Mezigdomide Plus Ixazomib and Dexamethasone for Relapsed and Refractory Multiple Myeloma

Inclusion Criteria: 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, 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 Hematologic laboratory parameters of: Absolute neutrophil count (ANC) > 1,000/mm3 Hemoglobin > 8g/dL Platelet count > 75,000/μL if plasma cells account for < 50% bone marrow Nucleated cells and > 50,000/μL if plasma cells account for > 50% of bone marrow nucleated cells Non-hematologic laboratory parameters of: Total Bilirubin of < 2 times the upper limit of normal ALT and 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: o Have two negative pregnancy tests prior to starting study treatment and agree to ongoing pregnancy testing during the course of the study, and after end 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, POEMS syndrome or Light Chain (AL) AmyloidosisF Prior refractoriness to a proteasome inhibitor (bortezomib, carfilzomib, ixazomib), defined as documented progression within 60 days of a 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 QTc >470ms or chronic obstructive pulmonary disease with 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