Cellular therapy for multiple myeloma: what's now and what's next

Abstract

Despite significant improvement in the treatment of multiple myeloma (MM), a cure remains elusive, and patients failing proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies remain a challenge due to a lack of standard of care treatment and a dismal survival rate. The development of T-cell redirecting therapies, including bispecific T-cell engagers and chimeric antigen receptor (CAR) T cells, have transformed the outcome of triple-class exposed relapsed and refractory MM (RRMM). B-cell maturation antigen (BCMA) has proven to be an important target in MM, and BCMA-directed CAR T cells have shown unprecedented efficacy with a prolonged duration of response in a population with advanced RRMM, leading to the approval of 2 different BCMA CAR T-cell products. Still, and in contrast to prior experience in the field of CD19-directed CARs, no plateau has been seen in the survival curves, and relapses continue to occur. Therefore, further improvement is needed. Early use in the course of the disease as well as of next- generation CARs may further augment the efficacy of these therapies. In this review we address current state-of-the-art approved BCMA-directed CAR T-cell therapy in RRMM, as well as potential future developments focused on optimizing patient care and novel CAR designs.

Graphical abstract

Figure 1.

Several strategies are being evaluated to improve the current clinical efficacy of CAR T-cell therapy in the context of RRMM. These strategies can be divided into patient-related factors, aspects related to the manufacturing process and CAR design, patient management during bridging time and infusion, and finally, understanding the mechanisms of resistance and CAR failure. CCR, chimeric costimulatory receptor; EMD, extramedullary disease; HR-CA, high-risk cytogenetic abnormalities.

Figure 2.

Possibilities for the future development of CAR T-cell therapy. Depicted are some of the novel new-generation CAR T constructs, including third-generation CARs incorporating 2 different costimulatory domains; fourth-generation CARs (also named “armored” CARs) incorporating transducible genes codifying for cytokines, antibodies, or receptors (among others); and novel target (non-BCMA) and dual targeting strategies, including tandem CAR and dual CAR.