At Multiple Dose Levels, Mezigdomide Elicits Responses in Combination With Bortezomib or Carfilzomib in R/R Myeloma

Albert Oriol, PhD

Mezigdomide in combination with either bortezomib (Velcade) and dexamethasone or carfilzomib (Kyprolis) and dexamethasone showed encouraging responses across multiple dose levels in patients with relapsed/refractory multiple myeloma, according to longer follow-up of the phase 1/2 dose-escalation/-expansion CC-92480-MM-002 trial (NCT03989414).¹

Results, which were presented at the 2023 IMS Annual Meeting, showed that, in a dose-escalation cohort (cohort A), the triplet regimen elicited an 77.8% objective response rate (ORR) at the 0.3-mg mezigdomide dose (n = 9), which included a 22.2% stringent complete response (sCR) rate, a 22.2% very good partial response (VGPR) rate, and a 33.3% partial response (PR) rate. One patient had stable disease (SD) and 1 patient had progressive disease (PD).

At the 0.6-mg dose of mezigdomide (n = 9), the ORR was 88.9%, and 1 person each had an sCR, complete response (CR), and VGPR; the PR rate was 55.6%. One patient had SD. At the 1-mg dose (n = 10), the ORR was 60.0% and 1 patient had an sCR; the VGPR rate was 30.0%, the PR rate was 20.0%, 1 patient had a molecular response (MR) and 3 patients (30.0%) had SD.

In a dose-expansion cohort of the combination treatment (cohort D), the ORR at the 0.6-mg dose (n = 11), was 90.9% and the sCR rate was 27.3%. The VGPR rate was 54.5%, the PR rate was 9.1%, and 1 patient had SD. At the 1.0-mg dose in this cohort (n = 38), the ORR was 84.2%, which included a 7.9% sCR rate, a 10.5% CR rate, a 44.7% VGPR rate, a 21.1% PR rate, and a 2.6% MR rate. The SD rate was 7.9%, the PD rate was 2.6%, and 1 patient was not evaluable.

“Responses were deep and durable, with many patients remaining on treatment after 1 year,” lead study author Albert Oriol, PhD, head of the Clinical Research Unit at Catalan Institute of Oncology and Josep Carreras Institute, Hospital Germans Trias i Pujol, in Badalona, Spain, said in a presentation during the meeting.

Mezigdomide is a potent, oral CRBN E3 ligase modulator (CELMoD), that is created to have rapid and maximal degradation of Ikaros and Aiolos. In myeloma cells, this leads to immune-modulatory effects and enhanced tumoricidal activity.

When studied in combination with dexamethasone alone, mezigdomide elicited clinical activity and had a manageable safety profile in patients with relapsed/refractory multiple myeloma.²

In a phase 1 study, mezigdomide plus bortezomib/dexamethasone and carfilzomib/dexamethasone in this patient population also had encouraging data. Here, the 1.0-mg dose plus bortezomib/dexamethasone was identified to use in a dose-expansion cohort.³

In the phase 1/2 CC-92480-MM-002 study, investigators evaluated mezigdomide with various treatment regimens in multiple myeloma. To be eligible for enrollment, patients must have had measurable multiple myeloma that had progressed during or after their most recent antimyeloma treatment and had a molecular response or better to at least 1 of their prior regimens, which include 2-4 for cohorts A and C, 1-3 for cohort D, and lenalidomide (Revlimid) for at least 2 consecutive cycles.

At the 2023 IMS, updated data from the mezigdomide plus bortezomib/dexamethasone (MeziVd; cohort A) and carfilzomib/dexamethasone (MeziKd; cohort C) dose-escalation cohorts, and the MeziVd dose-expansion cohort (D) were reported. Cohort B, which comprised mezigdomide plus daratumumab (Darzalex) and dexamethasone, and cohort H, of mezigdomide plus elotuzumab (Empliciti) and dexamethasone, were not reported.

In cohort A, oral mezigdomide was given at 0.3, 0.6, or 1.0 mg on days 1 to 14; subcutaneous bortezomib was given at 1.3 mg/m² on days 1, 4, 8, and 11 in cycles 1 through 8, followed by days 1 and 8 in cycles 9 and beyond. Oral dexamethasone was given at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 in cycles 1 through 8 and on days 1, 2, 8, and 9 in cycles 9 and beyond. All cycles were 21 days.

In cohort D, mezigdomide was given at 0.6 or 1.0 mg on days 1 to 14; subcutaneous bortezomib was given at 1.3 mg/m² on days 1, 4, 8, and 11 in cycles 1 through 8, followed by days 1 and 8 in cycles 9 and beyond. Oral dexamethasone was given at 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 in cycles 1 through 8 and on days 1, 2, 8, and 9 in cycles 9 and beyond. All cycles were 21 days.

In cohort C, mezigdomide was given at 0.3, 0.6, or 1.0 mg on days 1 to 21; intravenous (IV) carfilzomib was given at 20 mg/m² on day 1 of cycle 1, followed by 56 mg/m² on days 8 and 15 of cycle 1, on days 1, 8, and 15 in cycles 2 through 12, and on days 1 and 15 of cycles 13 and beyond. Oral or IV dexamethasone was given at 40 mg on days 1, 8, 15, and 22. All cycles were 28 days.

The primary end points were the recommended dose and regimen for cohorts A and C, safety, and efficacy as it relates to ORR.

Regarding baseline characteristics in cohort A (n = 28), the median age was 65.5 years (range, 46-86) and 57.1% of patients were female. The median time since initial diagnosis was 4.8 years (range, 1.9-17.1), more than half (53.6%) had an ECOG performance status of 1, and the International Staging System (ISS) was I, II, and III in 71.4%, 21.4%, and 7.1% of patients, respectively. A total 17.9% of patients had plasmacytomas present and 42.9% of patients had high-risk cytogenetics.

In cohort D (n = 49), the median age was 64.0 years (range, 43-83) and 32.7% of patients were female. The median time since initial diagnosis was 4.4 years (range, 0.9-20.5), more than half (51.0%) had an ECOG performance status of 1, and the ISS was I, II, and III in 69.4%, 18.4%, and 12.2% of patients, respectively. A total 10.2% of patients had plasmacytomas present and 55.1% of patients had high-risk cytogenetics.

In cohort C (n = 27), the median age was 68.0 years (range, 41-76) and 66.7% of patients were female. The median time since initial diagnosis was 5.4 years (range, 0.7-15.7), more than half (55.6%) had an ECOG performance status of 1, and the ISS was I, II, and III in 77.8%, 11.1%, and 11.1% of patients, respectively. A total 11.1% of patients had plasmacytomas present and 59.3% of patients had high-risk cytogenetics.

Most patients had been exposed to a proteasome inhibitor (cohort A, 96.4%; cohort D, 89.8%; cohort C, 100%), and were refractory to immunomodulatory agents (85.7%, 63.3%, and 88.9%), respectively. Fifty percent of patients in cohort A were refractory to a proteasome inhibitor vs 16.4% and 51.9% in cohorts D and C, respectively. Additionally, half of patients in cohort A were refractory to an anti-CD38 monoclonal antibody vs 34.7% in cohort D and 74.1% in cohort C. In cohorts A, D, and C, 32.1%, 2.0%, and 37.0% were triple-class refractory, respectively.

Most patients in cohort A (89.3%) discontinued treatment compared with 67.3% and 70.4% in cohorts D and C, respectively; this was due to adverse effects (AEs) in 7.1%, 14.3%, and 14.8% of patients, respectively. Two patients died in cohort D and 1 in cohort C.

Additional efficacy findings showed that, in cohort A, the median time to first response (TTFR) was 1.38 months (range, 0.7-3.3), the median duration of response (DOR) was 10.9 months (95% CI, 8.8-32.8), and the follow-up time was 13.6 months (range, 3.2-44.7). In cohort D, the median TTFR was 0.89 months (range, 0.7-2.4), the median DOR was not reached (NR; 95% CI, 12.1-NR), and the median follow-up time was 12.71 months (range, 1.5-26.1).

In the dose-escalation cohort (cohort C), in patients who received the 0.3-mg dose (n = 9), the ORR was 88.9%, which included a 22.2% CR rate, a 33.3% VGPR rate, a 33.3% PR rate, and a 11.1% MR rate. The ORR was also 88.9% with the 0.6-mg dose (n = 9); the sCR rate was 11.1%, the VGPR rate was 22.2%, the PR rate was 55.6%, and 11.1% of patients had PD.

Finally, at the 1.0 mg-dose in cohort C (n = 9), the ORR with mezigdomide and carfilzomib/dexamethasone was 77.8%, with 1 CR, a 33.3% VGPR rate, a 33.3% PR rate, 1 MR, and 1 patient had SD. The median TTFR was 0.95 months (range, 0.9-5.1), the median DOR was 12.3 months (95% CI, 6.4-NR), and the median follow-up time was 12.45 months (95% CI, 1.1-31.5).

Mezigdomide also elicited responses regardless of patients being refractory to prior therapy with pomalidomide (Pomalyst) as well as lenalidomide and an anti-CD38 monoclonal antibody.

Pharmacodynamic activity was also observed with mezigdomide in combination with either carfilzomib or bortezomib at all tested dose levels; the 1.0-mg dose of mezigdomide showed the greatest substrate degradation and immune modulation across cohorts.

In the dose-escalation phase 1 portion, all-grade treatment-emergent adverse effects (TEAEs) at all doses in cohort A included neutropenia (53.6%), anemia (46.4%), and thrombocytopenia (35.7%). Infections occurred in 71.4% of patients at all doses in the form of upper respiratory tract infection (25.0%), pneumonia (10.7%), and COVID-19 (10.7%). Oriol noted that grade 3/4 AEs were mostly hematologic; there were few non-hematologic grade 3/4 AEs.

In the phase 2 dose-expansion portion, all-grade TEAEs at all doses in cohort D included neutropenia (77.6%), anemia (44.9%), and thrombocytopenia (49.0%). Infections occurred in 79.6% of patients at all doses in the form of pneumonia (28.6%) and COVID-19 (38.8%).

Similar results were observed in the phase 1 dose-escalation portion for cohort C. Here, all-grade TEAEs included neutropenia which was reported in 55.6% of patients, followed by thrombocytopenia (51.9%) and anemia (37.0%). Infections occurred in 70.4% of patients at all doses in the form of pneumonia (22.2%) and COVID-19 (51.9%).

These data, Oriol noted, support additional studies of mezigdomide in the phase 3 SUCCESSOR-1 (NCT05519085) and SUCCESSOR-2 (NCT05552976) trials in this patient population.

References

1. Oriol A, Sandhu I, Raab MS, et al. Mezigdomide (MEZI) plus dexamethasone (DEX) and bortezomib (BORT) or carfilzomib (CFZ) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): results from the CC-92480-MM-002 trial. Presented at: International Myeloma Symposium; September 27-30, 2023; Athens, Greece. Abstract OA-49.
2. Richardson PG, Trudel S, Popat R, et al. Mezigdomide plus dexamethasone in relapsed and refractory multiple myeloma. N Eng J Med. 2023;389(11):1009-1022. doi:10.1056/NEJMoa2303194
3. Richardson PG, at 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