Mezigdomide plus Ixazomib and Dexamethasone for the Treatment of Relapsed and Refractory Multiple Myeloma

Inclusion Criteria

• Males and females > 18 years of age
• Must provide voluntary, informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status < 2
• Patients must have a confirmed diagnosis of multiple myeloma and have received 1-3 prior lines of therapy and must be: Exposed to a proteasome inhibitor, immunomodulatory drugs (IMiD), and anti-CD38 antibody prior to enrollment
• Patients must have measurable evidence of multiple myeloma defined as one of the following: * Serum M protein ≥ 0.5 g/dL * Abnormal free light chain ratio, provided involved light chain is >10mg/dL * Urine M protein ≥ 200 mg/24 hours
• Absolute neutrophil count (ANC) > 1,000/mm^3
• Hemoglobin > 8g/dL
• Platelet count > 75,000/uL if plasma cells account for < 50% bone marrow
• Nucleated cells and > 50,000/uL if plasma cells account for > 50% of bone marrow nucleated cells
• Total bilirubin of < 2 times the upper limit of normal
• Alanine transaminase (ALT) and aspartate aminotransferase (AST) < 3 times the upper limit of normal
• Corrected serum calcium > 13 mg/dL
• Estimated creatinine clearance (CrCl) of ≥ 45 mL/min, calculated using the formula of Cockroft and Gault (may need adjusted per mezigdomide pharmacokinetic report)
• Access to ixazomib
• Females of childbearing potential (FCBP) must: * Have two negative pregnancy tests as verified by the Investigator prior to starting study treatment. She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the participant practices true abstinence* from heterosexual contact * Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use, and be able to comply with, 2 forms of contraception: one highly effective, and one additional effective (barrier) measure of contraception without interruption 28 days prior to starting study treatment, during the study treatment (including dose interruptions), and for at least 184 days after the last dose of ixazomib and mezigdomide * Note: A female of childbearing potential (FCBP) is a female who: 1) has achieved menarche at some point and, 2) has not undergone a hysterectomy or bilateral oophorectomy, or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time in the preceding 24 consecutive months) * Not donate ova (eggs) while participating in this study and for at least 184 days after discontinuation of ixazomib and mezigdomide
• Male participants must: * Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use of a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study (even during dose interruptions) and for at least 3 months after the last dose of mezigdomide and ixazomib, even if he has undergone a successful vasectomy
• Not donate sperm or semen while participating in this study, during dose interruptions, and for at least 94 days after the last dose of ixazomib and mezigdomide. All participants must agree to refrain from donating blood while on study treatment for 28 days after the last dose of study treatment
• All male and female participants must follow all requirements defined in the pregnancy prevention plan

Exclusion Criteria

• Central nervous system involvement of multiple myeloma
• Plasma cell leukemia defined as clonal plasma cells constituting > 20% of peripheral leukocyte differential
• Waldenstrom’s macroglobulinemia, polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes (POEMS) syndrome or light chain (AL) amyloidosis
• Prior refractoriness to a proteasome inhibitor (bortezomib, carfilzomib, ixazomib), defined as documented progression within 60 days of a proteasome inhibitors (PI)-containing regimen
• Prior intolerance of ixazomib
• Prior exposure to mezigdomide
• Females with positive pregnancy test during screening or females who wish to become pregnant
• Unwillingness to strictly adhere to the Pregnancy Prevention Plan
• Concomitant or recent (within 2 weeks of starting study therapy) use of strong CYP3A modulators and proton pump inhibitors (PPIs)
• Active cardiopulmonary conditions including documented myocardial ischemia within 6 months, unstable angina, congestive heart failure (New York Heart Association class III or IV), uncontrolled arrythmias, grade 3 conduction block without a pacemaker, uncontrolled hypertension, baseline corrected QT (QTc) > 470ms or chronic obstructive pulmonary disease with forced expiratory volume (FEV1) < 50%
• Any other malignancy diagnosed within 2 years of enrollment with documented or presumed residual disease, excluding non-melanomatous skin cancer if completely resected
• Active bacterial or fungal infection requiring antimicrobial therapy (not standard prophylactic prophylaxis)
• HIV, chronic or active hepatitis B, or active hepatitis A or C
• Unwillingness to adhere to antithrombotic and antiviral prophylaxis
• Major surgery within 30 days of enrollment
• Radiotherapy within 14 days of initiating study treatment
• Known allergy to any study compounds (mezigdomide, ixazomib)
• Intolerance of dexamethasone
• Documented gastrointestinal disease resulting reduced absorption of oral medications
• Grade > 3 neuropathy
• Active participation in another clinical trial or recent participation within 1 month of enrollment
• Any medical or psychiatric condition interfere with the patient’s ability to tolerate or complete this treatment protocol, as determined by principal investigator