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Clinical Trial
. 2025 Apr;31(4):1195-1202.
doi: 10.1038/s41591-024-03485-7. Epub 2025 Feb 5.

Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial

Saad Z Usmani  1 , Thierry Facon  2 , Vania Hungria  3 , Nizar J Bahlis  4 , Christopher P Venner  5   6 , Marc Braunstein  7 , Ludek Pour  8 , Josep M Martí  9 , Supratik Basu  10 , Yael C Cohen  11   12 , Morio Matsumoto  13 , Kenshi Suzuki  14 , Cyrille Hulin  15 , Sebastian Grosicki  16 , Wojciech Legiec  17 , Meral Beksac  18 , Angelo Maiolino  19   20 , Hiroyuki Takamatsu  21 , Aurore Perrot  22 , Mehmet Turgut  23 , Tahamtan Ahmadi  24 , Weiping Liu  25 , Jianping Wang  26 , Katherine Chastain  27 , Jessica Vermeulen  28 , Maria Krevvata  26 , Lorena Lopez-Masi  27 , Jodi Carey  26 , Melissa Rowe  29 , Robin Carson  26 , Sonja Zweegman  30
Affiliations
Clinical Trial

Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial

Saad Z Usmani et al. Nat Med. 2025 Apr.

Erratum in

Abstract

Frontline daratumumab-based triplet and quadruplet standard-of-care regimens have demonstrated improved survival outcomes in newly diagnosed multiple myeloma (NDMM). For patients with transplant-ineligible NDMM, triplet therapy with either daratumumab plus lenalidomide and dexamethasone (D-Rd) or bortezomib, lenalidomide and dexamethasone (VRd) is the current standard of care. This phase 3 trial evaluated subcutaneous daratumumab plus VRd (D-VRd) in patients with transplant-ineligible NDMM or for whom transplant was not planned as the initial therapy (transplant deferred). Some 395 patients with transplant-ineligible or transplant-deferred NDMM were randomly assigned to eight cycles of D-VRd or VRd followed by D-Rd or Rd until progression. The primary endpoint was overall minimal residual disease (MRD)-negativity rate at 10-5 by next-generation sequencing. Major secondary endpoints included complete response (CR) or better (≥CR) rate, progression-free survival and sustained MRD-negativity rate at 10-5. At a median follow-up of 58.7 months, the MRD-negativity rate was 60.9% with D-VRd versus 39.4% with VRd (odds ratio, 2.37; 95% confidence interval (CI), 1.58-3.55; P < 0.0001). Rates of ≥CR (81.2% versus 61.6%; P < 0.0001) and sustained MRD negativity (≥12 months; 48.7% versus 26.3%; P < 0.0001) were significantly higher with D-VRd versus VRd. Risk of progression or death was 43% lower for D-VRd versus VRd (hazard ratio, 0.57; 95% CI, 0.41-0.79; P = 0.0005). Adverse events were consistent with the known safety profiles for daratumumab and VRd. Combining daratumumab with VRd produced deeper and more durable MRD responses versus VRd alone. The present study supports D-VRd quadruplet therapy as a new standard of care for transplant-ineligible or transplant-deferred NDMM. ClinicalTrials.gov registration: NCT03652064 .

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Conflict of interest statement

Competing interests: S.Z.U. received research funding from Amgen, Array BioPharma, Bristol Myers Squibb, Celgene, GSK, Janssen, Merck, Pharmacyclics, Sanofi, Seattle Genetics, SkylineDx and Takeda and consulted for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Edo Pharma, Genentech, Gilead, GSK, Janssen, Oncopeptides, Sanofi, Seattle Genetics, Secura Bio, SkylineDx, Takeda and TeneoBio. V.H. received honoraria for lectures/advisory boards from AbbVie, Amgen, Bristol Myers Squibb, GSK, Johnson & Johnson, Pfizer, Regeneron, Sanofi and Takeda. N.J.B. consulted for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, GSK, Genentech, Karyopharm Therapeutics, Kite, Novartis, Pfizer, Roche, Sanofi and Takeda, received research funding from Janssen and Pfizer and honoraria from AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, GSK, Genentech, Karyopharm Therapeutics, Kite, Novartis, Pfizer, Roche, Sanofi and Takeda and served on the Board of Directors or advisory committees for AbbVie, Amgen, Bristol Myers Squibb, Celgene, Janssen, GSK, Genentech, Karyopharm Therapeutics, Kite, Novartis, Pfizer, Roche, Sanofi and Takeda. C.P.V. received honoraria from Janssen, Bristol Myers Squibb, GSK, Sanofi, Pfizer, AbbVie and Forus. M. Braunstein participated in speakers bureaus for Bristol Myers Squibb, Janssen, Takeda and Sanofi. J.M.M. served as a consultant for Bristol Myers Squibb, Medison Pharma, Pfizer and Roche. Y.C.C. served as a consultant for, received research funding and honoraria from and served on the Board of Directors or advisory committees for Bristol Myers Squibb, Janssen, Takeda, Sanofi and GSK. M.M. received honoraria from Janssen Pharmaceuticals, Ono Pharmaceutical, Takeda Pharmaceuticals, Sanofi K.K. Nippon Kayaku and SymBio Pharmaceuticals and received research funding from Janssen Pharmaceuticals, Bristol Myers Squibb K.K., GSK and Pfizer. K.S. received lecture fees from Takeda, Ono Pharmaceutical, Novartis, Sanofi, Bristol Myers Squibb and Janssen and received advisory fees from SRL. M. Beksac served as a consultant for Bristol Myers Squibb, Takeda, Janssen, Menarini, Amgen and GSK and participated in speakers bureaus for Bristol Myers Squibb, Janssen, Takeda and Sanofi. A.M. served as a consultant for Janssen, Takeda, Amgen, Bristol Myers Squibb, Sanofi, Novartis, AstraZeneca, Pfizer and AbbVie and received honoraria from Janssen, Takeda, Amgen, Bristol Myers Squibb, Sanofi, Novartis, AstraZeneca, Pfizer and AbbVie. H.T. served as a consultant for SRL, received honoraria from Janssen, Ono Pharmaceutical, Sanofi and Bristol Myers Squibb and received research funding from Bristol Myers Squibb. A.P. received research funding from Bristol Myers Squibb, Sanofi and Takeda. T.A. is an employee of Genmab and owns stock. W. Liu, J.W., K.C., J.V., M.K., L.L.-M., J.C., M.R. and R.C. are employees of Janssen. S.Z. received research funding from Janssen and Takeda and participated in advisory boards (fees to institute) for Janssen, Bristol Myers Squibb, Sanofi, Oncopeptides, Amgen and Takeda. The other authors declare no competing interests.

Figures

Fig. 1
Fig. 1. CONSORT patient flow diagram.
Patient disposition at the data cutoff date of 7 May 2024.
Fig. 2
Fig. 2. MRD-negativity rates.
a, The primary endpoint of overall MRD-negativity rates in the intention-to-treat population. The overall MRD-negativity rate was defined as the proportion of patients who achieved ≥CR and MRD negativity (at or below a sensitivity threshold of 10−5) after randomization but before disease progression, subsequent antimyeloma therapy or both. b, An exploratory analysis of the MRD-negativity rate at or below a sensitivity threshold of 10−6. c, Sustained MRD-negativity rate in the intention-to-treat population. The sustained MRD-negativity rate was defined as the proportion of patients who achieved ≥CR and MRD-negative status (at or below a sensitivity threshold of 10−5) at two examinations a minimum of 1 year apart without MRD-positive status in between. MRD status was assessed using bone marrow samples and evaluated using a next-generation sequencing assay (clonoSEQ assay, v.2.0; Adaptive Biotechnologies) in accordance with International Myeloma Working Group guidelines for assessing MRD. The Mantel–Haenszel estimate of the common odds ratio for stratified tables was used. The stratification factors were ISS disease stage (I, II or III) and age/transplant eligibility (<70 years and transplant ineligible, <70 years and transplant deferred or ≥70 years). An odds ratio >1 indicates an advantage for D-VRd. The P value (two sided) was calculated using a Fisher’s exact test.
Fig. 3
Fig. 3. PFS.
The results of the Kaplan–Meier estimates of PFS among patients in the intention-to-treat population. The final analysis of PFS was performed after 162 events of disease progression or death occurred. Of these, eight were censored as a result of missing two or more consecutive disease evaluations preceding the event. The P value was calculated using the stratified log(rank test).
Fig. 4
Fig. 4. ≥CR rates.
≥CR rates in the intention-to-treat population. The tumor response was assessed using a validated computer algorithm in accordance with the International Myeloma Working Group response criteria. Complete response (CR) or stringent CR (sCR) was achieved at any time during the trial. The Mantel–Haenszel estimate of the common odds ratio for stratified tables was used. The stratification factors were ISS disease stage (I, II or III) and age/transplant eligibility (<70 years and transplant ineligible, <70 years and transplant deferred or ≥70 years). An odds ratio >1 indicates an advantage for D-VRd. The P value (two sided) was calculated using the Cochran–Mantel–Haenszel χ2 test. PR, partial response; VGPR, very good partial response.
Extended Data Fig. 1
Extended Data Fig. 1. Prespecified subgroup analysis of overall MRD-negativity rate.
Shown are the results of an analysis of overall MRD-negativity rate in prespecified subgroups in the intention-to-treat population. Data are presented as odds ratios and 95% CIs. Overall MRD-negativity rate was defined as the proportion of patients who achieved complete response or better and MRD negativity (at or below a sensitivity threshold of 10–5) after randomization but prior to disease progression, subsequent antimyeloma therapy or both. The ISS consists of three stages, with higher stages indicating more severe disease: stage I, serum β2-microglobulin level <3.5 mg per liter (300 nmol per liter) and albumin level ≥3.5 g per deciliter; stage II, neither stage I or III; and stage III, serum β2-microglobulin level ≥5.5 mg per liter (≥470 nmol per liter). Cytogenetic risk was assessed by fluorescence in situ hybridization. High risk was defined as the presence of del(17p), t(4;14) and/or t(14;16). Indeterminate includes patients with missing or unevaluable samples. CI, confidence interval; D-VRd, subcutaneous daratumumab plus bortezomib/lenalidomide/dexamethasone; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; MRD, minimal residual disease; VRd, bortezomib/lenalidomide/dexamethasone.
Extended Data Fig. 2
Extended Data Fig. 2. Cumulative incidence of MRD negativity.
Shown are the results of the cumulative incidence of MRD negativity. The overall MRD-negativity rate was defined as the proportion of patients who achieved complete response or better and MRD negativity (at or below a sensitivity threshold of 10–5) after randomization but prior to disease progression, subsequent antimyeloma therapy or both. D-VRd, subcutaneous daratumumab plus bortezomib/lenalidomide/dexamethasone; MRD, minimal residual disease; VRd, bortezomib/lenalidomide/dexamethasone.
Extended Data Fig. 3
Extended Data Fig. 3. Prespecified subgroup analysis of progression-free survival.
Shown are the results of an analysis of progression-free survival in prespecified subgroups in the intention-to-treat population. Data are presented as hazard ratios and 95% CIs. The ISS consists of three stages, with higher stages indicating more severe disease: stage I, serum β2-microglobulin level <3.5 mg per liter (300 nmol per liter) and albumin level ≥3.5 g per deciliter; stage II, neither stage I or III; and stage III, serum β2-microglobulin level ≥5.5 mg per liter (≥470 nmol per liter). Cytogenetic risk was assessed by fluorescence in situ hybridization. High risk was defined as the presence of del(17p), t(4;14) and/or t(14;16). Indeterminate includes patients with missing or unevaluable samples. CI, confidence interval; D-VRd, subcutaneous daratumumab plus bortezomib/lenalidomide/dexamethasone. ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; NE, could not be estimated; VRd, bortezomib/lenalidomide/dexamethasone.
Extended Data Fig. 4
Extended Data Fig. 4. Overall survival.
Shown are the results of the Kaplan–Meier estimates of overall survival among patients in the intention-to-treat population. D-VRd, subcutaneous daratumumab plus bortezomib/lenalidomide/dexamethasone; VRd, bortezomib/lenalidomide/dexamethasone.
Extended Data Fig. 5
Extended Data Fig. 5. Overall survival censoring death due to COVID-19.
Panel A censors death due to COVID-19, and Panel B considers COVID-19 as a competing risk (ie, considers COVID death as a competing event and non-COVID death as the event of interest). D-VRd, subcutaneous daratumumab plus bortezomib/lenalidomide/dexamethasone; VRd, bortezomib/lenalidomide/dexamethasone.
Extended Data Fig. 6
Extended Data Fig. 6. Quality of life.
Shown are the results of quality of life in the intention-to-treat population based on the EORTC QLQ-C30 global health status domain score. Data are presented as mean values ± SE. Scores range from 0–100, with higher scores indicating a better health status and quality of life. D-VRd, subcutaneous daratumumab plus bortezomib/ lenalidomide/dexamethasone; EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire–Core 30; SE, standard error; VRd, bortezomib/lenalidomide/dexamethasone.
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