Carfilzomib, Lenalidomide, and Dexamethasone in New Multiple Myeloma Patients
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 2

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.
    

Detailed description: 
      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.
    

Intervention name(s): Carfilzomib; Lenalidomide; Dexamethasone; Lenalidomide; Lenalidomide
Intervention type(s): Drug; Drug; Drug; Drug; Drug
Intervention description(s): 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
Other intervention name(s): Kyprolis; Revlimid; Ozurdex; Revlimid; Revlimid
Intervention MeSH terms: Dexamethasone; Lenalidomide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Novel Drug Combinations; Protease Inhibitors; Decreased Peripheral Neuropathy; Auto Stem Cell Transplant; Multiple Myeloma