RNA-Based Therapeutic Strategies in Multiple Myeloma: From Molecular Targets to Delivery and Clinical Translation

Multiple myeloma (MM) is a challenging hematologic malignancy characterized by clonal plasma cell proliferation, often leading to significant morbidity and mortality worldwide. Despite advances in chemotherapy and CAR-T therapies, MM remains incurable due to tumor heterogeneity, immune evasion, and microenvironment remodeling—exacerbated by toxicities like cytokine release syndrome and myelosuppression. This urgent unmet need demands innovative strategies. In this review, we assess cutting-edge RNA-based therapeutics for MM modulation, drawing on preclinical and clinical evidence on modalities including mRNA vaccines, small interfering RNAs (siRNAs), antisense oligonucleotides (ASOs), and microRNA (miRNA) mimics/inhibitors. We further explore RNA-engineered cell therapies, such as transient CAR-T platforms and lipid nanoparticle-delivered systems targeting the bone marrow niche. By integrating these insights, we underscore RNA technologies’ transformative potential to achieve durable remissions, overcome resistance, and reduce costs—paving the way for personalized, safer treatments in refractory MM.