Clinical Trial Finder

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

Mezigdomide is a novel cereblon E3 ligase modulator (CELMoD). It is an oral small-molecule compound that potentiates the cereblon-mediated ubiquitination of key cellular transcription factors (Ikaros and Aiolos), which ultimately results in multiple myeloma cell death and other immunomodulatory activity. Mezigdomide has demonstrated acceptable safety in two phase I clinical trials in combination with DEX as a "doublet," and as a "triplet" in combination with bortezomib and DEX. Early estimates of efficacy are high compared to historical date: 55% ORR in combination with DEX in a highly pre-treated and refractory patient population, and 75% in combination with bortezomib. By comparison, the most recent oral therapy approved by the FDA for RRMM was Selinexor, which demonstrated a 25% ORR in patients who received a median of 7 prior lines of therapy and 100% of whom were refractory to a PI, IMID and DARA. This comparison serves as very exploratory estimate as no conclusions can be drawn from cross-trial comparisons, especially with very small patient populations. While important efficacy measures such overall survival, progression-free survival and duration of response are maturing, these estimates suggest mezigdomide could be an efficacious, oral treatment option for patients with RRMM.

Arms

Experimental: Phase l: Mezigdomide + Ixazomib + Dexamethasone

Dose level -2: Mezigdomide: 0.3 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 2.3 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22 Dose level -1: Mezigdomide: 0.6 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 2.3 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22 Dose level 0 (Starting dose): Mezigdomide: 0.6 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 3.0 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22 Dose level +1: Mezigdomide: 1.0 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 3.0 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22 Dose level +2: Mezigdomide: 1.0 mg daily on days 1-21 of a 28-day schedule; Ixazomib: 4.0 mg PO weekly on days 1, 8 and 15 of a 28-day schedule; Dexamethasone: 40 or 20 mg on days 1, 8, 15 and 22

Experimental: Phase ll (RP2D): Mezigdomide + Ixazomib + Dexamethasone

Mezigdomide: RP2D daily on days 1-21 of a 28-day schedule Ixazomib: RP2D PO weekly on days 1, 8 and 15 of a 28-day schedule Dexamethasone: RP2D on days 1, 8, 15 and 22

Interventions

Drug: - Mezigdomide

Mezigdomide (MEZI), a novel oral CELMoD® agent with enhanced tumoricidal and immune-stimulatory effects compared to immunomodulatory drugs (IMiDs®), induces maximal degradation of Ikaros and Aiolos, leading to increased apoptosis in myeloma cells.

Drug: - Ixazomib

Ixazomib, a second-generation proteasome inhibitor, is used primarily in the treatment of multiple myeloma. This activity outlines the mechanism of action, indications, and contraindications for ixazomib as a valuable agent for treating multiple myeloma.

Drug: - Dexamethasone

Corticosteroids, such as dexamethasone and prednisone, are an important part of the treatment of multiple myeloma. They can be used alone or combined with other drugs as a part of treatment. Corticosteroids are also used to help decrease the nausea and vomiting that chemo might cause.