The Role of RNA Modifications in the Pathological Mechanisms and Therapeutic Targeting of Multiple Myeloma

Multiple myeloma (MM) remains largely incurable despite major therapeutic advances, underscoring the need to define novel pathogenic mechanisms and druggable targets. Epitranscriptomic dysregulation, encompassing reversible chemical modifications on RNA, has emerged as a post-transcriptional regulatory layer that may contribute to MM biology. This focused review discusses the emerging roles of major RNA modifications and their regulators in MM pathogenesis, bone disease, drug resistance, and immune escape. We summarize representative experimental and translational studies on RNA-modifying enzymes, non-coding RNAs, and the bone marrow microenvironment, with emphasis on mechanisms directly validated in MM. Evidence derived from AML, solid tumors, or pan-cancer analyses is discussed as hypothesis-generating and requiring MM-specific validation. We summarize MM-supported evidence that m6A demethylases such as FTO and ALKBH5, as well as writers such as METTL3 and NSUN2, may regulate the stability and translation of disease-relevant transcripts. We also discuss emerging cross-cancer data on the m7G writer METTL1 as a hypothesis-generating framework that requires MM-specific validation. We delineate how RNA modification–dependent non-coding RNA networks and extracellular vesicle cargo remodel osteoclast and osteoblast function, linking the epitranscriptome to osteolytic bone disease. We further describe RNA modification–driven drug resistance circuits and immune escape pathways involving FTO, METTL3, H19, MALAT1, YTHDF1, and m5C-defined molecular subtypes. Finally, we summarize current epitranscriptomic therapeutic strategies, including small molecule inhibitors of writers, erasers, and readers, RNA-based therapeutics targeting pathogenic non-coding RNAs, and RNA modification–derived prognostic signatures for risk stratification. Collectively, this review discusses RNA-modification machinery as a potentially actionable regulatory layer in MM and outlines key challenges for clinical translation.