Mezigdomide With Dexamethasone Appears Active in Heavily Pretreated Patients With Multiple Myeloma

Paul G. Richardson, MD

Remarkable clinical activity and a manageable safety profile was shown with the potent novel CELMoD compound, mezigdomide (CC-92480) when combined with dexamethasone in patients with triple-class relapsed or refractory multiple myeloma. Preliminary data from the phase-2 dose expansion cohort of the phase 1/2 CC-92480-MM-001 study (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 stringent complete response (CR) and 3 (3.0%) with CRs. 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,” Paul G. Richardson, MD, said in a presentation of the data. “The objective 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 median follow-up was only 7.46 months1, said Richardson, 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, albeit again early,” he said. The median duration of response (DOR) was 7.6 months (95% CI, 5.4-9.5) for 41 responders.1

Among patients who had extramedullary disease, as reflected by the category of soft tissue only as well as soft tissue bone-related plasmacytoma (n = 40), “we saw a response rate of 30%, which was particularly striking we thought,” he added.

In addition to the 2% who had a stringent CR and the 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 the 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 a PR was 5.1 months (95% CI, 2.6-8.3).1

Mezigdomide induces maximal 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 on treatment. Prior exposure to anti-BCMA therapy was permitted; 30 patients (29.7%) were treated with anti-BCMA therapy previously. Mezigtomide was given 3 weeks on and 1 week off, and dexamethasone was partnered at 40 mg on a weekly schedule, or 20 mg in patients aged at least 75 years.

The median age of the 101 patients enrolled 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 per International Staging System criteria at entry and Richardson noted, “More importantly, [patients in this cohort] were enriched for extramedullary disease, with approximately 40% of patients with this finding, as well as high risk cytogenetics in approximately one-third.” All patients were refractory to immunomodulatory drugs.1

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

Treatment-emergent AEs 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 very manageable with growth factor support, dose reduction, and dose interruption,” Richardson said. Other common all-grade hematologic AEs included anemia (52.5%), thrombocytopenia (42.6%), and febrile neutropenia (14.9%).

Nonhematologic AEs were generally manageable, Richardson said, and other than infection (65.3%) and fatigue (35.6%), consisted mainly of gastrointestinal disturbance. The incidence of any-grade pneumonia 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 as part of a large, ongoing phase 1/2 trial (NCT03989414), and 2 phase 3 trials—Successor-1 (NCT05519085) and Successor-2 (NCT05552976)—in combination with bortezomib (Velcade) and carfilzomib (Kyprolis) are enrolling patients. Richardson mentioned that enrollment is also ongoing in the mezigdomide monotherapy group of CC-92480-MM-001 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 potent, novel cereblon E3 ligase modulator (CELMoD), combined with dexamethasone (DEX) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): preliminary results from the dose-expansion phase of the CC-92480-MM-001 trial. Blood. 2022;140(suppl 1):1366-1368. doi:10.1182/blood-2022-157945}

_{2. Richardson PG, Vangsted AJ, Ramasamy K, et al. First-in-human phase I study of the novel CELMoD agent 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}