Carfilzomib, Lenalidomide, and Dexamethasone in New Multiple Myeloma Patients

Study Overview
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Brief Summary
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Background: - Carfilzomib is an experimental anti-cancer drug that has not yet been approved for treating multiple myeloma. Lenalidomide is a drug that may stop tumor growth and help the immune system kill cancer cells. Dexamethasone is a drug that helps stop inflammation. It is sometimes used to treat (alone or with other drugs) certain types of cancer, especially multiple myeloma. This combination of drugs has not been tested in people with multiple myeloma. Researchers want to see whether it is safe and effective for this group. Objectives: - To test the effectiveness of combined carfilzomib, lenalidomide, and dexamethasone in treating multiple myeloma. Eligibility: - People at least 18 years of age who have multiple myeloma that has not been treated. Design: Participants will be screened with a medical history and physical exam. They will also have blood and urine tests, a bone marrow sample, and molecular imaging studies. Participants will have eight 28-day cycles of treatment. The combined study drugs will be given as tablets and injections. Those in the study will be monitored with frequent blood tests, bone marrow samples, and molecular imaging studies. In addition to current standard measures to determine clinical responses, molecular tests will be conducted to define evidence of minimal residual disease. After the first four cycles of therapy, those who are eligible for a stem cell transplant will have stem cells collected and stored for use if the cancer returns. After stem cell collection, participants will have the second four treatment cycles. -, If the disease has improved or is stable at the end of eight cycles, those in the study may have another 12 cycles of low-dose (maintenance) lenalidomide alone. Participants will have regular follow-up visits after the end of the study chemotherapy.

Detailed Description
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Background: Multiple myeloma (MM) is an incurable plasma cell neoplasm with a median survival of 3-4 years. Novel agent combinations with proteasome inhibitors demonstrate improved response rates while increasing survival in MM patients. A common debilitating side effect of the proteasome inhibitor bortezomib is neuropathy. Carfilzomib is a new proteasome inhibitor with potent anti-MM effects and decreased peripheral neuropathy Objectives: -Evaluate toxicity, including peripheral neuropathy, of carfilzomib, lenalidomide, and dexamethasone (CRd) in untreated MM patients Eligibility: Newly diagnosed patients with histologically confirmed multiple myeloma Age greater than or equal to 18 years Creatinine Clearance (CrCl) greater than or equal to 60 ml/min. CrCl will be calculated using the Cockcroft- Gault method. If the calculated CrCl based on Cockcroft-Gault method is <60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must also be greater than or equal to 60 ml/min. Without serious co-morbidity that would interfere with receipt of CRd Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater than or equal to 8 g/dL, and platelet count greater than or equal to 75 K/uL Adequate hepatic function, with bilirubin less than 1.5 x the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3.0 x ULN Design: Single arm, single stage phase II trial of combination therapy (carfilzomib, lenalidomide, and dexamethasone) for untreated multiple myeloma patients with an early stopping rule for toxicity Patients will receive 8 cycles of induction combination therapy of CRd Each cycle consists of 28-days After 4 cycles of therapy, transplant eligible patients will undergo stem cell collection Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year. Patients will have routine blood work with serum protein electrophoresis (SPEP) and free light chains monthly Pre- and post-treatment bone marrow biopsies will be obtained for confirmation of diagnosis and correlative studies Patients will also undergo evaluation for minimal residual disease at regular interval time points, using multi-parametric flow cytometry and fludeoxyglucose 18F-positron emission tomography - computed tomography (FDG PET-CT) A single stage phase II design will be employed, with an early stopping rule. Unless 4 or more patients in the first 20 have Grade 3 or higher neurologic toxicity in the first 2 completed cycles, a total of 45 evaluable patients will be enrolled in this study.

Official Title
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Carfilzomib, Lenalidomide, and Dexamethasone in Newly Diagnosed Multiple Myeloma: Clinical and Correlative Phase II Study

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Drug: Carfilzomib
* Drug: Lenalidomide
* Drug: Dexamethasone
* Drug: Lenalidomide
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Newly diagnosed patients with histologically confirmed multiple myeloma (MM) based on the following criteria: Clonal plasma cells in the bone marrow Measurable disease within the past 4 weeks defined by any one of the following: Serum monoclonal protein greater than or equal to 1.0 g/dL Urine monoclonal protein greater than 200 mg/24 hour Serum immunoglobulin free light chain greater than 10 mg/dL AND abnormal kappa/lambda ratio Evidence of underlying end organ damage attributed to underlying plasma cell proliferative disorder meeting at least one of the following: Hypercalcemia: serum calcium greater than or equal to 2.65 mmol/L Renal Insufficiency: serum creatinine greater than 2.0 mg/dL Anemia: hemoglobin value less than10 g/dL or 2 g/dL less than normal reference Bone disease: lytic lesions, severe osteopenia or pathological fractures Creatinine Clearance (CrCl) greater than or equal to 60 ml/min. CrCl will be calculated by Cockcroft-Gault method. CrCl (calculated) = (140 Age) x Mass (in kilograms) x [0.85 if Female] 72 times Serum Creatinine (in mg/dL). If calculated CrCl based on Cockcroft-Gault method is <60 mL/min, patient will have a 24 hr urine collection to measure CrCl. The measured CrCl must be also greater than or equal to 60 ml/min. Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of carfilzomib in combination with lenalidomide in patients less than18 years of age, children are excluded from this study, but will be eligible for future pediatric trials. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 Absolute neutrophil count (ANC) greater than or equal to 1.0 K/uL, hemoglobin greater than or equal to 8 g/dL (transfusions are permissible), and platelet count greater than or equal to 75 K/uL Adequate hepatic function, with bilirubin less than 1.5 times the upper limit of normal (ULN), and aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 3.0 times ULN. All study participants must be able to tolerate one of the following thromboprophylactic strategies: aspirin, low molecular weight heparin or warfarin (coumadin). All study participants must be registered into the mandatory RevAssist program, and be willing and able to comply with the requirements of RevAssist . Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 10-14 days and again within 24 hours prior to prescribing lenalidomide for Cycle 1 (prescriptions must be filled within 7 days) 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 lenalidomide. Females of child bearing potential (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. Subjects must be able to give informed consent EXCLUSION CRITERIA: Prior or concurrent systemic treatment for MM. Treatment of hypercalcemia or spinal cord compression or aggressively progressing myeloma with corticosteroids is permitted. Bisphosphonates are permitted. Treatment with corticosteroids for indications other than MM is permitted. Radiotherapy is permitted. Treatment for smoldering myeloma is permitted. Plasma cell leukemia Pregnant or lactating females. Because there is a potential risk for adverse events in nursing infants secondary to treatment of the mother with carfilzomib in combination with lenalidomide, breastfeeding should be discontinued if the mother is treated with carfilzomib and lenalidomide. These potential risks may also apply to other agents used in this study. Uncontrolled hypertension or diabetes Active hepatitis B or C infection Has significant cardiovascular disease with New York Heart Association (NYHA) Class III or IV symptoms, or hypertrophic cardiomyopathy, or restrictive cardiomyopathy, or myocardial infarction within 3 months prior to enrollment, or unstable angina, or unstable arrhythmia as determined by history and physical examination. Echocardiogram will be performed if clinically warranted. Has refractory gastrointestinal (GI) disease with refractory nausea/vomiting, inflammatory bowel disease, or bowel resection that would prevent absorption Uncontrolled intercurrent illness including but not limited to active infection or psychiatric illness/social situations that would compromise compliance with study requirements Significant neuropathy greater than or equal to Grade 3 at baseline Contraindication to any concomitant medication, including antivirals, anticoagulation prophylaxis, tumor lysis prophylaxis, or hydration given prior to therapy Major surgery within 1 month prior to enrollment Recruitment Strategies: Patients that progress from the smoldering multiple myeloma (SMM) and monoclonal gammopathy of undetermined significance (MGUS) Natural History Study (NCI Protocol: 10-C-0096) will be potential candidates. Other participant sources will be from outside physician referrals. Our ongoing natural history study and outside physician referral network has a high representation of minorities.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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: Carfilzomib, Lenalidomide, Dexamethasone<br>Patients will receive 8 cycles of induction combination therapy of carfilzomib, lenalidomide, and dexamethasone (CRd). Patients achieving stable disease or better after 8 cycles of CRd will receive lenalidomide extended dosing (phase I) for 12 cycles. After 12 cycles, patients will have the option to continue extended dosing (phase II) for one additional year | Drug: Carfilzomib<br>* Cycle 1: 20 mg/m(2) intravenous (IV) infusion over 30 minutes on days 1 and 2, then 36 mg/m(2) IV on days 8, 9, 15, and 16 Cycle 2-8: 36mg/ m(2) IV infusion over 30 minutes on days 1, 2, 8, 9, 15, and 16<br>* Other names: Kyprolis;Drug: Lenalidomide<br>* Cycle 1: 25 mg oral days 2-21 of 28-day cycle; Cycle 2 - 8: 25 mg oral days 1-21 of 28-day cycle; After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles; After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year<br>* Other names: Revlimid;Drug: Dexamethasone<br>* Cycle 1: 20 mg oral or IV on days 2, 8, 9, 15, 16, 22, and 23 Cycle 2-4: 20 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23 Cycle 5-8: 10 mg oral or IV on days 1, 2, 8, 9, 15, 16, 22, and 23<br>* Other names: Ozurdex;Drug: Lenalidomide<br>* After 8 cycles of combination carfilzomib, lenalidomide, and dexamethasone (CRd), patients may continue Lenalidomide for 12 cycles<br>* Other names: Revlimid;Drug: Lenalidomide<br>* After 12 cycles of extended dosing of Lenalidomide, patients may continue Lenalidomide for one year<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 Serious and Non-serious Adverse Events | Here is the number of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned. | 4 years and 9 months and 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response Rate | Response is assessed by the International Myeloma Working Group Criteria. Patients who attained a partial response or better (BoR) response by the end of induction. Partial response is ≥50% reduction of serum M-protein and reduction in 24h urinary M-protein. | 48.3 months | 
| Progression Free Survival (PFS) at 48 Months | PFS is defined as time of start of treatment to time of progression or death, whichever occurs first. Response is assessed by the International Myeloma Working Group Criteria. Progressive disease requires any one or more of the following: increase of ≥25% from lowest response value in the following on 2 consecutive measurements: serum M-component and/or (the absolute increase must be ≥0.5g/dl). Urine M-component and/or (the absolute increase must be ≥200mg/24h. Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels. The absolute increase must be >10mg/dl. Bone marrow plasma cell percentage: the absolute % must be ≥10%. Definite development of new bone lesions or soft tissue plasmacytomas or definite increase in size of existing bone lesions or soft tissue plasmacytomas. Development of hypercalcemia that can be attributed solely to the plasma cell proliferative disorder. | 48 months | 
| Percentage of Responders With Duration of Response (DOR) at 48 Months | Response is assessed by the International Myeloma Working Group Criteria. DOR is measured from the time measurement criteria are met for a partial response or better until first date that recurrent or progressive disease is objectively documented. Partial response is ≥50% reduction of serum M-protein and reduction in 24-h urinary M-protein by ≥90% or to <200mg per 24h. Progressive disease requires any one or more of the following: increase of ≥25% from lowest response value in the following on 2 consecutive measurements: serum M-component and/or (the absolute increase must be ≥0.5g/dl). Urine M-component and/or (the absolute increase must be ≥200mg/24h. Only in patients without measurable serum and urine M-protein levels: the difference between involved and uninvolved free light chain (FLC) levels. The absolute increase must be >10mg/dl. Bone marrow plasma cell percentage: the absolute % must be ≥10%. | 48 months | 
| Overall Survival (OS) Rate | OS is defined as the time of start of treatment to death from any cause. | up to 6 months | 
| Cluster of Differentiation 138 (CD138) + Plasma Cells Gene Expression Profiling on Pre and Post Carfilzomib Exposure Bone Marrow Samples | Cluster of differentiation 138+ (CD138)+ plasma cells purified from bone marrow aspirates to identify potential markers of early progression. Changes in selected genes were confirmed by quantitative polymerase chain reaction (PCR) if suggested to be related to risk of progression to multiple myeloma. | Cycle 1 Day 1, an average of 28 days ± 2 days | 
| Rate of Minimal Residual Disease (MRD) by Flow Cytometry | Response is assessed by the International Myeloma Working Group Criteria. Complete response is negative immunofixation on the serum and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow. MRD is defined by M-spike, plasma cell burden, and abnormal free light chains. Immunophenotyping is performed by multi-parametric flow cytometry. | Day 100 | 
| Complete Response (CR) and Minimal Residual Disease Neg (MRDneg) CR Rates at Treatment Intervals With Carfilzomib, Lenalidomide & Dexamethasone (CRd) in New Multiple Myeloma Patients After 8 Cycles of Induction, 1 Year Maintenance, and 2 Years Maintenance | Response is assessed by the International Myeloma Working Group Criteria. MRD is defined by M-spike, plasma cell burden, and abnormal free light chains (FLC). Complete response is negative immunofixation on serum, and urine and disappearance of any soft tissue plasmacytomas and ≤ 5% plasma cells in bone marrow. Stringent complete response (sCR) is normal FLC ratio and absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence. Near complete response (nCR) is the absence of myeloma protein on electrophoresis, independent of immunofixation status. Very good partial response (VGPR) is serum and urine M-protein detectable by immunofixation but not on electrophoresis or 90% or greater reduction in serum M-protein plus urine M-protein level <100mg per 24h. Overall response rate (ORR) is patients who attained a partial response (PR) (≥50% reduction of serum M-protein and reduction in 24h urinary M-protein) or better (BoR) response. | up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Novel Drug Combinations, Protease Inhibitors, Decreased Peripheral Neuropathy, Auto Stem Cell Transplant, Multiple Myeloma