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Simple Summary: As the second most frequent hematological malignancy, multiple myeloma remains incurable with recurrent patient relapse due to drug resistance. Therefore, the development of novel and potent therapies is urgently required. Herein, we demonstrated the anti-tumor activity of 5,6 α- and 5,6 β-epoxycholesterol isomers against human myeloma cells. Our results highlighted a striking anti-myeloma efficiency of these bioactive molecules and their added value in future potential treatments including combination therapy of multiple myeloma. Multiple myeloma (MM) is an incurable plasma cell malignancy with frequent patient relapse due to innate or acquired drug resistance. Cholesterol metabolism is reported to be altered in MM; therefore, we investigated the potential anti-myeloma activity of two cholesterol derivatives: the 5,6 α- and 5,6 β-epoxycholesterol (EC) isomers. To this end, viability assays were used, and isomers were shown to exhibit important anti-tumor activity in vitro in JJN3 and U266 human myeloma cell lines (HMCLs) and ex vivo in myeloma patients' sorted CD138+ malignant cells. Moreover, we confirmed that 5,6 α-EC and 5,6 β-EC induced oxiapoptophagy through concomitant oxidative stress and caspase-3-mediated apoptosis and autophagy. Interestingly, in combination treatment a synergistic interaction was observed between 5,6 α-EC and 5,6 β-EC on myeloma cells. These data highlight a striking anti-tumor activity of 5,6 α-EC and 5,6 β-EC bioactive molecules against human myeloma cells, paving the way for their potential role in future therapeutic strategies in MM. [ABSTRACT FROM AUTHOR]