NCT06876142

Combination Therapy (Mirdametinib and Sirolimus) for RAS Mutated Relapsed Refractory Multiple Myeloma

A Phase 1b/2 Study of Combination Therapy (Mirdametinib and Sirolimus) for RAS Mutated Relapsed Refractory Multiple Myeloma (RRMM)

• Status: Suspended
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 54 (estimated)
• Sponsor: National Cancer Institute (NCI) · NIH
• Sex: All
• Age: 18 Years – 120 Years
• Healthy volunteers: Not accepted

Summary

Background: Multiple myeloma (MM) is a type of blood cancer that affects a person s immunity. MM returns after treatment (relapse) in almost all people; MM may also not respond to initial treatment (refractory). Many people with relapsed refractory MM (RRMM) also have changes in their KRAS and NRAS genes. Researchers want to try a new drug treatment that targets cancer with these changed genes. Objective: To test 2 drugs (mirdametinib and sirolimus) in people with RRMM. Eligibility: People aged 18 and older with RRMM who have changes in their KRAS or NRAS genes. Design: Participants will be screened. They will have blood tests and imaging scans. They will have an eye exam and a test of their heart function. They will need to provide proof of their disease status and of their KRAS or NRAS status. If neither is available, the tests will be repeated. Participants will have a bone marrow biopsy: A needle will be inserted into a hipbone to draw out some soft tissue. This study will be done in two parts. In the first part of this study, we will find a safe dose of mirdametinib combined with sirolimus. In the second part, we will learn more about how mirdametinib combined with sirolimus may work against RRMM. Mirdametinib (capsules) and sirolimus (tablets) are taken by mouth. Participants will take both drugs at home on a 4-week cycle. They will take mirdametinib twice a day for the first 3 weeks of each cycle. They will take sirolimus once a day, every day, during each cycle. Participants will have study visits once a week during the first cycle, and then on the first day of subsequent cycles. Blood, heart, imaging scans, and other tests will be repeated. Treatment with the study drugs will go on for 1 year. Then participants will have follow-up visits every 3 months for 4 more years.

Detailed description

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.

Conditions

• Multiple Myeloma
• Relapsed and/or Refractory Multiple Myeloma (RRMM)

Interventions

Type	Name	Description
DRUG	Mirdametinib	Capsules taken by mouth twice a day (2-12mg) for days 1-21 days of each 28 day cycle
DRUG	Sirolimus	Tablets taken by mouth once a day for days 1-28 days of each 28 day cycle. Loading dose of 12 mg on Day 1 Cycle 1 with 4 mg being taken for the remaining doses.

Timeline

• Start date: 2026-04-22
• Primary completion: 2033-01-01
• Completion: 2033-01-01
• First posted: 2025-03-14
• Last updated: 2026-04-17

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study