N Engl J Med 2021 07;385(1):46-58
From the Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens (E.K., M.A.D.); the Amyloidosis Research and Treatment Center, Fondazione IRCCS Policlinico San Matteo, and the Department of Molecular Medicine, University of Pavia, Pavia, Italy (G.P., G.M.); the Department of Hematology, University Medical Center Utrecht, University Utrecht, Utrecht (M.C.M.), the Amyloidosis Center of Expertise, University of Groningen, University Medical Center Groningen, Groningen (W.R.), and Janssen Research and Development, Leiden (B.T., J. Vermeulen) - all in the Netherlands; University College London, London (A.D.W.); Centre Hospitalier Universitaire (CHU) and Reference Center for AL Amyloidosis, Limoges (A.J.), Département de Néphrologie et Transplantation d'Organes, Centre de Référence des Maladies Rénales Rares, Hôpital Rangueil, CHU de Toulouse, Toulouse (A.H.), and the Department of Hematology, CHU Lille, University of Lille, Lille (S.M.) - all in France; the Department of Lymphoma and Myeloma, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston (H.C.L.); the Amyloidosis Center, Boston University School of Medicine and Boston Medical Center (V.S.), and the Division of Hematology/Oncology, John C. Davis Myeloma and Amyloid Program, Tufts Medical Center (R.L.C.) - both in Boston; the Victorian and Tasmanian Amyloidosis Service, Department of Haematology, Monash University Eastern Health Clinical School, Melbourne, VIC (S.G.), the Department of Haematology, Princess Alexandra Hospital and University of Queensland Medical School, Brisbane (P.M.), and the Department of Clinical Haematology, Westmead Hospital, Westmead, NSW (F.K.) - all in Australia; Cross Cancer Institute, University of Alberta, Edmonton (C.P.V.), the Division of Hematology, London Health Sciences Centre, London Regional Cancer Program, Western University, London, ON (S.L.), and the Division of Hematology, Vancouver General Hospital, BC Cancer, University of British Columbia, Vancouver (K. Song) - all in Canada; Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Collaborative Innovation Center of Hematology, Beijing (J.L.); Medical Department V (Hematology/Oncology/Rheumatology), Amyloidosis Center, Heidelberg University Hospital, Heidelberg (S.S.), and Hämatologisch-Onkologische Praxis Altona, Hamburg (T.H.) - both in Germany; the Department of Hematology, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem (M.E.G.); the Department of Hematology, Japanese Red Cross Medical Center, Tokyo (K. Suzuki), and the Department of Hematology, Japan Community Health Care Organization Kyoto Kuramaguchi Medical Center, Kyoto (C.S.) - both in Japan; the Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine (K.K.), and the Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine (J.-S.K.) - both in Seoul, South Korea; the Amyloidosis and Myeloma Unit, Hospital Clinic of Barcelona, August Pi i Sunyer Biomedical Research Institute, Barcelona (M.T.C.); the Department of Hematology, Ankara University, Ankara, Turkey (M.B.); the Division of Medical Oncology, Department of Medicine, University of Washington, Seattle (E.L.); the Department of Hematology and Medical Oncology, Taussig Cancer Center, Cleveland Clinic, Cleveland (J. Valent), and the Division of Hematology, Ohio State University Comprehensive Cancer Center, Columbus (N.B.) - both in Ohio; Clínica São Germano, São Paulo (V.H.), and Clinica CEHON, Rede D'Or Oncologia, Salvador (E.C.) - both in Brazil; the Department of Medicine, University of California, San Francisco, San Francisco (S.W.W.), the Department of Hematology and Hematopoietic Cell Transplantation, Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte (M.R.), and Janssen Research and Development, Los Angeles (N.T.) - all in California; the Department of Internal Medicine, Division of Hematology/Oncology, Columbia University Medical Center, New York (D.B.); the Penn Amyloidosis Program, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia (A.J.W.), and Janssen Research and Development, Spring House (X.Q., S.Y.V., B.M.W.) - both in Pennsylvania; Vanderbilt University Medical Center and Veterans Affairs Tennessee Valley Healthcare System, Nashville (S.A.G.); the Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit (J.A.Z.); the Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland (K.J.); and Genmab US, Princeton (T.A.), and Janssen Research and Development, Raritan (J.M.S., S.H.Z.) - both in New Jersey.
Background: Systemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease.
Methods: We randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response.
Results: A total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy.
Conclusions: Among patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.).