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Title: Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in relapsed and refractory multiple myeloma: follow-up analysis of the Phase 3 ICARIA-MM study.
Epworth Authors: Prince, Henry Miles
Other Authors: Richardson, Paul
Perrot, Aurore
San-Miguel, Jesus
Beksac, Meral
Spicka, Ivan
Leleu, Xavier
Schjesvold, Fedrik
Moreau, Phillipe
Dimopoulos, Meletios
Huang, Jeffrey Shang-Yi
Minarik, Jiri
Cavo, Michele
Malinge, Laure
Dubin, Franck
van de Velde, Helgi
Anderson, Kenneth
Keywords: ICARIA-MM study
relapsed and refractory multiple myeloma
proteasome inhibitor
disease progression
alkylating agents
monoclonal antibodies
cell death
natural killer cells.
disease progression
plasma cell leukaemia.
H2 antagonists
Issue Date: 23-Mar-2022
Publisher: Elsevier
Citation: Volume 23, Issue 3, Pages 416-427
Abstract: Abstract Background: The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis. Methods: In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2-3 vs >3) and aged (<75 vs ≥75 years), to isatuximab-pomalidomide-dexamethasone (isatuximab group) or pomalidomide-dexamethasone (control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequent cycles. Both groups received oral pomalidomide 4 mg on days 1-21 of each cycle, and weekly oral or intravenous dexamethasone 40 mg (20 mg if aged ≥75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Here' we report a prespecified second interim analysis of overall survival (time from randomisation to any-cause death), a key secondary endpoint, in the intention-to-treat population (ie, all patients who provided informed consent and allocated a randomisation number) at 24 months after the primary analysis. Safety was assessed in all patients who received at least one dose or part dose of study treatment. The prespecified stopping boundary for the overall survival analysis was when the derived p value was equal to or less than 0·0181. This study is registered with, NCT02990338, and is active, but not recruiting. Findings: Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5-37·4). Median overall survival was 24·6 months (95% CI 20·3-31·3) in the isatuximab group and 17·7 months (14·4-26·2) in the control group (hazard ratio 0·76 [95% CI 0·57-1·01]; one-sided log-rank p=0·028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 [50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection). Interpretation: Addition of isatuximab plus pomalidomide-dexamethasone resulted in a 6·9-month difference in median overall survival compared with pomalidomide-dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing. Funding: Sanofi.
Description: Randomised, Multicentre, Open-label, Phase 3 study
DOI: 10.1016/S1470-2045(22)00019-5
PubMed URL:
ISSN: 0140-6736
Journal Title: The Lancet Oncology
Type: Journal Article
Affiliated Organisations: Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
CHU de Toulouse, IUCT-O, Université de Toulouse, UPS, Service d'Hématologie, Toulouse, France.
Clínica Universidad de Navarra, Navarra, CCUN, CIMA, IDISNA, CIBER-ONC, Pamplona, Spain.
Department of Hematology, Ankara University, Ankara, Turkey.
General Faculty Hospital, and First Faculty of Medicine, Charles University, Prague, Czech Republic.
Service d'Hématologie et Thérapie Cellulaire, CHU and CIC Inserm 1402, Poitiers Cedex, France.
Oslo Myeloma Center, Department of Haematology, Oslo University Hospital and KG Jebsen Center for B Cell Malignancies, University of Oslo, Oslo, Norway.
Hematology Department, CHU Nantes, Nantes, France.
Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
Department of Hematology, National Taiwan University Hospital, Taipei, Taiwan.
Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Olomouc, Czech Republic.
IRCCS Azienda Ospedaliero-Universitaria di Bologna, Istituto di Ematologia "Seràgnoli", Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna, Italy.
Immunology and Molecular Oncology, Epworth Healthcare, University of Melbourne, Melbourne, VIC, Australia.
Sanofi R&D, Vitry, France.
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Type of Clinical Study or Trial: Multicentre Studies
Appears in Collections:MOCI

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