A phase 1b/2 study of mirdametinib in combination with sirolimus for patients with RAS-mutated relapsed/refractory multiple myeloma.

TPS7582 Background: Relapsed and refractory multiple myeloma (RRMM) remains a significant therapeutic challenge, particularly among patients with genomic alterations in the RAS pathway (KRAS/NRAS mutations). These mutations occur in 60-70% of RRMM and are associated with aggressive disease and poor outcomes. Preclinical evidence suggests that dual inhibition of MEK and mTOR is required to effectively suppress oncogenic signaling in RAS dependent MM. This study evaluates the combination of the MEK inhibitor mirdametinib and the mTOR inhibitor sirolimus in patients with RAS-mutated RRMM. Methods: This is an open-label, single center, Phase 1b/2 study in adults with RRMM who are penta-class exposed and have no remaining standard therapeutic options. Patients must have RAS dependent MM as evidenced by a KRAS or NRAS mutation. Patients will be screened for these mutations at the NIH clinical center if unknown prior to referral. The phase 1b portion uses a standard 3+3 dose-escalation design to determine the recommended phase 2 dose (RP2D) of mirdametinib in combination with sirolimus. Phase 2 is a dose-expansion cohort using a Simon two-stage design to evaluate preliminary efficacy at the RP2D by overall response rate per the IMWG. Key eligibility criteria include adults aged ≥18 years with relapsed or refractory multiple myeloma per IMWG criteria, documented KRAS or NRAS mutation, prior exposure to a proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody, ECOG performance status 0–2, and adequate organ function. Correlative studies include serial assessment of MAPK and mTOR pathway inhibition and pharmacodynamic biomarkers in peripheral blood and bone marrow samples. The study is actively enrolling at the NIH Clinical Center (NCT06876142), with a planned total enrollment of 54 patients. Clinical trial information: NCT06876142 .