Multiple myeloma (MM) is an incurable plasma cell cancer characterized by relapse and remission. Chimeric Antigen Receptor (CAR) T-cell therapy is a late-line treatment for relapsed or refractory MM, offering the potential for deep and durable responses. This therapy genetically engineers a patient’s T-cells to target a specific protein, most commonly B-cell maturation antigen (BCMA), found on myeloma cells. While initial success rates are high, many patients eventually experience disease progression. Understanding the resistance mechanisms is necessary for planning subsequent treatment.
How CAR T Failure is Defined
CAR T-cell therapy failure is categorized into two clinical scenarios based on the patient’s response. Primary resistance, or non-response, occurs when the disease shows no meaningful reduction or progresses immediately after the infusion. This indicates a pre-existing resistance mechanism, as the myeloma cells were never effectively cleared.
Acquired resistance, or relapse, is the more common scenario. This occurs after a patient initially achieves a successful response, such as a remission, but the disease returns after a period of control. Most treatment failures occur within six months of the initial therapy. Measurable Residual Disease (MRD) status is a sensitive metric used to define relapse. Sustained MRD negativity, where no myeloma cells are detectable at a sensitivity of one cell in 100,000, is associated with prolonged progression-free survival. The conversion from MRD-negative to MRD-positive serves as an early indicator of impending treatment failure.
Biological Mechanisms of Resistance
Resistance involves complex interactions between myeloma cells, T-cells, and the bone marrow environment. A common tumor mechanism is antigen escape, where myeloma cells lose or downregulate the target protein, BCMA, that CAR T-cells recognize. This loss can occur through genetic changes or by shedding BCMA into the bloodstream, hiding the target from the T-cells.
Issues related to the CAR T-cells themselves also contribute to failure. The engineered T-cells may exhibit poor persistence, meaning they do not survive long enough to maintain disease clearance. This lack of durability is often compounded by T-cell exhaustion, a state of dysfunction caused by prolonged exposure to tumor antigens or the immunosuppressive environment.
The tumor microenvironment (TME) within the bone marrow suppresses T-cell function. The TME contains immunosuppressive cell types, such as regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs), which inhibit CAR T-cell activation and proliferation. The presence of extramedullary disease (myeloma tumors outside the bone marrow) is also associated with a higher risk of resistance and relapse.
Subsequent Treatment Pathways
When CAR T-cell therapy fails, the goal is to establish a new salvage therapy using a different mechanism of action. A successful strategy involves switching to other T-cell engaging immunotherapies, such as Bispecific T-cell Engagers (BiTEs). BiTEs act as a bridge between a T-cell and a myeloma cell to facilitate tumor killing.
While approved BCMA-targeting BiTEs have shown activity, targeting a new, non-BCMA protein is often more effective. For example, talquetamab targets GPRC5D, which is highly expressed on myeloma cells, and has demonstrated favorable response rates after BCMA-targeted CAR T-cell failure. Switching the target antigen helps overcome BCMA-loss escape mechanisms.
Established anti-myeloma agents are also frequently used for re-induction. These include combination chemotherapy, proteasome inhibitors (PIs), and immunomodulatory drugs (IMiDs). Prior CAR T-cell therapy can sometimes re-sensitize myeloma cells to these older drug classes. Combination regimens, often including an anti-CD38 monoclonal antibody, are a standard salvage approach. Another pathway involves re-treatment with a cellular product. A second infusion of a CAR T-cell therapy, especially one that is structurally different or targets a second antigen, can be feasible and induce durable responses in some patients. The decision for re-treatment depends on the patient’s overall health and the specific mechanism driving the relapse.
Emerging Therapies and Clinical Trials
Myeloma research is investigating next-generation therapies designed to overcome resistance after CAR T-cell failure. New CAR T-cell products utilize dual-targeting or multi-targeting strategies to engage two or more antigens simultaneously, such as BCMA and GPRC5D. This approach aims to prevent antigen escape by requiring the myeloma cell to lose multiple targets. Clinical trials are also focusing on combination regimens to enhance CAR T-cell function and persistence.
Combination Strategies
Combining CAR T-cell infusion with a gamma-secretase inhibitor is being explored, as this drug class can increase BCMA surface expression on myeloma cells, boosting the target. Immune-checkpoint inhibitors are also under investigation to counteract T-cell exhaustion by blocking inhibitory signals in the bone marrow microenvironment.
Novel Cellular Therapies
Novel cellular therapies, including allogeneic or “off-the-shelf” CAR T-cells derived from healthy donors, are being tested post-CAR T failure. These products offer rapid availability compared to the personalized manufacturing process of autologous CAR T-cells. These experimental approaches, accessed through clinical trials, represent the future direction of treatment.