Multiple Myeloma (MM) is a bone marrow neoplasm characterized by clonal expansion of terminally differentiated B cells. The bone marrow (BM) niche promotes drug resistance and disease progression through soluble factors and cell-cell contact. The PI3K/AKT signaling pathway is activated in MM cells via the Insulin-like Growth Factor-1 receptor (IGF1R). We previously showed that negative regulation of Forkhead box O (FOXO) transcription factors is a key downstream function of AKT in MM, as FOXO activation induces cell death and metabolic shutdown in MM cells. We observed FOXO-dependent upregulation of IGF1R after AKT inhibition, suggesting an adaptive signaling pathway enabling MM cells to bypass AKT blockade. Combined AKT and IGF1R inhibition robustly induced cell death, but this was not replicated in a humanized mouse model. Further experiments revealed that microenvironmental factors induce parallel activation of mechanistic Target of Rapamycin Complex 1 (mTORC1). The mTORC1 inhibitor Rapamycin overcame microenvironment-induced resistance to AKT and IGF1R inhibitors. Additionally, mTORC1 inhibition reversed BM stromal cell (BMSC)-mediated resistance to the proteasome inhibitor Carfilzomib, indicating a generalized resistance mechanism in MM therapeutics. This project aims to comprehensively characterize pathways involved in cell-extrinsic resistance mechanisms.