Notch signaling activation was found in many human cancers including multiple myeloma. It was previously reported that notch contributes to drug resistant of myeloma cells upon chemotherapy treatment, inhibition of notch by inhibitors helped to overcome drug resistance. However, the mechanism of notch developed drug resistance is remained to be fully illustrated. In the current study, we reported that Notch signaling activation up-regulated expression of integrin alpha v beta 5 in myeloma cells companied with enhanced cells adhesion on vitronectin. Silencing Notch-1 receptor with siRNA or blocking cells with integrin alpha v beta 5 antibody reduced myeloma cells adhesion on vitronectin, importantly, vitronectin mediated adhesion confers protection of myeloma cells from drug induced apoptosis. Thus, we revealed a novel mechanism of myeloma cells resistance to drug induced apoptosis. This study first connected Notch signaling, VTN adhesion and drug resistance together. Therefore, blocking alpha v beta 5 receptor with antibody or knock down approach would be a novel promising strategy to treat MM. (C) 2015 Elsevier Inc. All rights reserved.