Targeting metabolic reprogramming in multiple myeloma: Molecular mechanisms and potential therapeutic targets

Multiple myeloma (MM) is a hematologic malignancy characterized by clonal proliferation of malignant plasma cells. While proteasome inhibitors and novel immunotherapies have markedly shifted the clinical trajectory of multiple myeloma, the persistence of therapeutic resistance and disease recurrence remains a formidable challenge. Metabolic reprogramming has emerged as a critical functional layer driving MM progression and drug resistance. It extends beyond mere energetic anomalies, integrating genetic context, bone marrow microenvironmental stress, and therapeutic selection pressure into a dynamic, systemic adaptive network. This review aims to systematically elucidate the molecular mechanisms underlying the rewiring of major metabolic pathways in MM, including the aberrant activation and interaction of glucose, lipid, amino acid, nucleotide, and trace element (iron/copper) metabolism. It also explores the role of the gut microbiota as a distal regulator influencing disease progression through its metabolites. Collectively, these pathways constitute an interconnected metabolic network that sustains tumor proliferation, stress adaptation, immune evasion, and drug resistance. Furthermore, it discusses how metabolic states encode functional information largely invisible to conventional staging systems, thereby positioning metabolic vulnerabilities as conditional therapeutic targets and a complementary layer for biomarker development, risk stratification, and treatment selection in MM. In conclusion, this framework establishes a conceptual and translational reference, defining stress-adaptive metabolic states as actionable biological insight guiding metabolism-informed therapeutic and biomarker strategies in multiple myeloma.