Background: Stromal remodeling in the tumor microenvironment contributes to multiple myeloma (MM) progression and drug resistance, but the extracellular mediators that drive these changes remain incompletely defined. Extracellular enolase-1 (ENO1), including membrane-associated and secreted forms, has been implicated in tumor progression; however, its role in cancer-associated fibroblast (CAF)-associated stromal reprogramming in MM is unclear. Methods: The effects of extracellular ENO1 on stromal activation and tumor-supportive functions were examined in MM using MM–bone marrow stromal cell (BMSC) co-cultures, lactate production and viability assays, immunoblotting, cytokine analyses, and a subcutaneous xenograft model of bortezomib (BTZ)-resistant MM in male 6–7-week-old NOD.Cg-Prkdc^scid Il2rg^tm1Vst/Vst (NPG) mice. HuL001, an anti-ENO1 monoclonal antibody, was used to evaluate the therapeutic relevance of extracellular ENO1 targeting. Results: Extracellular ENO1 promoted fibroblast activation protein expression through plasmin-mediated transforming growth factor-β (TGF-β) activation and induced a CAF-associated stromal phenotype marked by enhanced glycolytic activity and increased secretion of tumor-promoting cytokines in MM-BMSC co-cultures. HuL001 suppressed these ENO1-driven effects. HuL001-pretreated stromal cells also exhibited reduced tumor-supportive activity in a BTZ-resistant MM xenograft model. In addition, HuL001 combined with lenalidomide overcame BTZ resistance in MM. Conclusions: Extracellular ENO1 drives CAF-associated stromal reprogramming in the MM microenvironment through the ENO1/plasminogen/plasmin/TGF-β axis. Therapeutic targeting of extracellular ENO1 with HuL001 may disrupt these tumor-supportive stromal activities and help overcome drug resistance in MM.