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

NCT06876142 | Suspended Phase 1 FDA Drug

• 2 other identifiers: 10001811001811-C
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

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

Keywords

KRAS; NRAS

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (4)

• Duration of Response (DOR)

  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)

  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)

  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

  Until 30 days after the last dose of study agents

Study Arms (2)

Arm 1

EXPERIMENTAL

Sirolimus and escalating doses of mirdametinib

Drug: Mirdametinib; Drug: Sirolimus

Arm 2

EXPERIMENTAL

Sirolimus and RP2D of mirdametinib

Drug: Mirdametinib; Drug: Sirolimus

Interventions

Mirdametinib DRUG

Capsules taken by mouth twice a day (2-12mg) for days 1-21 days of each 28 day cycle

Arm 1; Arm 2

Sirolimus DRUG

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.

Arm 1; Arm 2

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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,
• 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:

You may not qualify if:

• 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).

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Multiple Myeloma

Interventions

mirdametinib; Sirolimus

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Macrolides; Lactones; Organic Chemicals

Study Officials

• Elizabeth M Hill, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 13, 2025
• First Posted: March 14, 2025
• Study Start (Estimated): June 17, 2026
• Primary Completion (Estimated): January 1, 2033
• Study Completion (Estimated): January 1, 2033
• Last Updated: June 12, 2026

Record last verified: 2026-03-19

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• 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.
• 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.

Locations

US (1)