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

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<sup>-</sup><sup>5</sup> 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<sup>-</sup><sup>5</sup>. 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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Publication Details

Journal
Nature Medicine
Published
2025-02-05
DOI
https://doi.org/10.1038/s41591-024-03485-7
Citations
87
Primary Topic
Multiple Myeloma Research and Treatments
Type
article
Field-Weighted Citation Impact
153.99
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article

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

Christopher P. Venner, Saad Z. Usmani, Marc Justin Braunstein, Ângelo Maiolino et al.
87 citations
Nature Medicine
Multiple Myeloma Research and Treatments
153.99
article

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

Christopher P. Venner, Saad Z. Usmani, Marc Justin Braunstein, Ângelo Maiolino, Thierry T.F. Facon, Jodi Carey, Meral Beksaç, Hiroyuki Takamatsu, Jessica Vermeulen, Sebastian Grosicki, Richard G. Carson, Nizar Jacques Bahlis, Tahamtan Ahmadi, Yael Chava Cohen, Aurore Perrot, Sonja Zweegman, Katherine Chastain, Maria Krevvata, Wojciech Maciej Legiec, Supratik Basu, Weiping Liu, Jianping Wang, Mehmet Turgut, Josep Maria Martí, Morio Matsumoto, Lorena Lopez-Masi, Kenshi Suzuki, Luděk Pour, Cyrille Hulin, Melissa Rowe, Vânia Hungria
article en
87 citations

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<sup>-</sup><sup>5</sup> 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<sup>-</sup><sup>5</sup>. 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 .

Nature MedicineVol. 31(4)
University of Wolverhampton (GB), Universidade Federal do Rio de Janeiro (BR), BC Cancer Agency (CA), Johnson & Johnson (United States) (US), Memorial Sloan Kettering Cancer Center (US), Université Toulouse III - Paul Sabatier (FR), University of British Columbia (CA), University of Alberta (CA), Tel Aviv University (IL), Medical University of Silesia (PL), University of Calgary (CA), Université Fédérale de Toulouse Midi-Pyrénées (FR), Ondokuz Mayıs University (TR), Université de Lille (FR), Genmab (United States) (US), Tel Aviv Sourasky Medical Center (IL), Centre Hospitalier Universitaire de Lille (FR), Centre Hospitalier Universitaire de Toulouse (FR), NYU Langone Health (US), Institute of Cancer Research (CA), University Hospital Mútua de Terrassa (ES), University Hospital Brno (CZ), Japanese Red Cross Medical Center (JP), Kanazawa University Hospital (JP), São Germano Oncologia (BR), Hôpital Cardiologique du Haut-Lévêque (FR), Istinye University (TR), Lublin Oncology Center (PL), Johnson Electric (China) (CN), National Hospital Organization (JP), Johnson & Johnson (United Kingdom) (GB), Amsterdam University Medical Centers (NL), Liv Hospital (TR), The Royal Wolverhampton NHS Trust (GB), Johnson & Johnson (Netherlands) (NL), Vrije Universiteit Amsterdam (NL)
Good health and well-being
Openalex Percentile: Top 0%
Multiple Myeloma Research and Treatments
153.99
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