BCMA loss in the epoch of novel immunotherapy for multiple myeloma: from biology to clinical practice

Abstract

The treatment of multiple myeloma (MM) is evolving rapidly. In the past few years, chimeric antigen receptor modified T cells and bispecific antibodies are bringing new treatment options to patients with relapsed/refractory MM. Currently, B-cell maturation antigen (BCMA) has emerged as the most commonly used target of T-cell-based immunotherapies for relapsed/refractory MM. Clinical data have demonstrated promising efficacy and manageable safety profiles of both chimeric antigen receptor T-cell and bispecific antibody therapies in heavily pretreated relapsed/refractory MM. However, most patients suffer from relapses at later time points, and the mechanism of resistance remains largely unknown. Theoretically, loss of antigen is a potential tumor-intrinsic resistance mechanism against BCMA-targeted immunotherapies. Strategies to overcome this kind of drug resistance are, therefore, needed. In this review, we discuss the loss of BCMA in the new epoch of immunotherapy for MM.

Figure 1.

BCMA loss following targeted immunotherapies. (A) BCMA-directed immunotherapies. At present, anti-BCMA chimeric antigen receptor modified (CAR) T cells, bispecific antibodies, and antibody-drug conjugates are available for the treatment of relapsed/refractory multiple myeloma (MM). γ-secretase can shed BCMA from the membrane of MM cells and can subsequently release soluble BCMA into the blood stream. An increase of soluble BCMA level can lead to a decline of BCMA-binding capacity on MM cells. BCMA could be transferred to CAR T cells via trogocytosis, resulting in reversible partial BCMA loss. (B) Irreversible complete BCMA loss. In patients with irreversible complete BCMA loss, which is caused by homozygous BCMA gene deletion, other immunotargets could be considered for further treatments, e.g. CD38, FcRH5, GPRC5D, CD19, and SLAMF7. Multi-specific immunotherapies targeting more than one antigen seem to be a promising strategy to prevent drug resistance due to the loss of a single antigen. (C) Reversible partial BCMA loss. γ-secretase inhibition is one option to increase BCMA density on MM cells. When the BCMA expression level recovers at later time-points, anti-BCMA retreatment could be considered. ADC: antibody drug conjugate; BCMA: B-cell maturation antigen; BsAb; bispecific antibody; CAR T-cell; chimeric antigen receptor modified T cell; FcRH5: Fc receptor-homolog 5; GPRC5D; G protein coupled receptor class C group 5 member D; MM: multiple myeloma; RR: relapsed/refractory; sBCMA; soluble BCMA; SLAMF7: signaling lymphocytic activation molecule F7.