In a phase I/II trial (CC-92480-MM-001) reported in The New England Journal of Medicine, Paul G. Richardson, MD, and colleagues found that the combination of the novel cereblon E3 ubiquitin ligase modulator mezigdomide and dexamethasone showed activity in heavily pretreated patients with relapsed or refractory multiple myeloma.

As stated by the investigators, “Mezigdomide … [has] potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide.”

Paul G. Richardson, MD

Study Details

In the international trial, which was performed at 40 sites, a total of 77 patients were enrolled in the dose-escalation phase by July 2022; as of September 2022, 101 patients were enrolled in the dose-expansion cohort at the mezigdomide dose selected for phase II testing. All patients in the dose-expansion cohort had disease refractory to an immunomodulatory agent (lenalidomide [in 88%] or pomalidomide [in 96%], or both), a glucocorticoid, a proteasome inhibitor, and an anti-CD38 antibody; 30% had received previous anti–B-cell maturation antigen (BCMA) therapy.

Responses

In phase I of the trial, the most common dose-limiting toxicities were neutropenia and febrile neutropenia, and the phase II dose of mezigdomide was selected as 1.0 mg once daily, combined with dexamethasone for 21 days followed by 7 days off in 28-day cycles.

In phase II, a partial response or better was observed in 41 patients (41%, 95% confidence interval [CI] = 31%–51%), with complete response or better in 5 (5%); stable disease was observed in an additional 39 patients (39%). With a median follow-up of 7.5 months (range = 0.5–21.9 months), median duration of response was 7.6 months (95% CI = 5.4–9.5 months, with data not mature) and median progression-free survival was 4.4 months (95% CI = 3.0–5.5 months). Partial repose or better was observed in 15 (50%) of patients who had received prior anti-BCMA therapy and in 12 (30%) of 40 patients with plasmacytomas.

Adverse Events

In phase II, the most common grade 3 or 4 adverse events included neutropenia (76%), anemia (36%), infections (35%, including pneumonia in 16%), thrombocytopenia (28%), febrile neutropenia (15%), and fatigue and dyspnea (5% each). Adverse events led to discontinuation of mezigdomide in six patients (6%) and were considered related to treatment in five (5%).

The investigators concluded, “The all-oral combination of mezigdomide plus dexamethasone showed promising efficacy in patients with heavily pretreated multiple myeloma, with … adverse events consisting mainly of myelotoxic effects.”

Dr. Richardson, of the Department of Medical Oncology, Dana-Farber Cancer Institute, is the corresponding author for The New England Journal of Medicine article.

Disclosure: The study was funded by Celgene, a Bristol Myers Squibb Company. For full disclosures of the study authors, visit nejm.org.