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Drug resistance (DR) is increasingly recognized as a dynamically evolving ecosystem shaped by tumor\u2010intrinsic plasticity and continuous remodeling of the bone marrow microenvironment (BMME), rather than as a single molecular lesion. This review summarizes the major mechanisms of resistance across key drug classes, including alterations in drug targets and signaling nodes, rewiring of apoptotic, proteostatic, and metabolic circuits, and BMME\u2010dependent protection. We highlight how these processes converge on a limited set of survival hubs and collectively raise the apoptotic threshold under therapeutic pressure. The key to overcoming DR is to conceptualize it as an evolving ecosystem, thereby enabling rational, mechanism\u2010based combination and sequencing strategies that may prolong progression\u2010free survival and move MM closer to a functional cure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cbf.70286","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T07:05:01Z","timestamp":1787295901000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Drug Resistance in Multiple Myeloma: Tumor\u2010Intrinsic Mechanisms and the Bone Marrow Microenvironment"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-3783-3404","authenticated-orcid":false,"given":"Yixuan","family":"Chen","sequence":"first","affiliation":[{"name":"Laboratory of Hematology Guilin Medical University Guilin 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