Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma
Thierry Facon, M.D., Shaji Kumar, M.D., Torben Plesner, M.D., Robert Z. Orlowski, M.D., Philippe Moreau, M.D., Nizar Bahlis, M.D., Supratik Basu, M.D., Hareth Nahi, M.D., Cyrille Hulin, M.D., Hang Quach, M.D., Hartmut Goldschmidt, M.D., Michael O’Dwyer, M.D., et al., for the MAIA Trial Investigators*
https://www.nejm.org/doi/full/10.1056/NEJMoa1817249?query=oncology-hematology
Abstract
BACKGROUND
Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.
METHODS
We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.
RESULTS
At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).
CONCLUSIONS
Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.)
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Supported by Janssen Research and Development.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Dr. Facon reports receiving fees for serving on a board of directors, advisory committee, and speakers bureau from Celgene, Janssen, and Takeda, and fees for serving on a board of directors and advisory committee from Amgen, Sanofi, Karyopharm, Oncopeptides, and Roche; Dr. Kumar, receiving grant support and fees for serving on a board of directors and advisory committee from AbbVie, Celgene, and Kite Pharma; Dr. Plesner, serving on an independent response assessment committee for Celgene; Dr. Orlowski, receiving consulting fees and fees for serving on a board of directors and advisory committee from Bristol-Myers Squibb, Celgene, Kite Pharma, Sanofi, and Amgen, consulting fees from Takeda, and grant support from BioTheryX and Spectrum Pharma; Dr. Moreau, receiving honoraria and fees for serving on a board of directors, advisory committee, and speakers bureau from Amgen, Celgene, Janssen, AbbVie, and Takeda; Dr. Bahlis, receiving grant support, consulting fees, and honoraria from Amgen and Celgene; Dr. Hulin, receiving grant support and honoraria from Celgene and Janssen, and honoraria from Amgen and Takeda; Dr. Goldschmidt, receiving consulting fees and fees for serving on a board of directors and advisory committee from Adaptive Biotechnologies, grant support, consulting fees, and fees for serving on a board of directors and advisory committee from Amgen, Sanofi, and Takeda, grant support, consulting fees, honoraria, and fees for serving on a board of directors and advisory committee from Bristol-Myers Squibb, Celgene, and Janssen, honoraria and research funding from Chugai, grant support from Mundipharma, grant support and honoraria from Novartis, and honoraria from Art Tempi; Dr. O’Dwyer, receiving consulting fees from Janssen; Dr. Perrot, receiving consulting fees, honoraria, and equity from Janssen; Dr. Venner, receiving grant support and honoraria from Janssen and Celgene, and honoraria from Amgen and Takeda; Dr. Weisel, receiving grant support, consulting fees, and honoraria from Janssen, consulting fees from Celgene and Juno, consulting fees, honoraria, and research funding from Amgen, consulting and honoraria from Bristol-Myers Squibb and Takeda, and grant support and consulting fees from Sanofi; Dr. Raje, receiving consulting fees from Amgen, Celgene, Bristol-Myers Squibb, Janssen, and Takeda, and grant support from AstraZeneca; Dr. Macro, receiving honoraria and travel support from Celgene and Amgen, and grant support, honoraria, and travel support from Janssen and Takeda; Dr. Leleu, receiving honoraria from Amgen, Takeda, Janssen, Bristol-Myers Squibb, Novartis, Roche, Merck, Mundipharma, Gilead, AbbVie, Karyopharm, Celgene, and Incyte; Dr. Ahmadi, being employed by and owning equity in Genmab; Dr. Chiu, being employed by and owning equity in Janssen; Dr. Wang, Dr. van Rampelbergh, Dr. Uhlar, Dr. Kobos, and Dr. Qi, being employed by Janssen; and Dr. Usmani, receiving consulting fees from AbbVie, Genmab, and Mundipharma, grant support and consulting fees from Amgen, Celgene, Merck, Janssen, and Seattle Genetics, and grant support from Bristol-Myers Squibb, Pharmacyclics, and Sanofi. No other potential conflict of interest relevant to this article was reported.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the patients who volunteered to participate in this trial, their families, and the staff members at the trial sites who cared for them; the members of the data and safety monitoring committee (Nikhil C. Munshi, M.D. [chair], Mario DiCato, M.D., and Weichung Shih, Ph.D.); representatives of the sponsor who were involved in data collection and analyses; Intergroupe Francophone du Myélome for their strong support and guidance during the trial start-up; and Jason Jung, Ph.D., and Melissa Brunckhorst, Ph.D., of MedErgy, for editorial assistance in the development of an earlier draft of the manuscript.
Author Affiliations
From University of Lille, Centre Hospitalier Universitaire (CHU) Lille, Service des Maladies du Sang, Lille (T.F.), Hematology Department, University Hospital Hôtel-Dieu, Nantes (P.M.), Department of Hematology, Hospital Haut Leveque, University Hospital, Pessac (C.H.), Hematology Department, University Hospital, Vandoeuvre lès Nancy (A.P.), Service d’Hématologie, CHU de Toulouse–Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse (M.A.), Department of Hematology, Vendée Hospital, La Roche sur Yon (M.T.), CHU de Caen, Caen (M.M.), Department of Clinical Hematology, Assistance Publique–Hôpitaux de Paris, Necker Hospital, Paris (L.F.), and Department of Hematology, CHU la Miletrie and INSERM CIC 1402, Poitiers (X.L.) — all in France; the Department of Hematology, Mayo Clinic Rochester, Rochester, MN (S.K.); Vejle Hospital and University of Southern Denmark, Vejle (T.P.); Department of Lymphoma–Myeloma, University of Texas M.D. Anderson Cancer Center, Houston (R.Z.O.); University of Calgary, Arnie Charbonneau Cancer Research Institute, Calgary, AB (N.B.), and the Division of Medical Oncology, University of Alberta, Edmonton (C.P.V.) — both in Canada; Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom (S.B.); Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm (H.N.); University of Melbourne, St. Vincent’s Hospital, Melbourne, VIC, Australia (H.Q.); University Hospital Heidelberg and National Center of Tumor Diseases (NCT), Heidelberg (H.G.), and the Department of Oncology, Hematology and Bone Marrow Transplantation, Section of Pneumology, University Medical Center Hamburg–Eppendorf, Hamburg (K.W.) — both in Germany; Department of Medicine–Haematology, National University of Ireland, Galway (M.O.); Florida Cancer Specialists and Research Institute, St. Petersburg (J.R.M.); the Department of Hematology–Oncology, Massachusetts General Hospital, Boston (N.R.); Genmab US, Princeton (T.A.), and Janssen Research and Development, Raritan (J.W., R.K.) — both in New Jersey; Janssen Research and Development, Spring House, PA (C.C., C.M.U., M.Q.); Janssen Research and Development, Beerse, Belgium (R.V.R.); and Levine Cancer Institute–Atrium Health, Charlotte, NC (S.Z.U.).
Address reprint requests to Dr. Facon at CHRU rue Michel Polonovski, 59037 Lille, France, or at thierry.facon@chru-lille.fr.
A complete list of investigators in the MAIA trial is provided in the Supplementary Appendix, available at NEJM.org.
Thierry Facon, M.D., Shaji Kumar, M.D., Torben Plesner, M.D., Robert Z. Orlowski, M.D., Philippe Moreau, M.D., Nizar Bahlis, M.D., Supratik Basu, M.D., Hareth Nahi, M.D., Cyrille Hulin, M.D., Hang Quach, M.D., Hartmut Goldschmidt, M.D., Michael O’Dwyer, M.D., et al., for the MAIA Trial Investigators*
https://www.nejm.org/doi/full/10.1056/NEJMoa1817249?query=oncology-hematology
Abstract
BACKGROUND
Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.
METHODS
We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.
RESULTS
At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%).
CONCLUSIONS
Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.)
Read this article and use 1 of your 3 remaining free subscriber-only articles.
USE 1 ARTICLE AND READ
Supported by Janssen Research and Development.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Dr. Facon reports receiving fees for serving on a board of directors, advisory committee, and speakers bureau from Celgene, Janssen, and Takeda, and fees for serving on a board of directors and advisory committee from Amgen, Sanofi, Karyopharm, Oncopeptides, and Roche; Dr. Kumar, receiving grant support and fees for serving on a board of directors and advisory committee from AbbVie, Celgene, and Kite Pharma; Dr. Plesner, serving on an independent response assessment committee for Celgene; Dr. Orlowski, receiving consulting fees and fees for serving on a board of directors and advisory committee from Bristol-Myers Squibb, Celgene, Kite Pharma, Sanofi, and Amgen, consulting fees from Takeda, and grant support from BioTheryX and Spectrum Pharma; Dr. Moreau, receiving honoraria and fees for serving on a board of directors, advisory committee, and speakers bureau from Amgen, Celgene, Janssen, AbbVie, and Takeda; Dr. Bahlis, receiving grant support, consulting fees, and honoraria from Amgen and Celgene; Dr. Hulin, receiving grant support and honoraria from Celgene and Janssen, and honoraria from Amgen and Takeda; Dr. Goldschmidt, receiving consulting fees and fees for serving on a board of directors and advisory committee from Adaptive Biotechnologies, grant support, consulting fees, and fees for serving on a board of directors and advisory committee from Amgen, Sanofi, and Takeda, grant support, consulting fees, honoraria, and fees for serving on a board of directors and advisory committee from Bristol-Myers Squibb, Celgene, and Janssen, honoraria and research funding from Chugai, grant support from Mundipharma, grant support and honoraria from Novartis, and honoraria from Art Tempi; Dr. O’Dwyer, receiving consulting fees from Janssen; Dr. Perrot, receiving consulting fees, honoraria, and equity from Janssen; Dr. Venner, receiving grant support and honoraria from Janssen and Celgene, and honoraria from Amgen and Takeda; Dr. Weisel, receiving grant support, consulting fees, and honoraria from Janssen, consulting fees from Celgene and Juno, consulting fees, honoraria, and research funding from Amgen, consulting and honoraria from Bristol-Myers Squibb and Takeda, and grant support and consulting fees from Sanofi; Dr. Raje, receiving consulting fees from Amgen, Celgene, Bristol-Myers Squibb, Janssen, and Takeda, and grant support from AstraZeneca; Dr. Macro, receiving honoraria and travel support from Celgene and Amgen, and grant support, honoraria, and travel support from Janssen and Takeda; Dr. Leleu, receiving honoraria from Amgen, Takeda, Janssen, Bristol-Myers Squibb, Novartis, Roche, Merck, Mundipharma, Gilead, AbbVie, Karyopharm, Celgene, and Incyte; Dr. Ahmadi, being employed by and owning equity in Genmab; Dr. Chiu, being employed by and owning equity in Janssen; Dr. Wang, Dr. van Rampelbergh, Dr. Uhlar, Dr. Kobos, and Dr. Qi, being employed by Janssen; and Dr. Usmani, receiving consulting fees from AbbVie, Genmab, and Mundipharma, grant support and consulting fees from Amgen, Celgene, Merck, Janssen, and Seattle Genetics, and grant support from Bristol-Myers Squibb, Pharmacyclics, and Sanofi. No other potential conflict of interest relevant to this article was reported.
A data sharing statement provided by the authors is available with the full text of this article at NEJM.org.
We thank the patients who volunteered to participate in this trial, their families, and the staff members at the trial sites who cared for them; the members of the data and safety monitoring committee (Nikhil C. Munshi, M.D. [chair], Mario DiCato, M.D., and Weichung Shih, Ph.D.); representatives of the sponsor who were involved in data collection and analyses; Intergroupe Francophone du Myélome for their strong support and guidance during the trial start-up; and Jason Jung, Ph.D., and Melissa Brunckhorst, Ph.D., of MedErgy, for editorial assistance in the development of an earlier draft of the manuscript.
Author Affiliations
From University of Lille, Centre Hospitalier Universitaire (CHU) Lille, Service des Maladies du Sang, Lille (T.F.), Hematology Department, University Hospital Hôtel-Dieu, Nantes (P.M.), Department of Hematology, Hospital Haut Leveque, University Hospital, Pessac (C.H.), Hematology Department, University Hospital, Vandoeuvre lès Nancy (A.P.), Service d’Hématologie, CHU de Toulouse–Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse (M.A.), Department of Hematology, Vendée Hospital, La Roche sur Yon (M.T.), CHU de Caen, Caen (M.M.), Department of Clinical Hematology, Assistance Publique–Hôpitaux de Paris, Necker Hospital, Paris (L.F.), and Department of Hematology, CHU la Miletrie and INSERM CIC 1402, Poitiers (X.L.) — all in France; the Department of Hematology, Mayo Clinic Rochester, Rochester, MN (S.K.); Vejle Hospital and University of Southern Denmark, Vejle (T.P.); Department of Lymphoma–Myeloma, University of Texas M.D. Anderson Cancer Center, Houston (R.Z.O.); University of Calgary, Arnie Charbonneau Cancer Research Institute, Calgary, AB (N.B.), and the Division of Medical Oncology, University of Alberta, Edmonton (C.P.V.) — both in Canada; Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, United Kingdom (S.B.); Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm (H.N.); University of Melbourne, St. Vincent’s Hospital, Melbourne, VIC, Australia (H.Q.); University Hospital Heidelberg and National Center of Tumor Diseases (NCT), Heidelberg (H.G.), and the Department of Oncology, Hematology and Bone Marrow Transplantation, Section of Pneumology, University Medical Center Hamburg–Eppendorf, Hamburg (K.W.) — both in Germany; Department of Medicine–Haematology, National University of Ireland, Galway (M.O.); Florida Cancer Specialists and Research Institute, St. Petersburg (J.R.M.); the Department of Hematology–Oncology, Massachusetts General Hospital, Boston (N.R.); Genmab US, Princeton (T.A.), and Janssen Research and Development, Raritan (J.W., R.K.) — both in New Jersey; Janssen Research and Development, Spring House, PA (C.C., C.M.U., M.Q.); Janssen Research and Development, Beerse, Belgium (R.V.R.); and Levine Cancer Institute–Atrium Health, Charlotte, NC (S.Z.U.).
Address reprint requests to Dr. Facon at CHRU rue Michel Polonovski, 59037 Lille, France, or at thierry.facon@chru-lille.fr.
A complete list of investigators in the MAIA trial is provided in the Supplementary Appendix, available at NEJM.org.
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