BCMA-targeted therapies for multiple myeloma part II: CAR T cells

Multiple B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR) T-cell therapies are currently under investigation for their application in relapsed/refractory multiple myeloma (MM). Here, we summarize the latest on BCMA-targeted CAR T-cell therapies, presenting their up-to-date clinical data.¹

In part I of this article series, we covered the latest updates on BCMA antibody-drug conjugates and BCMA-targeted bispecific antibodies which can be found here.

BCMA CAR T-cell therapy

CAR T-cells are autologous CD3+ T-cells that are engineered to contain an extracellular ligand binding domain. These domains are most commonly a single-chain variable fragment of a monoclonal antibody that recognizes tumor-associated antigens on malignant cells. Once activated, it initiates signaling through T-cell activation, the release of proinflammatory cytokines, and cytosis.²

Prior to reinfusion of the modified autologous T-cells, the patient undergoes lymphodepleting conditioning chemotherapy, usually with fludarabine and cyclophosphamide to decrease endogenous T-cells and increase levels of proliferative cytokines interleukin-7 and interleukin-15; thus, creating the most favorable environment for CAR T-cells to expand and action. Similar to bispecific antibodies, there is a risk of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, with rates of immune effector cell-associated neurotoxicity syndrome tending to be higher with CAR T-cells.²

Two autologous BCMA-targeting CAR T cells have been approved, and multiple are still in clinical development; these are summarized in Table 1.

Table 1. BCMA-targeted CAR T-cell therapy*

CAR T-cell therapy in combination and bispecific CAR T cells

Combinations of multiple CAR T-cell therapies and CAR T cells targeting multiple antigens are currently in development, with the most popular combination being BCMA and CD19. CD19 expression has been found on a small component of MM cells considered to be less differentiated, and as a result, they may lack usual markers such as BCMA.²

BM38 is a bispecific CAR T-cell therapy that targets BCMA and CD38 and is currently under evaluation in a phase I clinical trial.

Allogenic BCMA CAR T-cells

Allogenic CAR T-cell therapy has multiple advantages over autologous CAR T-cells, including its immediate availability, improved product standardization, redosing and combination treatments, and potential cost savings with a more scalable manufacturing process.² ALLO-715 is under investigation and a summary of the ongoing phase I trial (NCT04093596) can be found on the Multiple Myeloma Hub.

BCMA CAR natural killer cells

Natural killer (NK) cells are innate immune effector cells independent of antigens and human leukocyte antigen molecules that recognize abnormal cells through a combination of surface stimulatory and inhibitory receptors that target ligands on target cells. NK cells are being investigated as an alternative to T cells for CAR constructs. A significant advantage of this treatment strategy is the ability to transplant mature NK cells into a different host without loss of function or the occurrence of graft-versus-host disease. Several trials are currently investigating these agents.²

Conclusion

BCMA-directed therapies are highly efficacious; however, no agent has proven curative. Each class of agent has its own logistical challenges and unique safety profile. It is thought that T-cell stimulating agents used earlier in therapy may lead to more robust and durable responses, and several studies are currently considering the optimal sequencing of treatment, including trials of BCMA-targeted therapies in newly diagnosed patients with MM. Should a patient progress on a BCMA-targeting therapy, it is still unclear whether benefit could be derived from alternative BCMA-directed therapy. While further research is required to answer these questions, BCMA-directed therapies remain a critical and long-awaited addition to the treatment armamentarium of relapsed/refractory MM.