Mezigdomide-dexamethasone combination active in heavily pretreated multiple myeloma
The combination of mezigdomide and dexamethasone exhibited activity among patients with heavily pretreated multiple myeloma, according to study results published in The New England Journal of Medicine.
“This study represents the culmination of discoveries made over the past decade related to the mechanism of action of immunomodulatory agents in multiple myeloma,” Paul G. Richardson, MD, director of clinical research and clinical program leader at Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute and professor of medicine at Harvard Medical School, and colleagues wrote.
Although several effective treatments have been approved for multiple myeloma, the disease remains incurable.
Mezigdomide (Bristol Myers Squibb) is a novel cereblon E3 ubiquitin ligase modulator that has demonstrated promising activity in preclinical models of myeloma, including those resistant to pomalidomide and lenalidomide.
Richardson — a Healio | HemOnc Today Editorial Board Member — and colleagues conducted a phase 1/phase 2 study to assess oral mezigdomide plus dexamethasone for treatment of 178 patients with relapsed or refractory multiple myeloma.
In the phase 1 dose-escalation cohort, researchers evaluated safety and pharmacokinetics with the goal to determine the optimal phase 2 dose and schedule.
In the phase 2 dose-expansion cohort, researchers aimed to evaluate safety and efficacy — including overall response — with the combination at the dose and schedule identified in phase 1.
The most common dose-limiting toxic effects observed among the 77 patients enrolled in the phase 1 portion of the study included neutropenia and febrile neutropenia.
Researchers established the recommended phase 2 dose as 1 mg mezigdomide once daily in combination with dexamethasone for 21 days, followed by 7 days off, with treatment continuing in 28 day cycles.
In phase 2, 101 patients (median age, 67 years; range, 42-85) with triple-class-refractory multiple myeloma received the combination on that dose schedule. Forty patients (40%) had plasmacytomas and 30 (30%) had received prior anti-B-cell maturation antigen therapy (BCMA).
After median follow-up of 6.25 months, 41% (95% CI, 31-51) had responded to treatment, defined as at least 50% reduction in disease burden. Three patients achieved sustained complete response.
Researchers reported a 30% response rate among patients with extramedullary disease and a 50% response rate among patients who had been treated with anti-BCMA therapy and subsequently developed disease progression.
Researchers reported a 7.6-month (95% CI, 5.4-9.5) median duration of response, although response data had not matured. Results showed median PFS of 4.4 months (95% CI, 3-5.5).
"Our findings show that mezigdomide in combination with dexamethasone has important clinical activity in this group of patients with very hard to treat myeloma," Richardson said in a press release. “This was particularly noteworthy because we were able to see responses in patients who had received prior BCMA-targeted therapy and in myeloma that had spread beyond the bone marrow and developed aggressive extramedullary disease, which is associated with an especially poor prognosis."
The most common adverse events reported in phase 2 included neutropenia (77%) and infection (all grade, 65%; grade 3, 29%; grade 4, 6%). Nearly all of these events proved reversible, according to investigators.
Researchers observed no unanticipated adverse effects.
"We're hopeful that this body of data provides substantial evidence of the value of this approach to patients with an urgent unmet medical need, and further supports this oral agent being tested in combination with other backbone therapies, where our preliminary results are already promising, and now are being evaluated as part of larger, ongoing phase 3 clinical trials," Richardson said.
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