Vascular endothelial growth factor (VEGF) participates in myeloma-promoting cytokine cross-talk between plasma cells and accessory cells. This suggests that VEGF is a potentially attractive anti-MM target for novel therapeutic strategies. We have recently demonstrated that mammalian target of rapamycin (mTOR) inhibitors are effective against MM and which markedly curtail VEGF expression. Our recent studies also demonstrated that hyperactive AKT activity enhanced the effectiveness of mTOR inhibitors as well as the anti-angiogenic effects in vivo and that this could be partially explained by differential expression of VEGF. In the current proposal, we will identify the mechanism by which AKT can regulate this effect and test these implications on myeloma biology.