Bortezomib and Bendamustine to Treat Relapsed/Refractory Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Intervention: Bendamustine; Bortezomib
Intervention description: On days 1 and 4 of each cycle, bendamustine is given at 90 mg/m^2 after bortezomib . Patients will be dose reduced to 75 mg/m^2, and then to 60 mg/m^2 bendamustine on days 1 and 4 if ANC is not >1 x 10^9/L and platelets are not >50 x 10^9/L on day 1 of each cycle.
Patients will be treated until disease progression after at least one cycle of treatment.; On days 1 and 4 of each cycle, bortezomib is given first at 1.3 mg/m^2 followed by bendamustine given at 90 mg/m^2. Patients will be dose reduced to 75 mg/m^2, and then to 60 mg/m^2 bendamustine on days 1 and 4 if ANC is not >1 x 10^9/L and platelets are not >50 x 10^9/L on day 1 of each cycle.
Patients will be treated until disease progression after at least one cycle of treatment.
Intervention MeSH terms: Bortezomib; Bendamustine Hydrochloride
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 24.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: myeloma; multiple myeloma; relapsed myeloma; refractory myeloma

Summary:

      Patients with myeloma that has either not responded to previous treatment or has returned
      after previous treatment will be given a combination of the drugs bendamustine and
      bortezomib.

      The bortezomib and bendamustine will be given using an intravenous line (IV) on days 1 and 4
      of each cycle, with bortezomib being given first, before each dose of bendamustine. Each
      cycle will be 28 days long, so patients will be treated the first week of each cycle and then
      have 3 weeks 'off' (without any treatment). Disease assessments will be performed on day 22
      of each cycle. Patients will receive the study drugs until their disease progresses or they
      are withdrawn from the study.

      In other studies, bendamustine seems to work well with other drugs. Thus, this study hopes to
      show that the combination of bortezomib and bendamustine will have activity in
      relapsed/refractory myeloma.
    

Eligibility criteria:

        Inclusion Criteria:

          1. Voluntary written informed consent

          2. Age 18 years or older

          3. Female subject is either post-menopausal or surgically sterilized or willing to use an
             acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine
             device, diaphragm with spermicide, condom with spermicide, or abstinence) for the
             duration of the study.

          4. Male subject agrees to use an acceptable method for contraception for the duration of
             the study.

          5. Diagnosis of multiple myeloma based on standard criteria as follows:

             Major Criteria

               -  Plasmacytomas on tissue biopsy

               -  Bone marrow plasmacytosis (>30% plasma cells)

               -  Monoclonal immunoglobulin spike on serum electrophoresis (IgG >3.5 g/dL or IgA
                  >2.0 g/dL) or kappa or lambda light chain excretion >1 g/day on 24 hour urine
                  protein electrophoresis

             Minor Criteria

               -  Bone marrow plasmacytosis (10 to 30% plasma cells)

               -  Monoclonal immunoglobulin present but of lesser magnitude than given under major
                  criteria

               -  Lytic bone lesions

               -  Normal IgM <50 mg/dL, IgA <100 mg/dL, or IgG <600 mg/dL

               -  Any of the following sets of criteria will confirm the diagnosis of Multiple
                  Myeloma:

                    -  Any two of the major criteria or

                    -  1 major plus 2 minor criteria.

          6. Measurable disease, defined as a monoclonal immunoglobulin spike (M-Spike) on serum
             electrophoresis of ≥1 g/dL and/or urine monoclonal immunoglobulin spike of ≥200 mg/24
             hours. Non-secretors must have measurable protein by Freelite or measurable disease by
             plasmacytoma to be eligible.

          7. Patients must have refractory myeloma as defined by a greater than 25% increase in
             their M-protein. They should have progressed on bortezomib.

          8. Karnofsky performance status ≥50

          9. Patients treated with local radiotherapy with or without a brief exposure to steroids
             are eligible. Patients who require radiotherapy should have entry to the protocol
             deferred until the radiotherapy is completed by at least 4 weeks prior to initiation
             of study drug.

         10. Meets the following pretreatment laboratory criteria at baseline (Day 1 of Cycle 1,
             before study drug administration)

               -  Absolute neutrophil count ≥1 x 10^3/uL

               -  Platelet count ≥75 x 10^3/uL

               -  Hemoglobin ≥8.0 g/dL

               -  Calculated or measured CrCL ≥ 40 mL/min

               -  AST or ALT and total bilirubin < 3 x ULN

         11. Echocardiogram with a >50% Ejection Fraction

        Exclusion Criteria:

        Patients meeting any of the following exclusion criteria are not to be registered on study:

          1. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly,
             endocrinopathy, monoclonal protein (M-protein) and skin changes)

          2. Plasma cell leukemia

          3. Receiving steroids daily for other medical conditions, e.g., asthma, systemic lupus
             erythematosis, rheumatoid arthritis

          4. Infection not controlled by antibiotics

          5. HIV infection. Patients should provide consent for HIV testing according to the
             institution's standard practice.

          6. Known active hepatitis B or C

          7. New York Hospital Association (NYHA) Class III or IV heart failure, Echo or MUGA
             ejection fraction < 40% (if known), or EKG evidence of acute ischemic disease

          8. Other serious medical or psychiatric illness that could potentially interfere with the
             completion of treatment according to this protocol

          9. Second malignancy requiring treatment in the last 3 years

         10. Patient has a calculated or measured creatinine clearance of <40 mL/min within 14 days
             before enrollment

         11. Patient has >Grade 2 peripheral neuropathy within 14 days before enrollment

         12. Patient has hypersensitivity to bortezomib, boron or mannitol and bendamustine

         13. Positive pregnancy test in women of childbearing potential or subject is pregnant or
             breast-feeding. Confirmation that the subject is not pregnant must be established by a
             negative serum betaa human chorionic gonadotropin test result obtained during
             screening. Pregnancy testing is not required for post-menopausal or surgically
             sterilized women.

         14. Patient has received other investigational drugs with 14 days before enrollment

         15. Serious medical or psychiatric illness likely to interfere with participation in this
             clinical study.

         16. Diagnosed or treated for another malignancy within 3 years of enrollment, with the
             exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
             the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy.