Integrative multi-omics analysis to predict monoclonal gammopathies clinical evolution

This multi-disciplinary project aims to develop an integrative means for a multidimensional classification of patients affected by Monoclonal Gammopathy of Uncertain Significance (MGUS). a premalignant plasma cell dyscrasia, carrying a lifelong risk of transformation to multiple myeloma (MM), the second most diagnosed blood cancer, at a fixed but unremitting rate of approximately 1% per year. MGUS is a frequent finding in the older adult population, affecting 5% of white age 40 years or older and with prevalence increasing with age. The project is based on multi-omics integration of the genetic and functional profiling of the major players of MGUS disease evolution, including the microbiome composition, neoplastic plasma cells, bone-cells and immunome profiling,
Because MM remains an incurable disease with significant associated morbidity from skeletal and renal events, close monitoring of MGUS patients has been recommended to diagnose malignant transformation before the onset of serious complications. Once diagnosed, MM should be considered a chronic condition, as well. Currently, there is no cure for most cases, and relapses (often delayed by long remission periods) are inevitable for many patients. The recent introduction of immunotherapy regimens, which use daratumumab as backbone, have significantly improved patients¿ outcome and health- related quality of life, at the cost of continuous (until progression) expensive treatments.
Through the involvement of three large Hematology Units and two consolidated Translational Research Platforms in Emilia Romagna and Sicilia we will establish a structured program of patients' referral and sample/data transfer for multi-omics analysis to identify multidimensional biomarkers to predict monoclonal gammopathies clinical evolution.
In the frame of this project, we plan to:

• Address immunological and genetic profiles of monoclonal gammopathies leading to evolution from MGUS to MM;
• Address the contribution of microbiome composition to lead immune dysfunction in patients affected by monoclonal gammopathies;
• Challenge genetic profiles to delay development of osteolytic lesions and immune impairment in patients affected by monoclonal gammopathies.

The overall final goal of the project is the development of a costless minimally invasive diagnostic tool based on peripheral blood and/or gingival crevicular fluid for the identification of MM-evolving MGUS patients. This will pose the bases for the design of future interventional clinical trials aiming to the prevention of disease evolution with a consequent relevant impact on the National Health System.
Promising preliminary data support the rational of the study, including:

• The implementation of an integrative bio-banking of patients-derived biological specimens, including bone marrow, peripheral blood, plasma and gingival crevicular fluid;
• The establishment of a high-throughput methodology to warrant a multiomic approach including single cell (sc)-RNAseq, sc surface proteins profile, spatial transcriptomic, sc-TCR sequencing, oral microbiome profiling, a targeted gene mutation analysis, and a genome-wide assessment of copy number alterations by ultra-low-pass whole genome sequencing. The research Consortium includes leading scientists with active collaborations and a track record of scientific publications in the field and avails itself of the required infrastructures and scientific environment for a successful completion of this project.