Multiple myeloma is a cancer that originates in plasma cells, a type of white blood cell found in the bone marrow. These abnormal plasma cells, known as myeloma cells, can accumulate and interfere with the production of normal blood cells, leading to various health complications. In recent years, significant progress has been made in developing new, targeted therapies that aim to treat this blood cancer. Among these treatments, therapies that target a protein called B-cell maturation antigen, or BCMA, have shown considerable promise.
BCMA’s Role in Multiple Myeloma
BCMA, or B-cell maturation antigen, is a protein primarily found on the surface of plasma cells, including the cancerous plasma cells in multiple myeloma. In healthy individuals, BCMA plays a role in the survival and maturation of normal plasma cells, which are responsible for producing antibodies that fight infections. BCMA binds to specific growth factors like BAFF (B-cell activating factor) and APRIL (a proliferation-inducing ligand), helping these cells to survive and function correctly. BCMA’s high and consistent expression on myeloma cells makes it a compelling target for therapies. Its elevated expression on cancerous cells, combined with minimal expression on other healthy tissues, allows therapies to selectively attack cancer cells while sparing most healthy cells.
Targeting BCMA with Advanced Therapies
Targeting BCMA represents an advancement in treating multiple myeloma by harnessing the body’s immune system. This approach falls under the umbrella of immunotherapy, which aims to empower or redirect immune cells to recognize and destroy cancer cells. BCMA-targeted therapies involve creating therapeutic agents that specifically bind to the BCMA protein on myeloma cells. These advanced therapies operate on different principles, each designed to eliminate myeloma cells by engaging the immune system or delivering a toxic payload directly to the cancer. The three main categories of BCMA-targeted therapies include CAR T-cell therapy, bispecific antibodies, and antibody-drug conjugates.
Specific BCMA-Targeted Treatment Approaches
Chimeric Antigen Receptor (CAR) T-cell therapy involves genetically modifying a patient’s own T-cells. T-cells are collected from the patient, then engineered in a laboratory to express a Chimeric Antigen Receptor (CAR) on their surface. This CAR is designed to recognize and bind to the BCMA protein on myeloma cells. After engineering, these CAR T-cells are expanded and reinfused into the patient, where they seek out and destroy BCMA-expressing cancer cells.
Several BCMA-targeted CAR T-cell therapies have received regulatory approval for treating relapsed or refractory multiple myeloma. Idecabtagene vicleucel (Abecma) was approved, targeting BCMA for patients who have received multiple prior lines of therapy. Another approved CAR T-cell therapy is ciltacabtagene autoleucel (Carvykti), which has shown responses in patients with previously treated multiple myeloma.
Bispecific antibodies represent another class of BCMA-targeted therapies. These antibodies have two “arms”: one binds to the BCMA protein on myeloma cells, and the other binds to CD3, a protein found on a patient’s T-cells. By simultaneously binding to both the myeloma cell and the T-cell, the bispecific antibody effectively brings the T-cell into close proximity with the cancer cell. This direct connection activates the T-cell, prompting it to recognize and kill the myeloma cell.
Approved examples of BCMA-targeted bispecific antibodies include teclistamab (Tecvayli) and elranatamab (Elrexfio). Both are approved for treating adults with relapsed or refractory multiple myeloma who have received several previous treatments. These therapies provide a ready-to-use option that does not require the extensive cell collection and manufacturing process associated with CAR T-cell therapies.
Antibody-drug conjugates (ADCs) combine a monoclonal antibody that specifically recognizes BCMA with a potent chemotherapy drug, linked by a stable chemical bond, offering a different mechanism to target BCMA. Once infused, the antibody component selectively binds to BCMA on the surface of myeloma cells, facilitating internalization into the cancer cell. Inside the myeloma cell, the chemotherapy drug is released, delivering a concentrated dose directly to the cancer cell. This targeted delivery minimizes exposure of healthy tissues to the chemotherapy, potentially reducing systemic side effects. Belantamab mafodotin (Blenrep) is an example of an approved BCMA-targeted ADC, used in patients with relapsed or refractory multiple myeloma who have received other treatment options.
Patient Outcomes and Considerations
BCMA-targeted therapies have improved outcomes for patients with relapsed or refractory multiple myeloma. These therapies often lead to deep and durable responses, meaning a substantial reduction in cancer cells that can be sustained over time. They are used for patients who have received several prior lines of therapy and whose disease has progressed or returned.
These advanced treatments have specific side effects that require careful management. For CAR T-cell therapies and bispecific antibodies, common side effects include cytokine release syndrome (CRS) and neurotoxicity. CRS can cause fever, low blood pressure, and breathing difficulties, resulting from a widespread immune response. Neurotoxicity can manifest as confusion, tremors, or seizures.
Antibody-drug conjugates like belantamab mafodotin have a distinct side effect profile, including ocular toxicity, which affects vision. Regular eye exams and careful monitoring are necessary during treatment. Patient selection for these therapies considers factors such as overall health status, kidney and liver function, and the patient’s ability to tolerate potential side effects. A multidisciplinary team of specialists, including oncologists, neurologists, and ophthalmologists, often collaborates to provide comprehensive care and manage any treatment-related complications. These therapies represent progress in treating multiple myeloma, offering new options for patients.