BCMA biology and therapeutic targeting in multiple myeloma: From ligand signaling to antigen escape.

B-cell maturation antigen (BCMA; TNFRSF17) has rapidly evolved from a plasma cell survival receptor within the BAFF/APRIL network to a central therapeutic hub in multiple myeloma (MM). In this review, we first outline the gene organization, expression pattern, and ligand biology of BCMA in the context of its sister receptors BAFF-R and TACI, emphasizing shared structural motifs-such as the conserved helix-loop-helix hairpin and DxL motif-that govern APRIL/BAFF recognition. We next detail how BCMA-proximal signaling through TRAF adaptors integrates canonical and noncanonical NF-κB, MAPK, and PI3K-AKT pathways to sustain long-lived plasma cells and drive myeloma progression, and how γ-secretase-mediated shedding generates soluble BCMA (sBCMA), which function as both a dynamic disease biomarker and an antigen sink for BCMA-directed agents. We then summarize the clinical development and distinguishing features of currently approved BCMA-targeted modalities-CAR T-cell therapies (ide-cel, cilta-cel), bispecific T-cell engagers (teclistamab, elranatamab, linvoseltamab), and the antibody-drug conjugate (belantamab mafodotin)-highlighting their efficacy, toxicity profiles, and practical positioning in relapsed/refractory MM. Finally, we review emerging resistance mechanisms, including γ-secretase-driven sBCMA elevation, ligand-rich APRIL/BAFF niches, and therapy-induced TNFRSF17 lesions, ranging from biallelic deletions to epitope-altering missense mutations and in-frame deletions within the BCMA extracellular domain. These insights inform rational strategies such as γ-secretase inhibition, dual-target CAR T-cells and bispecific T-cell engagers.