patients with NDMM who were TIE or transplant deferred. The overall MRD-negativity rates (at 10-5 and 10-6 threshold) and sustained (≥12 months) MRD-negativity rates (10-5 threshold) were higher with D-VRd compared with VRd across the International Myeloma Working Group (IMWG) and Intergroupe Francophone de Myélome (IFM) frailty subgroups. A reduction in the risk of progression or death with D-VRd was reported to be 41% and 44% in the IMWG fit and intermediate-fit groups, and 42% and 49% in the IFM nonfrail and frail groups, respectively. Any grade 3/4 events reported in the D-VRd vs VRd arms were 89.5% vs 84.1% in the IMWG fit subgroup, 97.3% vs 88.9% in the IMWG intermediate fitness subgroup, 90.0% vs 84.6% in the IFM nonfrail subgroup, and 98.2% vs 89.7% in the IFM frail subgroup. Overall safety was consistent with the established profiles of DARZALEX FASPRO and VRd across frailty subgroups, with no detriment in health-related quality of life (HRQoL).
  • Sonneveld et al (2025)6 presented long-term PFS outcomes of D-VRd in the TIE NDMM subgroup of the CEPHEUS study using modeling approaches. PFS projections were significantly longer with D-VRd vs VRd arm across all 7 distributions in the TIE NDMM subgroup. The best fit projection estimated a 47-month PFS benefit with D-VRd vs VRd arm. Estimated median PFS in best fit was longer with D-VRd vs VRd (100 months vs 53 months) in the TIE NDMM subgroup.

PRODUCT LABELING

CLINICAL DATA

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 TIE or for whom transplant is not planned as initial therapy (transplant deferred).1-3

Study Design/Methods

  • The trial has enrolled 395 patients from 13 different countries including the United States.
  • The study design has been presented in the Figure: CEPHEUS Study Design.

CEPHEUS Study Design1,2

Abbreviations: CR, complete response; d, dexamethasone; D, daratumumab and hyaluronidase; ECOG PS, Eastern Cooperative Oncology Group performance status; MRD, minimal residual disease; NCI-CTCAE, National Cancer Institute - Common Terminology Criteria for Adverse Events; NDMM, newly diagnosed multiple myeloma; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression-free survival; PFS2, PFS on next line of therapy; PO, orally; PS, performance status; Q3W, every 3 weeks; Q4W, every 4 weeks; QW, once a week; R, lenalidomide; SC, subcutaneously; V, bortezomib; TIE, transplant ineligible; VGPR, very good partial response.
aD in 15 mL recombinant human hyaluronidase 2000 U/mL.

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.
  • 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%).
    • 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%).
    • 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 not reached in the D-VRd arm, while it was 52.6 months in the VRd arm.
  • 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).
  • 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).
  • 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 coronavirus disease 2019 (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).
  • OS data were immature, and follow-up is ongoing.
  • A lower proportion of patients who received subsequent therapy received an anti-cluster of differentiation 38 (CD38)-based therapy in the D-VRd arm (3 of 22 patients [13.6%]) vs the VRd arm (39 of 65 patients [60%]).
  • 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.

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: 27 (13.7%) vs 51 (26.2%) patients.
      • Adverse events (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

Zweegman et al (2024)4 presented an expanded analysis of MRD outcomes from CEPHEUS study in NDMM patients who were ineligible for SCT or transplant deferred.

Results

Efficacy

  • A summary of the cumulative and sustained MRD-negativity (≥CR) rates is presented in Table: Summary of Cumulative and Sustained MRD-negativity (≥CR) Rates.
    • The addition of DARZALEX FASPRO to VRd improved cumulative MRD-negativity rates (both 10-5 and 10-6 sensitivity) vs VRd alone at all prespecified timepoints.
    • D-VRd almost doubled sustained MRD-negativity (≥CR) rates 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 MRD-negativity status (10-6 sensitivity).
    • The overall MRD-negativity rates (10-6 sensitivity) for D-VRd vs VRd were 46.2% vs 27.3% and the MRD-positivity rates (10-6 sensitivity) were 53.8% vs 72.7%, respectively.
    • At 54 months, the estimated PFS by MRD-negativity status (10-6 sensitivity) was 86.2% vs 79% and by 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 prespecified subgroups and is summarized in Table: MRD-negativity (≥CR) Rates in Prespecified Subgroups.

Summary of Cumulative and Sustained MRD-negativity (≥CR) Rates4 
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 (10-5 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)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)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 on study.
bProportion of patients who achieved CR or better response and achieved MRD-negative status at 2 bone marrow assessments that are 1 year apart with an allotted window of +/- 1 month, without any MRD-positive status in between.
cAchieving MRD-negative status at 2 bone marrow assessments that are 24 months apart with an allotted window of +/- 3 months, without any MRD-positive status in between.
dAchieving MRD-negative status at 2 bone marrow assessments that are 36 months apart, with an allotted window of +/- 3 months, without any MRD-positive status in between.

MRD-negativity (≥CR) Rates in Prespecified Subgroups4 
Subgroups, n/N (%)
D-VRd
VRd
ORa
(95% CI)
D-VRd
VRd
ORa
(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
(2.03-12.60)
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 riskb
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; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; HR, hazard ratio; ISS, International Staging System; MRD, minimal residual disease; OR, odds ratio; VRd, bortezomib + lenalidomide + dexamethasone.
aMantel-Haenszel estimate of the commons OR for unstratified tables is used. An OR >1 indicates an advantage for D-VRd.
bAssessed by fluorescence in situ hybridization; high risk was defined as the presence of del(17p), t(4;14), and/or t(14;16).

Subgroup Analysis by Frailty Status in TIE or Transplant Deferred NDMM Patients

Zweegman et al (2025)5presented a subgroup analysis to assess the efficacy and safety outcomes from the CEPHEUS study based on frailty status in patients with NDMM who were TIE or transplant deferred.

Results

Patient Characteristics


Baseline Demographics and Disease Characteristics Across Frailty Subgroups5
Parameter
IMWG Fit
IMWG Intermediate Fitness
IFM Nonfrail
IFM Frail
D-VRd
(n=124)
VRd
(n=132)
D-VRd
(n=73)
VRd
(n=66)
D-VRd
(n=140)
VRd
(n=157)
D-VRd
(n=57)
VRd
(n=41)
Median age (range), years
68
(42-75)
69
(31-75)
74
(49-79)
75
(51-80)
69
(42-79)
70
(31-79)
74
(49-79)
75
(51-80)
ECOG PS,an (%)
   0
54 (43.5)
61 (46.2)
17 (23.3)
23 (34.8)
71 (50.7)
84 (53.5)
0
0
   1
61 (49.2)
66 (50.0)
42 (57.5)
34 (51.5)
69 (49.3)
73 (46.5)
34 (59.6)
27 (65.9)
   2
9 (7.3)
5 (3.8)
14 (19.2)
9 (13.6)
0
0
23 (40.4)
14 (34.1)
TIEb, n (%)
82 (66.1)
88 (66.7)
62 (84.9)
57 (86.4)
96 (68.6)
110 (70.1)
48 (84.2)
35 (85.4)
ISS stagec, n (%)
   I
47 (37.9)
54 (40.9)
21 (28.8)
14 (21.2)
56 (40.0)
63 (40.1)
12 (21.1)
5 (12.2)
   II
45 (36.3)
49 (37.1)
28 (38.4)
26 (39.4)
51 (36.4)
53 (33.8)
22 (38.6)
22 (53.7)
   III
32 (25.8)
29 (22.0)
24 (32.9)
26 (39.4)
33 (23.6)
41 (26.1)
23 (40.4)
14 (34.1)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; IFM, Intergroupe Francophone du Myelome; IMWG, International Myeloma Working group; ISS, International Staging System; VRd, bortezomib + lenalidomide + dexamethasone; TIE, transplant ineligible.
aECOG PS is scored on a scale from 0 to 5, with 0 indicating no symptoms and higher scores indicating increasing disability.
bBased on randomization stratification factors from interactive web response system. TIE group consisted of subjects with randomization stratification factors <70 years and ineligible, or age ≥70 years.
cBased on the combination of serum β2-microglobulin and albumin levels. Higher stages indicate more advanced disease.

Efficacy

  • Across IMWG and IFM frailty subgroups, MRD-negativity rates (overall at 10⁻⁵ and 10⁻⁶ thresholds, and sustained ≥12 months at 10⁻⁵ threshold) and the proportion of patients achieving ≥CR were higher with D-VRd than with VRd. See Table: Summary of MRD Status and Response Rates Across Frailty Subgroups for additional details.
  • PFS increased for D-VRd vs VRd, irrespective of the frailty status.
    • A reduction in the risk of progression or death with D-VRd was reported to be 41% and 44% in the IMWG fit and intermediate-fit groups, and 42% and 49% in the IFM nonfrail and frail groups, respectively.

Summary of MRD Status and Response Rates Across Frailty Subgroups5
Response
IMWG Fit
IMWG Intermediate Fitness
IFM Nonfrail
IFM Frail
D-VRd
(n=124)
VRd
(n=132)
P Value
D-VRd
(n=73)
VRd
(n=66)
P Value
D-VRd
(n=140)
VRd
(n=157)
P Value
D-VRd
(n=57)
VRd
(n=41)
P Value
Overall MRD-negativitya,%
   10-5
63.7
44.7
0.0026
56.2
28.8
0.0019
63.6
42.0
0.0003
54.4
29.3
0.0148
   10-6
46.8
31.8
0.0153
45.2
18.2
0.0010
47.9
29.3
0.0012
42.1
19.5
0.0283
Sustained (≥12 Months) MRD-negativity (10-5)a,%
49.2
30.3
0.0022
47.9
18.2
0.0003
51.4
29.3
0.0001
42.1
14.6
0.0040
≥CR rate, OR (95% CI)b
2.84 (1.51-5.33)
0.0009
2.99 (1.48-6.06)
0.0021
3.24 (1.82-5.75)
<0.0001
2.47 (1.07-5.69)
0.0329
≥CR, %
86.3
68.9
-
72.6
47.0
-
85.7
65.0
-
70.2
48.8
-
   sCR
71.0
51.5
-
54.8
30.3
-
70.7
47.8
-
50.9
31.7
-
   CR
15.3
17.4
-
17.8
16.7
-
15.0
17.2
-
19.3
17.1
-
VGPR, %
6.5
22.0
-
20.5
31.8
-
5.7
24.2
-
26.3
29.3
-
PR, %
4.0
6.1
-
4.1
6.1
-
5.7
5.7
-
-
7.3
-
Median PFS, months
NR
60.6
-
NR
38.7
-
NR
60.6
-
NR
31.7
-
   HR (95% CI)c
0.59 (0.39-0.91)
0.0149
0.56 (0.34-0.91)
0.0189
0.58 (0.39-0.86)
0.0054
0.51 (0.28-0.93)
0.0242
Abbreviations: CI, confidence interval; CR, complete response; D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; IFM, Intergroupe Francophone du Myelome; IMWG, International Myeloma Working Group;  MRD, minimal residual disease; OR, odds ratio; PFS, progression-free survival; HR, hazard ratio; NR, not reached; PR, partial response; sCR, stringent complete response; VGPR, very good partial response; VRd, bortezomib + lenalidomide + dexamethasone.
aP values were calculated using Fisher's exact test.
bThe Mantel-Haenszel estimate of the common OR was used. P values were calculated using the Cochran Mantel-Haenszel Chi-Squared test.
cHR and 95% CI from a Cox proportional hazards model with treatment as the sole explanatory variable.

Safety

  • Safety profiles were generally consistent with the established profiles of DARZALEX FASPRO and VRd across frailty subgroups. See Tables: Safety Overview by Frailty Subgroups and Grade 3/4 TEAEs Across Frailty Subgroups for additional details.
  • Treatment duration was generally shorter in less fit patients, but much longer with D-VRd vs VRd.
  • Lower rates of treatment discontinuation due to TEAEs for D-VRd vs VRd was reported.
  • Grade 3/4 rates were generally higher in less fit patients in both D-VRd and VRd. arms

Safety Overview by Frailty Subgroups5
Parameter
IMWG Fit
IMWG Intermediate Fitness
IFM Nonfrail
IFM Frail
D-VRd
(n=124)
VRd
(n=132)
D-VRd
(n=73)
VRd
(n=63)
D-VRd
(n=140)
VRd
(n=156)
D-VRd
(n=57)
VRd
(n=39)
Median duration of treatment (range), months
57.1
(0.3-64.6)
40.1
(0.5-63.8)
45.8
(0.1-63.7)
32.4
(0.5-62.4)
57.1
(0.1-64.6)
36.2
(0.5-63.8)
44.7
(0.5-63.7)
25.7
(0.5-62.4)
TEAE leading to discontinuation of all study drugs, n (%)
9 (7.3)
18 (13.6)
6 (8.2)
13 (20.6)
8 (5.7)
24 (15.4)
7 (12.3)
7 (17.9)
Any grade 3/4 TEAE,n (%)
111
(89.5)
111
(84.1)
71
(97.3)
56
(88.9)
126
(90.0)
132
(84.6)
56
(98.2)
35
(89.7)
Grade 5 TEAEs
   Non-COVID-19a, n (%)
13 (10.5)
8 (6.1)
8 (11.0)
7 (11.1)
14 (10.0)
8 (5.1)
7 (12.3)
7 (17.9)
   COVID-19a,b, n (%)
5 (4.0)
4 (3.0)
7 (9.6)
2 (3.2)
9 (6.4)
4 (2.6)
3 (5.3)
2 (5.1)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; TEAE, treatment-emergent adverse event; VRd, bortezomib, lenalidomide, and dexamethasone.
aDeaths on or within 30 days of treatment.
bIncludes COVID-19 and COVID-19 pneumonia.

Grade 3/4 TEAEs Across Frailty Subgroups5
Parameter, n (%)
IMWG Fit
IMWG Intermediate Fitness
IFM Nonfrail
IFM Frail
D-VRd
(n=124)
VRd
(n=132)
D-VRd
(n=73)
VRd
(n=63)
D-VRd
(n=140)
VRd
(n=156)
D-VRd
(n=57)
VRd
(n=39)
Hematologic
   Neutropenia
51 (41.1)
36 (27.3)
36 (49.3)
22 (34.9)
60 (42.9)
47 (30.1)
27 (47.4)
11 (28.2)
   Thrombocytopenia
27 (21.8)
27 (20.5)
29 (39.7)
12 (19.0)
32 (22.9)
31 (19.9)
24 (42.1)
8 (20.5)
Nonhematologic
   Infections
49 (39.5)
39 (29.5)
30 (41.1)
23 (36.5)
53 (37.9)
44 (28.2)
26 (45.6)
18 (46.2)
      COVID-19a
18 (14.5)
10 (7.6)
12 (16.4)
3 (4.8)
22 (15.7)
11 (7.1)
8 (14.0)
2 (5.1)
   Peripheral sensory
   neuropathy
11 (8.9)
9 (6.8)
5 (6.8)
7 (11.1)
12 (8.6)
14 (9.0)
4 (7.0)
2 (5.1)
   Gastrointestinal
   disorder
26 (21.0)
28 (21.2)
15 (20.5)
12 (19.0)
28 (20.0)
30 (19.2)
13 (22.8)
10 (25.6)
      Diarrhea
16 (12.9)
12 (9.1)
8 (11.0)
6 (9.5)
17 (12.1)
13 (8.3)
7 (12.3)
5 (12.8)
      Constipation
2 (1.6)
4 (3.0)
2 (2.7)
1 (1.6)
3 (2.1)
4 (2.6)
1 (1.8)
1 (2.6)
   Fatigue
9 (7.3)
9 (6.8)
9 (12.3)
7 (11.1)
10 (7.1)
10 (6.4)
8 (14.0)
6 (15.4)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; TEAE, treatment-emergent adverse event; VRd, bortezomib, lenalidomide, and dexamethasone.
aIncludes COVID-19 and COVID-19 pneumonia.

Health-Related Quality of Life

  • No detriment in HRQoL with DVRd compared to VRd was reported across frailty subgroups.
  • Numerically larger increases in global health status (GHS) score from baseline were reported with DVRd in the intermediate fitness group compared to VRd. Similar results were observed when using the IFM frailty index.

Long-Term PFS Projections from the TIE NDMM Subgroup

Sonneveld et al (2025)6 presented long-term PFS outcomes of D-VRd in the TIE NDMM subgroup of the CEPHEUS study using modeling approaches.

Study Design/Methods

  • The National Institute for Health and Care Excellence United Kingdom (NICE UK) health technology assessment guidelines for survival data extrapolation were adhered to, ensuring the use of rigorous and standardized methodologies.
    • PFS data were modeled using 7 standard parametric distributions.
    • An age cap was introduced based on known UK general population mortality rates.

Results

Patient Characteristics


Baseline Demographics of TIE NDMM Subgroup6
Parameter
DVRd
(n=144)
VRd
(n=145)
Median age, years (range)
72 (58-79)
72 (51-80)
Male, n (%)
65 (45.1)
82 (56.6)
ECOG PS score, n (%)
   0
52 (36.1)
57 (39.3)
   1
75 (52.1)
78 (53.8)
   2
17 (11.8)
10 (6.9)
   3
0
0
ISS disease stage, n (%)
   I
50 (34.7)
48 (33.1)
   II
54 (37.5)
57 (39.3)
   III
40 (27.8)
40 (27.6)
High-risk cytogeneticsa, n (%)
20 (13.9)
18 (12.4)
Months since diagnosis, median (range)
1.2 (0.4-5.8)
1.2 (0.3-8.0)
Abbreviations: D-VRd, DARZALEX FASPRO + bortezomib + lenalidomide + dexamethasone; ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; VRd, bortezomib + lenalidomide + dexamethasone.
aHigh-risk cytogenetics included patients who were positive for any of del17p, t(14;16), or t(4;14) by fluorescence in situ hybridization.

Efficacy

  • PFS projections were significantly longer with DVRd vs VRd across all 7 distributions in patients with TIE NDMM.
  • Median PFS was not reached with D-VRd in TIE NDMM patients.
    • Estimated median PFS across all distributions for D-VRd vs VRd was 96-118 months vs 52-54 months, respectively.
    • Estimated median PFS in best fit for D-VRd vs VRd was 100 months (8.3 years) vs 53 months (4.4 years), respectively.
  • The best-fit projection estimates a 47-month PFS benefit with DVRd vs VRd.

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 16 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 16]. Available from: https://clinicaltrials.gov/ct2/show/NCT03652064 NLM 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 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.  
6 Sonneveld P, Zweegman S, Facon T, et al. Modeling long-term progression-free survival in transplant-eligible and transplant-ineligible newly diagnosed multiple myeloma treated with daratumumab, bortezomib, lenalidomide, and dexamethasone. Oral Presentation presented at: The 6th European Myeloma Network (EMN) meeting; April 10-12, 2025; Athens, Greece.