Promoting Diagnosis and Management of AL in Italy (ProDigALIty) (ProDigALIty)

The investigators plan to establish a dedicated network of Italian Hematologic Departments interconnected with the Amyloidosis Research and Treatment Center in Pavia to:

1. Implement a biomarker-based screening strategy to promote early diagnosis of AL amyloidosis among at-risk patients, including patients with monoclonal gammopathy of undetermined significance, MGUS, and altered free light chain ratio (aFLCR), and patients with smoldering multiple myeloma (SMM)
2. Expedite and facilitate patients' referral and their enrollment in ongoing pre-clinical/clinical studies, also to reflect a broader spectrum of the real-world population of patients with AL amyloidosis in Italy;
3. Investigate the clinical utility of novel diagnostic technologies, including light chain sequencing and N-glycosylation analysis

Study Overview

• Status: Recruiting
• Conditions: AL Amyloidosis; Monoclonal Gammopathy of Undetermined Significance; Smoldering Multiple Myeloma
• Intervention / Treatment: Other: no intervention

Detailed Description

AL amyloidosis (AL) is a rare, severe protein conformational disease caused by misfolding and extracellular deposition of patients-specific monoclonal immunoglobulin light chains in form of amyloid fibrils. This process can affect virtually any body site and result in potentially fatal organ dysfunction.

In a significant proportion of cases, AL is diagnosed late, when advanced, often irreversible organ involvement limits therapeutic options and greatly limits survival. Thus, efforts at promoting early diagnosis are urgently needed.

The presence of a monoclonal protein (M protein) or an abnormally increased concentration of serum free LCs (FLCs) invariably precedes clinically overt AL amyloidosis by several years. Moreover, about 95% of patients with AL have an altered FLC ratio (FLCR) at diagnosis. Yet, AL is often diagnosed late also in patients with known monoclonal gammopathy under hematological follow-up. Screening of at-risk patients with biomarkers of early amyloid organ involvement has been advocated, but not largely implemented.

Diagnosis and management of AL patients require access to sophisticated technologies and expertise available at large tertiary Amyloid Centers. Yet, new models of patients' care are required to intercept those patients who cannot travel to distant, tertiary centers, in order to provide state-of-the-art care to all and to be able to analyze and describe the natural history of the disease in a contemporary, real-world setting.

New molecular features associated with the propensity of light chains to form amyloid are emerging, but their potential clinical utility is unknown. Building on >30 years-experience of the Italian Referral Center for Systemic Amyloidoses and leveraging on an already existing disease registry and a one-of-a-kind biorepository of clinically annotated biological samples, the study plans to extend and corroborate the activity of the Italian Amyloidosis Network, through the involvement of large Hematology Departments strategically distributed across the Country and the establishment of a structured program of patients' referral and sample/data transfer.

The study will be conducted as follows:

Part A: an active biomarker-based surveillance of pre-symptomatic signs of amyloid organ involvement in at-risk subjects (patients with MGUS and aFLCR and patients with SMM) will be implemented in the participating Italian Hematologic Departments. This will enable the verification of the feasibility of such biomarker-based screening, allow the description of baseline characteristics of at-risk patients, and promote early diagnosis of AL amyloidosis.

Part B: newly diagnosed AL amyloidosis patients (either from Part A or from patients with clinically overt AL amyloidosis evaluated in the frame of routine clinical assessments) will be either referred to the Amyloidosis Research and Treatment Center in Pavia or managed locally, with clinical data prospectively entering a disease registry and diagnostic leftovers from biospecimens stored in a biorepository. This will aim to increase referral and increment inclusion of real-world cases of AL amyloidosis in the disease registry and linked biorepositories, as well as patients' enrollment in other already approved and funded pre-clinical and clinical studies on basic disease mechanisms, as well as new diagnostic/therapeutic approaches in AL amyloidosis.

Part C: exploiting data collected from patients enrolled in both part A and part B, the clinical utility of clonal light chain profiling (including light chain sequencing, evaluation of the N-glycosylation status, and artificial intelligence-based amyloidogenicity prediction) will be assessed.

• Study Type: Observational
• Enrollment (Estimated): 760

Contacts and Locations

Study Locations

• Italy
  • Bari, Italy
    • Recruiting
    • Azienda Ospedaliera Policlinico Consorziale
    • Principal Investigator: Pellegrino Musto, MD
    • Contact: PELLEGRINO MUSTO, MD; Phone Number: 080 5593471; Email: ematologiacontrapianto@policlinico.ba.it
    • Sub-Investigator: Angela Minervini, MD, PhD
  • Catania, Italy
    • Recruiting
    • Azienda Ospedaliero Universitaria Policlinico G.Rodolico - San Marco
    • Principal Investigator: Francesco Di Raimondo, MD
    • Contact: Francesco Di Raimondo, MD; Phone Number: 095/378.1956; Email: segremat@unict.it
    • Sub-Investigator: Concetta Maria Sebastiana Conticello, MD, PhD
  • Pavia, Italy
    • Recruiting
    • Fondazione IRCCS Policlinico San Matteo
    • Principal Investigator: Luca Arcaini, MD
    • Contact: GIOVANNI PALLADINI, MD, PhD; Phone Number: +390382502994; Email: segreteria.amiloidosi@smatteo.pv.it
    • Principal Investigator: Giovanni Palladini, MD, PhD
    • Sub-Investigator: Mario Ulisse Nuvolone, MD, PhD
  • Torino, Italy
    • Recruiting
    • EMATOLOGIA - Città della Scienza e Salute - Torino
    • Contact: FRANCESCA MARIA GAY, MD, PhD; Phone Number: 011.633.5550 - 5935; Email: ematologia@cittadellasalute.to.it
    • Principal Investigator: FRANCESCA MARIA GAY, MD, PhD
    • Sub-Investigator: Stefania Oliva, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

The participating Departments of Hematology will be involved in screening at-risk patients with monoclonal gammopathies and refer suspected/confirmed AL cases to the Amyloidosis Center in Pavia.

Description

PART A

Inclusion Criteria:

• diagnosis of MGUS with altered FLCR or SMM;
• treatment-naïve;
• age ≥18 years;
• ability to understand and willingness to sign an informed consent;
• planned follow-up at participating center.

Exclusion Criteria:

• Diagnosis of symptomatic monoclonal gammopathies;
• Previous treatment for monoclonal gammopathies.

PART B

Inclusion criteria:

• diagnosis of systemic AL amyloidosis;
• treatment-naïve;
• age ≥18 years;
• ability to understand and willingness to sign an informed consent;
• planned follow-up at participating center.

Exclusion criteria:

• non-AL amyloidosis;
• previous treatment for AL amyloidosis.

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Intervention / Treatment

Patients with MGUS and aFLCR and with SMM; Part A: Patients with MGUS and aFLCR and patients with SMM undergoing an active, biomarker-based screening of presymptomatic amyloid organ involvement. Part B: Newly diagnosed patients with AL amyloidosis identified through Part A or with clinically overt AL amyloidosis evaluated in the frame of routine clinical assessments and referred to the Amyloidosis Research and Treatment Center in Pavia or managed locally at the participating Italian Hematologic Departments

Other: no intervention; no intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assess proportion of patients with newly diagnosed AL identified through the biomarker-based screening of at-risk patient	Part A of the study: the proportion of patients with newly diagnosed AL through the biomarker-based screening of at-risk patients with a known monoclonal gammopathy will be identified.	2 years
Assess the proportion of patients with deep haematological response after frontline therapy (best response evaluation) in the new enhanced, contemporary, real-world series of AL patients enrolled during the study.	Part B of the study: The proportion of patients with deep hematological response after frontline therapy will be assessed	2 years
3. Identify associations of clonal light chain features with different clinical features at baseline.	Part C of the study: Associations of clonal light chain features with different clinical features at baseline, including organ tropism and clonal burden, will be assessed.	2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Description of the baseline characteristics and 6-months outcome, as well as the time to AL development for patients with AL identified through the biomarker-based screening	Part A: the baseline characteristics and 6-months outcome, as well as the time to AL development for patients with AL identified through the biomarker-based screening will be evaluated	6 months
Description of the baseline characteristics of MGUS/SMM patients with abnormal FLCR	Part A: the baseline characteristics of MGUS/SMM patients with abnormal FLCR will be described	2 years
Identification of clinical and biological correlates of hematological response	part B: clinical and biological correlates of hematological response will be identified	2 years
To verify whether implementing a dedicated pipeline for referral of AL patients to the National Referral Center will increase the proportion of patients from spoke centers	Part B: it will be verified if implementing a dedicated pipeline for referral of AL patients to the National Referral Center will increase the proportion of patients from spoke centers	2 years
Identification of associations of clonal light chain features with event-free survival	Part C: associations of clonal light chain features with event-free survival will be identified.	2 years
Validation of existing algorithms for predicting AL amyloidosis status	Part C: The diagnostic performance of existing algorithms for predicting clonal light chain amyloidogenicity will be evaluated.	2 years

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2023
• Primary Completion (Estimated): May 1, 2026
• Study Completion (Estimated): May 1, 2026

Study Registration Dates

• First Submitted: April 19, 2024
• First Submitted That Met QC Criteria: April 19, 2024
• First Posted (Actual): April 25, 2024

Study Record Updates

• Last Update Posted (Actual): April 16, 2026
• Last Update Submitted That Met QC Criteria: April 13, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Metabolic Diseases; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Precancerous Conditions; Neoplasms, Plasma Cell; Paraproteinemias; Blood Protein Disorders; Proteostasis Deficiencies; Hypergammaglobulinemia; Amyloidosis; Nutritional and Metabolic Diseases; Hemic and Lymphatic Diseases; Immunoglobulin Light-chain Amyloidosis; Smoldering Multiple Myeloma; Monoclonal Gammopathy of Undetermined Significance
• Other Study ID Numbers: AC-020-IT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No