Dr Siegel on the Evaluation of Mezigdomide for R/R Myeloma

“Mezigdomide, which is the centerpiece of this [phase 1/2 CA057-003] trial, is a newer derivative of thalidomide, and for those uninformed, the thalidomide derivatives are probably the most important drugs that have been developed in myeloma over the last 3 decades.”

David S. Siegel, MD, chief of the Division of Multiple Myeloma at the John Theurer Cancer Center at Hackensack University Medical Center, explained the rationale for evaluating mezigdomide (CC-92480) in patients with relapsed/refractory multiple myeloma.

Mezigdomide is a novel derivative of thalidomide, which has made a significant mark in the multiple myeloma treatment paradigm for approximately 30 years, Siegel began. The novel derivative maximizes the features of thalidomide and other thalidomide derivatives, he noted. Specifically, mezigdomide has direct tumoricidal effects and can modulate the way immune responses interact with tumors, Siegel said.

Preliminary results from the phase 1/2 CA057-003 trial (NCT05372354) revealed that mezigdomide plus the EZH2 inhibitor tazemetostat (n = 16), the BET inhibitor BMS-986158 (n = 20), or the MEK inhibitor trametinib (Mekinist; n = 20) demonstrated overall response rates of 50%, 35%, or 75% in the respective combination groups. Of note, a trend toward deeper responses, including very good partial responses or better, was seen in patients who received mezigdomide at 1.0 mg with tazemetostat or BMS-986158. Deeper responses were observed in the trametinib cohort with mezigdomide at 0.6 mg or higher, with 11 patients at the 1.0-mg dose level (n = 13) continuing on treatment. No new safety signals were observed among the 3 cohorts, most of which were hematologic toxicities.

Based on early work with mezigdomide, investigators established that potential pathways could be receptive to intervention, Siegel added. Therefore, the phase 1/2 trial was intended to identify ways to maximize the interactions with mezigdomide in relapsed/refractory multiple myeloma by targeting other pathways, he concluded.