Bendamustine and Melphalan in Myeloma
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      Two high-dose chemotherapy regimens (melphalan alone versus the combination of melphalan and
      bendamustine) used for conditioning treatment before autologous stem cell transplantation
      will be compared in a 1:1 randomization in myeloma patients. The experimental arm is the
      bendamustine and melphalan (BenMel) combined regimen. The melphalan alone (Mel) regimen is
      the control (standard) treatment. Despite remarkable progress using novel agents both for
      induction before ASCT as well for maintenance after ASCT, definite cure in myeloma patients
      remains exceptional due to residual disease escaping intensive treatment. The aim of the
      study is to show an improvement of the rate of complete Remission 60 days after ASCT in
      myeloma patients from 50% with melphalan alone to 65% with the combination of bendamustine
      and melphalan.
    

Detailed description: 
      Background and Rationale:

      High-dose chemotherapy with melphalan and autologous stem cell transplantation (ASCT) remains
      an integral component of the myeloma treatment algorithm for patients considered eligible for
      the procedure, nowadays performed in myeloma patients up to the age of 75 years. Despite
      remarkable progress using novel agents both for induction before ASCT as well for maintenance
      after ASCT, definite cure in myeloma patients remains exceptional due to residual disease
      escaping intensive treatment. Martino et al. recently reported data on the feasibility and
      efficacy of the combination of bendamustine and melphalan (BenMel) as a conditioning regimen
      to second ASCT in patients with myeloma. In addition, extensive experience is available on
      the use of bendamustine (200mg/m2/day given on days -7 and -6) together with melphalan
      (140mg/m2/day day -1) and two additional drugs, cytarabine and etoposide (each on days -5 to
      -2) in the BeEAM conditioning regimen which is increasingly used as the standard conditioning
      regimen in lymphoma patients, also in the investigators' clinic, with an acceptable
      tolerability and safety profile. In summary, these data suggest that combinations of
      melphalan and bendamustine are usually well tolerated and that the maximum tolerated dose of
      bendamustine is not reached with the doses of 200mg/m2/day given on two days added to
      melphalan,etoposide and cytarabine (BeEAM regimen). The investigators therefore suggest in
      this study to directly compare bendamustine 200 mg/m2/day (on days -4 and -3) plus melphalan
      100mg/m2/day (on days -2 and -1) with melphalan 100mg/m2/day (days -2 and -1) in a randomized
      trial.

      Objectives:

      Primary objective To show a clinically meaningful improvement by 15% of the rate of complete
      remission (CR1) 60 days after ASCT in myeloma patients from 50% with melphalan alone to 65%
      with the combination of bendamustine and melphalan.

      Secondary objectives To assess acute and late toxicities/adverse events (CTCAE 4.0) during
      the study period in patients treated with the combination of bendamustine and melphalan as
      compared to melphalan alone.

      To assess the hematologic engraftment in patients treated with the combination of
      bendamustine and melphalan as compared to melphalan alone.

      To particularly assess early renal toxicity in patients treated with the combination of
      bendamustine and melphalan as compared to melphalan alone.

      To assess differences in overall survival and progression free survival in patients treated
      with the combination of bendamustine and melphalan as compared to melphalan alone after one
      year.

      To assess the quality of life prior to ASCT and at day 60 assessment thereafter

      Outcome:

      To assess the rate of complete remission (CR1) 60 days after ASCT in myeloma patients treated
      with the combination of bendamustine and melphalan as compared to melphalan alone by routine
      laboratory myeloma parameters (serum M-gradient and light chain ratio) and bone marrow
      assessments in patients with CR1.

      Number of Participants with Rationale: Applying a statistical power of 80% and a one-sided
      significance level of 20%, 60 evaluable patients will be needed in each group to show a
      clinically meaningful improvement by 15% of the rate of complete remission (CR1) 60 days
      after ASCT in myeloma patients, from 50% with melphalan alone to 65% with the combination of
      bendamustine and melphalan.

      Study Duration: The total study duration is 36 months. Study design: Randomized two-arm
      open-label prospective phase II trial. Monitoring will be performed by the Clinical Trial
      Unit (CTU) of the University of Berne, Switzerland.

      This study will be conducted in compliance with the protocol, the current version of the
      Declaration of Helsinki, the ICH-GCP as well as all national legal and regulatory
      requirements.
    

Intervention name(s): Melphalan; Bendamustine
Intervention type(s): Drug; Drug
Intervention description(s): High-dose chemotherapy regimen for conditioning treatment before autologous stem cell Transplantation. Patients will receive melphalan at a total dose of 200mg/m2, divided in two doses of 100mg/m2/day on days -2 and -1, with the ASCT at day 0.; High-dose chemotherapy regimen for conditioning treatment before autologous stem cell Transplantation. Patients will receive bendamustine at a total dose of 400mg/m2, divided in two doses of 200mg/m2/day on days -4 and -3. Melphalan is given at a total dose of 200mg/m2, divided in two doses of 100mg/m2/day, each on days -2 and -1, with the ASCT at day 0.
Other intervention name(s): Alkeran; Ribomustin
Intervention MeSH terms: Melphalan; Bendamustine Hydrochloride
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized prospective non-blinded clinical phase II trial investigating the drugs bendamustine hydrochloride and melphalan.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Multiple Myeloma; Bendamustine; Melphalan; ASCT