What is amyloidosis, how is it diagnosed, and what are the treatment options?

What is Amyloidosis?

Amyloidosis is a group of disorders characterized by extracellular deposition of misfolded proteins that aggregate as insoluble fibrils in tissues, leading to progressive organ dysfunction and ultimately organ failure. 1

Understanding the Disease Process

• Amyloid proteins share common ultrastructural and chemical characteristics despite having different origins, with more than 28 types identified 2
• The deposits infiltrate peripheral organs including kidneys, heart, gastrointestinal tract, liver, and nervous system, with cardiac involvement being the primary driver of mortality 1
• More than 69% of patients already have multiple organ involvement at diagnosis, making early detection before irreversible damage absolutely critical 1

Major Types of Amyloidosis

• AL (light chain) amyloidosis is the most common and severe type, affecting approximately 10 per million people annually, caused by a slowly proliferating bone marrow plasma cell clone secreting unstable immunoglobulin free light chains 1, 3
• ATTR (transthyretin) amyloidosis has two subtypes: hereditary (caused by TTR gene mutations) and wild-type (acquired), both involving abnormal transthyretin protein deposition 3
• AA (reactive) amyloidosis results from chronic inflammatory or infectious diseases such as rheumatoid arthritis, Crohn's disease, or ulcerative colitis, caused by deposition of amyloid type A protein 3

Diagnosis of Amyloidosis

The diagnostic approach requires both confirmation of amyloid deposition and accurate identification of the specific amyloid protein type, as treatment differs dramatically between types. 3, 4

Essential Diagnostic Tests

• Serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) are mandatory initial screening tests 3
• Tissue biopsy with Congo Red staining showing characteristic apple-green birefringence under polarized light confirms amyloid presence 3, 2
• Typing of amyloid protein using mass spectrometry (gold standard with 88% sensitivity and 96% specificity), immunohistochemistry, or immunofluorescence is essential before initiating treatment 3, 5, 2

Critical Diagnostic Pitfalls

• Immunohistochemistry and immunofluorescence have significant limitations including variable antibody specificity and sensitivity, making mass spectrometry-based analysis (LC-MS/MS) the preferred typing method 5, 2
• In suspected concomitant systemic AL and ATTR cardiac amyloidosis (such as MGUS with abnormal nuclear scintigraphy), cardiac biopsy is necessary to definitively establish the cardiac pathology 5
• Abdominal fat aspiration has varying sensitivity: 84% for AL cardiac amyloidosis, 45% for hereditary ATTR, and only 15% for wild-type ATTR 6

When to Suspect Amyloidosis

• Consider amyloidosis in patients presenting with multisystem disorders involving heart, kidney, liver, or nervous system, particularly with unexplained heart failure, nephrotic syndrome, or peripheral neuropathy 3
• All cases of suspected localized amyloidosis require serum and urine immunofixation to exclude systemic AL amyloidosis, as subclinical involvement of other organs may be present but not yet detectable 6

Treatment of Amyloidosis

Treatment is entirely dependent on the amyloid type, making accurate protein identification absolutely essential before initiating therapy to avoid inappropriate and potentially harmful treatment. 3, 4

AL Amyloidosis Treatment

For transplant-eligible patients (approximately 20% of cases), daratumumab-CyBorD (daratumumab, cyclophosphamide, bortezomib, dexamethasone) is the first-line therapy, with high-dose melphalan followed by autologous stem cell transplantation (ASCT) remaining the standard of care. 1, 3

• For transplant-ineligible patients, daratumumab-CyBorD is the preferred first-line option, with CyBorD alone as an alternative 3
• Bortezomib plays a central role in upfront treatment for ASCT-ineligible patients, with daratumumab recently added to the emerging standard of care 1
• Treatment aims to achieve deep, durable responses targeting the underlying plasma cell clone, with very close monitoring for early detection of relapse or refractory disease 1

ATTR Amyloidosis Treatment

Tafamidis (VYNDAQEL 20 mg or VYNDAMAX 61 mg) is FDA-approved for treatment of cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. 7

• Both 80-mg and 20-mg doses of tafamidis showed statistically significant results versus placebo for all-cause mortality, cardiovascular hospitalization frequency, 6-minute walk test at Month 30, and Kansas City Cardiomyopathy Questionnaire Overall Summary score at Month 30 7
• Tafamidis stabilizes transthyretin protein, preventing its misfolding and deposition, representing a disease-modifying therapy for ATTR cardiomyopathy 7

Critical Treatment Considerations

• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma, requiring close monitoring for cardiac decompensation during therapy 3
• No absolute contraindications to plasma cell-directed therapies exist based solely on ejection fraction or cardiac status in AL cardiac amyloidosis 3
• Collaboration between hematologists, cardiologists, and nephrologists is crucial for optimal management 3, 6
• Treatment is not indicated for MGUS or localized AL amyloidosis unless there is evidence of progression to systemic disease 5

Prognostic Factors

• Cardiac involvement is the most important prognostic factor regardless of other organ involvement, with median survival dropping from 13 months to just 4 months when heart failure symptoms develop in AL amyloidosis 6
• The number and type of organs involved significantly impact survival, with age ≥65 years and cytogenetic abnormalities (particularly hyperdiploidy) associated with worse prognosis in AL amyloidosis 6