Myeloma patients may benefit from mezigdomide-dexamethasone doublet

In a study evaluating heavily pretreated patients with relapsed and refractory multiple myeloma (R/R MM), the combination of mezigdomide and dexamethasone showed promising preliminary efficacy, with myelosuppression and infection as primary toxicities.

“Mezigdomide is a novel [CELMoD*] with potent antiproliferative and tumoricidal activity in preclinical models of MM, including those resistant to lenalidomide and pomalidomide,” said the researchers.

“This study confirmed that the potent substrate degradation observed in preclinical studies of mezigdomide translated into clinical efficacy among patients with R/R MM, even [in those refractory] to lenalidomide and pomalidomide,” they continued.

Phase I: Dose-escalation

Seventy-seven patients (median age 65 years, 58 percent men) received oral mezigdomide + dexamethasone. The primary objectives were to evaluate safety and pharmacokinetics and to identify the dose and schedule for phase II. Two continuous** and two intermittent-intensive*** schedules in 28-day cycles were assessed. Median follow-up was 6.3 months. [N Engl J Med 2023;389:1009-1022]

The most common grade ≥3 AEs were neutropenia (71 percent), infection (40 percent), and anaemia (38 percent). Neutropenia and febrile neutropenia were the most frequent dose-limiting toxicities.

Of the 19 participants who had an overall response (OR), one had a complete response while the rest either had partial or very good partial response (n=9 each). Median duration of response (DoR) was 6 months.

Of the 11 patients who received the doublet for 21 days, OR was 55 percent, with a median DoR of 9.2 months. Efficacy was similar among those who received the 10-day regimen.

“[Based on] the pharmacokinetics, pharmacodynamics, safety, and preliminary efficacy data, the recommended phase II dose was determined to be 1.0 mg of mezigdomide + dexamethasone QD on the 21-day schedule,” said the researchers.

Phase II: Dose-expansion

Phase II assessed OR (partial response or better), safety, and efficacy of the doublet at the dose and schedule established in phase I. All patients (n=101; median age 67 years, 54 percent men) had TCR^# MM. Thirty patients had prior anti-B-cell maturation antigen (BCMA) therapy.

The most common grade ≥3 AEs were neutropenia, anaemia, and infection (76, 36, and 35 percent, respectively). The researchers noted that almost all of the most common AEs proved to be reversible.

After a median follow-up of 7.5 months, 41 percent of participants had an OR, median DoR was 7.6 months, and median progression-free survival (PFS) was 4.4 months.

“[The OR and PFS] confirm the activity of mezigdomide + dexamethasone in these patients, all of whom had TCR disease and had [previously received] lenalidomide and pomalidomide,” they said.

Of the 30 patients with prior anti-BCMA therapy, OR was 50 percent, while median PFS was 5.4 months. These findings imply that the doublet has an effect after failure of anti-BCMA therapy, they added.

Potential benefit in real world

“Despite a plethora of recent therapeutic advances, MM remains incurable; median survival is just above 5 years,” noted Dr Jake Shortt from Monash University, Clayton, Victoria, Australia, in an editorial. [N Engl J Med 2023;389:1046-1050]

Almost all patients who receive standard^## treatment ultimately relapse, become treatment-refractory, or both. Moreover, disease progression cuts remission periods short, and those with TCR MM have a very poor prognosis. [Hemasphere 2018;2:e45; Br J Haematol 2016;175:252-264; Leukemia 2017;31:2443-2448; Eur J Haematol 2018;100:494-501; Leukemia 2019;33:2266-2275]

“As such, alternative treatments with limited toxic 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 researchers said.

“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,” they said.

Shortt noted that while the median PFS was modest, the OR in phase II “is an encouraging outcome for an all-oral dexamethasone doublet.”