In this study, we investigated the differential MM phosphoproteome upon proteasome inhibition by using SILAC in combination with phosphoprotein enrichment and LC-MS/MS analysis. Many potential novel signaling proteins and associated signaling pathways were confidently identified. Our further functional results indicated that perturbations in stathmin phosphorylation play a significant functional role in mediating apoptosis in MM cells exposed to bortezomib and the bortezomib-induced changes in the MT stabilization can be attributed to the bortezomibinduced phosphorylation of stathmin. By correlating the phosphoproteomic data with functional studies, the current results provided novel insights into the mechanisms of bortezomib actions in MM cells.