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)

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.

Study Overview

• Status: Suspended
• Conditions: Multiple Myeloma; Relapsed and/or Refractory Multiple Myeloma (RRMM)
• Intervention / Treatment: Drug: Mirdametinib; Drug: Sirolimus

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.

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

• INCLUSION CRITERIA:

• Participants must have a documented diagnosis of multiple myeloma (MM) defined by the International Myeloma Working Group (IMWG) Criteria. Participants at diagnosis must have had a history of the serum-M protein >= 3 g/dL and or bone marrow plasma cells >= 10% and the history of at least one of the following:

  • Anemia: hemoglobin <= 10 g/dL or a 2g/dL decrease from the lower limit of normal,

OR

• Renal failure: creatinine clearance < 40 ml/min, OR
• Hypercalcemia: calcium (Ca) >= 11 mg/dL OR > 1 mg/dL higher than the upper limit of normal (ULN), OR
• Lytic bone lesions on X-Ray, Computed Tomography (CT), or Positron Emission Tomography (PET)/CT, OR
• >= 2 focal lesions on spinal Magnetic Resonance Imaging (MRI), OR
• >= 60% bone marrow plasma cells, OR

• Involved/un-involved serum-free light chain ratio >= 100.

  • Participants must have measurable disease per International Myeloma Working Group (IMWG) criteria.
  • Participants must have relapsed and/or refractory multiple myeloma (RRMM) with "penta-class exposed" disease, as defined by previous therapy with an anti-CD38 monoclonal antibody, 2 immunomodulatory drugs [IMiDs], and 2 proteasome inhibitors [Pis]), 3 previous lines of therapy, and no other available options.
  • Participants must have a history of known somatic mutation in KRAS or NRAS. Note: For participants that come to NIH without confirmation of KRAS or NRAS, their status will be determined by the TSO500 NSR device.
  • Participants must be off other myeloma-directed therapy (except for radiation) for at least 14 days prior to the study treatment initiation.
  • Age >= 18 years.
  • ECOG performance status <= 2.
  • Participants must have adequate organ and marrow function as defined below:

Absolute neutrophil count (ANC): >= 1,000 cells/microliter

Platelets: >= 75,000 cells/microliter

Total bilirubin: within normal institutional limits

Aspartate Aminotransferase (AST): <= 3 X ULN

Alanine Aminotransferase (ALT): <= 3 X ULN

Renal function: creatinine clearance (CrCl) >= 40 mL/min calculated by Cockcroft-Gault,

-Individuals of childbearing potential (IOCBP) must agree to use highly effective contraception (hormonal, intrauterine device [IUD], abstinence, surgical sterilization) at the study entry and for at least 12 weeks after the last dose of sirolimus or 6 months after the last dose of mirdametinib, whichever is longer. Barrier methods such as condoms (male or female) or occlusive caps (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream or vaginal suppository must be used in addition to hormonal contraception. Note: IOCBP is defined as any individual who has experienced menarche and who has not undergone successful surgical sterilization or who is not postmenopausal.

Individuals able to father a child must agree to use an effective method of contraception (barrier plus spermicide, surgical sterilization, abstinence) at the study entry and for 3 months after the last dose of mirdametinib. We also will recommend individuals able to father a child with partners of childbearing potential ask partners to be on highly effective birth control (hormonal, IUD, surgical sterilization) for at least 3 months after the last dose of mirdametinib. Individuals able to father a child must not freeze or donate sperm within the same period.

• Breastfeeding participants must be willing to discontinue breastfeeding after study treatment initiation.

• Participants seropositive for human immunodeficiency virus (HIV) infection must:

  • be on anti-retroviral therapy; and
  • have the undetectable viral load.

• Participants seropositive for Hepatitis C virus (HCV) infection must

  • have been treated and cured; or
  • if currently on treatment, have an undetectable HCV viral load.
• Participants seropositive for Hepatitis B virus (HBV) infection must
• be on suppressive therapy if necessary; and
• have viral load <100 IU/mL.
• Ability of the participant to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

• Received any investigational agents within 14 days prior to the study treatment initiation.
• Vaccinated with live, attenuated vaccines within 30 days prior to the study treatment initiation.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to mirdametinib and/or sirolimus.
• Current diagnosis of plasma cell leukemia.
• Current or history of amyloidosis.
• Current or history of New York Heart Association (NYHA) Stage III or IV heart failure
• Current or history of Interstitial Lung Disease.
• Current or history of glaucoma and/or an intraocular pressure > 22 mmHg, retinal pigment epithelial detachment, or other primary ocular/retinal diseases.
• Current or history of retinal vein occlusion (RVO).
• Comorbidities that put undue risk of RVO such as uncontrolled hypertension (chronic systolic blood pressures > 160 mm Hg) and/or uncontrolled diabetes mellitus type II (DMII) (chronic clinical signs/symptoms of hyperglycemia; diabetic participants must have a hemoglobin A1c value < 9% to be eligible).
• Participants receiving systemic or ocular glucocorticoid therapy equivalent to > 10 mg of prednisone daily within 14 days prior to the study treatment initiation. Note: Participants with endocrine deficiencies, who receive physiologic, or stress doses of steroids are eligible.
• Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 within 14 days prior to the study treatment initiation. Lists including medications and substances known or with the potential to interact with the CYP3A4 isoenzymes are provided here: http://medicine.iupui.edu/clinpharm/ddis/table.aspx.
• Participants receiving any medications or substances that are strong inhibitors of breast cancer resistance protein (BCRP) within 14 days prior to the study treatment initiation (i.e., curcumin, cyclosporine, darolutamide, eltrombopag, febuxostat, fostamatinib, rolapitant, sofosbuvir and velpatasvir and voxilaprevir, and teriflunomide).
• Positive beta-human chorionic gonadotropin (beta-HCG) serum or urine pregnancy test performed in IOCBP at screening.
• Participant has abnormal QT interval corrected by Fridericia s formula (QTcF >470 ms, as determined by the mean QTcF values from the ECG assessments at screening (one triplicate).
• Uncontrolled intercurrent illness or factors evaluated by medical history and physical exam that would potentially increase the risk of the participant.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm 1; Sirolimus and escalating doses of mirdametinib	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.
Experimental: Arm 2; Sirolimus and RP2D of mirdametinib	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: determine the RP2D of the mirdametinib in combination with sirolimus in participants with RAS-mutated RRMM	The RP2D will be determined by the dose found in the 3+3 design to cause < 33% toxicity as defined by the DLT criteria.	28 days
Phase 2: determine the preliminary efficacy of mirdametinib at RP2D in combination with sirolimus in participants with RAS-mutated RRMM as assessed by the ORR per IMWG	The fraction of participants with a RAS mutation who experience a response (PR, VGPR, CR, or sCR) while on the study treatment will be determined by dividing the number of responders by the total number of evaluable participants. The fraction will be reported along 95% two-sided confidence intervals.	Day 1 of every cycle, at suspected CR, End of cycles 6 and 12, Safety Follow Up visit, every 3 months after that until progression, initiation of another line of therapy, or 5 years since treatment initiation.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR)	DOR will be assess with blood tests and radiographic findings and reported using the Kaplan-Meier method.	Day 1 of every cycle, at suspected CR, End of cycles 6 and 12, Safety Follow Up visit, every 3 months after that until progression, initiation of another line of therapy, or 5 years since treatment initiation.
Progression Free Survival (PFS)	PFS will be assessed with blood tests and radiographic findings and reported using the Kaplan-Meier method.	Day 1 of every cycle, at suspected CR, End of cycles 6 and 12, Safety Follow Up visit, every 3 months after that until progression, initiation of another line of therapy, or 5 years since treatment initiation.
Overall Survival (OS)	OS will be assessed and reported using the Kaplan-Meier method and include any cause of death.	Day 1 of every cycle, EOT, Safety Follow-up visit, then every 3 months(+/-2 weeks) until disease progression or the initiation of another line of therapy for up to 5 years after the treatment initiation. After progression or initiation of a new treatment
Safety	The number and frequency of adverse events for participants as assessed per CTCAE version 5. Safety will be analyzed by reporting the number of patients experiencing toxicity, classified by type and grade to the experimental regimen.	Until 30 days after the last dose of study agents

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Elizabeth M Hill, M.D., National Cancer Institute (NCI)

Publications and helpful links

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Estimated): June 17, 2026
• Primary Completion (Estimated): January 1, 2033
• Study Completion (Estimated): January 1, 2033

Study Registration Dates

• First Submitted: March 13, 2025
• First Submitted That Met QC Criteria: March 13, 2025
• First Posted (Actual): March 14, 2025

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 11, 2026
• Last Verified: March 19, 2026

More Information

Terms related to this study

• Keywords: KRAS; NRAS
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Neoplasms; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Neoplasms, Plasma Cell; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Hemic and Lymphatic Diseases; Multiple Myeloma; Organic Chemicals; Macrolides; Lactones; Sirolimus; mirdametinib
• Other Study ID Numbers: 10001811; 001811-C

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All collected IPD will be shared. In addition, all large scale genomic sequencing data will be shared with subscribers to dbGaP.
• IPD Sharing Time Frame: Clinical data will be made available during the study and indefinitely. Genomic data are available once genomic data are uploaded per protocol GDS plan for as long as database is active.
• IPD Sharing Access Criteria: Clinical data will be made available upon request and with the permission of the study PI. Genomic data are made available via dbGAP through requests to the data custodians.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No