Bortezomib has been reported to trigger pleiotropic signaling pathways in MM cells, including: (a) stabilizing cytoplasmic IkB and blocking NFkB nuclear translocation [4] ; (b) activation of stress response proteins such as heat shock proteins Hsp27, Hsp70, and Hsp90 [5] ; (c) up-regulation of c-jun NH2-terminal kinase [6] ; (d) induction of intrinsic cell death pathway [7] ; (e) activation of extrinsic apoptotic signaling through Bid and caspase-8 cleavage [8] ; (f) impairment of DNA repair machinery via inactivation of DNA-dependent protein kinase [9] ; (g) down-regulation of mitogen-activated protein kinase and phosphatidylinositol 3kinase/Akt signaling pathways [10] ; and (h) down-regulation of the p44/42 MAPK signaling cascade [11] . All these signaling events may collectively contribute towards the overall anti-MM activity of bortezomib. However, the exact number and identity of cellular signaling events involved in proteasome inhibition and the mechanisms underlying the associated apoptotic response in MM cells remain to be elucidated.