Investigating mechanisms of sensitivity and resistance to immunomodulatory thalidomide analogues in multiple myeloma

Abstract

Multiple myeloma (MM) is an incurable plasma cell neoplasm. The incorporation of immunomodulatory imide drugs (IMiDs) – thalidomide, lenalidomide and pomalidomide - into clinical practice has improved survival and quality of life of MM patients. However, most patients develop therapeutic resistance to IMiDs, representing a significant clinical problem. IMiDs exert anti-MM effects by engaging Cereblon (CRBN), a ligand of the E3 ligase complex CUL4-DDB1-RBX1. By binding CRBN, IMiDs promote ubiquitination and proteasomal degradation of important MM cell transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos). Degradation of such neosubstrates has also been shown to augment an anti-cancer immun..