Carfilzomib, Lenalidomide, and Dexamethasone in New Multiple Myeloma Patients
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Carfilzomib; Lenalidomide; Dexamethasone; Lenalidomide; Lenalidomide
Intervention description: 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; 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; 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; 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
Intervention MeSH terms: Dexamethasone; Lenalidomide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 45.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: Novel Drug Combinations; Protease Inhibitors; Decreased Peripheral Neuropathy; Auto Stem Cell Transplant; Multiple Myeloma

Summary:

      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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  Newly diagnosed patients with histologically confirmed multiple myeloma (MM) based on
             the following criteria:

               1. Clonal plasma cells in the bone marrow

               2. Measurable disease within the past 4 weeks defined by any one of the following:

                    1. Serum monoclonal protein greater than or equal to 1.0 g/dL

                    2. Urine monoclonal protein greater than 200 mg/24 hour

                    3. Serum immunoglobulin free light chain greater than 10 mg/dL AND abnormal
                       kappa/lambda ratio

               3. Evidence of underlying end organ damage attributed to underlying plasma cell
                  proliferative disorder meeting at least one of the following:

                    1. Hypercalcemia: serum calcium greater than or equal to 2.65 mmol/L

                    2. Renal Insufficiency: serum creatinine greater than 2.0 mg/dL

                    3. Anemia: hemoglobin value less than10 g/dL or 2 g/dL less than normal
                       reference

                    4. 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.