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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.
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.
Figure 1. Dosing schedule in Cohorts A, C, and D*
*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:
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*
Patient characteristic, % (unless otherwise stated) |
Cohort A |
Cohort C |
Cohort D |
---|---|---|---|
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 |
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. |
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:
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.
The median duration of response was:
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.
Figure 2. Response rates across Cohorts A, C and D*
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
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.
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