B Cell Maturation AntigenEdit
B cell maturation antigen (BCMA), encoded by the gene TNFRSF17, is a receptor in the tumor necrosis factor (TNF) receptor superfamily that sits on the surface of mature B cells and long-lived plasma cells. Its natural role is to help B cells mature and to sustain antibody-producing plasma cells through signaling initiated by the ligands BAFF (B cell activating factor) and APRIL (A Proliferation-Inducing Ligand). Because malignant plasma cells in diseases such as multiple myeloma often retain or elevate BCMA expression, BCMA has emerged as a leading target for modern immunotherapies. These approaches include chimeric antigen receptor (CAR) T cells, antibody-drug conjugates (ADCs), and bispecific antibodies that recruit a patient’s own T cells to attack BCMA-expressing cells. See, for example, TNFRSF17 and BAFF APRIL for background on the biology, and B cell and plasma cell for broader context on the cell lineages involved.
BCMA lies at the intersection of normal immune function and therapeutic opportunity. Its engagement by BAFF or APRIL activates intracellular signaling cascades that promote B cell survival and differentiation into antibody-secreting cells. In healthy individuals, this helps maintain humoral immunity, but in multiple myeloma, malignant plasma cells exploit BCMA signaling to persist and resist conventional therapies. The surface receptor can also be cleaved by proteolytic enzymes to release a soluble form, soluble BCMA (sBCMA), which can circulate in the blood and reflect disease burden in several plasma cell disorders. The soluble form can modulate signaling by acting as a decoy or by altering ligand availability.
Structure and function
BCMA is a single-pass transmembrane protein in the TNF receptor superfamily. Its extracellular region contains cysteine-rich domains that bind ligands in the TNF superfamily, notably BAFF and APRIL. Upon ligand binding, BCMA initiates signaling through adaptor molecules such as TRAF proteins, leading to activation of NF-κB pathways that promote cell survival and resistance to apoptosis. The cytoplasmic tail of BCMA is relatively short, but sufficient to recruit signaling complexes that sustain plasma cell longevity. In addition to membrane-bound BCMA, proteolytic shedding by gamma-secretase generates soluble BCMA (sBCMA), which can be detected in blood and has become a biomarker of disease activity in disorders like multiple myeloma.
Expression and biology
BCMA expression is highest on mature B cells that have differentiated into plasmablasts and long-lived plasma cells, and it is less prominent on naïve B cells. This restricted expression pattern makes BCMA an attractive therapeutic target: attacking BCMA tends to spare most other B cell functions, reducing broad immunosuppression while aiming at malignant plasma cells. However, some normal plasma cells and certain immune compartments can be affected by BCMA-directed therapies, contributing to risks such as hypogammaglobulinemia and infection. The presence of sBCMA in the circulation also has clinical utility as a dynamic biomarker, correlating with tumor burden in several contexts and offering a noninvasive readout of disease activity.
Clinical relevance and targets
The prominence of BCMA as a target in plasma cell dyscrasias is driven by the high and relatively uniform expression of BCMA on malignant plasma cells in many patients with multiple myeloma and related disorders. Therapeutic approaches include:
- CAR-T therapies directed at BCMA, such as idecabtagene vicleucel (idecabtagene vicleucel) and ciltacabtagene autoleucel (ciltacabtagene autoleucel), which reprogram patient T cells to recognize and kill BCMA-expressing cells. These products have shown meaningful efficacy in relapsed or refractory disease and illustrate the can-do potential of patient-specific cellular therapies.
- Antibody-drug conjugates like belantamab mafodotin (belantamab mafodotin) that deliver cytotoxic payloads to BCMA-expressing cells. These agents highlight how targeted cytotoxic delivery can extend disease control but also raise issues such as ocular toxicity and cost considerations.
- Bispecific T-cell engaging antibodies such as teclistamab (teclistamab), which recruit cytotoxic T cells to BCMA-expressing tumor cells, potentially enabling redirected immune responses without ex vivo cell manipulation.
- Other BCMA-targeting modalities, including additional bispecifics and investigational agents, continue to expand the therapeutic landscape and offer options across lines of therapy.
In clinical practice, these BCMA-directed approaches have redefined the treatment paradigm for many patients with relapsed or refractory disease, while ongoing studies explore their use in earlier lines of therapy, combinations with other agents, and strategies to overcome resistance.
Therapeutic targeting and challenges
The BCMA-centric treatment paradigm reflects a broader shift toward precision immunotherapy. Each modality—CAR-T, ADCs, and bispecific antibodies—has distinctive advantages and challenges:
- CAR-T therapy provides potent, durable responses for a subset of patients but requires specialized manufacturing, logistical coordination, and management of immune-related toxicities such as cytokine release syndrome and neurotoxicity.
- Antibody-drug conjugates offer off-the-shelf dosing and can be used without the need for cellular engineering, but safety concerns (e.g., ocular events with belantamab mafodotin) and ongoing access considerations remain important.
- Bispecific antibodies enable off-the-shelf, readily available treatment options with different administration schedules but may require continuous or repeated dosing and can carry risks of cytokine-related toxicities.
A recurring theme is the interplay between efficacy, safety, and real-world access. Biomarkers, including sBCMA, may aid in monitoring disease activity and guiding treatment decisions. In some cases, strategies such as gamma-secretase inhibition are explored to increase surface BCMA density and potentially improve the effectiveness of BCMA-targeted therapies, though these approaches add layers of complexity and risk that require careful evaluation.
From a policy and market perspective, the rapid development of BCMA-directed therapies has highlighted tensions around cost, pricing models, and patient access. Proponents of a market-driven system argue that strong intellectual property protections and competitive innovation foster breakthroughs, faster approvals, and better outcomes, while critics point to affordability and equitable access concerns. The debate commonly centers on how to align incentives for continued innovation with value-based pricing, coverage decisions, and risk-sharing arrangements that ensure patients can obtain effective therapies without unsustainable financial burdens. Critics of price controls argue that excessive price regulation could dampen investment in next-generation immunotherapies and slow overall progress, while proponents contend that high prices must be offset by demonstrable value and patient outcomes. These discussions are ongoing in many health systems and policy forums, reflecting a broader negotiation about how best to sustain biomedical innovation while delivering broad access to transformative treatments.
Controversies and debates also touch on safety and long-term outcomes. While BCMA-targeted therapies have delivered meaningful clinical benefit for many patients, concerns persist about durability of response, the potential for antigen loss or downregulation leading to relapse, and the management of immune-related adverse events. Balancing aggressive disease control with quality of life and long-term immune competence remains a central consideration in treatment planning and guideline development.