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.