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 .

Arnie Charbonneau Cancer Research Institute University of Calgary Calgary Alberta Canada

BC Cancer Vancouver Centre University of British Columbia Vancouver British Columbia Canada

CHU de Toulouse IUCT O Université de Toulouse UPS Service d'Hématologie Toulouse France

Clínica Médica São Germano São Paulo Brazil

Department of Hematology Amsterdam UMC Vrije Universiteit Amsterdam Cancer Center Amsterdam Amsterdam The Netherlands

Department of Hematology and Bone Marrow Transplantation St John of Dukla Oncology Center of Lublin Land Lublin Poland

Department of Hematology and Cancer Prevention School of Public Health Medical University of Silesia Katowice Poland

Department of Hematology Hôpital Haut Lévêque University Hospital Pessac France

Department of Hematology Japanese Red Cross Medical Center Tokyo Japan

Department of Hematology Kanazawa University Hospital Kanazawa University Kanazawa Japan

Department of Hematology National Hospital Organization Shibukawa Medical Center Gunma Japan

Department of Hematology Ondokuz Mayıs University Faculty of Medicine Samsun Turkey

Department of Hematology Tel Aviv Sourasky Medical Center Tel Aviv Israel

Department of Medical Oncology Cross Cancer Institute University of Alberta Edmonton Alberta Canada

Faculty of Medical and Health Sciences Tel Aviv University Tel Aviv Israel

Genmab US Inc Plainsboro NJ USA

Hospital Universitario Mútua de Terrassa Terrassa Spain

Instituto Americas de Ensino Pesquisa e Inovação Rio de Janeiro Brazil

Istinye University Ankara Liv Hospital Ankara Turkey

Johnson and Johnson High Wycombe UK

Johnson and Johnson Leiden The Netherlands

Johnson and Johnson Raritan NJ USA

Johnson and Johnson Shanghai China

Johnson and Johnson Spring House PA USA

Memorial Sloan Kettering Cancer Center New York NY USA

Perlmutter Cancer Center NYU Langone Health New York NY USA

Royal Wolverhampton NHS Trust and University of Wolverhampton CRN West Midlands National Institute for Health and Care Research Wolverhampton UK

Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil

University Hospital Brno Brno Czech Republic

University of Lille CHU de Lille Service des Maladies du Sang Lille France

Nat Med. 2025 Feb 13. doi: 10.1038/s41591-025-03581-2. PubMed

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NCT03652064