The 3 main components of contemporary multiple myeloma (MM) therapy are immunomodulatory imide drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (MoAbs). Patients with MM who developed resistance to all 3 classes (referred to as triple-class refractory [TCR]) have typically had dismal prognoses.

Observational studies show that current treatments have an overall response rate of only ~30% and overall survival of less than 1 year. The anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T cells, anti-BCMA antibody-drug conjugates, and exportin 1 (XPO1) inhibitors all demonstrated effectiveness in TCR MM in single-arm studies, despite the fact that no randomized study has been completed in the situation.

Anti-BCMA bispecific T-cell engagers (TCE) and non-BCMA TCEs showed the strongest activity in patients among the medicines still in development. Venetoclax in t(11;14) MM is an example of how particular drugs may display distinctive action in biologically defined patient subgroups.

The key unanswered questions in TCR MM related to the best order for administering currently available treatments, the value of administering drugs with related mechanisms of action but different immunotherapy targets in succession, and the relative effectiveness of various anti-BCMA platforms. In the study, researchers summarized the body of research and offer broad recommendations for choosing a course of treatment for the difficult and diverse group of patients.