Immunoglobulin light chain amyloidosis

Abstract

Primary light chain amyloidosis is the most common form of systemic amyloidosis and is caused by misfolded light chains that cause proteotoxicity and rapid decline of vital organ function. Early diagnosis is essential in order to deliver effective therapy and prevent irreversible organ damage. Accurate diagnosis requires clinical skills and advanced technologies. The disease can be halted and the function of target organs preserved by the prompt reduction and elimination of the plasma cell clone producing the toxic light chains in the bone marrow. Heart damage is the major determinant of survival, and staging with cardiac biomarkers guides treatment. Two-thirds of patients can benefit from treatment with improved quality of life and extended survival. Future efforts should be directed at early diagnosis, improving the tolerability and efficacy of anti-plasma cell therapy, accelerating recovery of organ function via promoting resorption of amyloid deposits, and developing novel approaches to counter light chain proteotoxicity.

Keywords::

• amyloid cardiomyopathy
• biomarkers
• novel agents
• proteotoxicity

Financial & competing interests disclosure

G Merlini is supported by a grant from “Associazione Italiana per la Ricerca sul Cancro” Special Program Molecular Clinical Oncology 5 per mille n. 9965 RL Comenzo acknowledges support for clinical research from Millennium Pharmaceuticals, Teva and Prothena Biotech, and for laboratory research from the Amyloidosis and Myeloma Research Fund at Tufts, the Cam Neely and John Davis Myeloma Research Fund the Demarest Lloyd Jr Foundation and the Werner and Elaine Dannheiser Fund for Research on the Biology of Aging of the Lymphoma Foundation. DC Seldin acknowledges support from NIH (HL68705 and DK090696) and the Gruss and Wildflower Foundations. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Light chain amyloidosis is the most common monoclonal protein-related condition, occurring de novo or in association with myeloma, Waldenström’s macroglobulinemia or B-cell lymphoma.

• The amyloidogenic clone represents an early stage of plasma cell malignant transformation, and may be more susceptible to chemotherapy.

• The amyloid light chain exerts a systemic proteotoxic effect that frequently leads to rapid deterioration of vital organ function.

• Early diagnosis is essential to preserve organ function and to enable administration of the most effective therapy.

• The severity of amyloid heart involvement is the major determinant of survival.

• Therapy is highly individualized and must be risk-adapted based on cardiac biomarkers and response-tailored.

• Available treatments can significantly improve the quality of life and extend survival in two-thirds of patients.

• Novel therapeutic approaches to attack the clone and protect organ function are under development.

Notes

dFLC: Difference between involved and uninvolved free light chains; NT-proBNP: Amino-terminal pro-natriuretic peptide type-B; NYHA: New York Heart Association.

Data taken from [43].