Evaluation and Treatment of Amyloidosis

Diagnostic Evaluation

The cornerstone of amyloidosis diagnosis requires tissue biopsy with Congo red staining demonstrating characteristic apple-green birefringence under polarized light, followed by mandatory amyloid typing using mass spectrometry before initiating any treatment. 1, 2

Initial Diagnostic Steps

Obtain tissue biopsy from affected organ (heart, kidney, fat pad, or bone marrow) with Congo red staining to confirm amyloid deposits 1, 3
Perform mass spectrometry (LC-MS/MS) on tissue specimen as the gold standard for amyloid typing, with 88% sensitivity and 96% specificity 1, 2
Complete monoclonal protein screening simultaneously with three tests: serum free light chain assay (sFLC) with kappa/lambda ratio, serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) 1
Avoid standard protein electrophoresis (SPEP/UPEP) alone due to inadequate sensitivity 1

Typing Algorithm

For patients with monoclonal protein detected:

Proceed with bone marrow biopsy to demonstrate clonal plasma cell proliferation, confirming AL amyloidosis 1

For patients without monoclonal protein:

Perform technetium-99m pyrophosphate (Tc-99m-PYP) bone scintigraphy to confirm ATTR cardiac amyloidosis 2, 4
If ATTR confirmed, obtain TTR gene sequencing to differentiate hereditary (ATTRv) from wild-type (ATTRwt) forms 2

Treatment of AL (Light Chain) Amyloidosis

Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line treatment for AL amyloidosis, achieving very good partial response or better in 78.5% of patients compared to 49.2% with CyBorD alone. 1, 2, 3

Treatment Selection Algorithm

For ASCT-eligible patients (age <65, Mayo stage 1-2, NYHA class <3, ejection fraction >40-45%, eGFR >50 ml/min/1.74 m²):

First-line option: Daratumumab-CyBorD 1
Alternative: High-dose melphalan (200 mg/m²) followed by autologous stem cell transplantation (ASCT), with treatment-related mortality approximately 3% in experienced centers 1, 3

For ASCT-ineligible patients:

Preferred: Daratumumab-CyBorD as first-line therapy 1
Alternative: CyBorD (cyclophosphamide, bortezomib, dexamethasone) alone 1

For patients age 60-65 with serum creatinine ≥2 mg/dL:

Reduce melphalan dose to 100 mg/m² and proceed with extreme caution 1

Critical Monitoring During AL Treatment

Monitor cardiac decompensation closely during therapy, as cardiac involvement drives mortality 1, 2
Check platelet counts weekly with inotersen due to thrombocytopenia risk 5
Monitor serum creatinine and urine protein-creatinine ratio every 2 weeks with inotersen due to glomerulonephritis risk 5
Supplement with vitamin A 3,000 IU daily when using TTR silencers (patisiran, inotersen, vutrisiran) as these medications impair retinol transport 5

Important Cardiac Toxicity Considerations

Daratumumab carries risks of cardiac failure (12%), arrhythmias (8%), and atrial fibrillation (6%) 1
Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) can cause Grade 3 heart failure, decreased LVEF, and pulmonary hypertension 1
Corticosteroids require monitoring for peripheral edema, pulmonary edema, and fluid overload 1
There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis 1

Treatment of ATTR (Transthyretin) Amyloidosis

Tafamidis is FDA-approved for treatment of ATTR cardiomyopathy in adults with NYHA Class I-III symptoms to reduce cardiovascular mortality and cardiovascular-related hospitalization. 6, 1, 2

ATTR Cardiac Amyloidosis (ATTR-CM)

Tafamidis demonstrated lower all-cause mortality (29.5% vs 42.9%) and reduced cardiovascular-related hospitalizations (0.48 vs 0.70 per year) after 30 months compared to placebo 2
Tafamidis is indicated for both wild-type and hereditary ATTR-CM with NYHA Class I-III symptoms 6, 1

ATTR Polyneuropathy (ATTRv)

For hereditary ATTR with polyneuropathy, TTR silencers are the disease-modifying therapy of choice:

Patisiran (0.3 mg/kg IV every 3 weeks, maximum 30 mg): FDA-approved for ATTRv polyneuropathy 5, 7
- Requires premedication with dexamethasone 10 mg IV, acetaminophen 500 mg, diphenhydramine 50 mg, famotidine 20 mg at least 60 minutes before infusion 5
- Requires vitamin A 3,000 IU daily supplementation 5
Inotersen (284 mg SC once weekly): FDA-approved for ATTRv polyneuropathy 5
- Requires vitamin A 3,000 IU daily supplementation 5
- Monitor platelet count weekly and serum creatinine/UPCR every 2 weeks 5
Vutrisiran (25 mg SC every 3 months): FDA-approved for ATTRv polyneuropathy 5
- Requires vitamin A 3,000 IU daily supplementation 5

Critical caveat: Early diagnosis and treatment is essential, as patients treated earlier have better neuropathy outcomes than those whose treatment is delayed by 1 year or more 5

Important limitation: Tafamidis is not FDA-approved for neuropathy, and there is currently no evidence that TTR stabilizers or silencers benefit polyneuropathy associated with ATTRwt amyloidosis 5

Supportive Cardiac Management

Judicious diuresis remains the cornerstone of heart failure therapy in cardiac amyloidosis, but standard heart failure medications must be used with extreme caution or avoided entirely. 1, 2

Medications to Use with Caution

Diuretics: Essential for symptom management but avoid overdiuresis and volume contraction that can result in hypotension 5
Beta-blockers: May increase diastolic filling time and control heart rate in atrial fibrillation, but use with caution in low cardiac output and severe restrictive physiology 5
ACE inhibitors/ARBs: Use at lowest dose with extreme caution due to high risk of hypotension; probably should be avoided 2

Medications to Avoid

Digoxin should be avoided as it binds to amyloid fibrils and predisposes to toxicity even with normal serum levels 5
Calcium channel blockers (nifedipine, verapamil) should not be administered as they bind to amyloid fibrils and cause exaggerated hypotensive and negative inotropic responses 5

Anticoagulation

Warfarin (INR 2-3) or direct thrombin inhibitors are indicated for patients with cardiac amyloidosis and paroxysmal or chronic atrial fibrillation or history of embolic stroke/TIA 5
Anticoagulation is reasonable in cardiac amyloidosis with atrial fibrillation independent of CHA₂DS₂-VASc score to reduce stroke risk 1, 2

Management of Neuropathic Symptoms

Sensory Neuropathy Pain Management

Pregabalin (75 mg twice daily, titrate to 300-600 mg/day maximum) for neuropathic pain 5
Gabapentin for neuropathic pain 5
Duloxetine for neuropathic pain 5
Avoid tricyclic antidepressants when possible due to increased side effects in patients with orthostatic hypotension, urinary retention, erectile dysfunction, or constipation 5

Autonomic Dysfunction and Orthostatic Hypotension

Increased salt/fluid intake and salt tablets as first-line non-pharmacologic measures 5
Pyridostigmine is preferred for orthostatic hypotension without risks of fluid retention or supine hypertension 5
Fludrocortisone, midodrine, or droxidopa may be used but are poorly tolerated in patients with cardiac involvement and restrictive physiology 5
Compression stockings (knee- or thigh-high) and abdominal binders can be helpful without drug side effects 5

Organ-Specific Supportive Care

Renal Management

Avoid NSAIDs and IV contrast to prevent further renal dysfunction 1
Provide supportive care including blood pressure control 1
Consider dialysis if needed 1

Gastrointestinal Management

Refer to gastroenterology for significant malnutrition, unexplained weight loss, severe nausea, vomiting, diarrhea, constipation, or GI bleeding 1
Octreotide for diarrhea management 1

Multidisciplinary Care Requirements

Effective management of amyloidosis requires close collaboration between hematology, cardiology, and nephrology, as cardiac involvement is the main driver of disease prognosis and mortality. 1

Hematologist directs anti-plasma cell therapies and coordinates overall care 1
Cardiologist manages cardiac involvement present in most cases 1
Nephrologist manages kidney involvement, proteinuria, and renal dysfunction 1
Neurologist addresses peripheral or autonomic nervous system involvement 1
Transplant specialists evaluate stem cell or organ transplantation candidacy 1

Monitoring Response to Treatment

AL Amyloidosis Response Assessment

Hematologic response: Monitor serum free light chains and aim for complete response (undetectable involved light chain) 1
Organ response: Assess NT-proBNP and troponin levels, echocardiography with strain measurements, NYHA functional class 2
Timeline: Hematologic response typically occurs within 3-6 months; organ-specific response within 6-12 months 3

ATTR Amyloidosis Monitoring

Regular assessment of NT-proBNP, troponin, echocardiography, ECG, Holter monitoring, and NYHA functional class 2

Transplantation Considerations

Cardiac Transplantation

In AL amyloidosis, cardiac transplantation alone is generally not recommended due to high risk of recurrence in the transplanted heart, with 5-year survival only 20-30% 2
Survival improves if cardiac transplantation is followed by bone marrow transplantation, achieving 5-year survival of 35-55% 2
Cardiac and liver transplantation for hereditary ATTR might be considered in selected patients 5

What are the evaluation and treatment options for a patient with amyloidosis?

Help us tailor your experience