Mezigdomide + dexamethasone for the treatment of RRMM

Mezigdomide is an oral cereblon E3 ligase modulator which acts to degrade transcription factors Ikaros and Aiolos, ultimately resulting in multiple myeloma (MM) cell death. Mezigdomide is currently being investigated in combination with dexamethasone for the treatment of heavily pre-treated patients with MM.¹

Here, we summarize key efficacy and safety data from the phase I and subsequent phase II trials (NCT03374085) of mezigdomide + dexamethasone combination therapy in patients with relapsed/refractory MM.

Phase I (Dose-escalation)¹

The phase I dose-escalation study included 77 patients who had been treated with ≥3 prior lines of therapy. Four dosing schedules in 28-day cycles were assessed with the optimal dose brought forward to treat all patients in phase II.

Phase II (Dose-expansion)¹

The phase II dose-expansion study included 101 patients with triple-class refractory MM. These patients were treated within 28-day cycles of mezigdomide/dexamethasone combination therapy following the recommended dosing schedule determined in phase I.

Patient characteristics¹

A summary of the key baseline patient characteristics of the dose-escalation and dose-expansion cohorts are outlined in Table 1.

Table 1. Baseline patient characteristics*

ADC, antibody drug conjugate; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor; ECOG, Eastern Cooperative Oncology Group; IMiD, immunomodulatory agent; ISS, International Staging System; PI, proteasome inhibitor. *Adapted from Richardson, et al.1
Characteristic (%, unless otherwise specified)	Dose-escalation cohort (N = 77)	Dose-expansion cohort (N = 101)
Median age (range), years	65 (40–78)	67 (42–85)
Sex
Male	58	54
Female	42	46
Race
White	90	76
Black	4	4
Asian	1	7
Other	1	4
ISS stage
I	32	39
II	44	41
III	22	21
ECOG status score
0	27	35
1	64	56
2	9	9
Cytogenetic high-risk	30	37
Previous therapy
Stem-cell transplant	78	77
PI	100	100
Lenalidomide	99	100
Pomalidomide	92	100
Anti-CD38 antibody	78	100
Anti-BCMA therapy	12	30
ADC	9	22
T-cell engager	1	8
CAR T-cell	1	3
Refractory status
IMiD	95	100
Lenalidomide	81	88
Pomalidomide	84	96
PI	75	100
Anti-CD38 antibody	70	100
Triple-class	56	100

Efficacy¹

Dose-escalation cohort

In the dose-escalation cohort, two of the four regimens with highest overall response rates included:

• 1.0 mg mezigdomide in combination with dexamethasone administered once daily in 28-day cycles consisting of either:
  • 21 days treatment, followed by a break of 7 days, or
  • 10 days of treatment, followed by a break of 4 days

The final response data for all patients included in phase I, as well as data for each of the above regimens are outlined in Figure 1. Ultimately, the 21-day cycle dosing regimen was elected as optimal and carried forward to all patients in the subsequent dose-expansion trial.

CR, complete response; ORR, overall response rate; PR, partial response; VGPR, very good partial response.
*Data from Richardson, et al.¹

Dose-expansion cohort

At a median follow up of 7.5 months, an overall response rate of 41% was observed across the whole cohort. A subset of patients treated with a previous BCMA-targeted therapy presented with an overall higher response rate of 50% (Figure 2.). However, stringent complete response was not reached by any of these patients versus 2% of patients with no prior anti-BCMA therapy.

CR, complete response; ORR, overall response rate; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.
*Data from Richardson, et al.¹

Additional data on responses in the total dose-expansion cohort includes:

• Median duration of response, 7.6 months
• Median progression-free survival, 4.4 months
• Stable disease, 39%
• Progressive disease, 10%

Safety¹

The most common adverse events in both the dose-escalation and dose-expansion cohorts were hematologic. Neutropenia was the most common, occurring in 81% and 77% of patients in dose-escalation and dose-expansion cohorts, respectively. All Grade ≥3 adverse events in both cohorts are shown in Figure 3.

*Data from Richardson, et al.¹ 

Conclusion

Mezigdomide combined with dexamethasone in patients with triple-class refractory MM resulted in safety and efficacy data deemed favorable by researchers. However, it is important to note that the phase II part of this trial was single-armed; therefore, comparisons between the intervention versus no therapy or standard-of-care therapies was not established. Nonetheless, the data from the trial does present a feasible dosing regimen and the basis for further research.