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Amyloid light-chain (AL) amyloidosis is a rare hematological disease that produces abnormal monoclonal immunoglobulin light chains to form amyloid fibrils that are deposited in tissues, resulting in organ damage and dysfunction. Advanced AL amyloidosis has a very poor prognosis with a high risk of early mortality. The combination of anti-plasma cell therapy and amyloid fibrils clearance is the optimal treatment strategy, which takes into account both symptoms and root causes. However, research on anti-amyloid fibrils lags far behind research on anti-plasma cells, and there is currently no approved treatment that could clear amyloid fibrils. Nevertheless, anti-amyloid fibril therapies are being actively investigated recently and have shown potential in clinical trials. In this review, we aim to outline the preclinical work and clinical efficacy of fibril-directed therapies for AL amyloidosis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Amyloidosis is a group of disorders characterized by a misfolded protein that deposits in organs and compromise their function. Clinician should have a high index of suspicion because in most cases, the clinical picture is non-specific. Typing of amyloid is of utmost importance and should be an integral part of accurately diagnosing a patient. AL amyloidosis is the most common systemic amyloidosis in the western world in which the misfolded proteins are immunoglobulin light chains secreted by clonal plasma cells. New data about prognostication of AL amyloidosis patients are accumulating. The treatment goal is to eradicate the amyloidogenic plasma cell clone, by using high dose melphalan and/or novel agents (proteasome inhibitors, immunomodulatory drugs, monoclonal antibodies against CD38). Early diagnosis is important for effectively treating the patient as late diagnosis hampers chances for organ recovery. ATTR amyloidosis is less recognized but is increasingly seen due to better recognition and improved diagnostic tools. New data about treatment options (patisiran, inotersen and tafamidis) have recently been published and are discussed., Competing Interests: Declaration of competing interest # Dr. Gertz reports personal fees from Ionis/Akcea, personal fees from Alnylam, personal fees from Prothena, personal fees from Celgene, personal fees from Janssen, grants and personal fees from Spectrum, personal fees from Annexon, personal fees from Appellis, personal fees from Amgen, personal fees from Medscape, personal fees from Physicians Education Resource, personal fees for Data Safety Monitoring board from Abbvie, personal fees from Research to Practice, speaker fees from Teva, Speaker fees from Johnson and Johnson; Speaker fees from Medscape, Speaker fees DAVA oncology; Advisory Board for Pharmacyclics Advisory Board for Proclara outside the submitted work; Development of educational materials for i3Health. Educational Program development i3Health. Royalties from Springer Publishing. Grant Funding Amyloidosis Foundation; International Waldenstrom's Macroglobulinemia Foundation. NCI SPORE MM SPORE 5P50 CA186781-04. # Dr Angela Dispenzieri - Research dollars from Alnylam, Prothena, Celgene, Takeda, Janssen, and Pfizer. # Dr Eli Muchtar - Nothing to declare. # Dr Iuliana Vaxman - Advisory Board for Celgene; Advisory Board for Takeda; Advisory Board for Promedicao; Speaker fees from Takeda., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Amyloid light-chain (AL) amyloidosis is a plasma-cell dyscrasia, as well as the most common type of systematic amyloidosis. Pathogenic plasma cells that have distinct cytogenetic and molecular properties secrete an excess amount of amyloidogenic light chains. Assisted by post-translational modifications, matrix components, and other environmental factors, these light chains undergo a conformational change that triggers the formation of amyloid fibrils that overrides the extracellular protein quality control system. Moreover, the amyloidogenic light-chain itself is cytotoxic. As a consequence, organ dysfunction is caused by both organ architecture disruption and the direct cytotoxic effect of amyloidogenic light chains. Here, we reviewed the molecular mechanisms underlying this sequence of events that ultimately leads to AL amyloidosis and also discuss current in vitro and in vivo models, as well as relevant novel therapeutic approaches., (Copyright © 2017 Elsevier Ltd. All rights reserved.)