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

Zobrazit více v PubMed

Greipp PR, San Miguel J, Durie BGM, Crowley JJ, Barlogie B, Bladé J, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23:3412–20. PubMed DOI

Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. Revised International Staging System for multiple myeloma: A report from International Myeloma Working Group. J Clin Oncol. 2015;33:2863–9. PubMed DOI PMC

Tandon N, Rajkumar SV, LaPlant B, Pettinger A, Lacy MQ, Dispenzieri A, et al. Clinical utility of the Revised International Staging System in unselected patients with newly diagnosed and relapsed multiple myeloma. Blood Cancer J. 2017;7:e528. PubMed DOI PMC

Schavgoulidze A, Lauwers-Cances V, Perrot A, Cazaubiel T, Chretien ML, Moreau P, et al. Heterogeneity in long-term outcomes for patients with Revised International Staging System stage II, newly diagnosed multiple myeloma. Haematologica. 2023;108:1374–84. PubMed DOI PMC

D’Agostino M, Cairns DA, Lahuerta JJ, Wester R, Bertsch U, Waage A, et al. Second Revision of the International Staging System (R2-ISS) for overall survival in multiple myeloma: A European Myeloma Network (EMN) report within the HARMONY project. J Clin Oncol. 2022;40:3406–18. PubMed DOI

Shah V, Sherborne AL, Walker BA, Johnson DC, Boyle EM, Ellis S, et al. Prediction of outcome in newly diagnosed myeloma: a meta-analysis of the molecular profiles of 1905 trial patients. Leukemia. 2018;32:102–10. PubMed DOI PMC

Weinhold N, Salwender HJ, Cairns DA, Raab MS, Waldron G, Blau IW, et al. Chromosome 1q21 abnormalities refine outcome prediction in patients with multiple myeloma - a meta-analysis of 2,596 trial patients. Haematologica. 2021;106:2754–58. PubMed DOI PMC

Goldman-Mazur S, Jurczyszyn A, Castillo JJ, Waszczuk-Gajda A, Grząśko N, Radocha J, et al. A multicenter retrospective study of 223 patients with t(14;16) in multiple myeloma. Am J Hematol. 2020;95:503–09. PubMed DOI

Mina R, Joseph NS, Gay F, Kastritis E, Petrucci MT, Kaufman JL, et al. Clinical features and survival of multiple myeloma patients harboring t(14;16) in the era of novel agents. Blood Cancer J. 2020;10:40. PubMed DOI PMC

Grzasko N, Hus M, Pluta A, Jurczyszyn A, Walter-Croneck A, Morawska M, et al. Additional genetic abnormalities significantly worsen poor prognosis associated with 1q21 amplification in multiple myeloma patients. Hematol Oncol. 2013;31:41–8. PubMed DOI

Deckert J, Wetzel MC, Bartle LM, Skaletskaya A, Goldmacher VS, Vallée F, et al. SAR650984, a novel humanized CD38-targeting antibody, demonstrates potent antitumor activity in models of multiple myeloma and other CD38+ hematologic malignancies. Clin Cancer Res. 2014;20:4574–83. PubMed DOI

Martin TG, Corzo K, Chiron M, van de Velde H, Abbadessa G, Campana F, et al. Therapeutic opportunities with pharmacological inhibition of CD38 with isatuximab. Cells. 2019;8:1522. PubMed DOI PMC

van de Donk NWCJ, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. Blood. 2018;131:13–29. PubMed DOI

Zhu C, Song Z, Wang A, Srinivasan S, Yang G, Greco R, et al. Isatuximab acts through Fc-dependent, independent, and direct pathways to kill multiple myeloma cells. Front Immunol. 2020;11:1771. PubMed DOI PMC

Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, et al. ICARIA-MM study group. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394:2096–107. PubMed DOI

Sarclisa® (isatuximab-irfc). Bridgewater, NJ: Sanofi-Aventis U.S. LLC. 2022. https://products.sanofi.us/Sarclisa/sarclisa.pdf. Accessed February 8, 2023.

European Medicines Agency (EMA). Medicines. Sarclisa. 2023. https://www.ema.europa.eu/en/medicines/human/EPAR/sarclisa. Accessed February 8, 2023.

Pharmaceuticals and Medical Devices Agency. Sarclisa. 2020. https://www.pmda.go.jp/files/000242148.pdf. Accessed March 14, 2023.

Richardson PG, Perrot A, San-Miguel J, Beksac M, Spicka I, Leleu X, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): follow-up analysis of a randomised, phase 3 study. Lancet Oncol. 2022;23:416–27. PubMed DOI

Moreau P, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, et al. IKEMA study group. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397:2361–71. PubMed DOI

Martin T, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, et al. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: updated results from IKEMA, a randomized Phase 3 study. Blood Cancer J. 2023;13:72. PubMed DOI PMC

Yong K, Martin T, Dimopoulos MA, Mikhael J, Capra M, Facon T, et al. Isatuximab plus carfilzomib-dexamethasone versus carfilzomib-dexamethasone in patients with relapsed multiple myeloma (IKEMA): overall survival analysis of a phase 3, randomised, controlled trial. Lancet Haematol. 2024;11:e741–e750. PubMed DOI

Richardson PG, Attal M, Campana F, Le-Guennec S, Hui AM, Risse ML, et al. Isatuximab plus pomalidomide/dexamethasone versus pomalidomide/dexamethasone in relapsed/refractory multiple myeloma: ICARIA Phase III study design. Future Oncol. 2018;14:1035–47. PubMed DOI

Moreau P, Dimopoulos MA, Yong K, Mikhael J, Risse ML, Asset G, et al. Isatuximab plus carfilzomib/dexamethasone versus carfilzomib/dexamethasone in patients with relapsed/refractory multiple myeloma: IKEMA Phase III study design. Future Oncol. 2020;16:4347–58. PubMed DOI

Facon T, Moreau P, Baker R, Pour L, Min CK, Leleu X, et al. Isatuximab plus carfilzomib and dexamethasone in patients with early versus late relapsed multiple myeloma: IKEMA subgroup analysis. Blood. 2022;140:1820–22. PubMed DOI PMC

Terpos E, Caers J, Gamberi B, Heibl S, Sohne M, Suzan F, et al. Response to carfilzomib regimens among patients with early or late relapse following prior multiple myeloma therapy: a subgroup analysis from a prospective observational study across Europe and Israel. Poster presented at: European Hematology Association Congress 2020; Virtual. Accessed February 23, 2023.

Weisel K, Geils GF, Karlin L, Mollee P, Chung T-H, Min CK, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in relapsed or refractory multiple myeloma: subgroup analysis of the Phase 3 CANDOR study in patients with early or late relapse. Blood. 2020;136:37–8. DOI

Tan JLC, Wellard C, Moore EM, Mollee P, Rajagopal R, Quach H, et al. The second revision of the International Staging System (R2-ISS) stratifies progression-free and overall survival in multiple myeloma: Real world data results in an Australian and New Zealand Population. Br J Haematol. 2023;200:e17–21. PubMed DOI

Richardson PG, San Miguel JF, Moreau P, Hajek R, Dimopoulos MA, Laubach JP, et al. Interpreting clinical trial data in multiple myeloma: translating findings to the real-world setting. Blood Cancer J. 2018;8:109. PubMed DOI PMC