Mezigdomide is a novel cereblon E3 ubiquitin ligase modulator designed to achieve deep and sustained Ikaros and Aiolos degradation and overcome cereblon down-regulation and mutations observed in some patients. The phase I/II CC-92480-MM-001 study aimed to determine the therapeutic window and achieve rapid, prolonged, and maximal substrate degradation for rapid disease response while mitigating haematologic side effects.

Mezigdomide plus dexamethasone showed promising preliminary efficacy in heavily pretreated relapsed and refractory multiple myeloma population with myelosuppression and infection as the main side effects. The study findings are published by Dr. Paul G. Richardson of the Department of Medical Oncology, Dana–Farber Cancer Institute in Boston, MA, US, and colleagues on 30 August 2023 in The New England Journal of Medicine.  

Combinations of immunomodulatory agents, proteasome inhibitors, and anti-CD38 monoclonal antibodies are the standard of care in early lines of multiple myeloma therapy. However, nearly all the patients who receive these treatments ultimately have a relapse, refractory disease, or both. Patients with triple class refractory multiple myeloma have a very poor prognosis. Although therapies that target BCMA are newly available, relapse will occur in most patients, and ultimately, these agents will need to be used in combination to improve outcomes. Alternative treatments with limited side effects, ease of administration, and different mechanisms of action are needed to address resistance in refractory disease and serve as backbones across established and new treatment methods.

The cereblon E3 ligase modulator compounds are a class of novel protein degraders that co-opt cereblon, the adaptor protein for the cullin-RING E3 ubiquitin ligase. The degradation of Ikaros and Aiolos induced by mezigdomide leads to enhanced cytotoxic effects in myeloma cells in vitro, including cells that are resistant to lenalidomide and pomalidomide and those with cereblon down-regulation, as well as to direct T-cell and natural killer cell immune-stimulatory activities. Mezigdomide also has marked synergistic effects when used in combination with dexamethasone and other myeloma therapies in vitro.

The phase I/II CC-92480-MM-001, multicentre, dose-escalation and dose-expansion study evaluated multiple doses and schedules of mezigdomide plus dexamethasone in patients with heavily pretreated relapsed and refractory multiple myeloma. Mezigdomide was administered orally in combination with dexamethasone to patients with relapsed and refractory myeloma. The primary objectives of phase I (dose-escalation cohort) were to assess safety and pharmacokinetics and to identify the dose and schedule for phase II. In phase II (dose-expansion cohort), objectives included the assessment of the overall response (partial response or better), safety, and efficacy of mezigdomide plus dexamethasone at the dose and schedule determined in phase I.

In phase I, a total of 77 patients were enroled in the study. The most common dose-limiting side effects were neutropenia and febrile neutropenia. Based on the phase I findings, investigators determined the recommended phase II 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 II, a total of 101 patients received the dose identified in phase I in the same schedule. All patients in the dose-expansion cohort had triple class refractory multiple myeloma, 30 patients (30%) had received previous anti-BCMA therapy, and 40 patients (40%) had plasmacytomas. The most common adverse events, almost all of which proved to be reversible, included neutropenia occurred in 77% of the patients and infection in 65% of which grade 3 in 29% and grade 4 in 6%. No unexpected side 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 (PFS) 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).

The authors commented that this study represents the culmination of discoveries made over the past decade related to the mechanism of action of immunomodulatory agents in multiple myeloma. Lenalidomide and pomalidomide were developed empirically based on clinical observations. The understanding that they act as molecular glues to co-opt cereblon to target Ikaros and Aiolos for ubiquitination and proteasomal degradation came after their approval. This finding also led to novel insights into mechanisms of resistance, including cereblon dysregulation. Mezigdomide was designed based on these insights.

In an accompanied editorial article that aimed to explain the science behind the study, Dr. Jake Shortt of the Department of Medicine, School of Clinical Sciences at Monash Health, Faculty of Medicine, Nursing, and Health Sciences, Monash University, and Monash Haematology, Monash Health, both in Clayton, VIC, Australia wrote that an overall response to mezigdomide occurred in 41% of the patients in a heavily pretreated and immunomodulatory imide drugs refractory population, which is an encouraging outcome for an all-oral dexamethasone doublet. However, the effect on median PFS of 4.4 months was modest.

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. Further studies will determine the safety and efficacy of mezigdomide concomitant with other antimyeloma therapies. A phase III study 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 revolutionised by immunotherapies such as bispecific antibodies and chimeric antigen receptor T cells. Because mezigdomide bears the same immunostimulatory hallmarks as its immunomodulatory imide drugs forebears, it may also partner well with these immune effector cell-based approaches according to editorialist.

The study was supported by Celgene, a Bristol-Myers Squibb Company.