Integrative Multi-omics Analysis to Predict Monoclonal Gammopathies Clinical Evolution (PNRR-2022-1237)

April 22, 2026 updated by: Azienda USL Reggio Emilia - IRCCS
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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of antibody-secreting plasma cells in the bone marrow. It accounts for approximately 10% of all blood cancers, with an incidence of 3-5per 100.000 individuals in Westen countries. MM is an incurable disease that leads to severe bone destruction and fractures due to the abnormal interaction between malignant plasma cells and the bone marrow microenvironment. Although new therapies have improved survival, MM remains a complex and genetically heterogeneous disease. Genomic instability is a hallmark of MM and includes both chromosomal abnormalities and gene mutations. Tumors may presenta s hyperdiploid - with multiple trisomies - or non-hyperdiploid, often involving translocations at the immunoglobulin heavy chain locus (IGH). These genetic differences impact prognosis. Additional recurrent alterations, such as deletions (13q, 17q), gains (1q), and mutations in genes like KRAS, NRAS, TP53, and BRAF, further illustrate the disease's biological diversity. Molecular profiling techniques, such as RNA sequencing and gene expression arrays, have identified gene expression patterns that correlate with prognosis, though only a few are currently used in clinical practice. MM is consistently preceded by two asymptomatic precursor conditions: monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). These conditions are prevalent in older adults and share many molecular features with symptomatic MM, yet only a small fraction of cases progress annually - about 1% for MGUS and 10% for SMM. Disease evolution appears to depend not only on intrinsic genetic changes but also on interactions with the bone marrow microenvironment, which includes stromal cells, dendritic cells, T cells (especially Th17), NK cells and myeloid-derived suppressors cells. Immune dysfunction, antigen presentation defects, expansion of immunosuppressive cells, and high levels of inhibitory cytokines contribute to the emergence of an immunosuppressive niche that enables myeloma cells to escape immune surveillance and progress. Immunomodulatory drugs (ImiDs) and monoclonal antibodies, which can reactivate immune responses, are therefore central to treatment strategies. Recent evidence also suggests a link between the microbiota and disease progression. In experimental models, alterations in gut microbiota have been shown to affect immune responses, influencing disease onset. Currently available prognostic tools mainly reflect tumor burden rather than underlying biology. As such, they fail to accurately predict disease progression.

Study Type

Observational

Enrollment (Estimated)

60

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Bologna, Italy
        • Active, not recruiting
        • Istituto Ortopedico Rizzoli IRCCS
      • Catania, Italy
        • Active, not recruiting
        • UO Ematologia Azienda Ospedaliero-Universitaria "Policlinico Rodolico San Marco"
      • Palermo, Italy
        • Active, not recruiting
        • UOC di Ematologia, Dipartimento di Oncologia, AOU Policlinico "Paolo Giaccone"
      • Reggio Emilia, Italy

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

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)

Description

Inclusion Criteria:

  • 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

HEALTHY VOLUNTEERS (HV)

  • Age >60 years
  • Diagnosis of osteoarthritis (OA)
  • Scheduled for hospitalization for surgical treatment of OA (endoprosthesis or arthroplasty)
  • Willing and able to provide written informed consent

Exclusion Criteria:

  • Patients:

    • 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

Healthy Volunteers:

  • Prior joint surgery or severe joint deformity
  • Recent trauma, osteonecrosis, or OA caused by prior/current joint infection
  • Metabolic disorders
  • Previous or current cancer diagnosis
  • Autoimmune diseases (e.g., rheumatoid arthritis)

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
MGUS, SMM and MM patients
Patients with monoclonal gammopathy of undeterminated significance, smoldering multiple myeloma, or multiple myeloma
Other: Collection of biological material

For 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).
Healthy volunteers
Patients with a clinical and radiological diagnosis of osteoarthritis who undergo endo or arthro-prosthesis surgery
Other: Collection of biological material

For 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Bone marrow and peripheral blood immunophenotypic characterization
Time Frame: up to 24 months
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.
up to 24 months
Genomic and transcriptomic profiling of plasma cell
Time Frame: Up to 24 months
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.
Up to 24 months
Single-cell and spatial transcriptomic analyses
Time Frame: up to 24 months
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.
up to 24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evaluation of oral microbiome composition
Time Frame: up to 24, months
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.
up to 24, months
Functional validation of genetic profiles in osteolytic disease
Time Frame: 24 months
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.
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Azienda USL Reggio Emilia - IRCCS

Collaborators

European Union
Ministero della Salute, Italy

Investigators

  • Study Chair: Antonino Neri, MD, PhD, Azienda USL - IRCCS di Reggio Emilia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

March 17, 2025

Primary Completion (Actual)

August 12, 2025

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

October 2, 2025

First Submitted That Met QC Criteria

October 2, 2025

First Posted (Actual)

October 9, 2025

Study Record Updates

Last Update Posted (Actual)

April 23, 2026

Last Update Submitted That Met QC Criteria

April 22, 2026

Last Verified

October 1, 2025

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 849/2022/TESS/IRCCSRE

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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