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Novel CELMoD Agents for Multiple Myeloma

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Cereblon E3 ligase modulatory drugs (CELMoDs) are novel orally administered small-molecule agents that target the cereblon E3 ligase complex, generating a downstream effect that sets them apart from the closely related immunomodulators pomalidomide and lenalidomide. The larger design of the CELMoD agents allows for tighter binding to the cereblon E3 ligase complex, resulting in rapid degradation of a specific set of proteins and ultimately leads to direct apoptosis of myeloma cells.

Currently 2 CELMoDs are under investigation, iberdomide (CC220) and mezigdomide (CC92480). Mezigdomide has shown impressive activity in preclinical models, and iberdomide has shown to be 20 to 40 times more potent than pomalidomide and lenalidomide in similar models. In these preclinical models, the CELMoDs are able to overcome pomalidomide and lenalidomide resistance and are synergistic with dexamethasone, daratumumab, and proteasome inhibitors (PIs).

From the success of preclinical models, a high priority has been placed on translating these results into clinical investigations. Comprehensive trials have shown that many demonstrated preclinical effects have translated into clinical effects with promising activity in patients. Iberdomide demonstrated response rates of approximately 30% as monotherapy in heavily pretreated patients who are triple-class or B-cell maturation antigen refractory. When combined with other therapies, including PIs or CD38 antibodies, iberdomide showed an increase in response rates to approximately 50% to 60%. Mezigdomide, which is particularly active in extramedullary disease, demonstrated response rates >50% as monotherapy, and response rates have been >70% when combining mezigdomide with a PI or monoclonal antibody.

Iberdomide is being investigated as first-line treatment and as a maintenance strategy, and mezigdomide is being studied in relapsed/refractory disease as a new oral approach in combination with other therapies.

Iberdomide is well tolerated with a manageable safety profile and minimal grade 3/4 toxicities. Due to the potency of mezigdomide, greater myelosuppression and occasional non-hematologic toxicities have been reported; however, most have been manageable. Low rates of infection were noted with CELMoDs, including few cases of lethal COVID-19. It is expected that these agents, especially with early and maintenance iberdomide, will not be associated with secondary cancers.

Overall, the future of CELMoDs is promising in complementing existing and new therapies. Further studies are being conducted to solidify results.

Source: Richardson P. Iberdomide- Combinations- New Directions. Presented at: Lymphoma, Leukemia & Myeloma Congress; October 18-22, 2022; New York, NY.

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