The International Staging System for multiple myeloma recently underwent a second revision (R2-ISS) to include gain/amplification of 1q21 and account for the additive prognostic significance of multiple high-risk features. The phase 3 ICARIA-MM (isatuximab-pomalidomide-dexamethasone vs. pomalidomide-dexamethasone) and IKEMA (isatuximab-carfilzomib-dexamethasone vs. carfilzomib-dexamethasone) studies provide large datasets for retrospectively validating the prognostic value of the R2-ISS in relapsed/refractory multiple myeloma. Of 609 pooled patients, 68 (11.2%) were reclassified as R2-ISS stage I, 136 (22.3%) as R2-ISS stage II, 204 (33.5%) as R2-ISS stage III, 55 (9.0%) as stage IV, and 146 (24.0%) "Not classified". Median progression-free survival was shorter among those reclassified as R2-ISS stage II (HR 1.52, 95% CI 0.979-2.358), stage III (HR 2.59, 95% CI 1.709-3.923), and stage IV (HR 3.51, 95% CI 2.124-5.784) versus stage I. Adding isatuximab led to longer progression-free survival versus doublet therapy (adjusted HR 0.544 [95% CI 0.436-0.680]), with a consistent treatment effect observed across all R2-ISS stages. This is the first study to validate the R2-ISS with novel agents, including anti-CD38 monoclonal antibodies, and to show that R2-ISS, as a prognostic scoring system, can be applied to patients with relapsed/refractory multiple myeloma.

Applied Cancer Research and Drug Discovery Translational Genomics Research Institute City of Hope Cancer Center Phoenix AZ USA

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

CHU Toulouse IUCT O Université de Toulouse UPS Service d'Hématologie Toulouse France

Department of Hematology Ankara University Ankara Turkey

Department of Medicine University of California San Francisco CA USA

Erasmus University Medical Center Cancer Institute Rotterdam The Netherlands

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

Hematology Department CHU Nantes Nantes France

Jerome Lipper Multiple Myeloma Center Department of Medical Oncology Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Sanofi Cambridge MA USA

Sanofi Chilly Mazarin France

Sanofi Tokyo Japan

Struttura Complessa Città della Salute e della Scienza di Torino Turin Italy

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