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