Longer-term outcomes with the anti-CD38 antibody isatuximab in combination with carfilzomib-dexamethasone (Isa-Kd) were evaluated in the randomized Phase 3 trial IKEMA (NCT03275285), in a prespecified, follow-up analysis of progression-free survival (PFS, primary study endpoint), final complete response (CR) using Hydrashift Isa immunofixation assay, minimal residual disease (MRD) negativity, and safety. Enrolled patients had relapsed/refractory multiple myeloma (1-3 prior treatment lines). Isa 10 mg/kg was administered intravenously weekly in cycle 1 then biweekly. Efficacy analyses were performed in the intent-to-treat population (Isa-Kd: n = 179, Kd: n = 123) and safety evaluated in treated patients (Isa-Kd: n = 177, Kd: n = 122). Consistent with the primary interim analysis, the addition of Isa to Kd prolonged PFS (HR 0.58, 95.4% CI: 0.42-0.79; median PFS 35.7 [95% CI: 25.8-44.0] vs 19.2 [95% CI: 15.8-25.0] months). PFS benefit was observed with Isa-Kd across subgroups, including patients with poor prognosis. The stringent CR/CR rate was 44.1% vs 28.5% (odds-ratio: 2.09, 95% CI: 1.26-3.48), the MRD negativity rate 33.5% vs 15.4% (odds-ratio: 2.78, 95% CI: 1.55-4.99) and the MRD negativity CR rate 26.3% vs 12.2%, with Isa-Kd vs Kd. The safety profile of Isa-Kd was similar to that reported in the prior interim analysis. These findings further support Isa-Kd as a standard-of-care treatment for relapsed multiple myeloma patients.Clinical trial information: ClinicalTrials.gov, NCT03275285.

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

Department of Haematology Lille University Hospital Lille France

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

Department of Hematology Seoul St Mary's Hospital The Catholic University of Korea Seoul South Korea

Department of Hematology University Hospital Hôtel Dieu Nantes France

Department of Hematology University of California at 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 São Paulo Brazil

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

Ividata Life Science Levallois Perret France

Myeloma Amyloidosis Center Japanese Red Cross Medical Center Tokyo Japan

Perth Blood Institute Murdoch University Perth 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 Cedex France

The National and Kapodistrian University of Athens Athens Greece

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

Blood Cancer J. 2023 Sep 27;13(1):152. doi: 10.1038/s41408-023-00923-6. PubMed

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Cowan AJ, Green DJ, Kwok M, Lee S, Coffey DG, Holmberg LA, et al. Diagnosis and management of multiple myeloma: a review. JAMA. 2022;327:464–77. doi: 10.1001/jama.2022.0003. PubMed DOI

Legarda MA, Cejalvo MJ, de la Rubia J. Recent advances in the treatment of patients with multiple myeloma. Cancers. 2020;12:3576. doi: 10.3390/cancers12123576. PubMed DOI PMC

Podar K, Leleu X. Relapsed/refractory multiple myeloma in 2020/2021 and beyond. Cancers. 2021;13:5154. doi: 10.3390/cancers13205154. PubMed DOI PMC

Cowan AJ, Allen C, Barac A, Basaleem H, Bensenor I, Curado MP, et al. Global burden of multiple myeloma: a systematic analysis for the global burden of disease study 2016. JAMA Oncol. 2018;4:1221–7. doi: 10.1001/jamaoncol.2018.2128. PubMed DOI PMC

Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hájek R, et al. ENDEAVOR Investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17:27–38. doi: 10.1016/S1470-2045(15)00464-7. PubMed DOI

Dimopoulos MA, Goldschmidt H, Niesvizky R, Joshua D, Chng WJ, Oriol A, et al. Carfilzomib or bortezomib in relapsed or refractory multiple myeloma (ENDEAVOR): an interim overall survival analysis of an open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18:1327–37. doi: 10.1016/S1470-2045(17)30578-8. PubMed DOI

Jayaweera SPE, Kanakanamge SPW, Rajalingam D, Silva GN. Carfilzomib: A promising proteasome inhibitor for the treatment of relapsed and refractory multiple myeloma. Front Oncol. 2021;11:740796. doi: 10.3389/fonc.2021.740796. PubMed DOI PMC

Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, et al. Therapeutic opportunities with pharmacological inhibition of CD38 with isatuximab. Cells. 2019;8:1522. doi: 10.3390/cells8121522. PubMed DOI PMC

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. doi: 10.1158/1078-0432.CCR-14-0695. PubMed DOI

Moreno L, Perez C, Zabaleta A, Manrique I, Alignani D, Ajona D, et al. The mechanism of action of the anti-CD38 monoclonal antibody isatuximab in multiple myeloma. Clin Cancer Res. 2019;25:3176–87. doi: 10.1158/1078-0432.CCR-18-1597. 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. doi: 10.3389/fimmu.2020.01771. PubMed DOI PMC

Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, 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): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394:2096–107. doi: 10.1016/S0140-6736(19)32556-5. PubMed DOI

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. doi: 10.1016/S1470-2045(22)00019-5. PubMed DOI

Dimopoulos M, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, 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;396:186–97. doi: 10.1016/S0140-6736(20)30734-0. PubMed DOI

Moreau P, Dimopoulos MA, Mikhael J, Yong K, Capra M, Facon T, et al. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): a multicentre, open-label, randomised phase 3 trial. Lancet. 2021;397:2361–71. doi: 10.1016/S0140-6736(21)00592-4. PubMed DOI

Sarclisa. Prescribing information. Sanofi; July 2022. https://products.sanofi.us/Sarclisa/sarclisa.pdf. Accessed 3 October 2022.

European Medicines Agency. Sarclisa, INN-Ixatuximab. Summary of product characteristics. 2021. https://www.ema.europa.eu/en/documents/product-information/sarclisa-epar-product-information_en.pdf. Accessed 3 October 2022.

SARCLISA® (isatuximab). Prescribing Information. Nishi Shinjuku, Tokyo, 2021. https://www.pmda.go.jp/PmdaSearch/iyakuDetail/ResultDataSetPDF/780069_4291454A1021_1_02. Accessed 3 October 2022.

Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15:e538–48. doi: 10.1016/S1470-2045(14)70442-5. PubMed DOI

Finn F, Macé S, Chu R, van de Velde H, Menad S, Melki M-T, et al. Development of a Hydrashift 2/4 isatuximab assay to mitigate interference with monoclonal protein detection on immunofixation electrophoresis in vitro diagnostic tests in multiple myeloma. Blood. 2020;136((Suppl.1):15.

Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17:e328–46. doi: 10.1016/S1470-2045(16)30206-6. PubMed DOI

Ching T, Duncan ME, Newman-Eerkes T, McWhorter MME, Tracy JM, Steen MS, et al. Analytical evaluation of the clonoSEQ assay for establishing measurable (minimal) residual disease in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and multiple myeloma. BMC Cancer. 2020;20:612. doi: 10.1186/s12885-020-07077-9. PubMed DOI PMC

Usmani SZ, Quach H, Mateos MV, Landgren O, Leleu X, Siegel D, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for patients with relapsed or refractory multiple myeloma (CANDOR): updated outcomes from a randomised, multicentre, open-label, phase 3 study. Lancet Oncol. 2022;23:65–76. doi: 10.1016/S1470-2045(21)00579-9. PubMed DOI

Landgren O, Weisel K, Rosinol Dachs L, Moreau P, Turgut M, Hajek R, et al. Evaluation of minimal residual disease (MRD) negativity in patients with relapsed or refractory multiple myeloma treated in the CANDOR study. Blood. 2020;136(Suppl. 1):32–4. doi: 10.1182/blood-2020-141291. DOI

Mateos MV, Sonneveld P, Hungria V, Nooka AK, Estell JA, Barreto W, 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;20:509–18. doi: 10.1016/j.clml.2019.09.623. PubMed DOI

Richardson PG, Oriol A, Beksac M, Liberati AM, Galli M, Schjesvold F, et al. OPTIMISMM trial investigators. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20:781–94. doi: 10.1016/S1470-2045(19)30152-4. PubMed DOI

Sonneveld P. Management of multiple myeloma in the relapsed/refractory patient. Hematol Am Soc Hematol Educ Program. 2017;2017:508–17. doi: 10.1182/asheducation-2017.1.508. PubMed DOI PMC

Mohty M, Avet-Loiseau H, Harousseau JL. Requirements for operational cure in multiple myeloma. Blood. 2021;138:1406–11. doi: 10.1182/blood.2021012854. PubMed DOI

Munshi NC, Avet-Loiseau H, Anderson KC, Neri P, Paiva B, Samur M, et al. A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma. Blood Adv. 2020;4:5988–99. doi: 10.1182/bloodadvances.2020002827. PubMed DOI PMC

Quach H, Parmar G, Ocio EM, Prince HM, Oriol A, Tsukada N, et al. Subcutaneous isatuximab administration by an on-body delivery system (OBDS) in combination with pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma: Phase 1b expansion study results. Blood. 2022;140(Suppl. 1):4412–4. doi: 10.1182/blood-2022-166840. DOI

Allocation and validation of the second revision of the International Staging System in the ICARIA-MM and IKEMA studies

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ClinicalTrials.gov
NCT03275285