Mezigdomide shows encouraging activity with dexamethasone in heavily pretreated patients with multiple myeloma

Paul G. Richardson, MD

Mezigdomide (CC-92480), a potent new CELMoD compound with a preclinical profile differentiated from immunomodulatory agents, has shown remarkable clinical activity and a manageable safety profile when combined with dexamethasone in patients with relapsed or refractory triple-class multiple myeloma. Preliminary data from the Phase 2 dose expansion cohort from Phase 1/2 study CC-92480-MM-001 (NCT03374085) were presented at the 2022 ASH Annual Meeting.1

Among patients who received a median of 6 (range, 3-15) prior lines of therapy (n = 101), the objective response rate (ORR) to mezigdomide plus dexamethasone was 40.6%, including 2 ( 2.0%) patients with strict complete therapy response (CR) and 3 (3.0%) with CR. Among the 30 patients who received prior anti-BCMA therapy, the ORR was 50.0% with 1 CR (3.1%).1

“In our Phase 1 study, at the recommended Phase 2 dose [1 mg daily 3 weeks on, 1 week off] we were able to show a response of 54.5%2,” said Paul G. Richardson, MD, in a presentation of the data. “The goal of this Phase 2 dose expansion cohort was to report on the efficacy and safety of the combination strategy in a significantly larger group of patients”.

In an intention-to-treat (ITT) analysis, the median progression-free survival (PFS) was 4.4 months (95% CI, 3.0-5.5), with the caveat that follow-up median was just 7.46 months,1 said Richardson, MD, director of clinical research, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School, Boston “The duration of response is encouraging, even though early again,” he said. The median duration of response (DOR) was 7.6 months (95% CI, 5.4-9.5) for 41 responders.1

Among patients with extramedullary disease, as evidenced by the soft tissue-only category and soft tissue bone-related plasmacytoma (n = 40), “we saw a 30% response rate, which was particularly surprising,” he has declared. added.

In addition to the 2% who had a strict CR and 3% with a CR, 19.8% had a very good partial response (VGPR) and 15.8% had a partial response (PR) in the ITT population . Of patients with plasmacytomas, the CR rate was 5.0%, 17.5% had a VGPR, and 7.5% had a PR. Of those exposed to prior anti-BCMA therapy, 9 patients (30.0%) had a VGPR and 5 (16.7%) had a PR. Time to first response in all patients was a median of 0.95 months, a median of 2.17 months in patients with plasmacytomas, and a median of 2.1 months in those with prior anti-BCMA exposure.1

Stable disease was reported in 38.6%, 52.5%, and 36.7% of patients in the ITT, plasmacytoma, and anti-BCMA populations, respectively.

The median DOR for patients with VGPR or better was 9.2 months (95% CI, 6.4-not reached) and the DOR for those with PR was 5.1 months (95% CI, 2.6- 8.3).1

Mezigdomide induces the greatest degradation of Ikaros and Aiolos, leading to increased apoptosis in myeloma cells, Richardson noted. From the Phase 1 portion of the study, the recommended Phase 2 dose of mezigdomide in combination with dexamethasone was selected at 1 mg once daily for 21/28 days.

Key study eligibility criteria were at least 3 prior lines of therapy, refractoriness to immunomodulators, proteasome inhibition, and anti-CD38 antibodies, defined as progression or refractoriness within 60 days or during treatment. Prior exposure to anti-BCMA therapy was permitted; 30 patients (29.7%) were previously treated with anti-BCMA therapy. Mezigtomide was given for 3 weeks on and 1 week off, and dexamethasone was combined with 40 mg on a weekly schedule or 20 mg in patients 75 years of age and older.

The mean age of the 101 enrolled patients was 67 years (range 42-85) and the median time since initial diagnosis was 7.4 years (range 1.1-37.0). Twenty-one patients (20.8%) had stage III disease according to the International Staging System criteria at entry, and Richardson noted: “More importantly, [patients in this cohort] were enriched for extramedullary disease, with about 40% of patients having this finding, as well as high-risk cytogenetics in about a third. All patients were refractory to immunomodulatory drugs.1

Treatment is ongoing in 10 patients. A total of 91 patients discontinued treatment, 60.4% due to progressive disease. Eight (7.9%) patients died during the study, 5 (5%) due to adverse events (AEs). One death was related to COVID-19 infection; A total of 17 (16.8%) patients developed COVID-19. The median number of cycles received was 4. The relative dose strength of mezigdomide was 0.88. The incidence of dose interruptions was 88.1% and the incidence of dose reductions was 31.7%.1 “Few patients discontinued treatment due to adverse events, with related mortality to minimal treatment,” he said.

Treatment-emergent adverse events were primarily hematologic dominated by neutropenia, with an all-grade incidence of 77.2%, grade 3 incidence of 21.8%, and grade 4 incidence of 53.5%. %. “[Neutropenia] generally proved to be very manageable with growth factor support, dose reduction, and dose interruption,” Richardson said. Other common hematologic adverse events of all grades included anemia (52.5%), thrombocytopenia ( 42.6%) and febrile neutropenia (14.9%).

Nonhematologic adverse events were generally manageable, Richardson said, and in addition to infection (65.3%) and fatigue (35.6%), consisted mostly of gastrointestinal discomfort. The incidence of any grade pneumonitis was 21.8%, with grade 3 and 4 reported in 13 patients (12.9%) and 3 patients (3.0%), respectively.

Mezigdomide is being evaluated in combination with standard therapies in MM in a large ongoing Phase 1/2 study (NCT03989414) and 2 Phase 3 studies—Successor-1 (NCT05519085) and Successor-2 (NCT05552976)— in combination with bortezomib (Velcade) and carfilzomib (Kyprolis) are enrolling patients. Richardson said enrollment in the mezigdomide monotherapy group of CC-92480-MM-001 is also ongoing, as well as for a targeted strategy for colleagues evaluating the agent in Japan.

References

  1. Richardson PG, Trudel S, Quach H, et al. Mezigdomide (CC-92480), a new and potent modulator of cereblon E3 ligase (CELMoD), combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): preliminary results from the dose expansion phase of the study Try CC-92480-MM-001. Blood. 2022;140(suppl 1):1366-1368. doi:10.1182/blood-2022-157945
  2. Richardson PG, Vangsted AJ, Ramasamy K, et al. First phase I human study of the novel agent CELMoD CC-92480 combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2020;38(suppl 15):8500. doi:10.1200/JCO.2020.38.15_suppl.8500

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