Dual-antigen-targeting T-cell immunotherapies in MM: circumventing tumor heterogeneity and preventing antigen escape

B-cell maturation antigen (BCMA)- or G protein-coupled receptor class C group 5 member D (GPRC5D)-directed T-cell immunotherapies have substantially improved the survival of patients with relapsed/refractory multiple myeloma (MM). Despite these advances, a subset of patients does not respond, and most patients will eventually relapse. Tumor heterogeneity, resulting in rapid selection of both antigen-negative and antigen-low cells, is a critical issue affecting response to T-cell immunotherapies targeting single tumor-associated antigens. In addition, antigen escape (due to deletions, mutations, or epigenetic alterations) is frequently observed in patients who experience disease progression after chimeric antigen receptor (CAR) T-cell infusion or during bispecific antibody (BsAb) treatment. Simultaneous targeting of 2 tumor-associated antigens may improve efficacy by addressing heterogeneous target expression and preventing antigen escape. Various dual-targeting strategies are currently evaluated in MM, including the combination of 2 single-antigen-targeting BsAbs. Of note, the efficacy of the combination of teclistamab and talquetamab appears to have enhanced anti-MM activity, compared with the corresponding conventional BsAbs alone in similar patient populations. Furthermore, dual-antigen targeting with T-cell-redirecting trispecific antibodies (eg, ramantamig [BCMA×GPRC5D] and ISB 2001 [BCMA×CD38]) has already demonstrated promising results in heavily pretreated MM. Studies with limited numbers of patients have demonstrated that CAR T-cell products with specificity for >1 antigen are also effective in advanced MM; however, at this time, none of the dual-targeting CAR T-cell products has been shown to be clearly superior to targeting BCMA alone with ciltacabtagene autoleucel. Dual targeting should eventually be compared in large phase 3 trials with the classical approach of serial treatment with monotargeting agents with target switch.