Multiple myeloma (MM) is a malignant hematologic malignancy that arises from the clonal transformation of plasma cells in the bone marrow. It has evolved various strategies to evade immune surveillance and develop drug resistance, including uncontrolled proliferation of malignant plasma cells, genetic mutations, and deletion of tumor antigens. Despite advances in treatment, MM remains incurable. This review summarizes the intrinsic and extrinsic mechanisms, as well as the role of microbiota, that MM uses to evade immune responses and develop resistance. The intrinsic mechanisms include immune editing, reduced immune recognition of tumor antigens, and genomic alterations. The extrinsic mechanisms involve the lymphoid and myeloid compartments, including T cells, B cells, NK cells, MDSCs, dendritic cells, and macrophages. The microbiota also plays a role in MM by influencing immune responses and drug resistance through metabolites such as short-chain fatty acids and L-glutamine, as well as by promoting Th17 cell activity. Understanding these mechanisms is essential for developing targeted therapies to improve patient outcomes.Multiple myeloma (MM) is a malignant hematologic malignancy that arises from the clonal transformation of plasma cells in the bone marrow. It has evolved various strategies to evade immune surveillance and develop drug resistance, including uncontrolled proliferation of malignant plasma cells, genetic mutations, and deletion of tumor antigens. Despite advances in treatment, MM remains incurable. This review summarizes the intrinsic and extrinsic mechanisms, as well as the role of microbiota, that MM uses to evade immune responses and develop resistance. The intrinsic mechanisms include immune editing, reduced immune recognition of tumor antigens, and genomic alterations. The extrinsic mechanisms involve the lymphoid and myeloid compartments, including T cells, B cells, NK cells, MDSCs, dendritic cells, and macrophages. The microbiota also plays a role in MM by influencing immune responses and drug resistance through metabolites such as short-chain fatty acids and L-glutamine, as well as by promoting Th17 cell activity. Understanding these mechanisms is essential for developing targeted therapies to improve patient outcomes.