Dose modifications of mezigdomide when coadministered with CYP3A4 inhibitors for patients with relapsed/refractory multiple myeloma

Abstract Introduction: Mezigdomide (MEZI), an oral CELMoD™ agent with potent antimyeloma and immunostimulatory effects, has demonstrated encouraging efficacy in relapsed/refractory multiple myeloma (RRMM) as monotherapy and in combination with dexamethasone/standard treatments (CC-92480-MM-001 [NCT03374085]; CC-92480-MM-002 [NCT03989414]). MEZI exhibits linear and comparable pharmacokinetics (PK) between healthy individuals and patients (pts) with RRMM, up to a single dose of 3.2 mg and multiple doses of 2.0 mg. A phase 1 clinical drug–drug interaction (DDI) study in healthy participants evaluated MEZI as a substrate of cytochrome P450 3A4 (CYP3A4), using rifampin (strong inducer) and itraconazole (strong inhibitor). This study showed that dose-normalized MEZI area under the curve (AUC) reduced by 95% with rifampin and increased 14.1-fold with itraconazole. Therefore, strong CYP3A4 inhibitors (CYP3A4is) and inducers are contraindicated in ongoing RRMM MEZI trials, and MEZI must be interrupted for the period in which a strong CYP3A4i is required. Use of moderate CYP3A4is or CYP3A4 inducers is discouraged but permitted if necessary. To inform potential alternative dosing strategies for MEZI in the presence of CYP3A4is, we used physiologically-based PK (PBPK) modelling. Here, we report model-predicted MEZI clearance (CL) and simulated exposures to guide MEZI dosing regimen when coadministered with strong and moderate CYP3A4is. Methods: A whole-body PBPK model was developed using the Simcyp® PBPK Simulator, based on available physicochemical, in vitro, and clinical data, including single-dose studies in healthy participants (Burnett JP, et al. Clin Pharmacol Ther 2024;115(S1):PII-178) and emerging data from multiple-dose MEZI monotherapy in the CC-92480-MM-001 trial. PBPK-derived CL of posaconazole, voriconazole (both strong CYP3A4is), and fluconazole (a moderate CYP3A4i) were used to simulate MEZI exposure under various doses (0.4, 0.6, or 1.0 mg) with a once daily (QD) 21/28-day or 14/21-day dosing schedule, using mrgsolve package in R. The exposure ratios of maximum concentration (Cmax) and accumulated AUC over a dosing cycle (AUC[0–28] or AUC[0–21]) under various dosing regimens were calculated and compared with those of MEZI without any CYP3A4i. The treatment-emergent adverse event (TEAE) profile of CC-92480-MM-001 and CC-92480-MM-002 pts (≤28 days after the start or last dose of CYP3A4i, whichever was later) treated with moderate CYP3A4is was evaluated. Results:Coadministration of MEZI with a CYP3A4i significantly reduced its CL, resulting in increased exposure. Specifically, MEZI CL was reduced 0.15-, 0.11- and 0.38-fold when administered with posaconazole, voriconazole, and fluconazole, respectively. To achieve comparable exposures (Cmax and AUC[0-28]) to MEZI 1.0-mg monotherapy on a 21/28-day schedule, dose adjustments are recommended. For pts requiring a strong CYP3A4i, MEZI dose should be reduced to 0.3 mg every 3 days (Q3D). For pts on a moderate CYP3A4i, a reduced MEZI dose of 0.3 mg QD is appropriate. These recommendations also apply to the 14/21-day dosing schedule. For pts initiating MEZI at lower doses, 0.3 mg every 4 days (Q4D) for a 0.6-mg starting dose, and 0.2 mg Q4D or 0.3 mg every 5 days for a 0.4-mg starting dose are advised when combined with a strong CYP3A4i. When combined with a moderate CYP3A4i, a dose of 0.2 mg QD is recommended. Across the CC-92480-MM-001 (N=200) and CC-92480-MM-002 trials (N=192), 81 pts received moderate CYP3A4is; 61.5% of pts had ≥1 MEZI dose interruption and 12.8% had ≥1 MEZI dose reduction. Grade ≥3 TEAEs occurred in 66 (81.5%) pts, with neutropenia (33.5%) and thrombocytopenia (14.2%) being the most common. These findings agree with the established safety profile of MEZI and support the model-based recommendation that MEZI dose reduction when combined with a moderate CYP3A4i may enhance safety. Conclusions: MEZI is a sensitive CYP3A4 substrate. Modeling and simulation provide a robust framework to guide dose adjustments and manage potential DDI risks while preserving efficacy. For pts requiring concomitant use of strong or moderate CYP3A4is, MEZI can be continued safely with dose modifications to maintain exposure levels, thereby minimizing the risk of exposure-related AEs. MEZI treatment does not need to be interrupted when a strong CYP3A4i is necessary, allowing continued clinical benefit. Dose reduction of moderate CYP3A4is may enhance safety without compromising efficacy.