Mezigdomide Regimens Show Promise in Pretreated R/R Multiple Myeloma

Mezigdomide with dexamethasone and bortezomib or carfilzomib led to a median PFS exceeding 1 year across 3 cohorts in those with relapsed/refractory MM.

Mezigdomide (Mezi) plus dexamethasone and bortezomib (Velcade; MeziVd) or carfilzomib (Kyprolis; MeziKd) demonstrated promising efficacy and a manageable safety profile across all dose levels in patients with relapsed or refractory multiple myeloma, as shown in the results of the phase 1/2 CC-92480-MM-002 trial (NCT03989414) shared at the European Hematology Association 2025 Congress.

In dose-escalation cohort A (n = 28), with a median follow-up of 13.7 months, MeziVd led to a median progression-free survival (PFS) of 12.3 months; at the 0.3 mg dose level, it was 13.4 months (95% CI, 0.7-not evaluable [NE]); at the 0.6 mg dose level, it was 11.2 months (95% CI, 2.1-NE); and at the 1.0 mg dose level, it was 12.3 months (95% CI, 3.5-NE). The overall response rate (ORR) and median duration of response (DOR) at all doses was 75.0% (95% CI, 55.1%-89.3%) and 10.9 months (95% CI, 8.8-18.7); at 1.0 mg, they were 60.0% (95% CI, 55.1%-89.3%) and 11.6 months (95% CI, 5.3-not applicable [NA]).

In dose-expansion cohort D (n = 49), with a median follow-up of 18.3 months, MeziVd led to a median PFS of 17.5 months; at the 0.6 mg dose level, it was 20.8 months (95% CI, 8.3-NE); and at the 1.0 mg dose level, it was 16.6 months (95% CI, 6.7-24.0). At all dose levels, the ORR and median DOR were 85.7% (95% CI, 72.8%-94.1%) and 19.4 months (95% CI, 9.7-NA), and at 1.0 mg, they were 84.2% (95% CI, 68.7%-94.0%) and 19.4 months (95% CI, 7.0-NA).

In dose-escalation cohort C (n = 27), with a median follow-up of 15.2 months, MediKd led to a median PFS of 13.5 months; at the 0.3 mg dose level, it was 11.7 months (95% CI, 2.1-NE); at the 0.6 mg dose level, it was 13.5 months (95% CI, 1.0-NE); and at the 1.0 mg dose level, it was 13.8 months (95% CI, 1.2-NE). At all dose levels, the ORR was 85.2% (95% CI, 66.3%-95.8%), and the median DOR was 11.9 months (95% CI, 6.4-35.9). At 1.0 mg, the ORR was 77.8% (95% CI, 40.0%-97.2%), and the median DOR was 11.9 months (95% CI, 0.2-NA).

“MeziVd and MeziKd in [relapsed/refractory multiple myeloma] confirmed promising efficacy at all dose levels tested, including at the 1.0 mg dose, in patients with [relapsed/refractory multiple myeloma] previously exposed to [immunomodulatory drug agents], [proteasome inhibitors], and anti-CD38 [monoclonal antibodies],” wrote lead study author Irwindeep Sandhu, MD, assistant professor of medicine at the University of Alberta in Edmonton, Alberta, Canada. “These results support the investigation of Mezi in phase 3 trials of patients with [relapsed/refractory multiple myeloma].”

The trial enrolled patients with a documented diagnosis of multiple myeloma and measurable diseases with documented progression during or after the last antimyeloma therapy. Additionally, patients had a minimal response or better to at least 1 prior regimen; patients were permitted 2 to 4 prior regimens in cohorts A and C and 1 to 3 prior regimens in cohort D, or exposure to lenalidomide (Revlimid) for at least 2 consecutive cycles.

Patients in cohorts A and C received 0.3, 0.6, or 1.0 mg of mezigdomide, and those in cohort D received 0.6 or 1.0 mg. In cohorts A and D, bortezomib and oral dexamethasone were administered at 1.3 mg/m2 and 20 or 10 mg; in cohort C, carfilzomib was given at 20 mg/m2 on cycle 1, day 1 then 56 mg/m2, and oral dexamethasone at 40 or 20 mg.

The median age of patients in cohort A, cohort D, and cohort C were 65.5 years, 64.0 years, and 68.0 years, respectively; an ECOG performance status of 1 was observed in 53.6%, 51.0%, and 55.6%; and International Staging System (ISS) stage I disease at study entry was observed in 71.4%, 69.4%, and 77.8%.

The median number of prior therapies was 3 in cohort A, 1 in cohort D, and 2 in cohort C; a proteasome inhibitor was received by 96.4%, 89.8%, and 100.0%, respectively; an immunomodulatory drug agent by 100.0% in all cohorts; and anti-CD38 monoclonal antibodies by 50.0%, 38.8%, and 81.5%.

The trial’s primary end points were recommended dose, safety, and preliminary efficacy as ORR.

Treatment was discontinued by 89.3% of cohort A, 81.6% of cohort D, and 81.5% of cohort C; reasons were progressive disease (64.3%, 53.1%, and 48.1%, respectively) and adverse events (AEs; 7.1%, 16.3%, and 14.8%).

Regarding safety, in cohort A, grade 3 or 4 hematologic treatment-emergent AEs (TEAEs) were neutropenia (16.7% at 0.3 and 0.6 mg; 70.0% at 1.0 mg), thrombocytopenia (27.8%; 10.0%), and anemia (16.7%; 10.0%). Grade 3 to 4 infection-related TEAEs occurred in 27.8% and 0%.

In cohort D, they were neutropenia (72.7% at 0.6 mg; 60.5% at 1.0 mg), thrombocytopenia (18.2%; 28.9%), and anemia (0%; 7.9%). Grade 3 or 4 infection-related TEAEs occurred in 18.2% and 36.8%.

In cohort C, they were neutropenia (33.3% at 0.3 and 0.6 mg; 66.7% at 1.0 mg), thrombocytopenia (5.6% and 33.3%), and anemia (11.1% and 22.2%). Grade 3 or 4 infection-related TEAEs occurred in 33.3% and 33.3%.

Reference

Sandhu I, Richardson PG, Oriol A, et al. Mezigdomide (Mezi) plus dexamethasone (Dex) and bortezomib (Bort) or carfilzomib (Cfz) in patients with relapsed/refractory multiple myeloma (RRMM): updated results from the CC-92480-MM-002 trial. Presented at: European Hematology Association 2025 Congress; June 12-15, 2025; Milan, Italy. Abstract PF723.