Multiple myeloma (MM) is a malignant hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow. The disease evolves various strategies for immune escape and drug resistance, including genetic mutations, deletion of tumor antigens, and the formation of an immunosuppressive tumor microenvironment. Despite advancements in treatment options such as immunomodulatory drugs, protease inhibitors, targeted monoclonal antibodies, and hematopoietic stem cell transplantation, MM remains incurable. This review aims to provide an integrative overview of intrinsic and extrinsic evasion mechanisms and the role of microbiota in immune evasion and drug resistance in MM. Intrinsic mechanisms include immune editing, reduced immune recognition of tumor antigens, and genomic alterations. Extrinsic mechanisms involve the lymphocytic and myeloid compartments, where T cells, B cells, NK cells, and myeloid-derived suppressive cells (MDSCs) play crucial roles. The tumor microenvironment (TME) also contributes to immune evasion and drug resistance through cell-cell interactions and soluble factors. Microbiota, particularly through short-chain fatty acids (SCFAs) and L-glutamine, can influence immune cell function and drug metabolism, affecting treatment outcomes. Understanding these mechanisms can inform the design of specific immunotherapies and drug combinations to improve patient survival and overcome drug resistance.Multiple myeloma (MM) is a malignant hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow. The disease evolves various strategies for immune escape and drug resistance, including genetic mutations, deletion of tumor antigens, and the formation of an immunosuppressive tumor microenvironment. Despite advancements in treatment options such as immunomodulatory drugs, protease inhibitors, targeted monoclonal antibodies, and hematopoietic stem cell transplantation, MM remains incurable. This review aims to provide an integrative overview of intrinsic and extrinsic evasion mechanisms and the role of microbiota in immune evasion and drug resistance in MM. Intrinsic mechanisms include immune editing, reduced immune recognition of tumor antigens, and genomic alterations. Extrinsic mechanisms involve the lymphocytic and myeloid compartments, where T cells, B cells, NK cells, and myeloid-derived suppressive cells (MDSCs) play crucial roles. The tumor microenvironment (TME) also contributes to immune evasion and drug resistance through cell-cell interactions and soluble factors. Microbiota, particularly through short-chain fatty acids (SCFAs) and L-glutamine, can influence immune cell function and drug metabolism, affecting treatment outcomes. Understanding these mechanisms can inform the design of specific immunotherapies and drug combinations to improve patient survival and overcome drug resistance.