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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

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

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.

Mezigdomide

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.

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.

Linda J Elias, RN

Kathleen A Dorritie, MD

Multiple myeloma (MM) is the second most common hematologic malignancy with an estimated annual incidence of nearly 35,000 cases. While still considered an incurable disease, new treatments have improved outcomes dramatically over the last two decades. Around the turn of the millennium, classical cytotoxic chemotherapy and radiation were the only available treatment modalities and median OS was estimated at 2-3 years. Currently, there are now 17 FDA-approved anti-myeloma agents and median OS is approaching 10 years. More recently, next generation cellular and immune therapies are demonstrating unprecedented efficacy in highly refractory patients with otherwise a very short life expectancy. In this study, the starting dose of ixazomib will be reduced to 3mg, as this is the first FDA-recommended dose recommendation (from 4mg). The starting dose of mezigdomide will be 0.6mg. Frequent toxicity and AE monitoring as outlined in this trial (weekly in C1, every 2 weeks in C2-C4) asserts maximization of patient safety. Dexamethasone (DEX) will be dosed at 40mg weekly in patients \< 75 years old and 20mg for patients \> 76 years old. Additionally, the staring dose of DEX may be reduced to 20mg in any patient, per study provider discretion, based on several factors such frailty, prior adverse side effects or existing comorbidities.

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.

Mezigdomide Plus Ixazomib and Dexamethasone for Relapsed and Refractory Multiple Myeloma

Phase I/II Trial of Mezigdomide Plus Ixazomib and Dexamethasone for Relapsed and Refractory Multiple Myeloma

Dose-limiting toxicity (DLT) per adverse events as defined using National Cancer Institute (NCI) CTCAE v5.0. Hematologic DLTs: Grade 4 neutropenia \< 500/μL for more than 5 days, Grade 3 neutropenia with fever \> 38.3°C (one time) or fever \> 38.0°C sustained for one hour, Grade 4 thrombocytopenia, Grade 3 thrombocytopenia with bleeding; Non-Hematologic DLTs: Grade 3 diarrhea lasting \>3 days (not recovering to \< grade 2) despite supportive care, Grade 3 nausea or vomiting \>3 days (not recovering to \< grade 2) days despite supportive care, Grade 3 fatigue lasting \>7 days (not recovering to \< grade 2) days despite supportive care, Grade 4 diarrhea, Grade 4 nausea or vomiting, Allergic reaction or hypersensitivity if unable to be corrected to \<grade 1 within 48 hours, Any other non-hematologic grade \>3 toxicity for which there is not a clear alternative explanation; General: dose modification or delay of mezigdomide or ixazomib during cycle 1 due to treatment related toxicity.

Preliminary efficacy of mezigdomide when given in combination with ixazomib and dexamethasone as estimated by ORR, as defined by the International Myeloma Working Group (IMWG) response criteria. This will be expressed as the proportion of patients who achieve complete response (CR) or partial response (PR). CR is defined as negative serum and urine M-protein immunofixation (IF), along with the presence of \< 5% plasma cells (PCs) in bone marrow (BM) biopsy. PR is defined as ≥ 50% reduction of serum M-Protein and reduction in 24-hour urinary M-protein by ≥ 90% or to \< 200 mg per 24 hours.

Incidence and severity of adverse events AEs, as defined by the NCI-Common Terminology Criteria for Adverse Events v5.0, tabulated by type, grade and relatedness to treatment for each dose level achieved in the study and overall.

Depth of Response will be measured as the proportion of participants in each category, given IMWG Uniform Response Criteria at each dose level and overall.

The time from the date of the earliest documented response (PR, VGPR, CR or sCR) to the earliest date of disease progression or death, whichever occurred first. Disease progression will be determined by the investigator per IMWG Uniform Response Criteria.

The time from the date of first treatment to the earliest date of disease progression or death, whichever occurred first. Disease progression will be determined by the investigator per IMWG Uniform Response Criteria.

Spots Global Cancer Trial Database for cellular transcription factors (ikaros and aiolos)