DESTINY – Detecting Spatial Heterogeneity in Multiple Myeloma patients through a Liquid Biopsy approach

Description

Multiple Myeloma (MM) is a clonal plasma cell (PC) proliferative disorder characterized by the proliferation in the bone marrow of a plasma cell clone, which synthesizes monoclonal immuno-globulins; in the most aggressive cases, or in the advanced stages of the disease, the plasma cell clone tends to infiltrate other parts of the body. Genomic studies in MM have led to a better understanding of the complex molecular biology of the disease, including its genetic heterogeneity, evolutions patterns over time, and identification of potential molecular drivers. MM PCs clones are characterized by a dynamic intra-patient sub-clonal heterogeneity and by a non-homogeneous distribution within BM. Recently, distinct focal lesions within a single patient have been shown to display divergent molecular profiles, sometimes associated with different risk of progression and leading to poor outcome. Genomic characterization, diagnosis and therapeutic monitoring in MM rely on sequential single-site BM biopsies, poorly representative of the disease, as they fail to capture its genetic spatial heterogeneity .Therefore, alternative, more practical strategies to address the MM spatial and temporal heterogeneity are needed.
Over the past 15 years, MM treatment has been challenged by the introduction of novel drugs and the design of intensive- continuous treatments, which are aimed to achieve as faster as possible the levels of minimal residual disease (MRD). This represents a clear benefit for MM pts, whose progression free and overall survival have been significantly improved. Therefore, tracking the disease dynamics has become an important objective both to establish patients prognosis and to pave the way for future MRD-driven clinical trials. However, emerging data suggested that the patchy nature of the disease and quality of residual cells might lead to inadequate MRD results, stressing the importance to consider a re-definition of MRD, not only quantitative, but also qualitative.
In this context, liquid biopsy (such as cell free-DNA, cfDNA), is currently being explored for the qualitative and quantitative characterization of disease genome and as a mode of non-invasive therapeutic disease monitoring. This new blood-based method carries the potential to provide both a rapidly evaluable genomic characterization of patients tumor and a precise readout of disease spreading.
The rationale of this study is to investigate an innovative diagnostic strategy based on liquid biopsies, to stratify up-front newly diagnosed MM, according to the presence of spatial heterogeneity. It will be assessed how liquid biopsy might qualitatively resume MM spatial heterogeneity, using a commercial targeted panel. Moreover, it will be evaluated two different NGS assays for MRD monitoring, to compare the generic characteristic of each methods. Overall objective of the study is to explore and possibly to validate the use of liquid biopsy approaches to measure the spread of the disease and to detect spatial heterogeneity in patients with newly diagnosed MM.