Schematic summary of the determinants of anti-BCMA TCE therapeutic response. (A) Anti-BCMA TCE cytotoxicity is dependent on the ratio of T-cell engagement per mBCMA molecules that is factorized by the combinatorial effect of sBCMA, mBCMA, E:T ratio, and TCE dosing. The figure is a representative schematic of the results of the experimental study in Figure 3H. Inset numbers in the circle (MM cell) represent the relative the degree of T-cell–mediated cytotoxicity, ranging from low (1×) to high (5×). (B) Summary of the determinants of anti-BCMA TCE therapeutic response. The collective effect of elevated sBCMA levels, reduced mBCMA expression, and high tumor burden (low E:T) attenuates anti-BCMA TCE efficacy and leads to primary refractory MM. Tumor sensitivity to anti-BCMA TCEs may be restored by the use of GSIs, reducing tumor bulk by other anti-MM agents or non-BCMA-targeting TCE or CAR T therapy, and by enhancing T-cell activity through immunomodulatory drugs. TCEs that target other antigens, such as GPRC5D, can also overcome the effect of high sBCMA, but not that of a high tumor burden. Acquired resistance to anti-BCMA TCE is caused by selective clonal expansion of BCMA antigen escape clones that have biallelic deletions of TNFRSF17 or mutations in the ECD of BCMA. Figure created with BioRender.com.