Are we there yet? CAR-T therapy in multiple myeloma

The last few years have seen a revolution in cellular immunotherapies for multiple myeloma (MM) with novel antigen targets. The principle new target is B-cell maturation antigen (BCMA). Autologous chimeric antigen receptor T-cell (CAR-T) therapy directed against BCMA was first approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021, although approval by the National Institute for Health and Care Excellent (NICE) is awaited. Initial response rates in patients with heavily pretreated MM have been impressive, but patients are still relapsing. Furthermore, CAR-T manufacturing is expensive and time-consuming, and T-cell fitness is impaired by prior MM treatment. Numerous strategies to improve outcomes and delivery of cellular immunotherapy are under investigation, including next-generation CARs, allogeneic 'off-the-shelf' CARs and targeting of other MM antigens including G protein-coupled receptor, class C, group 5, member D (GPRC5D), Fc receptor homologue 5 (FcRH5), cluster of differentiation (CD)19, signalling lymphocyte activation molecule family member 7 (SLAMF7) and several others. In this exciting and rapidly evolving treatment landscape, this review evaluates the most recent clinical and preclinical data pertaining to these new cellular immunotherapies and explores strategies to overcome resistance pathways. On the protracted journey to a long-term cure, we outline the challenges that lie ahead and ask, 'Are we there yet?'