Incorporating isatuximab in the treatment of multiple myeloma

Isatuximab is a novel monoclonal antibody that binds selectively to CD38, which is widely expressed on plasma cells, and kills myeloma cells via multimodal mechanisms including antibody-dependent cellular cytoxicity, antibody-dependent cellular phagocytosis, complement-dependent cellular cytotoxicity, and immune cell depletion or inhibition of immunosuppressive cells, as has been described with daratumumab.6 Additionally, isatuximab, similar to other CD38 antibodies, modulates the NADase enzymatic activity of CD38.6 However, isatuximab differentiates itself from daratumumab in its ability to induce direct apoptosis without cross-linking, and in its binding epitope.7 Whether these differences result in improved clinical activity or can overcome resistance to other CD38 monoclonal antibodies is unknown. In phase 1/2 clinical trials, the addition of alkyaltors, proteosome inhibitors, and monoclonal antibodies to pomalidomide and dexamethasone have all shown improved clinical outcomes, with the proportion of patients achieving an overall response ranging from 48% to 86% and median progression-free survival ranging from 8·6 to 17·7 months.10 Thus, the results of ICARIA-MM compare favourably with studies of other pomalidomide-based triplet regimens; however, the advantage of combining isatuximab with pomalidomide rather than with other agents is not proven. The emerging use of daratumumab in first-line and second-line treatments will lead to a paradigm shift for the management of patients with relapsed and refractory multiple myeloma, increasing the pool of patients exposed or resistant to anti-CD38 therapy.