María-Victoria Mateos1, Meletios A Dimopoulos1, Michele Cavo1, Kenshi Suzuki1, Andrzej Jakubowiak1, Stefan Knop1, Chantal Doyen1, Paulo Lucio1, Zsolt Nagy1, Polina Kaplan1, Ludek Pour1, Mark Cook1, Sebastian Grosicki1, Andre Crepaldi1, Anna M Liberati1, Philip Campbell1, Tatiana Shelekhova1, Sung-Soo Yoon1, Genadi Iosava1, Tomoaki Fujisaki1, Mamta Garg1, Christopher Chiu1, Jianping Wang1, Robin Carson1, Wendy Crist1, William Deraedt1, Huong Nguyen1, Ming Qi1, Jesus San-Miguel1. 1. From University Hospital of Salamanca-Instituto de Investigación Biomédica de Salamanca, Salamanca (M.-V.M.), and Clínica Universidad de Navarra-Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Centro de Investigación Biomédica en Red de Cáncer, Pamplona (J.S.-M.) - both in Spain; National and Kapodistrian University of Athens, Athens (M.A.D.); the Institute of Hematology, Department of Experimental, Diagnostic, and Specialty Medicine, University of Bologna, Bologna (M. Cavo), and Azienda Ospedaliera "Santa Maria," Terni (A.M.L.) - both in Italy; Japanese Red Cross Medical Center, Department of Hematology, Tokyo (K.S.); University of Chicago Medical Center, Chicago (A.J.); Würzburg University Medical Center, Würzburg, Germany (S.K.); Université Catholique de Louvain (UCL), Centre Hospitalier Universitaire UCL Namur, Yvoir (C.D.), and Janssen Research and Development, Beerse (W.D.) - both in Belgium; Champalimaud Center for the Unknown, Lisbon, Portugal (P.L.); Semmelweis Egyetem, Budapest, Hungary (Z.N.); Dnepropetrovsk City Clinical Hospital #4, Dnepropetrovsk, Ukraine (P.K.); University Hospital Brno, Brno, Czech Republic (L.P.); University Hospitals Birmingham NHS Foundation Trust, Birmingham (M. Cook), and Leicester Royal Infirmary-Haematology, Leicester (M.G.) - both in the United Kingdom; the Department of Cancer Prevention, School of Public Health, Silesian Medical University, Katowice, Poland (S.G.); Clínica de Tratamento E, Cuiaba, Brazil (A.C.); Andrew Love Cancer Centre, Geelong, VIC, Australia (P.C.); Clinic of Professional Pathology, Saratov, Russia (T.S.); the Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea (S.-S.Y.); LTD "Medinvent" Institute of Health, Tbilisi, Georgia (G.I.); Matsuyama Red Cross Hospital, Matsuyama, Japan (T.F.); Janssen Research and Development, Spring House, PA (C.C., R.C., W.C., M.Q.); and Janssen Research and Development, Raritan, NJ (J.W., H.N.).
Abstract
BACKGROUND: The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles ofbortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival. RESULTS: At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab-associated infusion-related reactions occurred in 27.7% of the patients. CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined withbortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).
RCT Entities:
BACKGROUND: The combination of bortezomib, melphalan, and prednisone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. Daratumumab has shown efficacy in combination with standard-of-care regimens in patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 706 patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation to receive nine cycles of bortezomib, melphalan, and prednisone either alone (control group) or with daratumumab (daratumumab group) until disease progression. The primary end point was progression-free survival. RESULTS: At a median follow-up of 16.5 months in a prespecified interim analysis, the 18-month progression-free survival rate was 71.6% (95% confidence interval [CI], 65.5 to 76.8) in the daratumumab group and 50.2% (95% CI, 43.2 to 56.7) in the control group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The overall response rate was 90.9% in the daratumumab group, as compared with 73.9% in the control group (P<0.001), and the rate of complete response or better (including stringent complete response) was 42.6%, versus 24.4% (P<0.001). In the daratumumab group, 22.3% of the patients were negative for minimal residual disease (at a threshold of 1 tumor cell per 105 white cells), as compared with 6.2% of those in the control group (P<0.001). The most common adverse events of grade 3 or 4 were hematologic: neutropenia (in 39.9% of the patients in the daratumumab group and in 38.7% of those in the control group), thrombocytopenia (in 34.4% and 37.6%, respectively), and anemia (in 15.9% and 19.8%, respectively). The rate of grade 3 or 4 infections was 23.1% in the daratumumab group and 14.7% in the control group; the rate of treatment discontinuation due to infections was 0.9% and 1.4%, respectively. Daratumumab-associated infusion-related reactions occurred in 27.7% of the patients. CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation, daratumumab combined with bortezomib, melphalan, and prednisone resulted in a lower risk of disease progression or death than the same regimen without daratumumab. The daratumumab-containing regimen was associated with more grade 3 or 4 infections. (Funded by Janssen Research and Development; ALCYONE ClinicalTrials.gov number, NCT02195479 .).
Authors: Peter M Voorhees; Jonathan L Kaufman; Jacob Laubach; Douglas W Sborov; Brandi Reeves; Cesar Rodriguez; Ajai Chari; Rebecca Silbermann; Luciano J Costa; Larry D Anderson; Nitya Nathwani; Nina Shah; Yvonne A Efebera; Sarah A Holstein; Caitlin Costello; Andrzej Jakubowiak; Tanya M Wildes; Robert Z Orlowski; Kenneth H Shain; Andrew J Cowan; Sean Murphy; Yana Lutska; Huiling Pei; Jon Ukropec; Jessica Vermeulen; Carla de Boer; Daniela Hoehn; Thomas S Lin; Paul G Richardson Journal: Blood Date: 2020-08-20 Impact factor: 22.113
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Authors: Giovanni Palladini; Efstathios Kastritis; Mathew S Maurer; Jeffrey Zonder; Monique C Minnema; Ashutosh D Wechalekar; Arnaud Jaccard; Hans C Lee; Naresh Bumma; Jonathan L Kaufman; Eva Medvedova; Tibor Kovacsovics; Michael Rosenzweig; Vaishali Sanchorawala; Xiang Qin; Sandra Y Vasey; Brendan M Weiss; Jessica Vermeulen; Giampaolo Merlini; Raymond L Comenzo Journal: Blood Date: 2020-07-02 Impact factor: 22.113