NCT06050512

Mezigdomide Plus Ixazomib and Dexamethasone for Relapsed and Refractory Multiple Myeloma

Phase I/II Trial of Mezigdomide Plus Ixazomib and Dexamethasone for Relapsed and Refractory Multiple Myeloma

• Status: Withdrawn
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 0 (actual)
• Sponsor: Kathleen Dorritie · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

Multiple myeloma (MM) is the second most common hematologic malignancy with an estimated annual incidence of nearly 35,000 cases. While still considered an incurable disease, new treatments have improved outcomes dramatically over the last two decades. Around the turn of the millennium, classical cytotoxic chemotherapy and radiation were the only available treatment modalities and median OS was estimated at 2-3 years. Currently, there are now 17 FDA-approved anti-myeloma agents and median OS is approaching 10 years. More recently, next generation cellular and immune therapies are demonstrating unprecedented efficacy in highly refractory patients with otherwise a very short life expectancy. In this study, the starting dose of ixazomib will be reduced to 3mg, as this is the first FDA-recommended dose recommendation (from 4mg). The starting dose of mezigdomide will be 0.6mg. Frequent toxicity and AE monitoring as outlined in this trial (weekly in C1, every 2 weeks in C2-C4) asserts maximization of patient safety. Dexamethasone (DEX) will be dosed at 40mg weekly in patients \< 75 years old and 20mg for patients \> 76 years old. Additionally, the staring dose of DEX may be reduced to 20mg in any patient, per study provider discretion, based on several factors such frailty, prior adverse side effects or existing comorbidities.

Detailed description

Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD). It is an oral small-molecule compound that potentiates the cereblon-mediated ubiquitination of key cellular transcription factors (Ikaros and Aiolos), which ultimately results in multiple myeloma cell death and other immunomodulatory activity. Mezigdomide has demonstrated acceptable safety in two phase I clinical trials in combination with DEX as a "doublet," and as a "triplet" in combination with bortezomib and DEX. Early estimates of efficacy are high compared to historical date: 55% ORR in combination with DEX in a highly pre-treated and refractory patient population, and 75% in combination with bortezomib. By comparison, the most recent oral therapy approved by the FDA for RRMM was Selinexor, which demonstrated a 25% ORR in patients who received a median of 7 prior lines of therapy and 100% of whom were refractory to a PI, IMID and DARA. This comparison serves as very exploratory estimate as no conclusions can be drawn from cross-trial comparisons, especially with very small patient populations. While important efficacy measures such overall survival, progression-free survival and duration of response are maturing, these estimates suggest mezigdomide could be an efficacious, oral treatment option for patients with RRMM.

Conditions

• Relapsed and Refractory Multiple Myeloma

Interventions

Type	Name	Description
DRUG	Mezigdomide	Mezigdomide (MEZI), a novel oral CELMoD® agent with enhanced tumoricidal and immune-stimulatory effects compared to immunomodulatory drugs (IMiDs®), induces maximal degradation of Ikaros and Aiolos, leading to increased apoptosis in myeloma cells.
DRUG	Ixazomib	Ixazomib, a second-generation proteasome inhibitor, is used primarily in the treatment of multiple myeloma. This activity outlines the mechanism of action, indications, and contraindications for ixazomib as a valuable agent for treating multiple myeloma.
DRUG	Dexamethasone	Corticosteroids, such as dexamethasone and prednisone, are an important part of the treatment of multiple myeloma. They can be used alone or combined with other drugs as a part of treatment. Corticosteroids are also used to help decrease the nausea and vomiting that chemo might cause.

Timeline

• Start date: 2023-10-02
• Primary completion: 2026-10-01
• Completion: 2026-10-01
• First posted: 2023-09-22
• Last updated: 2024-11-19

Regulatory

• FDA-regulated drug study