Recent Advances in the Diagnosis, Risk Stratification, and Management of Systemic Light-Chain Amyloidosis

Abstract

The term amyloidosis refers to a group of disorders in which protein fibrils accumulate in certain organs, disrupt their tissue architecture, and impair the function of the effected organ. The clinical manifestations and prognosis vary widely depending on the specific type of the affected protein. Immunoglobulin light-chain (AL) amyloidosis is the most common form of systemic amyloidosis, characterized by deposition of a misfolded monoclonal light-chain that is secreted from a plasma cell clone. Demonstrating amyloid deposits in a tissue biopsy stained with Congo red is mandatory for the diagnosis. Novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies, venetoclax) and autologous stem cell transplantation, used for eliminating the underlying plasma cell clone, have improved the outcome for low- and intermediate-risk patients, but the prognosis for high-risk patients is still grave. Randomized studies evaluating antibodies that target the amyloid deposits (PRONTO, VITAL) were recently stopped due to futility and currently there is an intensive search for novel treatment approaches to AL amyloidosis. Early diagnosis is of paramount importance for effective treatment and prognosis, due to the progressive nature of this disease.

Patient outcomes in light chain (AL) amyloidosis: The clock is ticking from symptoms to diagnosis

“…Although it is possible that the inexact nature of this calculation may have resulted in misclassification of some subjects, the impact of any imprecise assignments is expected to be minor as this method for time calculation was used consistently. Other considerations regarding the generalizability of our results include the ever‐changing landscape of available treatments for AL amyloidosis, as well as the recent evidence suggesting the important impact of cytogenetics on prognosis and response to specific treatments 17,26,27 . The emergence of new investigational therapies over the past several years has assisted in improving both prognosis and survival in this patient population 28‐30 .…”

Human amyloidosis, still intractable but becoming curable: The essential role of pathological diagnosis in the selection of type‐specific therapeutics

“…The therapeutic target of this type of amyloidosis is to eliminate neoplastic plasma cells in the bone marrow 6 . The first step in deciding how to treat a newly diagnosed AL amyloid patient is determining whether they are eligible for the autologous stem cell transplantation (ASCT) after high‐dose melphalan chemotherapy.…”

“…During the last 20 years, the molecular pathogenesis of human amyloidosis has been elucidated greatly 4,5 . Various types of systemic amyloidosis are still intractable diseases, but based on the understanding of the molecular mechanisms of amyloid fibril formation and deposition, various kinds of new drugs and therapeutics have been emerging to improve the prognosis of amyloidosis and even cure this disease 6–10 . Among many types of systemic human amyloidosis, four major types are immunoglobulin light chain‐related (AL), transthyretin (TTR)‐related (ATTR), amyloid A‐associated (AA) and β 2 ‐microglobulin (β2‐m)‐related (Aβ2M) amyloidosis 2 .…”

Generation of polyclonal antibodies directed against AL-kappa light chain amyloid protein

“…Амилоидоз легких цепей (АL-амилоидоз) является наиболее частой формой системного амилоидоза и относится к группе болезней отложения моноклонального иммуноглобулина. На долю AL-амилоидоза приходится около 70% всех случаев системного амилоидоза [1][2][3].…”