B-cell maturation antigen (BCMA) is a protein found on the surface of certain immune cells.
Normal Role of BCMA
BCMA is part of the tumor necrosis factor receptor superfamily, regulating the survival and proliferation of B cells. It is primarily expressed on mature B lymphocytes and plasma cells, immune cells that produce antibodies. BCMA is important for the long-term survival of plasma cells, which maintain humoral immunity through sustained antibody production.
BCMA interacts with specific ligands: B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL). When these ligands bind to BCMA, they activate signaling pathways within the cell, promoting cell survival and proliferation. This contributes to the healthy functioning of the immune system. Soluble forms of BCMA (sBCMA) can be shed from the cell surface into the bloodstream, and their levels can reflect plasma cell activity.
BCMA’s Involvement in Multiple Myeloma
BCMA is particularly significant in multiple myeloma, a cancer of plasma cells. Myeloma cells consistently express high levels of BCMA on their surface, a distinguishing feature observed in almost all patient samples. Increased BCMA expression correlates with disease severity and can indicate a poorer prognosis.
Continuous BCMA signaling in myeloma cells contributes to their survival and uncontrolled proliferation. When BAFF and APRIL bind to BCMA on these malignant cells, they activate pathways that prevent cell death and promote growth. This high and relatively specific expression of BCMA on malignant cells, with limited expression on most normal tissues, makes it an attractive therapeutic target.
Therapeutic Strategies Targeting BCMA
The high expression of BCMA on multiple myeloma cells has led to several targeted therapeutic approaches. These strategies aim to eliminate cancer cells while sparing healthy tissues.
CAR T-cell therapy
Chimeric antigen receptor (CAR) T-cell therapy involves genetically engineering a patient’s T cells to recognize and attack BCMA-expressing cancer cells. T cells are collected, modified in a laboratory to express a CAR that binds to BCMA, and then reinfused. These modified T cells identify and destroy multiple myeloma cells.
Idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti) are two FDA-approved BCMA-targeted CAR T-cell therapies that have demonstrated significant efficacy in patients with relapsed or refractory multiple myeloma. Idecabtagene vicleucel showed an overall response rate of 73% in its registration study. Ciltacabtagene autoleucel achieved a 98% overall response rate and 80% complete response rate.
Bispecific Antibodies
Bispecific antibodies are engineered proteins designed to simultaneously bind to BCMA on multiple myeloma cells and to CD3, a receptor found on T cells. This dual binding brings T cells into close proximity with tumor cells, facilitating their destruction.
Teclistamab and elranatamab are examples of BCMA-directed bispecific antibodies that have shown promising results in clinical trials. Teclistamab was the first bispecific antibody to receive approval, with studies showing response rates around 63%. Elranatamab, another BCMA-targeting bispecific antibody, achieved an overall response rate of 61% in its phase 2 study, with a complete response or better in 35.8% of patients. These agents typically involve step-up dosing schedules to manage potential toxicities.
Antibody-Drug Conjugates (ADCs)
Antibody-drug conjugates (ADCs) are another approach, delivering a potent cytotoxic drug directly to BCMA-expressing cancer cells. These therapies consist of an antibody that targets BCMA, a linker, and a chemotherapy drug payload. Belantamab mafodotin (Blenrep) is an FDA-approved ADC that targets BCMA.
The antibody part of belantamab mafodotin binds to BCMA on the cancer cell surface, and the entire conjugate is then internalized. Once inside the cell, the cytotoxic drug, monomethyl auristatin F (MMAF), is released, disrupting microtubule formation and inducing cell death. This targeted delivery minimizes exposure of the potent chemotherapy drug to healthy cells.
Future Directions in BCMA Research
Ongoing research continues to explore new avenues for BCMA-targeted therapies, aiming to enhance efficacy and overcome potential treatment resistance. Scientists are investigating novel BCMA-targeting modalities beyond the currently approved therapies, including different types of antibodies or cell-based approaches. The exploration of new designs for CAR T cells, such as dual-targeting strategies or allogeneic (off-the-shelf) CAR T cells from healthy donors, is also underway to improve accessibility and broaden treatment options.
Combination therapies are a significant area of focus, where BCMA-targeted agents are being studied alongside other anti-myeloma drugs to achieve more profound and durable responses. For example, combinations of bispecific antibodies with immunomodulatory drugs are being evaluated to enhance overall response rates. Efforts are also directed at understanding and mitigating potential side effects, such as cytokine release syndrome and neurotoxicity, to improve patient safety and treatment tolerability.