Dr Siegel on the Rationale for Investigating KID in Multiple Myeloma

David Samuel Dicapua Siegel, MD, chief, Division of Multiple Myeloma, John Theurer Cancer Center, Hackensack University Medical Center, discusses the rationale for conducting a phase 1/2 trial (NCT05199311) of carfilzomib (Kyprolis), iberdomide (CC-220), and dexamethasone (KID) in patients with newly diagnosed, transplant-eligible multiple myeloma.

The multicenter trial included a phase 1 dose-escalation portion to determine the maximum tolerated dose of KID, followed by a phase 2 dose-expansion portion. The phase 1 portion is complete, and the phase 2 portion is actively enrolling patients. The primary end point of the phase 1 portion was the safety and tolerability of KID, and the primary end point of the phase 2 portion is the complete response (CR)/stringent CR rate after 2 to 4 cycles of KID. Key secondary end points included overall response rate and progression-free survival.

This phase 1/2 trial is one of the first studies to investigate iberdomide, a novel thalidomide derivative, Siegel says. Historically, thalidomide’s activity in myeloma was attributed to the drug’s ability to inhibit the inflammatory cytokine TNFα, Siegel explains. When investigators derivatized thalidomide, they identified the drugs lenalidomide (Revlimid) and pomalidomide (Pomalyst) based on their ability to inhibit TNFα, Siegel notes.

Although there may be a role for TNFα inhibition in multiple myeloma management, newer research has shown that thalidomide and its derivatives primarily work through their interaction with cereblon proteins. This mechanism changes the specificity of E3 ubiquitin ligases in the human body, Siegel emphasizes. Ubiquitin ligases tag specific proteins for proteasomal degradation within the cell, according to Siegel. The 2 most important proteins that have been recognized so far are the transcription factors Ikaros and Aiolos, Siegel says. Ikaros and Aiolos degradation is likely the most important mediator of activity in thalidomide and its derivatives, Siegel explains.

Based on this finding, investigators selected new agents for investigation: iberdomide and mezigdomide (CC-92480). Although the structure of iberdomide appears similar to that of lenalidomide, as they are both thalidomide derivatives, iberdomide is a CELMoD, whereas lenalidomide is an immunomodulatory agent, Siegel concludes.