Promoting Diagnosis and Management of AL in Italy (ProDigALIty)

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.

• 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 [Срок оценки: 6 months]
• Description of the baseline characteristics of MGUS/SMM patients with abnormal FLCR [Срок оценки: 2 years]
• Identification of clinical and biological correlates of hematological response [Срок оценки: 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 [Срок оценки: 2 years]
• Identification of associations of clonal light chain features with event-free survival [Срок оценки: 2 years]
• Validation of existing algorithms for predicting AL amyloidosis status [Срок оценки: 2 years]