B cell maturation antigen (BCMA)

Tnf receptor superfamily member 17 (TNFRSF17), known as B-cell maturation antigen (BCMA), is a transmembrane receptor of the tumor necrosis factor receptor superfamily. Its expression is acquired late in B-cell differentiation, appearing on plasmablasts and long-lived plasma cells while being largely absent from naive and memory B cells and from non-hematopoietic tissue. Its ligands APRIL and BAFF deliver survival signals through NF-κB, sustaining the long-lived plasma cell compartment of the bone marrow — the reservoir responsible for durable antibody production.

That restricted distribution is what makes BCMA an unusually clean target. It is upregulated on malignant plasma cells in multiple myeloma, so directing therapy at it spares nearly everything except the plasma cell compartment itself. Three modalities are now established in relapsed and refractory disease: antibody-drug conjugates, bispecific T-cell engagers that bridge BCMA to CD3, and chimeric antigen receptor (CAR) T cells, the last producing deep and sometimes prolonged responses in patients who have exhausted other options. The shared toxicity follows directly from the target — loss of normal plasma cells causes hypogammaglobulinemia and infection risk — while the T-cell-redirecting approaches add cytokine release syndrome and neurotoxicity.

Two features complicate the picture, both traceable to the receptor's biology. Gamma-secretase cleaves BCMA from the cell surface, lowering the density of target available to a CAR or bispecific while releasing a soluble form (sBCMA) that circulates and can absorb the drug as a decoy; the same soluble protein is a useful pharmacodynamic and disease-monitoring biomarker, and gamma-secretase inhibitors are being combined with BCMA-directed agents to raise surface expression. Relapse frequently occurs with antigen loss, including biallelic deletion of TNFRSF17, which has prompted dual-targeting constructs directed at BCMA together with a second plasma cell antigen.