Immunomodulatory agents (IMiDs) are a class of immunomodulatory drugs. Thalidomide analogs have induced significant antimyeloma effects via immune-modulation, antiangiogenesis, and antiproliferative effects. Specifically, identification of the mechanisms of resistance for immunomodulatory agents (IMiDs), which will have significant clinical implications, remains poorly understood. Besides, the down-regulation of cereblon resulted in acquiring IMiD resistance in human myeloma cells. Since, in the clinic, lowered cereblon expression levels correlated with myeloma patients acquiring IMiD resistance. And the presence of cereblon is confirmed as an essential requirement for the IMiD activity. Moreover, immunomodulatory agents revolutionized the way we treat myeloma. As oral agents, IMiDs have delivered exceptional antimyeloma outcomes in all phases of myeloma therapies. Not only that, the IMiDs conveniently partnered with all other classes of antimyeloma agents from PIs to the more current monoclonal antibodies and exhibited synergy. CC-92480 is a cereblon E3 ubiquitin ligase modulating drug (CELMoD).

CC-92480 is a cereblon E3 ubiquitin ligase modulating drug (CELMoD). In addition, CC-92480 shows a high affinity to cereblon, resulting in a potent antimyeloma activity. Cc-92480 is the second brain modulator in clinical trials. Loss of Aiolos and Ikaros in PBMC culture induced by cc-92480 resulted in T cell activation and increased the production of IL-2 and IFN – γ. Furthermore, the functional consequences of CC-92480–mediated T-cell activation and enhanced cytokine production are the most potent and effective immune-mediated killing of MM cells. Importantly, CC-92480 is effective in lenalidomide, pomalidomide, and CC-220-resistant cell lines. Nonetheless, it exerts a single-agent induction of apoptosis and exhibits remarkable synergy with dexamethasone. All in all, CC-92480 is a cereblon E3 ubiquitin ligase modulating drug with potent antimyeloma activity.


Nooka AK, et al. Cancer J. 2019 Jan/Feb;25(1):19-31.