Shamila D. Alipoor, Mariusz Shrestha, An Liu, Hong Chang
Multiple myeloma (MM) is a plasma cell malignancy that originates in the bone marrow (BM) and is characterized by the clonal expansion of Bcell-derived plasma cells producing abnormal monoclonal immunoglobulins. Despite significant therapeutic advances that have improved patient outcomes, drug resistance remains a major obstacle to effective disease management. Genetic and epigenetic heterogeneity are key features of MM that drive disease onset, progression, and therapeutic resistance. Both early and advanced stages of MM exhibit global and locus specific DNA methylation abnormalities that silence tumor suppressor genes and disrupt key regulatory pathways, including Wnt/β-catenin, JAK/STAT, and apoptotic signaling. Altered activity of histone modifiers, including methyltransferases (e.g., EZH2, MMSET) and deacetylases (e.g., HDAC4, HDAC6), promotes chromatin remodeling and myeloma cell survival, representing promising therapeutic targets. Dysregulated long non-coding RNAs (lncRNAs), such as MALAT1 and MIAT1, further contribute to genomic instability and drug resistance. Emerging epigenetic therapies targeting DNA methyltransferases, HDACs, and bromodomains show promise in overcoming therapeutic resistance and improving patient outcomes. In this article, we summarize current insights into the central role of epigenetic alterations including DNA methylation changes, histone post-translational modifications, and lncRNA dysregulation in MM pathogenesis, discuss their mechanistic and clinical implications, and highlight therapeutic opportunities emerging from these discoveries.