Advances in CD19-targeting CAR-T cell therapies for multiple myeloma

Emerging evidence suggests that, while CD19 is primarily expressed on immature B-cell precursors, it is also present on drug-resistant plasma cells that have been postulated to function as multiple myeloma (MM) stem cells, driving the progression of relapsing disease. Targeting CD19 with chimeric antigen receptor (CAR) T cells offers a promising strategy for addressing this residual disease burden, potentially leading to more durable treatments and enhanced relapse prevention.

This review examines the molecular basis of CD19-targeted CAR-T therapy in MM, highlighting its potential, key challenges, and efficacy and safety in early clinical trials for relapsed/refractory and newly diagnosed MM.

CD19 expression in MM correlates with poor prognosis and may be significantly underestimated, particularly following debulking therapy, as demonstrated by advanced visualization technologies like single molecule-sensitive direct stochastic optical reconstruction microscopy (dSTORM). Early-phase trials using CD19-directed CAR-T as post-transplant consolidation show promise in prolonging progression-free survival. Multi-target approaches, e.g. the bispecific BCMA×CD19 CAR-T product GC012F, are advancing through clinical development with encouraging safety and efficacy data. However, randomized controlled trials will be necessary to confirm the role and positioning of CD19-directed CAR-T cells within the current MM treatment landscape.