Project 1: Developing MRD-based therapeutic strategy in newly diagnosed multiple myeloma

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Project Summary – Project 1 CHU-Toulouse / DFCI To improve overall outcome in multiple myeloma (MM), period this project in the current funding achieved three major goals: 1: Defined the role of transplant in the era of novel agents with long term maintenance; 2: Established the feasibility of measuring minimal residual disease (MRD) at 10-6 sensitivity, and demonstrated its significant impact on prolongation of PFS irrespective of the type of treatment used; and 3) Demonstrated that quadruplet therapies achieve high frequency of MRD negative response. In this renewal application, we now propose to build upon our highly successful collaborative clinical study to address the next most important question, whether high-dose therapy (HDT) can still provide benefit in patients achieving MRD negative status. We hypothesize that quadruplet therapy followed by ASCT will achieve deeper MRD negative status (10-6), and that sustained MRD negativity will be of therapeutic importance. Our proposed study will: 1) define the role of ASCT in MM in the context of quadruplet induction therapy; determine whether ASCT further decreases tumor burden, increases MRD negativity rates (NGS, 10-6), and improves patient outcome; and define whether achieving early, late, and sustained MRD negativity impacts clinical outcome (Sp Aim 1). We will conduct a large (n=716) study using induction therapy with isatuximab, carfilzomib, lenalidomide and dexamethasone (IsaKRD) and then randomize those patients who are MRD negative to either further IsaKRD versus HDT. In Specific Aim 2, we will redefine new risk stratification incorporating MRD status and modern biochemical, genomic, epigenomic, and immune and microenvironmental correlates. Our proposed study will determine the impact of MRD informing prognosis and therapy. .