Impact of soluble BCMA and non-T-cell factors on refractoriness to BCMA-targeting T-cell engagers in multiple myeloma

• Soluble BCMA, surface antigen density, effector to target ratio, and TCE dose collectively mediate primary refractoriness to anti-BCMA TCE.

• Strategies to reduce soluble BCMA shedding or enhancing effector to target ratio circumvent primary refractories to anti-BCMA TCE.

Adoptive T cell therapy is a promising therapy for multiple myeloma (MM), but its efficacy hinges on understanding relevant biological and predictive markers of response. B cell maturation antigen (BCMA) is a key target antigen in MM, with active development of multiple anti-BCMA T cell engagers (TCE) and chimeric antigen receptor T cell (CAR T) therapies. The regulation of surface BCMA expression by MM cells, resulting in the shedding of soluble BCMA (sBCMA), has triggered debate surrounding the significance of sBCMA as a predictive marker and its potential impact on treatment outcomes. In order to address this, we leveraged whole genome sequencing and in vitro assays to demonstrate that sBCMA may independently predict primary refractoriness to anti-BCMA therapies. In addition to sBCMA, tumor burden and surface BCMA antigen density collectively influence anti-BCMA TCE cytotoxic efficacy. Correlative analyses of 163 patients treated with anti-BCMA TCE teclistamab validated and further underscored the association between elevated baseline sBCMA (>400 ng/mL) and refractoriness. Importantly, increasing TCE dose, the use of TCE against alternative targets (e.g.,GPRC5D), or gamma secretase inhibitors were able to overcome high sBCMA. These findings highlight the importance of accounting for baseline sBCMA levels, disease burden, and TCE dose intensity when administering anti-BCMA TCEs, offering critical insights for optimizing therapeutic strategies to overcome specific high-risk features and primary anti-BCMA TCE refractoriness.