Mezigdomide Plus Dexamethasone Elicits Responses With Acceptable Safety in R/R Myeloma

Paul G. Richardson, MD

Treatment with combination of mezigdomide (CC-92480) and dexamethasone produced responses with a safety profile that consisted primarily of myelotoxic adverse effects (AEs) in heavily pretreated patients with relapsed/refractory multiple myeloma, according to data from a phase 1/2 trial (NCT03374085) published in the New England Journal of Medicine.

Findings showed that at a median follow-up of 6.3 months (range, 0.6-33.1), patients treated in the phase 1 dose-escalation cohort (n = 77) experienced an overall response rate (ORR) of 25% (95% CI, 16%-36%), which included a complete response (CR) rate of 1%, a very good partial response (VGPR) rate of 12%, and a partial response (PR) rate of 12%. Minimal response was observed in 5% of patients, stable disease (SD) was reported in 44% of patients, and progressive disease occurred in 22% of patients; 4% of patients could not be evaluated for response.

At a median follow-up of 7.5 months (range, 0.5-21.9), patients treated in the phase 2 dose-expansion cohort (n = 101) achieved an ORR of 41% (95% CI, 31%-51%), including a stringent CR rate of 2%, a CR rate of 3%, a VGPR rate of 20%, and a PR rate 16%. The rates of minimal response, SD, and progressive disease were 6%, 39%, and 10%, respectively. Five percent of patients could not be evaluated for response.

“This study confirmed that the potent substrate degradation observed in preclinical studies of mezigdomide translated into clinical efficacy among patients with relapsed and refractory myeloma, even in patients with disease that was refractory to lenalidomide [Revlimid] and pomalidomide [Pomalyst],” lead study author Paul G. Richardson, MD, and colleagues, wrote in the article. Richardson is the clinical program leader and director of clinical research at the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Center, and the RJ Corman Professor of Medicine at Harvard Medical School, both in Boston, Massachusetts.

In the dose-escalation cohort, the most common AEs included neutropenia (any-grade, 81%; grade 3, 23%; grade 4, 48%), anemia (61%; 38%; 0%), thrombocytopenia (51%; 12%; 12%), infections/infestations (74%; 36%; 4%), and fatigue (40%; 10%; 0%). The most common dose-limiting toxicities (DLTs) were neutropenia and febrile neutropenia. Six patients died due to reasons other than disease progression; AEs led to 3 deaths: rhinovirus pneumonia, influenza, and brain abscess associated with meningoencephalitis caused by listeria infection. Only the brain abscess was considered related to study treatment. Two patients died due to malignant disease that did not meet the specific International Myeloma Working Group criteria for disease progression.

In the dose-expansion cohort, the most common AEs consisted of neutropenia (any-grade, 77%; grade 3, 22%; grade 4, 54%), anemia (52%; 35%; 1%), thrombocytopenia (43%; 14%; 14%), infections/infestations (65%; 29%; 6%), and fatigue (36%; 5%; 0%). Five deaths were attributed to AEs, including Pneumocystis jiroveci pneumonia (n = 2), pneumonia (n = 1), COVID-19 (n = 1), and septic shock (n = 1). Two patients died due to the malignant disease, and 1 died due to an unknown cause. The death due to unknown cause and 1 death due to Pneumocystis jiroveci pneumonia were considered treatment related.

During the dose-escalation portion of the open-label, multicenter trial, investigators enrolled patients at least 18 years of age with relapsed/refractory multiple myeloma who received at least 3 prior lines of therapy, including lenalidomide, pomalidomide, a proteasome inhibitor (PI), a glucocorticoid, and an anti-CD38 antibody. Patients were required to have disease progression during the 60 days following the final dose of their last anti-myeloma therapy. An ECOG performance status of 0 to 2, and adequate bone marrow, renal, and cardiac function were also necessary.

Patients enrolled in the dose-expansion portion of the study also needed to have disease that was refractory to lenalidomide and/or pomalidomide, a glucocorticoid, a PI, and an anti-CD38 antibody.

Phase 1 assessed 4 administration schedules of mezigdomide plus dexamethasone: 2 continuous schedules and 2 intermittent-intensive schedules. The continuous schedules featured 10 days of treatment, followed by 4 days off, then repeated (the 10-day schedule), or 21 consecutive days of treatment, followed by 7 days off (the 21-day schedule). Those treated on an intermittent-intensive schedule received treatment for 3 days, followed by 11 days off, then repeated (the 3-day schedule), or 7 days of treatment, followed by 7 days off, then repeated (the 7-day schedule). Mezigdomide was given up to a maximum tolerated dose of 1.0 mg.

In phase 2, patients received 1.0 mg of mezigdomide once daily plus dexamethasone on the 21-day schedule.

The primary end points for phase 1 portion of the research were safety, pharmacokinetics, and to determine the maximum tolerated dose and recommended phase 2 dose (RP2D). For phase 2, the primary end point was ORR. Secondary end points included safety, duration of response (DOR), progression-free survival (PFS), clinical benefit rate, and disease control rate.

In the dose-escalation cohort, the median age was 65 years (range, 40-78). Most patients were male (58%), White (90%), and had an ECOG performance status of 1 (64%). The median time since diagnosis was 7.2 years (range, 0.9-23.2). Patients had an International Staging System (ISS) score of I (32%), II (44%), III (22%), or missing data (1%). Thirty percent of patients had a high-risk cytogenetic profile, 6% had standard risk, and data were missing for 64%. Thirty-five percent of patients had plasmacytomas.

Patients treated in phase 1 received a median of 6 prior lines of therapy (range, 2-13), including stem cell transplant (78%), a PI (100%), lenalidomide (99%), pomalidomide (92%), and an anti-CD38 antibody (78%). Twelve percent of patients also received prior BCMA-targeted therapy, which included an antibody-drug conjugate (ADC; 9%), a T-cell engager (1%), and CAR T-cell therapy (1%). Patients were also refractory to an Immunomodulatory agent (95%), lenalidomide (81%), pomalidomide (84%), a proteasome inhibitor (75%), and an anti-CD38 antibody (70%). Fifty-six percent were triple-class refractory.

In the dose-expansion cohort, the median age was 67 years (range, 42-85). Most patients were male (54%), White (76%), and had an ECOG performance status of 1 (56%). The median time since diagnosis was 7.4 years (range, 1.1-37.0). ISS score included I (39%), II (41%), and III (21%). Thirty-seven percent of patients had high-risk cytogenetics, 8% had standard risk, and data were missing for 55%. Forty percent of patients had plasmacytomas.

Patients received a median of 6 prior lines of therapy (range, 3-15). All patients previously received a proteasome inhibitor, lenalidomide, pomalidomide, and an anti-CD38 antibody. Seventy-seven percent of patients received a prior stem cell transplant, and 30% received previous BCMA-directed therapy. Prior anti-BCMA therapy included an ADC (22%), a T-cell engager (8%), and CAR T-cell therapy (3%). All patients were triple-class refractory. Eighty-eight percent and 96% of patients were refractory to lenalidomide and pomalidomide, respectively.

Additional data from phase 1 showed that the median DOR was 6.0 months (95% CI, 1.9-11.1). 

Patients treated on the 10-day schedule (n = 10) experienced an ORR of 40%, and those treated on the 21-day schedule with 1.0 mg of mezigdomide (n = 11) achieved an ORR of 55%. In those 11 patients treated on the 21-day schedule at the RP2D, the median DOR was 9.2 months (95% CI, 1.0-12.2).

For the overall dose-expansion cohort, the median DOR was 7.6 months (95% CI, 5.4-9.5), although data were not yet mature. The median PFS was 4.4 months (95% CI, 3.0-5.5), and overall survival data were not mature.

In patients treated in phase 2 who had plasmacytomas (n = 40) and received prior anti-BCMA therapy (n = 30), the ORRs were 30% (95% CI, 17%-46%) and 50% (95% CI, 31%-69%), respectively. Those who received prior BCMA-directed therapy experienced a median DOR or 6.9 months (95% CI, 4.5–not estimable [NE]) and a median PFS of 5.4 months (95% CI, 2.1-9.4).

Patients who harbored high-risk cytogenetics (n = 37) achieved an ORR of 32% (95% CI, 18%-50%) with a median DOR of 10.0 months (95% CI, 1.9-NE) and a median PFS of 2.8 months (95% CI, 1.9-4.7).

In phase 1, AEs led to dose reductions in 25% of patients. In phase 2, 29% of patients underwent dose reductions due to AEs, and 6% of patients discontinued treatment due to AEs. Discontinuations were attributed to mezigdomide in 5% of patients. Additionally, 10% of patients experienced 2 or more dose reductions.

“Disease-related AEs were the most common cause of death during the study in this heavily pretreated population, with only a small number of AEs considered to be related to the study drug,” study authors concluded. “Given the safety profile of the 1.0-mg dose, dosing options for mezigdomide plus dexamethasone in combination with other agents will continue to be explored.”

Reference

Richardson PG, Trudel S, Popat R, et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Engl J Med. Published online August 30, 2023. doi:10.1056/NEJMoa2303194