Busulfan & Melphalan Conditioning for Autologous Stem Cell Transplant (ASCT) and Lenalidomide Maintenance
Condition: Multiple Myeloma
MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell
Study type: Interventional
Phase: Phase 2

Summary: 
      A number of strategies have been proposed to improve the outcome of ASCT. The three main
      strategies are to incorporate novel agents into the induction regimen, using maintenance
      therapy following ASCT and the final strategy is to enhance conditioning regimens.

      Investigators would like to explore all these three strategies in this study: Investigators
      propose to take patients who have had standard novel agent (bortezomib) based induction
      regimens into this study and then use a dose-adjusted combination of busulfan and melphalan
      as conditioning regimen and finally Investigators would like to incorporate lenalidomide
      maintenance post ASCT until disease progression.
    

Detailed description: 
      STUDY RATIONALE AND PURPOSE:

      A number of strategies have been proposed to improve the outcome of ASCT. The three main
      strategies are to incorporate novel agents into the induction regimen, using maintenance
      therapy following ASCT and the final strategy is to enhance conditioning regimens.

      Investigators would like to explore all these three strategies in this study: Investigators
      propose to take patients who have had standard novel agent (bortezomib) based induction
      regimens into this study and then use a dose-adjusted combination of busulfan and melphalan
      as conditioning regimen and finally Investigators would like to incorporate lenalidomide
      maintenance post ASCT until disease progression.

      The conventional immunological markers used to define myeloma disease status have also been a
      subject of debate recently with some reports suggesting that more accurate disease assessment
      tools are needed to better decide on management of this disease. One of the most promising
      assays which is increasingly accepted as a more sensitive indicator of myeloma disease status
      is the Minimal Residual Disease (MRD) analysis. Therefore, Investigators plan to use MRD
      analysis as a disease assessment tool throughout this study and will correlate it with
      conventional myeloma disease assessment tools. Investigators would also like to incorporate a
      newly developed assay - Heavy lite (HevyLite) Chain assay and to explore the feasibility of
      using optional cell free DNA (cfDNA) to detect and monitor response assessments in multiple
      myeloma, - which will be done at the same time points as the other disease assessments
      thereby allowing us to explore the viability of these assays in clinical practice.

      INTERVENTIONS:

      Conditioning Regimen IV Busulfan 3.2mg/kg or equivalent pharmacokinetics directed dose once
      daily as a 3-hour infusion on days -5, -4 and -3 (option 1) or on days -6, -5, -4 (option
      2).IV Melphalan 140mg/m2 once on day -2 (for option 1) or day -3 ( for option 2) Maintenance
      Regimen Oral Lenalidomide 10 mg once daily for 28 days of a 28 days cycle for first three
      cycles and then dose escalation to 15 mg daily if clinically appropriate to do so.

      STUDY ENDPOINTS

      Primary:

      • MRD negativity at day 100 post ASCT

      Secondary:

        -  To determine the pattern of MRD analysis during lenalidomide maintenance.

        -  To determine the response rate using conventional immunoglobulin-based markers at day
           100 post ASCT and best response using lenalidomide maintenance.

        -  To determine the effectiveness of using the Heavy lite (HevyLite) Chain assay to assess
           anti-tumour response at day 100 post ASCT and during lenalidomide maintenance.

        -  To determine the toxicity of busulfan and melphalan when used as a high-dose
           conditioning therapy for ASCT.

        -  To determine the toxicity of lenalidomide maintenance post busulfan and melphalan
           conditioning ASCT.

        -  To determine the progression free survival (PFS) and overall survival (OS) of this
           program.

        -  To determine, through whole exome sequencing in individual Multiple Myeloma (MM)
           patients, the type and frequencies of somatic abnormalities (point mutations, indels,
           and copy number abnormalities) and their evolution overtime as the clinical disease
           progresses.

        -  To explore the feasibility of using optional cell free DNA (cfDNA) to detect and monitor
           response assessments in multiple myeloma.
    

Intervention name(s): Busulfan; Melphalan; Lenalidomide
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Once daily intravenous (IV) busulfan at a dose of 3.2 mg/kg or equivalent pharmacokinetics directed dose for three consecutive days (days -5 to -3), option 1 OR Once daily intravenous (IV) busulfan at a dose of 3.2mg/kg or equivalent pharmacokinetics directed dose for three consecutive days (days -6 to -4), option 2.; I.V. reduced dose of melphalan (140mg/m2) on day -2, followed by an autologous stem cell transplant on day 0 (day -1 will be a rest day) - this is referred to as "Option 1" dosing schema OR I.V. reduced dose of melphalan (140mg/m2) on day -3 followed by autologous stem cell transplant on day 0 (days -2 and -1 will be rest days). This is referred to as "Option 2"; Oral lenalidomide 10mg per day (on all 28 days of a 28 day cycle) for the first three cycles and then escalated to 15 mg daily if clinically appropriate to do so. The lenalidomide maintenance will start on day 100 post ASCT and continue till disease progression.
Other intervention name(s): Busulfex; Alkeran; Revlimid
Intervention MeSH terms: Lenalidomide; Melphalan; Busulfan
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Newly Diagnosed multiple myeloma