Harnessing CAR-NK cells against multiple myeloma: current landscape and future directions

Multiple myeloma (MM) remains an aggressive and largely incurable plasma cell malignancy, with relapse common despite therapeutic advances. Although CAR-T cells have transformed the field, their clinical use is constrained by toxicity, complex manufacturing, and limited accessibility. These limitations have accelerated interest in CAR-engineered natural killer (CAR-NK) cells as a safer, more scalable, and potentially off-the-shelf immunotherapeutic platform.

This review goes beyond a descriptive summary of CAR-NK research in MM by providing an integrated framework that connects antigen targeting, synthetic engineering, tumor microenvironment adaptation, biomarker-guided response monitoring, and translational manufacturing barriers. In doing so, it highlights not only what has been achieved, but also what currently limits clinical implementation and where the field is most likely to advance next.

We performed a comprehensive literature analysis of preclinical and clinical studies on CAR-NK cell therapy in MM, focusing on target selection, persistence-enhancing strategies, immune evasion, biomarker development, combination approaches, and GMP-compatible manufacturing platforms.

CAR-NK cells offer several advantages over CAR-T therapy, including lower risks of cytokine release syndrome, neurotoxicity, and graft-versus-host disease. Beyond summarizing currently explored targets such as BCMA, CD138, SLAMF7, and GPRC5D, this review identifies the main design principles driving next-generation CAR-NK development: cytokine armoring, genome editing, dual-targeting strategies, and nanotechnology-enabled delivery. Importantly, we also synthesize emerging translational priorities, including predictive biomarkers for patient stratification, serial monitoring of treatment response, and scalable closed-system manufacturing approaches that may determine clinical feasibility.

CAR-NK therapy is evolving from a promising concept into a realistic therapeutic platform for MM. This review contributes a forward-looking translational roadmap by integrating engineering innovation, biomarker-based precision medicine, and manufacturing scalability, thereby defining the key steps needed to move CAR-NK cells toward durable and clinically meaningful impact in refractory MM.