Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma

María-Victoria Mateos, Meletios A Dimopoulos, Michele Cavo, Kenshi Suzuki, Andrzej Jakubowiak, Stefan Knop, Chantal Doyen, Paulo Lucio, Zsolt Nagy, Polina Kaplan, Ludek Pour, Mark Cook, Sebastian Grosicki, Andre Crepaldi, Anna M Liberati, Philip Campbell, Tatiana Shelekhova, Sung-Soo Yoon, Genadi Iosava, Tomoaki FujisakiMamta Garg, Christopher Chiu, Jianping Wang, Robin Carson, Wendy Crist, William Deraedt, Huong Nguyen, Ming Qi, Jesus San-Miguel, ALCYONE Trial Investigators, Pellegrino Musto

Research output: Contribution to journalArticle

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 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 105white 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 .).

Original languageEnglish
Pages (from-to)518-528
Number of pages11
JournalNew England Journal of Medicine
Volume378
Issue number6
DOIs
Publication statusPublished - Feb 8 2018

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Keywords

  • Adult
  • Aged
  • Antibodies, Monoclonal
  • Antineoplastic Combined Chemotherapy Protocols
  • Bortezomib
  • Disease-Free Survival
  • Female
  • Follow-Up Studies
  • Humans
  • Infection
  • Intention to Treat Analysis
  • Kaplan-Meier Estimate
  • Male
  • Melphalan
  • Middle Aged
  • Multiple Myeloma
  • Prednisone
  • Survival Rate
  • Clinical Trial, Phase III
  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

Cite this

Mateos, M-V., Dimopoulos, M. A., Cavo, M., Suzuki, K., Jakubowiak, A., Knop, S., Doyen, C., Lucio, P., Nagy, Z., Kaplan, P., Pour, L., Cook, M., Grosicki, S., Crepaldi, A., Liberati, A. M., Campbell, P., Shelekhova, T., Yoon, S-S., Iosava, G., ... Musto, P. (2018). Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. New England Journal of Medicine, 378(6), 518-528. https://doi.org/10.1056/NEJMoa1714678