Monoclonal Gammopathies

Active, not recruiting

• Conditions: Monoclonal Gammopathy of Undetermined Significance (MGUS); Smoldering Multiple Myeloma (SMM); Multiple Myeloma (MM)

• Registration Number: NCT07214324
• Lead Sponsor: Azienda USL Reggio Emilia - IRCCS

Brief Summary

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.

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 Timeline

• Study Start: 2023-01-01
• Primary Completion: 2025-08-12
• Status Verified: 2025-10
• Study First Submitted: 2025-10-02
• Study First Submitted QC: 2025-10-02
• Last Update Submitted: 2025-10-02
• Study First Posted: 2025-10-09
• Last Update Posted: 2025-10-09
• Study Completion: 2025-12-31

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 60

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 & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Bone marrow and peripheral blood immunophenotypic characterization	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.
Genomic and transcriptomic profiling of plasma cell	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.
Single-cell and spatial transcriptomic analyses	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.

Secondary Outcome Measures

Name	Time	Method
Evaluation of oral microbiome composition	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.
Functional validation of genetic profiles in osteolytic disease	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.

Trial Locations

Locations (4)

Istituto Ortopedico Rizzoli IRCCS; 🇮🇹 Bologna, Italy

UO Ematologia Azienda Ospedaliero-Universitaria "Policlinico Rodolico San Marco"; 🇮🇹 Catania, Italy

UOC di Ematologia, Dipartimento di Oncologia, AOU Policlinico "Paolo Giaccone"; 🇮🇹 Palermo, Italy

S.C Ematologia - Azienda USL IRCCS di Reggio Emilia; 🇮🇹 Reggio Emilia, Italy