A novel cereblon E3 ubiquitin ligase modulator with potent antiproliferative and tumoricidal activity, oral mezigdomide showed “promising efficacy in patients with heavily pretreated multiple myeloma, with treatment-related adverse events consisting mainly of myelotoxic effects,” when given in combination with dexamethasone, researchers report. The phase 1/2 study “represents the culmination of discoveries made over the past decade related to the mechanism of action of immunomodulatory agents in multiple myeloma.”
The all-oral combination of mezigdomide and dexamethasone was tested in a dose-escalation cohort (phase 1; assessment of safety and pharmacokinetics and identification of dose for phase 2) and a dose-expansion cohort (phase 2; assessment of the overall response, safety, and efficacy). “In phase 1, a total of 77 patients were enrolled in the study. The most common dose-limiting toxic effects were neutropenia and febrile neutropenia. On the basis of the phase 1 findings, investigators determined the recommended phase 2 dose of mezigdomide to be 1.0 mg, given once daily in combination with dexamethasone for 21 days, followed by 7 days off, in each 28-day cycle.…
“In phase 2, a total of 101 patients received the dose identified in phase 1 in the same schedule. All patients in the dose-expansion cohort had triple-class–refractory multiple myeloma, 30 patients (30%) had received previous anti–B-cell maturation antigen (anti-BCMA) therapy, and 40 (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia (in 77% of the patients) and infection (in 65%; grade 3, 29%; grade 4, 6%). No unexpected toxic effects were encountered. An overall response occurred in 41% of the patients (95% confidence interval [CI], 31 to 51), the median duration of response was 7.6 months (95% CI, 5.4 to 9.5; data not mature), and the median progression-free survival was 4.4 months (95% CI, 3.0 to 5.5), with a median follow-up of 7.5 months (range, 0.5 to 21.9).”
Editorial: “Although mezigdomide is active in cells with low levels of cereblon, it cannot work in the complete absence of cereblon or overcome cereblon-independent resistance mechanisms,” an editorialist writes. “Further studies will determine the safety and efficacy of mezigdomide concomitant with other antimyeloma therapies. A phase 3 study (ClinicalTrials.gov number, NCT05519085) comparing the efficacy of mezigdomide and pomalidomide, both in combination with bortezomib and dexamethasone, is under way. Combination of mezigdomide with drug classes that also cause susceptibility to neutropenia may prove to be less feasible. Concurrently, the myeloma field is being revolutionized by immunotherapies such as bispecific antibodies and chimeric antigen receptor T cells. Because mezigdomide bears the same immunostimulatory hallmarks as its [immunomodulatory imide drug] forebears, it may also partner well with these immune effector cell–based approaches.”