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.
Donk et al. (Thu,) studied this question.