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.

1st Department of Medicine Department of Hematology 1st Faculty of Medicine Charles University and General Hospital Prague Prague Czech Republic

Centro Integrado de Hematologia e Oncologia Hospital Mãe de Deus Porto Alegre Brazil

Department of Haematology University College Hospital London UK

Department of Hemato Oncology University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Hematology Catholic Hematology Hospital and Leukemia Research Institute Seoul South Korea

Department of Hematology University Hospital Hôtel Dieu Nantes France

Department of Hematology University of California San Francisco San Francisco CA USA

Department of Internal Medicine Hematology and Oncology University Hospital Brno Brno Czech Republic

Department of Internal Medicine Seoul National University Hospital Seoul South Korea

Division of Hematology Oncology Department of Medicine Samsung Medical Center Sungkyunkwan University School of Medicine Seoul South Korea

Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo Sao Paolo Brazil

Institut Josep Carreras and Institut Catala d'Oncologia Hospital Germans Trias 1 Pujol Badalona Spain

Lille University Hospital Lille France

Myeloma Amyloidosis Center Japanese Red Cross Medical Center Tokyo Japan

Perth Blood Institute Murdoch University Perth WA Australia

Sanofi R and D Chilly Mazarin France

Sanofi R and D Vitry sur Seine France

Service d'Hématologie et Thérapie Cellulaire CHU and CIC Inserm 1402 Poitiers France

The National and Kapodistrian University of Athens Athens Greece

Translational Genomics Research Institute City of Hope Cancer Center Phoenix AZ USA

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Lancet. 2021 Jun 19;397(10292):2311-2313. doi: 10.1016/S0140-6736(21)00729-7. PubMed

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ClinicalTrials.gov
NCT03275285