Lenalidomide and Dexamethasone With or Without Anakinra in Treating Patients With Early Stage Multiple Myeloma

Study Overview
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Brief Summary
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This partially randomized phase I/II trial studies the side effects and best dose of anakinra when given together with lenalidomide and dexamethasone in treating patients with early stage multiple myeloma. Biological therapies, such as lenalidomide and anakinra, may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Drugs used in chemotherapy, such as dexamethasone, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether lenalidomide and dexamethasone are more effective with or without anakinra in treating patients with multiple myeloma.

Detailed Description
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PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD)/maximum allowable dose (MAD) of anakinra that can be combined with lenalidomide and dexamethasone. (Phase I) II. To compare the time to progression of the standard treatment arm (lenalidomide/dexamethasone) to the experimental arm (lenalidomide/dexamethasone + anakinra). (Phase II) SECONDARY OBJECTIVES: I. To compare the response rate of the standard treatment arm (lenalidomide/dexamethasone) to the experimental arm (lenalidomide/dexamethasone + anakinra). II. To compare the toxicity of the standard treatment arm (lenalidomide/dexamethasone) to the experimental arm (lenalidomide/dexamethasone + anakinra). III. To compare the overall survival of the standard treatment arm (lenalidomide/dexamethasone) to the experimental arm (lenalidomide/dexamethasone + anakinra). OUTLINE: This is a phase I, dose-escalation study of anakinra followed by a phase II study. PHASE I: Patients receive lenalidomide orally (PO) on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Patients also receive anakinra subcutaneously (SC) on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. PHASE II: Patients are randomized to 1 of 2 treatment arms. ARM A: Patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Patients also receive anakinra SC on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. ARM B: Patients receive lenalidomide and dexamethasone as in Arm A. Patients also receive placebo SC on days 1-28. 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 months.

Official Title
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Phase I/II Double Blind Randomized Trial of Lenalidomide/Dexamethasone/Anakinra vs. Lenalidomide/Dexamethasone/Placebo in Patients With Early Stage Multiple Myeloma and High Plasma Cell Growth Rate

Conditions
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Indolent Plasma Cell Myeloma, Plasma Cell Myeloma, Smoldering Plasma Cell Myeloma

Intervention / Treatment
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* Biological: Anakinra
* Drug: Dexamethasone
* Other: Laboratory Biomarker Analysis
* Drug: Lenalidomide
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Absolute neutrophil count (ANC) >= 1700/mm^3 Platelet count >= 100,000/mm^3 Hemoglobin >= 8.0 g/dL Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3 x upper limit of normal (ULN) Creatinine clearance >= 30 mL/min (as determined by Cockroft-Gault equation) Diagnosis of multiple myeloma according to International Myeloma Working Group criteria and one of the following: Smoldering multiple myeloma (SMM) Indolent multiple myeloma (IMM) Newly diagnosed multiple myeloma (MM) Note: patients with lytic disease and anemia are eligible High risk disease defined by all of the following: >= 10% bone marrow plasma cells AND Abnormal serum free light chain (FLC) ratio (< 0.26 or > 1.65) by serum FLC assay AND Monotypic plasma cell S-phase >= 0.3% Measurable level of M-protein > 1 g/dL on serum protein electrophoresis or > 200 mg of M-protein on a 24 hour urine protein electrophoresis Negative tuberculosis (TB) testing (Quantiferon - TB blood test or skin test) =< 7 days prior to registration Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 Provide signed informed consent Negative (serum or urine) pregnancy test done =< 7 days prior to registration, for women of childbearing potential only; NOTE: a second pregnancy test must be performed within 24 hours prior to the start of lenalidomide; the subject may not receive lenalidomide until the study doctor has verified that the results of these pregnancy tests are negative Willing to return to enrolling institution for follow-up (during the active monitoring phase of the study) Willing and able to comply with the requirements of the Revlimid Risk Evaluation and Mitigation Strategy (REMS) program Females of childbearing potential must be willing to adhere to the scheduled pregnancy testing as required by the Revlimid REMS program Exclusion Criteria: Prior treatment with any other agent that may affect M-protein =< 30 days prior to registration Acute/chronic infections, open wounds, or any active infection requiring intravenous antibiotic therapy =< 12 weeks prior to registration Other active malignancy (=< 3 years) prior to registration; exceptions: basal cell skin cancer or carcinoma-in-situ of the cervix or low-risk prostate cancer after curative therapy Any of the following: Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception New York Heart Association (NYHA) class 3 or 4 congestive heart failure (CHF) symptoms Other concurrent chemotherapy, radiotherapy, or any ancillary therapy considered investigational; NOTE: bisphosphonates are allowed while on protocol treatment

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A (lenalidomide, dexamethasone, anakinra)<br>Patients receive lenalidomide PO on days 1-21 and dexamethasone PO on days 1, 8, 15, and 22. Patients also receive anakinra SC on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity | Biological: Anakinra<br>* Given SC<br>* Other names: rIL1RN;Drug: Dexamethasone<br>* Given PO<br>* Other names: Mymethasone;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;|
| Active Comparator: Arm B (lenalidomide, dexamethasone, placebo)<br>Patients receive lenalidomide and dexamethasone as in Arm A. Patients also receive placebo SC on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Dexamethasone<br>* Given PO<br>* Other names: Mymethasone;Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Lenalidomide<br>* Given PO<br>* Other names: Revlimid;Other: Placebo<br>* Given SC<br>* Other names: sham therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Experiencing a Dose-limiting Toxicity (DLT) | Number of participants experiencing a dose-limiting toxicity (DLT) is reported below. Dose-limiting toxicity is graded by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. | 28 days | 
| Number of Participants Who Experienced at Least One Grade 3+ Adverse Events Deemed at Least Possibly Related to Treatment, Graded According to NCI CTCAE Version 4.0 | The number of participants who experienced at least one grade 3+ adverse events deemed at least possibly related to treatment, graded according to NCI CTCAE version 4.0, is reported below. | Up to 41 months | 
| Best Response | The following response terms will be used: stringent Complete Response (sCR), complete response (CR), very good partial response (VGPR), partial response (PR), Minimal Response (MR), stable disease (SD), and progressive disease (PD). The International Myeloma Working Group (IMWG) uniform response criteria (Rajkumar et al, 2011) will be used to assess response to therapy. PR defined as: ≥50% reduction of serum M-protein and reduction in 24-hour urinary M-protein by ≥90% or to <200 mg/24hrs; ≥ 50% reduction in the size of soft tissue plasmacytomas. MR defined as: ≥25% but ≤ 49% reduction of serum M protein and reduction in 24-hour urine M-protein by 50-89% which still exceeds 200mg/24 hours; 25-49% reduction in the size of soft tissue plasmacytoma and No increase in the size or number of lytic bone lesions. VGPR defined as: Serum and urine M-protein detectable by immunofixation but not on electrophoresis or ≥90% reduction in serum M-protein and urine M-protein <100 mg/24 h | Up to 41 months |