Pomalidomide, Ixazomib Citrate, and Dexamethasone in Treating Patients With Previously Treated Multiple Myeloma or Plasma Cell Leukemia

Study Overview
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Brief Summary
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This phase II trial studies how well pomalidomide, ixazomib citrate, and dexamethasone work in treating patients with previously treated multiple myeloma or plasma cell leukemia. Biological therapies, such as pomalidomide and dexamethasone, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Ixazomib citrate may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Giving pomalidomide, ixazomib citrate, and dexamethasone together may be more effective in treating multiple myeloma.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the confirmed response rate (>= partial response [PR]) of ixazomib citrate (ixazomib), used in combination with pomalidomide and dexamethasone in patients with previously treated multiple myeloma (MM) with extramedullary disease. SECONDARY OBJECTIVES: I. To determine the toxicities associated with ixazomib in combination with pomalidomide and dexamethasone in patients with previously treated MM with extramedullary disease. II. To determine the differential response rates (biochemical versus extramedullary disease) with ixazomib in combination with pomalidomide and dexamethasone in patients with previously treated MM with extramedullary disease. III. To determine the progression free survival following treatment with ixazomib in combination with pomalidomide and dexamethasone in patients with previously treated MM with extramedullary disease. TERTIARY OBJECTIVES: I. To assess the proportion of patients achieving minimal residual disease (MRD) negative status. OUTLINE: Patients receive ixazomib citrate orally (PO) on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 or 6 months for up to 3 years.

Official Title
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Phase 2 Trial of Pomalidomide, Ixazomib and Dexamethasone in Patients With Multiple Myeloma With Extramedullary Disease or Plasma Cell Leukemia

Conditions
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Plasma Cell Leukemia, Plasma Cell Myeloma, Plasmacytoma

Intervention / Treatment
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* Drug: Dexamethasone
* Drug: Ixazomib Citrate
* Other: Laboratory Biomarker Analysis
* Drug: Pomalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Previously treated myeloma, currently with extramedullary disease (defined as plasmacytoma outside bone marrow that is not contiguous with a bone lesion) with at least one lesion that has a single diameter of >= 2 cm or plasma cell leukemia (defined as circulating plasma cells exceeding 5% of peripheral blood leukocytes or 0.5 X 10^9/L or 200 cells/150000 events by flow cytometry) Calculated creatinine clearance (using Cockcroft-Gault equation) >= 30 mL/min Absolute neutrophil count (ANC) >= 1000/mm^3 Platelet count >= 50,000/mm^3 Hemoglobin >= 8.0 g/dL Patients with measurable disease defined as at least one of the following: For patients with extramedullary disease (EMD) measurable disease by computed tomography (CT) or magnetic resonance imaging (MRI) or the CT portion of the positron emission tomography (PET)/CT: must have at least one lesion that has a single diameter of >= 2 cm; skin lesions can be used if the area is >= 2 cm in at least one diameter and measured with a ruler Plasma cell count >= 0.5 X 10^9/L or 5 percent of the peripheral blood white cells Plasma cell count if determined by flow cytometry, >= 200/150,000 events Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 Provide informed written consent Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only All study participants must be registered into the mandatory pomalidomide (POMALYST) Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of the POMALYST REMS program Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study) Willing to provide bone marrow and blood samples for correlative research purposes Exclusion Criteria: Other malignancy requiring active therapy EXCEPTIONS: Non-melanoma skin cancer, ductal breast carcinoma in situ (DCIS) or carcinoma-in-situ of the cervix NOTE: If there is a history or prior malignancy, they must not be receiving other specific treatment for their cancer Females of childbearing potential (FCBP)* must have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours prior to prescribing pomalidomide for cycle 1 (prescriptions must be filled within 7 days as required by RevAssist [lenalidomide REMS program]), and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method; AT THE SAME TIME, at least 28 days before she starts taking pomalidomide FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy; patient must follow pregnancy testing requirements as outlined in the POMALYST REMS program A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception Other co-morbidity which would interfere with patient's ability to participate in trial, e.g. uncontrolled infection, uncompensated heart or lung disease Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational NOTE: Bisphosphonates are considered to be supportive care rather than therapy, and are thus allowed while on protocol treatment Patient has >= grade 3 peripheral neuropathy, or grade 2 with pain on clinical examination during the screening period Major surgery =< 14 days before study registration Systemic treatment with strong CYP3A4 inducers (e.g. rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenobarbital, gingko biloba, St. John's wort) within 7 days before registration Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure, angina, or myocardial infarction within the past 6 months; Note: prior to study entry, any electrocardiogram (ECG) abnormality at screening must be documented by the investigator as not medically relevant Corrected QT Interval (QTc) > 470 milliseconds (msec) on a 12-lead ECG obtained during the screening period Note: If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG Known human immunodeficiency virus (HIV) positive Known hepatitis B surface antigen-positive status, or known or suspected active hepatitis C infection Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol Known allergy to any of the study medications, their analogues or excipients in the various formulations Known gastrointestinal (GI) disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib including difficulty swallowing Diarrhea > grade 1, based on the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grading, in the absence of antidiarrheals

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (ixazomib citrate, pomalidomide, dexamethasone)<br>Patients receive ixazomib citrate PO on days 1, 8, and 15, pomalidomide PO on days 1-21, and dexamethasone PO on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Dexamethasone<br>* Given PO<br>* Other names: Visumetazone;Drug: Ixazomib Citrate<br>* Given PO<br>* Other names: Ninlaro;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Pomalidomide<br>* Given PO<br>* Other names: Pomalyst;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response Rate | A confirmed response is defined as a patient who has achieved a stringent complete response (sCR), complete response (CR), very good partial response (PR), or PR on two consecutive evaluations. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Ninety-five percent confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Biochemical Response Rate | The biochemical response rate will be estimated by the number of responders(patients that achieved partial or complete response) divided by the number of evaluable patients who have measurable disease by serum M-protein, urine M-protein, or serum FLC assay at baseline. Exact binomial confidence intervals will be calculated. | 4 years | 
| Extramedullary Response Rate | Extramedullary response, defined as a response by extramedullary plasmacytoma or plasma cell count parameters. The extramedullary response rate will be estimated by the number of responders(patients that achieved a partial or complete response) divided by the number of evaluable patients. Exact binomial confidence intervals will be calculated. | 4 years | 
| Incidence of Adverse Events Graded According to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 | Number of patients with adverse events is reported here, the full list of those adverse events and their frequency is reported in the adverse event section. | 4 years 1 month | 
| Progression-free Survival | The distribution of progression-free survival will be estimated using the method of Kaplan-Meier. | 4 years 8 months |