Mezigdomide with bortezomib or carfilzomib for RRMM

Mezigdomide is an oral cereblon E3 ligase modulator (CELMoD) that induces apoptosis in multiple myeloma cells, creating a tumoricidal effect.¹ The Multiple Myeloma Hub previously spoke to Paul Richardson about CELMoD; you can listen to the podcast here.

The first-in-human phase I dose escalation trial of mezigdomide, the CC-92480-MM-001 trial, showed promising preliminary results when mezigdomide was used in combination with dexamethasone, with an overall response rate of 55%.¹ At the 19th International Myeloma Society Annual Meeting, Paul Richardson presented results from the CC-92480-MM-002 phase I/II dose escalation trial, where mezigdomide is evaluated in combination with dexamethasone and a proteasome inhibitor.¹ We are pleased to provide a summary of this presentation here.

Study design

Phase I of the trial involved dose escalation, with patients receiving a 1 mg dose of mezigdomide in combination with two other drugs. Phase II of the trial involved dose expansion, using the results from phase I to determine the dosing regimen. In total, there were ten cohorts in this trial, evaluating mezigdomide with bortezomib, carfilzomib, daratumumab, elotuzumab, and isatuximab. The phase I results from Cohort A (mezigdomide with bortezomib and dexamethasone; Mezi-Vd) and Cohort C (mezigdomide with carfilzomib and dexamethasone; Mezi-Kd) and phase II results from Cohort D (Mezi-Vd) are shown in this article.

Dosing schedules for Cohorts A, C and D are shown in Figure 1. The primary endpoints of the trial were to determine a dose and regimen (phase I) and to evaluate the safety and overall response rate of the regimen.

*Adapted from Richardson.^1
†10 mg given if >75 years old.
^‡On Cycle 1 Day 1, 20 mg/m² was given.
^§20 mg given if >75 years old.

Cycles could be continued past the number shown in Figure 1, with some with schedule adjustments. Adjustments were:

• In Cohort A and Cohort D, for Cycle 9 onwards, bortezomib was given on Day 1 and Day 8 only, and dexamethasone was given on Day 1, 2, 8 and 9 only.
• In Cohort C, for Cycle 13 onwards, carfilzomib was given on Day 1 and Day 15 only.

Results

Patient characteristics are shown in Table 1. A high proportion of patients were refractory to lenalidomide treatment. In general, Cohort D patients were less refractory and had received fewer lines of therapy compared to Cohort A and C. By protocol, patients in Cohort D had to be responsive to pomalidomide.

Table 1. Baseline patient characteristics*

ECOG PS, Eastern Cooperative Oncology Group performance status; ISS, International Staging System; mAb, monoclonal antibody; MeziKd, mezigdomide, carfilzomib, and dexamethasone; MeziVd, mezigdomide, bortezomib, and dexamethasone. *Adapted from Richardson.1 †Defined by the presence of any abnormality for del(17p) and/or translocation t(4, 14), and/or translocation (t14, 16), and/or amplification 1q21. ‡11/28 patients non-evaluable. §8/26 patients non-evaluable. ‖9/38 patients non-evaluable. ¶Defined as refractory to ≥1 immunomodulatory drug, 1 proteasome inhibitor, and 1 anti-CD38 mAb.
Patient characteristic, % (unless otherwise stated)	Cohort A (MeziVd) (n = 28)	Cohort C (MeziKd) (n = 26)	Cohort D (MeziVd) (n = 38)
Median age (range), years	65.5 (46–86)	68 (41–76)	64 (43–83)
Male	42.9	34.6	71.1
ECOG PS
0	39.3	38.5	39.5
1 or 2	60.7	61.5	60.5
ISS at study entry
I	71.4	76.9	68.4
II	21.4	11.5	21.1
III	7.1	11.5	10.5
Extramedullary disease	17.9	3.8	7.9
High-risk cytogenetics†	39.3‡	53.8§	34.2‖
Median prior therapies (range), n	3 (2–4)	2 (2–4)	1 (1–3)
Lenalidomide refractory	85.7	80.8	65.8
Anti-CD38 mAb refractory	50.0	73.1	36.8
Triple-class refractory¶	32.1	34.6	2.6

Safety

At the point of data cut-off (July 18, 2022), 53.6%, 42.3%, and 42.1% of patients had discontinued treatment in Cohort A, C, and D respectively. Discontinuation due to disease progression was 32.1% for Cohort A, 15.4% for Cohort C, and 26.3% for Cohort D. One patient died in Cohort C, which was due to sepsis and was not treatment related.

The most common treatment-emergent adverse events (any grade) were:

• infections (53.6%), neutropenia (50%), anemia (39.3%), and diarrhea (39.3%) in Cohort A;
• neutropenia (42.3%), infections (42.3%), and diarrhea (38.5%) in Cohort C; and
• neutropenia (71.1%), infections (65.8%), thrombocytopenia (47.4%), anemia (39.5%), and peripheral sensory neuropathy (39.5%) in Cohort D.

Discontinuation due to adverse events was 7.1% in Cohort A, 15.4% in Cohort C, and 13.2% in Cohort D. In total, 21.4%, 23.1%, and 36.8% of patients require a dose reduction of mezigdomide in Cohorts A, C, and D, respectively.

Efficacy

The median duration of response was:

• 14.5 months in Cohort A;
• 11.9 months in Cohort C; and
• not reached in Cohort D.

Partial response rates were similar across Cohorts A, C, and D. Very good partial response and complete response was higher in Cohort D compared with the other two cohorts. The overall response rates for Cohorts A, C, and D are shown in Figure 2.

CR, complete response; MeziKd, mezigdomide, carfilzomib, and dexamethasone; MeziVd, mezigdomide, bortezomib, and dexamethasone; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Adapted from Richardson.¹

Conclusion

In Cohorts A, C, and D, mezigdomide was well tolerated, with low levels of discontinuation due to adverse events. The overall response rate of 81.6% in Cohort D, with over 50% of patients achieving very good partial response or better, suggests higher doses mezigdomide in combination with bortezomib and dexamethasone can be an effective treatment option for patients with relapsed/refractory multiple myeloma. However, 36.8% of patients in Cohort D required a dose reduction, which highlights the need for further trials to determine the optimum mezigdomide dose and schedule, while maintaining high efficacy. The combination used in Cohort C (mezigdomide with carfilzomib and dexamethasone) is also being continued to phase II, although results are not yet available.