Unlocking the Potential of CC-92480: A Dual-Action CELMoD Overcoming Therapy Resistance in Multiple Myeloma

Lenalidomide and pomalidomide are established treatments for multiple myeloma (MM), yet many patients develop resistance or relapse. CC-92480, a novel cereblon (CRBN) E3 ligase modulator (CELMoD), is under investigation in a phase 1 clinical trial for relapsed/refractory MM (RRMM) due to its immunomodulatory and antiproliferative effects.

The study explores how CC-92480, as a CELMoD, binds to CRBN, enhancing the E3 ubiquitin ligase's ability to degrade specific substrates, including the transcription factors Ikaros and Aiolos, which are vital for myeloma cell survival. CC-92480 demonstrated a rapid and sustained degradation of these factors, outperforming other agents in antimyeloma activity. It showed a higher binding affinity for CRBN compared to lenalidomide and was more effective in recruiting Ikaros to the CRBN E3 ligase complex.

CC-92480 also induced the degradation of additional transcription factors, c-Myc and interferon regulatory factor 4, associated with apoptosis. Its tumoricidal activity was CRBN dependent, ceasing with the loss of CRBN or stabilization of Ikaros and Aiolos. The drug showed significant antiproliferative effects across a range of MM cell lines, including those resistant to standard therapies, with high sensitivity in approximately half of the evaluated cell lines.

Furthermore, CC-92480 induced the destruction of Ikaros and Aiolos in peripheral blood mononuclear cells (PBMCs), leading to T cell activation and increased cytokine production, which in turn led to effective immune-mediated killing of MM cells in co-cultures.

CC-92480's unique degradation profile and its ability to induce apoptosis in a CRL4^CRBN-dependent manner, even with low or mutated CRBN protein, highlight its potential as a potent anti-MM agent. Its immunomodulatory activity, similar to lenalidomide, supports the ongoing clinical investigation of CC-92480 for RRMM patients.