• Meletios A Dimopoulos, Peter M Voorhees, Fredrik Schjesvold, Yael C Cohen, Vania Hungria, Irwindeep Sandhu, Jindriska Lindsay, Ross I Baker, Kenshi Suzuki, Hiroshi Kosugi, Mark-David Levin, Meral Beksac, Keith Stockerl-Goldstein, Albert Oriol, Gabor Mikala, Gonzalo Garate, Koen Theunissen, Ivan Spicka, Anne K Mylin, Sara Bringhen, Katarina Uttervall, Bartosz Pula, Eva Medvedova, Andrew J Cowan, Philippe Moreau, Maria-Victoria Mateos, Hartmut Goldschmidt, Tahamtan Ahmadi, Linlin Sha, Annelore Cortoos, Eva G Katz, Els Rousseau, Liang Li, Robyn M Dennis, Robin Carson, S Vincent Rajkumar, and AQUILA Investigators.
• From Alexandra General Hospital, National and Kapodistrian University of Athens, Athens (M.A.D.); Levine Cancer Institute, Atrium Health Wake Forest University School of Medicine, Charlotte, NC (P.M.V.); Oslo Myeloma Center, Department of Hematology, Oslo University Hospital, Oslo (F.S.); Tel-Aviv Sourasky (Ichilov) Medical Center and Tel Aviv University, Tel Aviv, Israel (Y.C.C.); Clínica Medica São Germano, São Paulo (V.H.); Cross Cancer Institute, University of Alberta, Edmonton, Canada (I. Sandhu); Kent and Canterbury Hospital, Canterbury, United Kingdom (J.L.); Perth Blood Institute, Murdoch University, Perth, WA, Australia (R.I.B.); Japanese Red Cross Medical Center, Tokyo (K.S.); Ogaki Municipal Hospital, Ogaki City, Japan (H.K.); Albert Schweitzer Hospital, Dordrecht, the Netherlands (M.-D.L.); Ankara University, Ankara, Turkey (M.B.); Washington University School of Medicine, St. Louis (K.S.-G.); Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona (A.O.); South Pest Central Hospital, National Institute for Hematology and Infectious Diseases, Budapest, Hungary (G.M.); Hospital Alemán, Buenos Aires (G.G.); Jessa Hospital, Hasselt, Belgium (K.T.); Charles University and General Hospital, Prague, Czech Republic (I. Spicka); Rigshospitalet, University of Copenhagen, Copenhagen (A.K.M.); SSD Clinical Trials in Oncol-ematologia e Mieloma Multiplo, AOU Città della Salute e della Scienza di Torino, Turin, Italy (S.B.); Medical Unit Hematology, Karolinska University Hospital, Stockholm (K.U.); Institute of Hematology and Transfusion Medicine, Warsaw, Poland (B.P.); Knight Cancer Institute, Oregon Health and Science University, Portland (E.M.); University of Washington and Fred Hutchinson Cancer Center, Seattle (A.J.C.); University Hospital Hôtel-Dieu, Nantes, France (P.M.); University Hospital of Salamanca, IBSAL, and Cancer Research Center, IBMCC, Salamanca, Spain (M.-V.M.); GMMG Study Group at University Hospital Heidelberg, Internal Medicine V, Heidelberg, Germany (H.G.); Genmab US, Plainsboro, NJ (T.A.); Janssen Research and Development, Shanghai, China (L.S., L.L.); Janssen Scientific Affairs, Horsham, PA (A.C.); Janssen Research and Development, Raritan, NJ (E.G.K., R.M.D.); Janssen Research and Development, Beerse, Belgium (E.R.); Janssen Research and Development, Spring House, PA (R.C.); and Mayo Clinic, Rochester, MN (S.V.R.).
• N. Engl. J. Med. 2024 Dec 9.

BackgroundDaratumumab, an anti-CD38 monoclonal antibody, has been approved for the treatment of multiple myeloma. Data are needed regarding the use of daratumumab for high-risk smoldering multiple myeloma, a precursor disease of active multiple myeloma for which no treatments have been approved.MethodsIn this phase 3 trial, we randomly assigned patients with high-risk smoldering multiple myeloma to receive either subcutaneous daratumumab monotherapy or active monitoring. Treatment was continued for 39 cycles, for 36 months, or until confirmation of disease progression, whichever occurred first. The primary end point was progression-free survival; progression to active multiple myeloma was assessed by an independent review committee in accordance with International Myeloma Working Group diagnostic criteria.ResultsAmong the 390 enrolled patients, 194 were assigned to the daratumumab group and 196 to the active-monitoring group. With a median follow-up of 65.2 months, the risk of disease progression or death was 51% lower with daratumumab than with active monitoring (hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.67; P<0.001). Progression-free survival at 5 years was 63.1% with daratumumab and 40.8% with active monitoring. A total of 15 patients (7.7%) in the daratumumab group and 26 patients (13.3%) in the active-monitoring group died (hazard ratio, 0.52; 95% CI, 0.27 to 0.98). Overall survival at 5 years was 93.0% with daratumumab and 86.9% with active monitoring. The most common grade 3 or 4 adverse event was hypertension, which occurred in 5.7% and 4.6% of the patients in the daratumumab group and the active-monitoring group, respectively. Adverse events led to treatment discontinuation in 5.7% of the patients in the daratumumab group, and no new safety concerns were identified.ConclusionsAmong patients with high-risk smoldering multiple myeloma, subcutaneous daratumumab monotherapy was associated with a significantly lower risk of progression to active multiple myeloma or death and with higher overall survival than active monitoring. No unexpected safety concerns were identified. (Funded by Janssen Research and Development; AQUILA ClinicalTrials.gov number, NCT03301220.).Copyright © 2024 Massachusetts Medical Society.

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