Clinical trial NCT06383143: Promoting Diagnosis and Management of AL in Italy (ProDigALIty)
Official title: Promoting Diagnosis and Management of AL in Italy (ProDigALIty)
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: AL Amyloidosis
Smoldering Multiple Myeloma
Monoclonal Gammopathy of Undetermined Significance
Lead sponsor: Fondazione IRCCS Policlinico San Matteo di Pavia
Sponsor class: OTHER
First posted: 2024-04-25
Enrollment: 760
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_ONLY
Time perspective: PROSPECTIVE
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.

Brief summary: 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

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Assess proportion of patients with newly diagnosed AL identified through the biomarker-based screening of at-risk patient
timeFrame: 2 years
measure: 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.
timeFrame: 2 years
measure: 3. Identify associations of clonal light chain features with different clinical features at baseline.
timeFrame: 2 years
Secondary outcomes:
measure: 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
timeFrame: 6 months
measure: Description of the baseline characteristics of MGUS/SMM patients with abnormal FLCR
timeFrame: 2 years
measure: Identification of clinical and biological correlates of hematological response
timeFrame: 2 years
measure: 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
timeFrame: 2 years
measure: Identification of associations of clonal light chain features with event-free survival
timeFrame: 2 years
measure: Validation of existing algorithms for predicting AL amyloidosis status
timeFrame: 2 years
Other outcomes:
Locations:
city: Bari
country: Italy
facility: Azienda Ospedaliera Policlinico Consorziale
city: Catania
country: Italy
facility: Azienda Ospedaliero Universitaria Policlinico G.Rodolico - San Marco
city: Pavia
country: Italy
facility: Fondazione Irccs Policlinico San Matteo
city: Torino
country: Italy
facility: EMATOLOGIA - Città della Scienza e Salute - Torino
Study officials:
References: