Philippe Moreau1, Meletios-Athanasios Dimopoulos2, Joseph Mikhael3, Kwee Yong4, Marcelo Capra5, Thierry Facon6, Roman Hajek7, Ivan Špička8, Ross Baker9, Kihyun Kim10, Gracia Martinez11, Chang-Ki Min12, Ludek Pour13, Xavier Leleu14, Albert Oriol15, Youngil Koh16, Kenshi Suzuki17, Marie-Laure Risse18, Gaelle Asset19, Sandrine Macé18, Thomas Martin20. 1. Department of Hematology, University Hospital Hôtel-Dieu, Nantes, France. Electronic address: philippe.moreau@chu-nantes.fr. 2. The National and Kapodistrian University of Athens, Athens, Greece. 3. Translational Genomics Research Institute, City of Hope Cancer Center, Phoenix, AZ, USA. 4. Department of Haematology, University College Hospital, London, UK. 5. Centro Integrado de Hematologia e Oncologia, Hospital Mãe de Deus, Porto Alegre, Brazil. 6. Lille University Hospital, Lille, France. 7. Department of Hemato-Oncology, University Hospital Ostrava and Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic. 8. 1st Department of Medicine-Department of Hematology, 1st Faculty of Medicine, Charles University and General Hospital in Prague, Prague, Czech Republic. 9. Perth Blood Institute, Murdoch University, Perth, WA, Australia. 10. Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 11. Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, Sao Paolo, Brazil. 12. Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul, South Korea. 13. Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Brno, Czech Republic. 14. Service d'Hématologie et Thérapie Cellulaire, CHU and CIC Inserm 1402, Poitiers, France. 15. Institut Josep Carreras and Institut Catala d'Oncologia, Hospital Germans Trias I Pujol, Badalona, Spain. 16. Department of Internal Medicine, Seoul National University Hospital, Seoul, South Korea. 17. Myeloma/Amyloidosis Center, Japanese Red Cross Medical Center, Tokyo, Japan. 18. Sanofi R&D, Vitry-sur-Seine, France. 19. Sanofi R&D, Chilly-Mazarin, France. 20. Department of Hematology, University of California San Francisco, San Francisco, CA, USA.
Abstract
BACKGROUND: Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma. METHODS: This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. FINDINGS: Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77-not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32-0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. INTERPRETATION: The addition of isatuximab to carfilzomib-dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. FUNDING: Sanofi. VIDEO ABSTRACT.
BACKGROUND: Isatuximab is an anti-CD38 monoclonal antibody approved in combination with pomalidomide-dexamethasone and carfilzomib-dexamethasone for relapsed or refractory multiple myeloma. This phase 3, open-label study compared the efficacy of isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma. METHODS: This was a prospective, randomised, open-label, parallel-group, phase 3 study done at 69 study centres in 16 countries across North America, South America, Europe, and the Asia-Pacific region. Patients with relapsed or refractory multiple myeloma aged at least 18 years who had received one to three previous lines of therapy and had measurable serum or urine M-protein were eligible. Patients were randomly assigned (3:2) to isatuximab plus carfilzomib-dexamethasone (isatuximab group) or carfilzomib-dexamethasone (control group). Patients in the isatuximab group received isatuximab 10 mg/kg intravenously weekly for the first 4 weeks, then every 2 weeks. Both groups received the approved schedule of intravenous carfilzomib and oral or intravenous dexamethasone. Treatment continued until progression or unacceptable toxicity. The primary endpoint was progression-free survival and was assessed in the intention-to-treat population according to assigned treatment. Safety was assessed in all patients who received at least one dose according to treatment received. The study is registered at ClinicalTrials.gov, NCT03275285. FINDINGS: Between Nov 15, 2017, and March 21, 2019, 302 patients with a median of two previous lines of therapy were enrolled. 179 were randomly assigned to the isatuximab group and 123 to the control group. Median progression-free survival was not reached in the isatuximab group compared with 19·15 months (95% CI 15·77-not reached) in the control group, with a hazard ratio of 0·53 (99% CI 0·32-0·89; one-sided p=0·0007). Treatment-emergent adverse events (TEAEs) of grade 3 or worse occurred in 136 (77%) of 177 patients in the isatuximab group versus 82 (67%) of 122 in the control group, serious TEAEs occurred in 105 (59%) versus 70 (57%) patients, and TEAEs led to discontinuation in 15 (8%) versus 17 (14%) patients. Fatal TEAEs during study treatment occurred in six (3%) versus four (3%) patients. INTERPRETATION: The addition of isatuximab to carfilzomib-dexamethasone significantly improves progression-free survival and depth of response in patients with relapsed multiple myeloma, representing a new standard of care for this patient population. FUNDING: Sanofi. VIDEO ABSTRACT.
Authors: Shaji Kumar; Lawrence Baizer; Natalie S Callander; Sergio A Giralt; Jens Hillengass; Boris Freidlin; Antje Hoering; Paul G Richardson; Elena I Schwartz; Anthony Reiman; Suzanne Lentzsch; Philip L McCarthy; Sundar Jagannath; Andrew J Yee; Richard F Little; Noopur S Raje Journal: Blood Cancer J Date: 2022-06-29 Impact factor: 9.812