Bone marrow stromal cell (BMSC)-derived small extracellular vesicles (sEVs) promote drug resistance to bortezomib in multiple myeloma (MM) cells. Elucidating the components of BMSC sEV that induce drug resistance in MM cells could help identify strategies to overcome resistance. Considering the hypoxic nature of the myeloma microenvironment, we explored the role of hypoxia in regulating BMSC sEV cargo and investigated whether hypoxia-driven sEV miRNAs contribute to the drug resistance in MM cells. Hypoxia increased the release of sEVs from BMSCs, and these sEVs more strongly attenuated bortezomib sensitivity in MM cells than sEVs from BMSCs under normoxic conditions. RNA sequencing revealed that significantly elevated levels of miR-140-5p and miR-28-3p were enclosed in hypoxic BMSCs-derived sEVs. Both miR-140-5p and miR-28-3p conferred bortezomib resistance in MM cells by synergistically targeting SPRED1, a member of the Sprouty protein family that regulates MAPK activation. SPRED1 inhibition reduced sensitivity to bortezomib in MM cells through activating MAPK-related pathways and significantly promoted MM bortezomib resistance and tumor growth in a mouse model. These findings shed light on the role of hypoxia-induced miRNAs shuttled in BMSC-derived sEVs to MM cells in inducing drug resistance and identify the miR-140-5p/miR-28-3p/SPRED1/MAPK pathway as a potential targetable axis for treating MM.