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.
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.