Phase II Study of IRD (Ixazomib, Lenalidomide, Dexamethasone) Post Autologous Stem Cell Transplantation Followed by Maintenance Ixazomib or Lenalidomide for Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this research study is to evaluate a treatment regimen called IRD which will be given to participants after their stem cell transplant in an effort to help prolong the amount of time the participants are disease-free after transplant. IRD is a three-drug regimen consisting of ixazomib, lenalidomide (also called Revlimid), and dexamethasone. After 4 cycles of IRD, the participants will be randomized to receive maintenance therapy either with ixazomib or lenalidomide.

Detailed Description
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Based on the further need to improve progression-free survival and overall survival post-autologous stem cell transplantation (ASCT) for multiple myeloma and the benefits seen of consolidation/maintenance treatment with immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, the natural next step is to evaluate combination regimens of immunomodulatory drugs and proteasome inhibitors as consolidation/maintenance post-ASCT. The regimen consisting of ixazomib, lenalidomide, and dexamethasone (IRD) has been shown to have low toxicity, and the availability of an oral formulation of ixazomib allows for easier administration when compared to bortezomib. In this study, following consolidation with IRD, patients will be randomized to maintenance therapy with lenalidomide or ixazomib in order to collect pilot data comparing the toxicity and efficacy of maintenance therapy with immunomodulatory drugs and proteasome inhibitors. 09/23/2019: Upon review of the interim analysis, there will be no further randomizations into the maintenance portion of the trial. All patients will be enrolled into the lenalidomide arm with the exception of those who discontinue lenalidomide during the consolidation phase due to toxicity. Patients who discontinue lenalidomide may be enrolled into the ixazomib arm following approval from the principal investigator. 09/30/2021: Following analysis 4 in 2021, analysis of the primary endpoint, all patients receiving lenalidomide maintenance will be transitioned off-study. Patients receiving ixazomib may remain on trial until disease progression or unacceptable toxicity at the discretion of the treating physician and the site principal investigator.

Official Title
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A Phase II Study of IRD (Ixazomib, Lenalidomide, & Dexamethasone) for Consolidation Therapy Post Autologous Stem Cell Transplantation Followed by Maintenance Ixazomib or Lenalidomide for Multiple Myeloma

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: Ixazomib
* Drug: Lenalidomide
* Drug: Dexamethasone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Each patient must meet all of the following inclusion criteria to begin IRD Consolidation: Between the ages of 18 and 70 years of age (inclusive) at time of enrollment Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care Confirmed diagnosis of symptomatic multiple myeloma. (Patients with multiple myeloma with secondary amyloidosis are eligible.) Received at least two cycles of any regimen as initial systemic therapy for multiple myeloma and are within 2-16 months of the first dose of initial therapy Eastern Cooperative Oncology Group (ECOG) performance status and/or other performance status 0, 1, or 2 Adequate organ function as defined below: Absolute neutrophil count (ANC) >= 1,000 mm^3 Platelet count >= 75,000/mm^3; platelet transfusions to help patient meet eligibility criteria are not allowed within 7 days before study enrollment Total bilirubin <= 1.5 x upper limit of normal range (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) <=3 x ULN Calculated creatinine clearance >= 30 mL/min Women of childbearing potential must follow pregnancy testing requirements as outlined in the Revlimid REMS program material. This is defined as either committing to continued abstinence from heterosexual intercourse or beginning TWO acceptable methods of contraception (one highly effective method and one additional effective method AT THE SAME TIME) at least 28 days prior to the start of lenalidomide, for the duration of study participation, and for 28 days following the last dose of lenalidomide. Women of childbearing potential must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a woman of childbearing potential even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately. All study participants must be registered into the mandatory Revlimind REMS program and be willing to comply with its requirements. Per standard Revlimid REMS program requirements, all physicians who prescribe lenalidomide for research subjects enrolled into this trial, must be registered in, and must comply with, all requirements of the Revlimid REMS program. Exclusion Criteria Patients meeting any of the following exclusion criteria are not to be enrolled in the study: Female patients who are lactating or have a positive serum pregnancy test during the screening period Evidence of MM disease progression any time prior to enrollment. Progression from smoldering/asymptomatic MM to symptomatic MM is not exclusionary. Tandem autologous transplantation History of plasma cell leukemia or MM CNS involvement Administration or planned administration of any other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy which would be considered a treatment of multiple myeloma until Day +28 post-transplant through discontinuation from study. Patients may be on corticosteroids if they are being given for disorders other than multiple myeloma (e.g., adrenal insufficiency, rheumatoid arthritis, etc.) Any serious medical or psychiatric illness that could, in the investigator's opinion, potentially interfere with the completion of treatment according to this protocol. Prior organ transplant requiring immunosuppressive therapy Active hepatitis A, B or C virus infection, or known human immunodeficiency virus (HIV) positive Known allergy to any of the study medications, their analogues, or excipients in the various formulations of any agent Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of ixazomib Concurrent hematologic or non-hematologic malignancy requiring treatment (other than multiple myeloma and secondary amyloidosis) Cardiac syncope, uncompensated NYHA Class 3 or 4 congestive heart failure, myocardial infarction within the previous six months, unstable angina pectoris, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, severe orthostatic hypotension, or clinically important autonomic disease Grade >= 3 peripheral neuropathy, or Grade 2 with pain on clinical examination during the screening period Major surgery within 14 days prior to enrollment Infection requiring systemic antibiotic therapy or other serious infection within 14 days prior to enrollment Participation in other clinical trials, including those with other investigational agents not included in this trial, within 30 days prior to enrollment and throughout the duration of this trial

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Consolidation: Ixazomib, Lenalidomide, & Dexamethasone<br>Consolidation therapy will begin between Day 80 and Day 120 following ASCT and will consist of four 28-day cycles of IRD (ixazomib, lenalidomide, & dexamethasone). Barring dose modifications for toxicity, 4 mg of ixazomib and 40 mg of dexamethasone will be administered on Days 1, 8, and 15, and 15 mg of lenalidomide will be administered on daily on Days 1-21. | Biological: Ixazomib<br> <br> * Other names: [14C]-MLN9708;Drug: Lenalidomide<br> <br> * Other names: Revlimid;Drug: Dexamethasone<br> <br> * Other names: Sk-Dexamethasone;|
| Experimental: Maintenance Arm 1: Ixazomib<br>Ixazomib will be administered on Days 1, 8, and 15 of a 28-day cycle at a starting dose of 4 mg until patient progresses or experiences an unacceptable toxicity. | Biological: Ixazomib<br> <br> * Other names: [14C]-MLN9708;|
| Experimental: Maintenance Arm 2: Lenalidomide<br>Lenalidomide will be administered daily continuously for a 28-day cycle at a starting dose of 10 mg. If lenalidomide is tolerated well (i.e. no dose modification required) during the first three cycles, lenalidomide dose will be increased to 15 mg daily and will continue until patient progresses or experiences an unacceptable toxicity. | Drug: Lenalidomide<br> <br> * Other names: Revlimid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Improvement in Minimal Residual Disease (MRD) | For the purposes of this study, a patient will be considered as having minimal residual disease if a positive result (1x10E06) is obtained using the Adaptive Clonoseq MRD testing. | After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MRD-negative Rate After ASCT | For the purposes of this study, a patient will be considered as having minimal residual disease if a positive result (1x10E06) is obtained using the Adaptive Clonoseq MRD testing | Prior to beginning consolidation treatment (Day -28 to Day 0) | 
| Toxicity of IRD Consolidation | For the purposes of this study, toxicity will be defined as inability to receive 4 cycles of IRD consolidation due to toxicity. | After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment) | 
| Response Rate of IRD Consolidation | For the purposes of this study, response rate is defined as the improvement in complete response rate. Response will be determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria. | After 4 cycles of IRD consolidation treatment (approximately Day 112 of consolidation treatment) | 
| Progression-free Survival of IRD Consolidation | Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout. | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | 
| Overall Survival of IRD Consolidation | Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout. | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | 
| Compare Toxicity Between the Two Maintenance Arms | The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. | 30 days after the completion of maintenance treatment (estimated to be Day 1125 of maintenance treatment) | 
| Compare Response Rate Between the Two Maintenance Arms | Response will be determined by the International Myeloma Working Group (IMWG) Uniform Response Criteria. Response includes stringent complete response (sCR) and complete response (CR). sCR requires all of the following: CR as defined below Normal free light chain ratio (0.26-1.65) Absence of clonal cells in the bone marrow by immunohistochemistry or immunofluorescence CR requires all of the following: Disappearance of monoclonal protein by both protein electrophoresis and immunofixation studies from the blood and urine If serum and urine monoclonal protein are unmeasurable, Normal free light chain ratio (0.26-1.65) <5% plasma cells in the bone marrow Disappearance of soft tissue plasmacytoma | Through completion of maintenance treatment (estimated to be day 1095 of maintenance treatment) | 
| Compare Progression-free Survival Between the Two Maintenance Arms | Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout. | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | 
| Compare Overall Survival Between the Two Maintenance Arms | Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout. | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | 
| Rate of MRD-positive to MRD-negative Conversion Between the Two Maintenance Arms |  | Cycle 13 Day 1 of maintenance treatment (Approximately Day 364 of maintenance treatment) | 
| Association of Progression-free Survival With MRD-negativity | Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout. | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | 
| Association of Progression-free Survival With MRD-positivity | Progression-free survival (PFS) will be defined as time from ASCT to progression, relapse, or death, whichever occurs first, and those event-free survivors will be censored at withdrawal or study closeout. | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | 
| Association of Overall Survival With MRD-negativity | Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout. | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | 
| Association of Overall Survival With MRD-positivity | Overall survival (OS) will be defined as time from ASCT to death due to any causes, and survivors will be censored at withdrawal or study closeout. | Up to 18 months after completion of maintenance therapy (Up to 5 years after starting the study) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple Myeloma, Autologous Stem Cell Transplantation, Ixazomib, Lenalidomide, Dexamethasone