Combination of the mTOR inhibitor Rapamycin and Revlimid (CC-5013) has synergistic activity in Multiple Myeloma

Previous studies have demonstrated the in vitro and in vivo activity of Revlimid(CC5013), an immunomodulatory analogue (IMiD) of thalidomide, in multiple myeloma (MM). In the present study, we have examined the anti-MM activity of rapamycin, a specific mTOR inhibitor, combined with Revlimid. Based on the Chou-Talalay method, combination indices of < 1 were obtained for all dose ranges of Revlimid when combined with rapamycin, suggesting strong synergism. Importantly, this combination was able to overcome drug resistance when tested against MM cell lines resistant to conventional chemotherapy. Moreover the combination, but not rapamycin alone, was able to overcome the growth advantage conferred on MM cells by Interleukin-6 (IL-6), Insulin-like growth factor-1 (IGF-1), or adherence to bone marrow stromal cells (BMSCs). The combination of rapamycin with Revlimid induced apoptosis of MM cells. Differential signaling cascades, including the MAPK and PI3-K/Akt pathways, were targeted by these drugs individually and in combination, suggesting the molecular mechanism by which they interfere with MM growth and survival. These studies therefore provide the framework for clinical evaluation of mTOR inhibitors combined with immunomodulatory agents to improve patient outcome in MM. For personal use only. on May 1, 2017. by guest www.bloodjournal.org From