This prospective, multicenter, observational study aims to identify molecular and immunological markers associated with disease progression in patients with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). By integrating genomic, transcriptomic, immunophenotypic, and oral microbiome analyses, the study seeks to characterize the biological mechanisms underlying the transition to symptomatic multiple myeloma (MM). The study also includes in vitro modeling to investigate bone damage and immune dysfunction. Healthy volunteers (HV) undergoing joint replacement surgery for osteoarthritis will serve as controls. The ultimate goal is to improve early risk stratification and support future preventive strategies through a multi-omics approach. There is a pressing need for new strategies to identify high-risk individuals based on biological rather than purely clinical parameters. This study proposes an integrative, multi-omics approach to investigate the transition from MGUS/SMM to MM. By analyzing the immunome and oral microbiome alongside molecular profiling, the goal is to identify reliable biomarkers of progression. The resulting insights could be enable more accurate risk stratification and guide the design of future preventive clinical trials aimed at delaying or halting disease evolution.
Age >18 years
Male or female patients
Histologically confirmed diagnosis of MGUS, SMM, or MM according to ESMO 2021 guidelines
Willing and able to provide written informed consent
Active current infection
Autoimmune disease
Women of childbearing potential unable to exclude pregnancy
Use of high-dose corticosteroids within the past 7 days, potentially affecting immunome composition
patients with MGUS, SMM, or MM (with or without bone lytic lesions), as well as patient with osteoarthritis undergoing joint surgery (endoprosthesis or artroplasty) (Healty Volunteers)
Cohort
Prospective
Collection of biological material
Other interventionFor MGUS, SMM and MM patients, biological material (bone marrow aspirate, bone marrow biopsy, peripheral blood) consists exclusively of left-over samples obtained during routine diagnostic procedures and clinical practice management of their disease. For healthy volunteers, biological material includes waste bone tissue obtained during orthopedic surgery (endo- or arthro-prosthesis) and peripheral blood collected for research purposes. Both cohort of patient will be asked to donate gingival crevicular fluid (GCF) (this is a non-invasive procedure with no associated risks).
Bone marrow and peripheral blood immunophenotypic characterization
Multiparametric flow cytometry of bone marrow CD138- cells and peripheral blood mononuclear cells (PBMCs) to define immune subsets and to assess alterations associated with monoclonal gammopathies progression.
Genomic and transcriptomic profiling of plasma cell
Next-generation sequencing (NGS) analysis of bone marrow CD138+ plasma cells, including targeted 14-gene mutation panels, copy number alterations by ultra-low-pass whole genome sequencing, RNA sequencing, and single-cell transcriptomics to identify molecular signatures of disease evolution.
Single-cell and spatial transcriptomic analyses
Single-cell RNAseq, antibody-based sequencing (ABseq), TCR sequencing, and spatial transcriptomics on bone marrow biopsies to characterize clonal heterogeneity, cell-cell interactions, and microenvironmental influences during progression from MGUS/SMM to Multiple Myeloma.
Evaluation of oral microbiome composition
Sequencing-based profiling (16S rRNA) of DNA extracted from gingival crevicular fluid (GCF) samples of patients and healthy volunteers to investigate oral microbiome dysbiosis and its association with immune dysfunction and disease progression.
Functional validation of genetic profiles in osteolytic disease
Use of CRISPR-Cas9 screening in myeloma cell lines and dynamic 3D co-culture models (osteoblasts, osteoclasts, immune and stromal cells) to evaluate the role of specific molecular pathways in osteolytic lesion development and immune impairment.
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Azienda USL Reggio Emilia - IRCCS
Lead sponsor
European Union
Collaborator
Ministero della Salute, Italy
Collaborator
