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

What this study involves

The registry does not currently label this study as recruiting. Ask about its status before planning a screening visit.

Study type

Interventional

Phase

Phase 1 / Phase 2

Age range

18 years - 120 years

Sex eligible

All sexes

Healthy volunteers

Not accepted

Participants

54 Estimated

These are starting points, not an eligibility decision. The research team must review the full requirements.

About the research

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.

Who may be able to participate?

The list below is the sponsor’s full registry wording. It can include conditions, prior treatment, test results and other requirements. A match in search does not mean you qualify.

• 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.

Treatment, groups and participation

The registry may describe treatments and study duration without a complete visit calendar. Ask the study team for the exact schedule, procedures, risks, costs and alternatives. Keep your usual care plan unless your treating clinician tells you otherwise.

Assignment

Not randomized

Masking

No masking

What researchers are measuring

Outcome measures describe what is being studied. They are not proof that a treatment works.

Primary measures

Secondary measures

Research locations (1)

The overall study status and a local site’s status can differ. Confirm that location’s availability before traveling.

1 locations

Study team and timeline

Lead sponsor

National Cancer Institute (NCI)

Study start

Nov 15, 2026 Estimated

Primary completion

Jan 1, 2033 Estimated

Study completion

Jan 1, 2033 Estimated

First posted

Mar 14, 2025 Actual

Last updated

Nov 10, 2026 Actual

Official study contacts

No central contact is listed. Check the locations and the official record.