Patient selection for CAR T or BiTE therapy in multiple myeloma: Which treatment for each patient?

Abstract

Multiple myeloma (MM) is a plasma cell malignancy that affects an increasing number of patients worldwide. Despite all the efforts to understand its pathogenesis and develop new treatment modalities, MM remains an incurable disease. Novel immunotherapies, such as CAR T cell therapy (CAR) and bispecific T cell engagers (BiTE), are intensively targeting different surface antigens, such as BMCA, SLAMF7 (CS1), GPRC5D, FCRH5 or CD38. However, stem cell transplantation is still indispensable in transplant-eligible patients. Studies suggest that the early use of immunotherapy may improve outcomes significantly. In this review, we summarize the currently available clinical literature on CAR and BiTE in MM. Furthermore, we will compare these two T cell-based immunotherapies and discuss potential therapeutic approaches to promote development of new clinical trials, using T cell-based immunotherapies, even as bridging therapies to a transplant.

Keywords: Adoptive cell therapy; BAT; BiTE; Bispecific T cell engager; Bispecific antibody; Bispecific antibody armed T cell; CAR T; Chimeric antigen receptor; Immunotherapy; Multiple myeloma; Stem cell transplantation.

Fig. 1

FDA-approved therapeutical options for MM and date of their first approval. PI—proteasome inhibitors, IMiDs—immunomodulatory drugs, HDACi—histone deacetylase inhibitors, mAbs—monoclonal antibodies, ADC—antibody–drug conjugates, SINEs—selective inhibitors of nuclear export, CAR—CAR T cell therapies, BiTE—bispecific T cell engagers

Fig. 2

A CARs structure. CD3zeta—stimulatory domain, 4-1BB—costimulatory domains; B receptor binding domains—scFv—single-chain variable fragments, F_ab—antigen-binding fragment, Nb—nanobody

Fig. 3

Bispecific antibody types. A IgG-like, formed by a crystallizable effector region and two variables, antigen-binding regions. IgG—immunoglobulin G, F_c—crystallizable region, F_ab—antigen-binding region, V_L—variable light chain, V_H—variable heavy chain, C_H—constant heavy chain; B BiTEs structure. scFv—single-chain variable fragments, Ab1—antibody 1, Ab2—antibody 2

Fig. 4

Surface antigens found on MM cells, studied in clinical trials. A CAR clinical trials; B BiTE clinical trials