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 Apr;31(4):1366. doi: 10.1038/s41591-025-03581-2. PubMed

Zobrazit více v PubMed

de Weers, M. et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J. Immunol.186, 1840–1848 (2011). PubMed

Lammerts van Bueren, J. et al. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood124, 3474 (2014).

Overdijk, M. B. et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 7, 311–321 (2015). PubMed PMC

Overdijk, M. B. et al. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcγ receptor-mediated cross-linking. J. Immunol.197, 807–813 (2016). PubMed

Krejcik, J. et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood128, 384–394 (2016). PubMed PMC

Adams, H. C. III et al. High-parameter mass cytometry evaluation of relapsed/refractory multiple myeloma patients treated with daratumumab demonstrates immune modulation as a novel mechanism of action. Cytometry A95, 279–289 (2019). PubMed PMC

Casneuf, T. et al. Deep immune profiling of patients treated with lenalidomide and dexamethasone with or without daratumumab. Leukemia35, 573–584 (2021). PubMed PMC

Facon, T. et al. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol.22, 1582–1596 (2021). PubMed

Mateos, M. V. et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. Lancet395, 132–141 (2020). PubMed

Moreau, P. et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab and followed by daratumumab maintenance or observation in transplant-eligible newly diagnosed multiple myeloma: long-term follow-up of the CASSIOPEIA randomised controlled phase 3 trial. Lancet Oncol.25, 1003–1014 (2024). PubMed

DARZALEX (daratumumab) injection (package insert) (Janssen Biotech, Inc., 2024).

European Medicines Agency. DARZALEX 20 mg/mL concentrate for solution for infusion (summary of product characteristics) (Janssen Biologics BV, 2024); www.ema.europa.eu/en/documents/product-information/darzalex-epar-product-information_en.pdf

Facon, T. et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N. Engl. J. Med.380, 2104–2115 (2019). PubMed PMC

Facon, T. et al. Final survival analysis of daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in transplant-ineligible patients with newly diagnosed multiple myeloma: MAIA study. Paper presented European Hematology Association (EHA) Hybrid Congress (2024).

Sonneveld, P. et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med.390, 301–313 (2024). PubMed

Durie, B. G. et al. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet389, 519–527 (2017). PubMed PMC

Durie, B. G. M. et al. Longer term follow-up of the randomized phase III trial SWOG S0777: bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT). Blood Cancer J.10, 53 (2020). PubMed PMC

Mateos, M. V. et al. Daratumumab plus bortezomib, melphalan, and prednisone for untreated myeloma. N. Engl. J. Med.378, 518–528 (2018). PubMed

Facon, T. et al. Daratumumab plus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: frailty subgroup analysis of MAIA. Leukemia36, 1066–1077 (2022). PubMed PMC

Kumar, S. K. et al. Daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM): updated analysis of the phase 3 MAIA study. Presented at the 64th American Society of Hematology (ASH) Annual Meeting and Exposition (2022).

Facon, T. et al. Isatuximab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med.391, 1597–1609 (2024). PubMed

Fonseca, R. et al. Frontline treatment patterns and attrition rates by subsequent lines of therapy in patients with newly diagnosed multiple myeloma. BMC Cancer20, 1087 (2020). PubMed PMC

Yong, K. et al. Multiple myeloma: patient outcomes in real-world practice. Br. J. Haematol.175, 252–264 (2016). PubMed PMC

McCurdy, A. et al. Redefining attrition in multiple myeloma (MM): a Canadian Myeloma Research Group (CMRG) analysis. Blood Cancer J.13, 111 (2023). PubMed PMC

Kumar, S. et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol.17, e328–e346 (2016). PubMed

Rajkumar, S. V. et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood117, 4691–4695 (2011). PubMed PMC

Rajkumar, S. V. et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol.15, e538–e548 (2014). PubMed

Palumbo, A. et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood125, 2068–2074 (2015). PubMed PMC

Tang, D. I. & Geller, N. L. Closed testing procedures for group sequential clinical trials with multiple endpoints. Biometrics55, 1188–1192 (1999). PubMed

EHA-EMN Evidence-Based Guidelines for diagnosis, treatment and follow-up of patients with multiple myeloma

Zobrazit více v PubMed

ClinicalTrials.gov
NCT03652064