Dr. Richardson on the Mechanism of Action of CC-92480 in Multiple Myeloma

Paul G. Richardson, MD, clinical program leader and director of clinical research, Jerome Lipper Multiple Myeloma Center; institute physician, Dana-Farber Cancer Institute; and RJ Corman Professor of Medicine at Harvard Medical School, discusses the mechanism of action of CC-92480 in patients with multiple myeloma.

Phase 1 of the first-in-human study of CC-92480 in combination with dexamethasone showed encouraging efficacy in patients with heavily pretreated relapsed/refractory multiple myeloma.

CC-92480 is a first-in-class CELMoD agent that builds upon a platform already established by the CC-220 compound that is now referred to as iberdomide. CELMoDs are distinct from immunomodulatory (IMIDs) agents, says Richardson. This agent has been designed for rapid, maximal degradation of target proteins, specifically Ikaros and Aiolos.

When thinking of these drugs, it’s important to understand how they engage with the E3 ligase complex. The size of the molecule is what sets it apart from others, says Richardson. IMIDs like pomalidomide (Pomalyst) are relatively small molecules. Although CC-92480 falls under the small molecule classification, it’s larger than most and engages to the binding site much more efficiently, adds Richardson.

CELMoDs were specifically developed to do this versus IMIDs, where their mechanism of action was understood later on. The former have been developed as a distinct group of agents that are capable of engaging the target much more efficiently, concludes Richardson.

In vitro, CC-92480 showed enhanced antiproliferative and tumoricidal activity in multiple myeloma cell lines, including those resistant to lenalidomide (Revlimid) and pomalidomide, with strong immune stimulatory activity.