Lenalidomide and Arsenic Trioxide Have Independent Non-Interfering Effects When Used in Combination on Myeloma Cell Lines in Vitro

Multiple myeloma (MM) is a plasma cell neoplasm characterized for its fast evolution and for being practically incurable, presenting a strong need for the development of therapies to target it. Among those under study are lenalidomide and arsenic trioxide (ATO) which show individual clinical promise, although never tested together. However, the combination of ATO with thalidomide, another immunomodulatory drug and lenalidomide’s structural albeit less potent analog, have been tried clinically with some success. Therefore, we investigated the effect the combination of lenalidomide and ATO have on the MM-derived U266 and RPMI 8226 cell lines. We observed that both compounds have separate, non-interfering, anti-myeloma mechanisms with ATO demonstrating strong cytotoxic effects while lenalidomide’s role remains cytostatic and immunomodulatory. However, ATO decreases cdc25c, which helps sensitize cells to lenalidomide effects enhancing the efficacy of their interaction. Mechanistically the combination of these two agents decreased the expression of MDM2, without affecting p53 activation or its expression. Therefore, this short study provides the foundation to continue mechanistic studies of the combination of lenalidomide and ATO as a foundation for future clinical application.