INTRODUCTION: The presence of high-risk chromosomal abnormalities [t(4;14), del(17p), and t(14;16)] has been linked with inferior outcomes in patients with multiple myeloma (MM). A prespecified interim analysis of the Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) + carfilzomib (K) and dexamethasone (d; Isa-Kd) significantly improved progression-free survival (PFS) versus Kd in patients with relapsed MM. This prespecified subgroup analysis of IKEMA examined efficacy and safety in patients with high-risk cytogenetics. METHODS: High-risk cytogenetics was assessed by central laboratory and patients were classified as high risk if abnormalities were present in ≥1 of the following: del(17p): 50% cutoff; t(4;14), and/or t(14;16): 30% cutoff. RESULTS: Of the randomized patients, 23.5% (Isa-Kd) and 25.2% (Kd) had ≥1 high-risk chromosomal abnormality. A PFS benefit was seen in favor of Isa-Kd for patients with standard-risk (HR 0.440; 95% CI 0.266-0.728) and high-risk cytogenetics (HR 0.724; 95% CI 0.361-1.451). Grade ≥3 treatment-emergent adverse events (TEAEs) were more common with Isa-Kd (85.7%) versus Kd (63.3%) in patients with high-risk cytogenetics; however, the incidence of serious TEAEs (64.3% vs. 66.7%) was similar. CONCLUSIONS: Isa-Kd is a new treatment option for the difficult-to-treat subgroup of patients with relapsed MM and high-risk cytogenetics.

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

Austin and Repatriation Medical Center Heidelberg Victoria Australia

Department of Haematology Lille University Hospital Lille France

Department of Haematology University College Hospital London UK

Department of Hematology and Stem Cell Transplantation National Institute for Hematology and Infectious Diseases South Pest Central Hospital Budapest Hungary

Dipartimento di Medicina Specialistica Diagnostica e Sperimentale Università di Bologna Bologna Italy

Gazi University Ankara Turkey

Hematology Department Institut Català d'Oncologia and Josep Carreras Institute Hospital Germans Trias i Pujol Badalona Spain

Hospital Clinic IDIBAPS Barcelona Spain

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

IRCCS Azienda Ospedaliero Universitaria di Bologna Istituto di Ematologia Seràgnoli Bologna Italy

Sanofi Cambridge Massachusetts USA

Sanofi R and D Chilly Mazarin France

Sanofi R and D Vitry Sur Seine France

Seoul National University Hospital Seoul South Korea

University of California San Francisco San Francisco California USA

University of Nantes Nantes France

See more in PubMed

Kazandjian D. Multiple myeloma epidemiology and survival: A unique malignancy. Semin Oncol. 2016;43(6):676‐681. PubMed PMC

Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2016;91(1):101‐119. PubMed PMC

Biran N, Jagannath S, Chari A. Risk stratification in multiple myeloma, part 1: characterization of high‐risk disease. Clin Adv Hematol Oncol. 2013;11(8):489‐503. PubMed

Sonneveld P, Avet‐Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high‐risk cytogenetics: a consensus of the international myeloma working group. Blood. 2016. Jun 16;127(24):2955‐2962. PubMed PMC

Lancman G, Tremblay D, Barley K, et al. The effect of novel therapies in high‐molecular‐risk multiple myeloma. Clin Adv Hematol Oncol. 2017;15(11):870‐879. PubMed PMC

Jiang H, Acharya C, An G, et al. SAR650984 directly induces multiple myeloma cell death via lysosomal‐associated and apoptotic pathways, which is further enhanced by pomalidomide. Leukemia. 2016;30(2):399‐408. PubMed

Sarclisa® (isatuximab‐irfc) . Prescribing information. Sanofi‐Aventis U.S. LLC; 2021.

Sarclisa® (isatuximab) . Prescribing information. Sanofi Co, Ltd; 2021.

Moreau P, Dimopoulos M, Mikhael J, et al. Isatuximab plus carfilzomib and dexamethasone vs carfilzomib and dexamethasone in relapsed/refractory multiple myeloma (IKEMA): interim analysis of a phase 3, randomized, open‐label study. 2020 European Hematology Association Congress Virtual; 2020.

Moreau P, Dimopoulos MA, Yong K, et al. Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA phase III study design. Future Oncol. 2020. Jan;16(2):4347‐4358. PubMed

Moreau P, Dimopoulos M, Mikhael J, et al. Isatuximab combined with carfilzomib and dexamethasone versus carfilzomib with dexamethasone in patients with relapsed multiple myeloma: interim analysis of the IKEMA phase 3 study. Lancet. 2021;397(10292):2361‐2371. doi: 10.1016/S0140-6736(21)00592-4 PubMed DOI

Palumbo A, Avet‐Loiseau H, Oliva S, et al. Revised international staging system for multiple myeloma: a report from international myeloma working group. J Clin Oncol. 2015. Sep 10;33(26):2863‐2869. PubMed PMC

Moreau P, Dimopoulos MA, Mikhael J, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open‐label, randomised phase 3 trial. Lancet. 2021;397(10292):2361‐2371. PubMed

Harrison SJ, Perrot A, Alegre A, et al. Subgroup analysis of ICARIA‐MM study in relapsed/refractory multiple myeloma patients with high‐risk cytogenetics. Br J Haematol. 2021;194:120‐131. PubMed PMC

Dimopoulos M, Quach H, Mateos MV, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): results from a randomised, multicentre, open‐label, phase 3 study. Lancet. 2020;396(10245):186‐197. PubMed

Weisel K, Spencer A, Lentzsch S, et al. Daratumumab, bortezomib, and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of CASTOR based on cytogenetic risk. J Hematol Oncol. 2020. Aug 20;13(1):115. PubMed PMC

Kaufman JL, Dimopoulos MA, White D, et al. Daratumumab, lenalidomide, and dexamethasone in relapsed/refractory myeloma: a cytogenetic subgroup analysis of POLLUX. Blood Cancer J. 2020. Nov 3;10(11):111. PubMed PMC

Mateos MV, Sonneveld P, Hungria V, et al. Daratumumab, Bortezomib, and dexamethasone versus Bortezomib and dexamethasone in patients with previously treated multiple myeloma: three‐year follow‐up of CASTOR. Clin Lymphoma Myeloma Leuk. 2020. Aug;20(8):509‐518. PubMed

Primary outcomes by 1q21+ status for isatuximab-treated patients with relapsed/refractory multiple myeloma: subgroup analyses from ICARIA-MM and IKEMA