Mirdametinib and Sirolimus

Background:

• Multiple myeloma (MM) is the second most prevalent hematologic malignancy. Despite advances in therapy, almost all patients who survive their original presentation eventually relapse. There remains an unmet need in patients who are primary refractory or who have exhausted available therapies.
• To date, the successful therapies in MM have targeted vulnerabilities in myeloma biology such as high protein turnover or overexpressed cell markers. Less success has been had in targeting the molecular pathogenesis or signaling pathways involved in MM oncogenesis.
• RAS mutations can be found in 40-60% of MM tumors and the incidence of RAS mutations goes up with more advanced and heavily pretreated disease.
• The RAS pathway leads to downstream MEK activation which in turn enhances survival, proliferation, and migration of MM cells.
• Preclinical studies suggest that inhibition of both MEK and mTOR is required to impede RAS-dependent pathogenic signaling in MM cells.
• This study will use a MEK inhibitor (mirdametinib) in combination with an mTOR inhibitor (sirolimus) to attempt to block the pathogenic RAS pathway in MM.

Objectives:

• Phase 1b: To determine the recommended phase 2 dose (RP2D) of mirdametinib in combination with sirolimus in participants with RAS mutated relapsed refractory multiple myeloma (RRMM)

Phase 2: To determine the preliminary efficacy of mirdametinib at RP2D in combination with sirolimus in participants with RAS mutated RRMM as assessed by the overall response rate (ORR) per International Myeloma Working Group (IMWG) criteria

Eligibility:

• Age >= 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance score <= 2.
• Participants must have a documented diagnosis of MM defined by the International Myeloma Working Group (IMWG) Criteria.
• Participants must have relapsed and/or refractory multiple myeloma (RRMM) with "pentaclass exposed" disease including previous therapy with an anti-CD38 monoclonal antibody, 2 immunomodulatory drugs (IMiDs), and 2 proteasome inhibitors (PIs).
• Participants must have a somatic NRAS or KRAS mutation.

Design:

• This is an open-label, non-randomized, prospective, single-center Phase 1b/2 study evaluating the combination of mirdametinib and sirolimus in participants with RASmutated RRMM.
• During Phase 1b we will find RP2D of mirdametinib in combination with sirolimus using a standard 3 + 3 design.
• During Phase 2 we will use RP2D of mirdametinib in combination with sirolimus to evaluate the efficacy of this combination.
• All participants will receive study drugs for 12 cycles (1 year) or until off-treatment criteria are met. Both drugs will be taken orally daily at home. There will be a one-week break from mirdametinib every cycle (3 weeks on and 1 week off). Sirolimus will be taken continuously.
• Participants will have regular evaluations for safety and response.