medwireNews: Mezigdomide, a novel cereblon E3 ubiquitin ligase modulator, has shown promising antitumor activity in combination with dexamethasone in a phase 1/2 trial comprising patients with relapsed and refractory multiple myeloma.
As reported in The New England Journal of Medicine, the combination achieved an overall response rate of 41% among the participants of phase 2 of the study, all of whom had triple-class–refractory disease (ie, refractory to at least one immunomodulatory agent, one proteasome inhibitor, and one anti-CD38 monoclonal antibody) and had received prior treatment with lenalidomide and pomalidomide.
The author of an accompanying editorial describes the outcome as “encouraging” for an all-oral dexamethasone doublet in a heavily pretreated and immunomodulatory imide drug (IMiD)-refractory population.
Jake Shortt (Monash University, Clayton, Victoria, Australia) adds that “[f]urther studies will determine the safety and efficacy of mezigdomide concomitant with other antimyeloma therapies.”
He continues: “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 IMiD forebears, it may also partner well with these immune effector cell–based approaches.”
The trial investigators explain that individuals with triple-class–refractory multiple myeloma “have a very poor prognosis,” and although B-cell maturation antigen (BCMA)-targeted therapies “are newly available” for these patients, “relapse will occur in most.”
The team therefore investigated mezigdomide, which has demonstrated “potent antiproliferative and tumoricidal activity in preclinical models of multiple myeloma, including those resistant to lenalidomide and pomalidomide.”
In the phase 1 dose-escalation cohort, comprising 77 patients, the researchers evaluated different doses and schedules, and selected a dose of mezigdomide of 1 mg/day given alongside dexamethasone in 28-day cycles involving 21 consecutive days on-treatment and 7 days off.
The 101 participants of phase 2 received treatment at this dose and schedule, leading to a stringent complete response in 2%, a complete response in 3%, a very good partial response in 20%, and a partial response in 16%, at a median follow-up of 7.5 months.
Responses lasted for a median of 7.6 months and the median progression-free survival was 4.4 months; the overall survival data were not mature at data cutoff.
In the subgroup of patients who had previously received anti-BCMA therapy (n=30), the overall response rate was 50%, while it was 30% in the subgroup with plasmacytomas (n=40) and 32% in the subgroup with high-risk cytogenetic abnormalities (n=37).
Turning to the safety, Paul Richardson (Dana–Farber Cancer Institute, Boston, Massachusetts, USA) and co-researchers note that adverse events (AEs) in phase 2 consisted “mainly of myelotoxic effects.” The most frequent AE of grade 3 or 4 was neutropenia, in 75% of patients, followed by anemia, infection, and thrombocytopenia, in a respective 36%, 35%, and 28% of patients.
AEs led to a dose reduction of mezigdomide in 29% of participants and treatment discontinuation in 6%. There were five AE-related deaths during the course of the study, of which two – one due to Pneumocystis jirovecii and the other due to an unknown cause – were deemed related to study treatment.
Richardson and colleagues say that “[t]his study confirmed that the potent substrate degradation observed in preclinical studies of mezigdomide translated into clinical efficacy among patients with relapsed and refractory myeloma, even in patients with disease that was refractory to lenalidomide and pomalidomide.”
They comment that although “[g]reater efficacy may be possible with CAR T-cell therapy in patients with at least three previous therapies,” they “may not be available or appropriate for all patients.”
And the team concludes: “Oral regimens such as mezigdomide and dexamethasone can readily translate a potential clinical benefit into real-world practice, especially among patients with limited access to specialized hospitals, since patients do not have to be hospitalized to receive these treatments.”
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N Engl J Med 2023; doi:10.1056/NEJMoa2303194
N Engl J Med 2023; doi:10.1056/NEJMe2307370