Treatment resistance in relapsed/refractory multiple myeloma (RRMM) is increasingly being driven by mechanisms such as BCMA alteration, T-cell exhaustion, and microenvironmental immunosuppression. Understanding these resistance pathways may help inform the sequencing and selection of next-line therapy.

In many ways, we are lucky to have a wonderful target like BCMA for RRMM. Today, we have 3 different classes of drugs that can target this important cell surface protein: ADCs, TCEs, and CAR T-cell therapy. One important challenge is that we need more data from large trials that have evaluated the optimal sequence of these drug classes in the setting of resistance.

One mechanism of resistance is antigen loss or mutation. Some patients have been found to have a low level of BCMA-mutated or -deleted MM cells even before exposure to an anti-BCMA therapy, and these can be less sensitive to a BCMA-targeted therapy. Also, new mutations that produce antigen loss or can alter binding to BCMA therapies can emerge under selective pressure once a BCMA therapy is started. Another mechanism is T-cell exhaustion—where the T cells are chronically exhausted or the tumor microenvironment is inflamed—which causes the suppression of T-cell function, resulting in less effective anti-MM benefits. This may especially be important for TCEs and CAR T cells. Other potential mechanisms involve immunosuppressive cells such as myeloid-derived suppressor cells, regulatory T cells, or cytokines that are produced by the microenvironment, which produce inflammation and immunosuppression.

Right now, we do not have a good way of evaluating which of these pathways is the major one in RRMM, and it is also possible that more than one pathway will be activated. In the hopefully very near future, genomic sequencing will be a big help to clinicians in identifying the best second-line treatment for RRMM. For example, a BCMA therapy is not going to work second line for patients with a BCMA deletion that prevents protein expression. However, if there is a small BCMA mutation, the location of the mutation may help determine which therapy to use, since not all antibodies bind to the same epitope.

T-cell health evaluation will also be important because if T cells are exhausted as the mechanism of resistance, then coming right back with another TCE or CAR T-cell therapy may not be ideal. Instead, you could use a therapy that enhances T-cell activity and/or reduces exhaustion (eg, lenalidomide or pomalidomide). Hopefully, we will also have iberdomide and mezigdomide as treatment options in the very near future; they also look like they have attractive T-cell effects. For example, if a patient with RRMM is treated with a BCMA TCE but then develops T-cell exhaustion, clinicians could offer one of these CRBN-targeted drugs or a combination with a GPRC5D TCE to restore T-cell function rather than switching to a GPRC5D TCE alone.

Currently, a number of leading expert groups have advocated for CAR T-cell therapy to be given as the first BCMA-targeted line of therapy if clinicians plan to prescribe more than one BCMA-targeted therapy. If patients relapse, then you think about using a TCE. Talquetamab is helpful in the post-BCMA setting because it targets GPRC5D. The opposite sequence (ie, TCE therapy followed by CAR T-cell therapy) has some concerns in terms of the higher risk for both antigen mutation or loss and T-cell exhaustion. We do not yet have enough information about the appropriate fit of ADCs into the CAR T-cell and TCE landscape, but, hopefully, we will learn more as people begin to use the DREAMM-7 and DREAMM-8 combinations. Finally, selinexor has a different mechanism of action that should not be cross-resistant since it inhibits the nuclear export of important oncogene-derived proteins.