Abstract Abstract 5043 Multiple myeloma (MM), the second most frequent hematological malignancy that remains incurable, is a disease of cell cycle dysregulation and loss of apoptotic control. Here we report that 6-O-angeloylplenolin (6-OAP), a sesquiterpene lactone extracted from Centipeda minima L. (Compositae), suppresses the proliferation of drug-sensitive and drug-resistant cell lines and primary CD138+ MM cells, but does not affect normal peripheral blood mononuclear cells. 6-OAP caused mitotic arrest, accompanied by upregulation of cyclin B1 and downregulation of phospharylated Cdc2, indicating activation of cyclin B1/Cdc2 complex which is critical to the control of G2-M transition. We show that 6-OAP activates spindle assembly checkpoint, enhances Mad2/Cdc20 binding activity, leading to inhibition of ubiquitiniation and subsequent proteasomal degradation of cyclin B1. 6-OAP potentiates cytotoxicity of dexamethasone, doxorubicin and bortezomib, and overcomes the protective effects of interleukin-6 and insulin-like growth factor-2 on MM cells. Moreover, 6-OAP inhibits tumor growth but does not affect animal body weight in an in vivo xenograft model for human MM. Taken together, these results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potential for treating MM. Disclosures: No relevant conflicts of interest to declare.