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 Fujisaki & 11 others Mamta 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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Melphalan
Prednisone
Multiple Myeloma
Control Groups
Stem Cell Transplantation
Disease Progression
Confidence Intervals
Disease-Free Survival
daratumumab
Bortezomib
Infection
Residual Neoplasm
Standard of Care
Neutropenia
Thrombocytopenia
Anemia
Survival Rate

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., ... 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

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

In: New England Journal of Medicine, Vol. 378, No. 6, 08.02.2018, p. 518-528.

Research output: Contribution to journalArticle

Mateos, M-V, Dimopoulos, MA, 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, AM, Campbell, P, Shelekhova, T, Yoon, S-S, Iosava, G, Fujisaki, T, Garg, M, Chiu, C, Wang, J, Carson, R, Crist, W, Deraedt, W, Nguyen, H, Qi, M, San-Miguel, J, ALCYONE Trial Investigators & Musto, P 2018, 'Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma', New England Journal of Medicine, vol. 378, no. 6, pp. 518-528. https://doi.org/10.1056/NEJMoa1714678
Mateos M-V, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S et al. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. New England Journal of Medicine. 2018 Feb 8;378(6):518-528. https://doi.org/10.1056/NEJMoa1714678
Mateos, María-Victoria ; Dimopoulos, Meletios A ; Cavo, Michele ; Suzuki, Kenshi ; Jakubowiak, Andrzej ; Knop, Stefan ; Doyen, Chantal ; Lucio, Paulo ; Nagy, Zsolt ; Kaplan, Polina ; Pour, Ludek ; Cook, Mark ; Grosicki, Sebastian ; Crepaldi, Andre ; Liberati, Anna M ; Campbell, Philip ; Shelekhova, Tatiana ; Yoon, Sung-Soo ; Iosava, Genadi ; Fujisaki, Tomoaki ; Garg, Mamta ; Chiu, Christopher ; Wang, Jianping ; Carson, Robin ; Crist, Wendy ; Deraedt, William ; Nguyen, Huong ; Qi, Ming ; San-Miguel, Jesus ; ALCYONE Trial Investigators ; Musto, Pellegrino. / Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma. In: New England Journal of Medicine. 2018 ; Vol. 378, No. 6. pp. 518-528.
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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 .).",
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",
author = "Mar{\'i}a-Victoria Mateos and Dimopoulos, {Meletios A} and Michele Cavo and Kenshi Suzuki and Andrzej Jakubowiak and Stefan Knop and Chantal Doyen and Paulo Lucio and Zsolt Nagy and Polina Kaplan and Ludek Pour and Mark Cook and Sebastian Grosicki and Andre Crepaldi and Liberati, {Anna M} and Philip Campbell and Tatiana Shelekhova and Sung-Soo Yoon and Genadi Iosava and Tomoaki Fujisaki and Mamta Garg and Christopher Chiu and Jianping Wang and Robin Carson and Wendy Crist and William Deraedt and Huong Nguyen and Ming Qi and Jesus San-Miguel and {ALCYONE Trial Investigators} and Pellegrino Musto",
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language = "English",
volume = "378",
pages = "518--528",
journal = "New England Journal of Medicine",
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TY - JOUR

T1 - Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma

AU - Mateos, María-Victoria

AU - Dimopoulos, Meletios A

AU - Cavo, Michele

AU - Suzuki, Kenshi

AU - Jakubowiak, Andrzej

AU - Knop, Stefan

AU - Doyen, Chantal

AU - Lucio, Paulo

AU - Nagy, Zsolt

AU - Kaplan, Polina

AU - Pour, Ludek

AU - Cook, Mark

AU - Grosicki, Sebastian

AU - Crepaldi, Andre

AU - Liberati, Anna M

AU - Campbell, Philip

AU - Shelekhova, Tatiana

AU - Yoon, Sung-Soo

AU - Iosava, Genadi

AU - Fujisaki, Tomoaki

AU - Garg, Mamta

AU - Chiu, Christopher

AU - Wang, Jianping

AU - Carson, Robin

AU - Crist, Wendy

AU - Deraedt, William

AU - Nguyen, Huong

AU - Qi, Ming

AU - San-Miguel, Jesus

AU - ALCYONE Trial Investigators

AU - Musto, Pellegrino

PY - 2018/2/8

Y1 - 2018/2/8

N2 - 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 .).

AB - 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 .).

KW - Adult

KW - Aged

KW - Antibodies, Monoclonal

KW - Antineoplastic Combined Chemotherapy Protocols

KW - Bortezomib

KW - Disease-Free Survival

KW - Female

KW - Follow-Up Studies

KW - Humans

KW - Infection

KW - Intention to Treat Analysis

KW - Kaplan-Meier Estimate

KW - Male

KW - Melphalan

KW - Middle Aged

KW - Multiple Myeloma

KW - Prednisone

KW - Survival Rate

KW - Clinical Trial, Phase III

KW - Journal Article

KW - Multicenter Study

KW - Randomized Controlled Trial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1056/NEJMoa1714678

DO - 10.1056/NEJMoa1714678

M3 - Article

VL - 378

SP - 518

EP - 528

JO - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 6

ER -