Ex Vivo Efficacy of SAR442257 anti-CD38 Trispecific T Cell Engager in Multiple Myeloma Relapsed After Daratumumab and BCMA Targeted Therapies.

T cell engaging antibodies (TCEs) are showing promising efficacy in relapsed/refractory multiple myeloma (MM), even in patients that relapsed after BCMA targeted therapy. MM patients may have compromised T cell health unaccounted for by preclinical models. Here, we use Myeloma Drug Sensitivity Testing (My-DST) for ex vivo measurement of anti-MM cytotoxicity for the trispecific CD38/CD28xCD3 TCE SAR442257 through activation of the patients' own endogenous T cells to inform clinical development of the compound in MM. My-DST incubates primary mononuclear cells in humanized media for 48-hours followed by flow cytometry for MM cell viability with or without drug treatment. SAR442257 was tested on 34 samples from MM patients across disease settings. Potential biomarkers, T cell dependence, and degranulation were assessed. SAR442257 was effective at low dose in My-DST cultures. High ex vivo response rates were observed in primary aspirates taken from MM patients at diagnosis, with modestly reduced response in MM recently treated with anti-CD38 monoclonal antibodies (mAbs). SAR442257 was highly effective in patients relapsing after BCMA therapy. The CD38/CD28xCD3 trispecific format was substantially more effective than a conventional bispecific CD38/CD3 antibody format and CD38 mAbs. Anti-MM cell cytotoxicity was dependent on the presence of endogenous T cells. Surface CD38 expression was the strongest biomarker of TCE response. My-DST is capable of measuring T cell-dependent killing using the MM patient's own bone-marrow derived T cells. SAR442257 shows promise for MM and may be best suited for patients declared resistant to both CD38 mAbs and BCMA targeted therapy.