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.
⁃ 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.