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

BCMA- or 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 CAR T-cell infusion or during BsAb treatment. Simultaneous targeting of two 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 two single-antigen targeting BsAbs. Notably, the efficacy of the combination of teclistamab and talquetamab appears to have enhanced anti-MM activity, compared to the corresponding conventional BsAbs alone in similar patient populations. Furthermore, dual-antigen targeting with T-cell redirecting trispecific antibodies (e.g., ramantamig [BCMAxGPRC5D] and ISB2001 [BCMAxCD38]) has already demonstrated promising results in heavily pretreated MM with several studies ongoing in earlier stages of the disease. Studies with limited numbers of patients have demonstrated that CAR T-cell products with specificity for more than one antigen are also effective in advanced MM, but at this time none of the dual-targeting CAR T-cell products is clearly superior to targeting BCMA alone with ciltacabtagene autoleucel (cilta-cel). Dual-targeting should eventually be compared in large phase 3 trials with the classical approach of serial treatment with mono-targeting agents with target switch.