Targets for CAR Therapy in Multiple Myeloma

Abstract

Multiple myeloma (MM or plasma cell myeloma) is a heterogenous B-cell malignant tumor that typically exhibits a high recurrence rate, resistance to drugs, and molecular diversity of tumor subclones. Given the limited efficacy of standard therapy options, cellular immunotherapy featuring a chimeric antigen receptor (CAR) has proven tangible potential in treatment for relapsed and refractory forms of MM. The rational choice of a tumor target which shows high selectivity, stable expression, and biological significance is key to the successful implementation of CAR therapy. This review has summarized and analyzed data from the literature on biological properties, the features of expression, and the clinical development stages of CAR cell products for MM treatment which target BCMA, GPRC5D, FcRH5, SLAMF7, CD38, CD138, TACI, APRIL, CD19, TNFR2, CD44v6, CD70, NKG2D ligands, etc. Special focus is on strategic approaches to overcoming antigenic escape, such as multi-specific CAR constructs, logical activation sequences, and controlled safety systems. The analysis underscores the need for integrating the molecular selection of targets with cutting-edge bioengineering solutions as a key trend for raising the efficacy, stability, and safety of cellular therapy in the case of MM.

Keywords: CAR-NK; CAR-T; antigen escape; cellular therapy; immunotherapy; logical activation; multi-specific CAR; multiple myeloma; safety of therapy; tumor targets.

Figure 1

Targets in multiple myeloma and stages of immunotherapeutic development. This schematic presents targets investigated in CAR-T and CAR-NK cell therapies for MM, categorized by their clinical development stage. Green indicates validated membrane-bound targets with approved CAR-T products (e.g., BCMA). Orange corresponds to targets in Phase I–II trials; light orange to those in Phase I; light pink to targets at the preclinical/Phase I interface; and pink to preclinical-stage targets. The color of each target represents the most advanced development stage achieved for either CAR-T or CAR-NK platforms. Circular markers with “T” or “NK” next to each target indicate whether the target is being explored in CAR-T cells, CAR-NK cells, or both (dual-labeled if applicable), based on available clinical or preclinical evidence. All targets are membrane-bound surface proteins suitable for direct CAR recognition, except APRIL, which is labeled with a “CAR” circle to indicate that it is not a target, but a ligand incorporated into CAR-T constructs as a binding domain, enabling simultaneous of BCMA and TACI. NKG2D ligands (e.g., MICA, MICB, ULBP family) are stress-induced molecules transiently expressed on the tumor cell surface and are targeted using CAR constructs that incorporate the native NKG2D receptor. This figure illustrates the diversity of immunotherapeutic targets in MM and highlights the rationale for multi-target strategies to overcome tumor heterogeneity and antigen escape. Figure created in https://BioRender.com (accessed on 15 June 2025).