Multiple myeloma is a cancer of the plasma cells, a type of white blood cell found in the bone marrow that normally produces antibodies to fight infection. In multiple myeloma, these plasma cells become abnormal, multiplying excessively and producing dysfunctional antibodies (M-proteins). CAR T-cell therapy represents a significant advancement in treating this disease, particularly for patients whose condition has relapsed or become resistant to other treatments.
CAR T-cell therapy involves collecting a patient’s own T-cells, a different type of immune cell, and genetically modifying them in a laboratory. These modified T-cells are engineered to express a Chimeric Antigen Receptor (CAR), which enables them to specifically recognize and target proteins, such as B-cell maturation antigen (BCMA), found on the surface of myeloma cells. Once reinfused into the patient, these CAR T-cells act as a “living drug,” multiplying and actively seeking out and destroying cancer cells. While CAR T-cell therapy has shown remarkable efficacy, some patients experience disease progression or relapse, meaning the cancer returns or does not achieve lasting remission.
Understanding Treatment Failure
Despite promising outcomes, multiple myeloma can recur after CAR T-cell therapy due to several biological and clinical factors. One reason is antigen escape, where myeloma cells reduce or stop expressing target proteins like BCMA, making them invisible to CAR T-cells. This allows cancer cells to evade detection and grow.
Another factor contributing to therapy failure is T-cell exhaustion or dysfunction. After prolonged exposure to cancer cells, CAR T-cells can become less effective, losing their ability to multiply and kill tumor cells. The suppressive tumor microenvironment, which includes various cells and molecules surrounding the cancer, can also inhibit the activity of CAR T-cells. This environment can release factors that dampen the immune response, protecting myeloma cells from the engineered T-cells.
Disease heterogeneity, where different myeloma cells within the same patient have varying characteristics, also plays a role. While some cells might be susceptible to CAR T-cell therapy, others may possess intrinsic resistance mechanisms from the outset. These resistant cells can then proliferate and lead to relapse.
Detecting Disease Relapse
When multiple myeloma recurs after CAR T-cell therapy, relapse is identified through a combination of diagnostic methods. Blood tests are regularly performed to monitor levels of M-protein, an abnormal antibody produced by myeloma cells. A sustained increase in M-protein levels, often identified as an “M-spike” on serum protein electrophoresis, indicates disease progression.
Monitoring free light chain levels in the blood is also important, especially for patients whose myeloma primarily produces these smaller antibody fragments. An increased ratio of involved to uninvolved free light chains can signal relapse. Bone marrow biopsies examine the percentage of plasma cells, providing direct evidence of myeloma cell proliferation. Imaging scans, such as PET/CT and MRI, help identify new or worsening bone lesions and other sites of disease activity.
In addition to laboratory and imaging tests, clinical signs and symptoms can indicate relapse. These may include bone pain, fatigue, anemia, or kidney dysfunction, which are common manifestations of multiple myeloma. Regular follow-up appointments allow healthcare providers to assess these symptoms alongside objective test results to confirm disease progression and initiate subsequent treatment.
Subsequent Treatment Approaches
For patients whose multiple myeloma relapses after CAR T-cell therapy, subsequent treatment approaches are tailored to individual circumstances. These include various drug classes and other therapeutic options.
Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are often used, sometimes with corticosteroids like dexamethasone. These drugs modulate the immune system and directly affect myeloma cells.
Proteasome inhibitors (PIs), including bortezomib, carfilzomib, and ixazomib, block the proteasome, a cellular complex that processes proteins. This leads to a buildup of toxic proteins within myeloma cells and their eventual death. PIs are frequently combined with other drugs to enhance effectiveness.
Monoclonal antibodies (mAbs) target specific proteins on myeloma cells, flagging them for destruction. Examples include daratumumab and isatuximab (targeting CD38), and elotuzumab (targeting SLAMF7). Bispecific antibodies are newer agents that simultaneously bind to a myeloma cell and a T-cell, bringing the T-cell closer to facilitate its destruction. Teclistamab and elranatamab, for example, target BCMA and GPRC5D.
Chemotherapy may also be considered, sometimes with other agents, to directly kill cancer cells. For select patients, a second autologous stem cell transplant might be an option, particularly if initial remission after the first transplant was prolonged. Participation in clinical trials offers access to novel therapies still under investigation.
Living with Relapsed Multiple Myeloma
Living with relapsed multiple myeloma after CAR T-cell therapy involves managing symptoms, maintaining quality of life, and providing psychological support. Supportive care addresses common symptoms like pain from bone lesions and fatigue from the disease or its treatments. Pain management strategies include medications, radiation therapy, or other interventional procedures.
Managing bone health is important, as multiple myeloma often affects the skeletal system. This involves medications to strengthen bones and prevent fractures. Patients benefit from a multidisciplinary care team, including oncologists, pain specialists, physical therapists, and dietitians, who provide holistic care and coordinate treatments.
Psychological and emotional support are essential, as cancer relapse can be distressing. Counseling, support groups, or palliative care services help patients and their families cope and maintain well-being. Regular communication with the healthcare team about new or worsening symptoms and emotional concerns ensures care plans adapt to evolving needs.