CELMoDs: Mechanism of action and immunomodulatory activity in MM

The Multiple Myeloma Hub spoke with Paul Richardson, Dana-Farber Cancer Institute, Boston, US. We asked about the mechanism of action and immunomodulatory activity of cereblon E3 ligase modulators (CELMoDs) in multiple myeloma (MM). 

During this interview, Richardson discusses how CELMoDs target the cereblon E3 ubiquitin ligase complex to induce selective protein degradation and immunomodulatory effects. Richardson explains how CELMoDs, such as iberdomide and mezigdomide, differ structurally and functionally from earlier immunomodulatory drugs (IMiDs), resulting in enhanced substrate degradation and immune activation. He notes that anti-MM activity has also been demonstrated in combination with established myeloma therapies. Richardson also discusses translational and preclinical findings on the ability of CELMoDs to overcome resistance and modulate the tumor microenvironment. 

Key points 

• CELMoDs are a distinct class of oral agents that target the cereblon E3 ubiquitin ligase complex.^1,2 
• Binding of CELMoDs to cereblon induces conformational changes that promote degradation of specific substrate proteins, including Ikaros and Aiolos.^1,2  
• Greater conformational closure of the cereblon E3 ligase complex with iberdomide and mezigdomide is associated with increased potency compared with earlier immunomodulatory drugs, lenalidomide and pomalidomide.^1,2  
• Enhanced protein degradation is associated with more profound tumor cell apoptosis, anti-proliferative effects, and immune stimulation.^1,2  
• In preclinical studies, CELMoDs have demonstrated early signs of reduced off-target effects on CK1α, which may reduce the risk of secondary malignancies.³  
• Anti-MM activity has also been demonstrated in combination with established therapies, including CD38 monoclonal antibodies, proteasome inhibitors, and corticosteroids.^4–6  
• In summary, CELMoDs induce immunomodulatory effects, including activation of natural killer cells and stimulation of T-cell responses.⁷  
• These effects may allow CELMoDs to overcome resistance to prior IMiDs and help reverse the immune-suppressive tumor microenvironment.⁸