What is the initial approach to treating amyloidosis (a condition characterized by the deposition of amyloid, a protein, in various organs)?

Initial Approach to Treating Amyloidosis

The initial approach to treating amyloidosis absolutely requires accurate diagnosis with tissue biopsy and amyloid typing via mass spectrometry before any treatment is initiated, as treatment is entirely type-specific and fundamentally different between AL and ATTR subtypes. 1, 2, 3

Step 1: Confirm Diagnosis with Tissue Biopsy

Before any treatment can begin, you must obtain tissue confirmation with Congo red staining showing apple-green birefringence under polarized microscopy. 1, 2

Biopsy site selection (in order of preference):

• Abdominal fat pad aspiration (84% sensitivity for AL amyloidosis, least invasive, office-based procedure) 1, 2
• Bone marrow biopsy (69% sensitivity for systemic AL, but mandatory to assess plasma cell burden) 1
• Affected organ biopsy (heart, kidney, liver) if surrogate sites are negative 1, 2

Step 2: Mandatory Amyloid Typing

Mass spectrometry (LC-MS/MS) is the gold standard and must be performed with 88% sensitivity and 96% specificity. 1, 2, 4 This step cannot be skipped because AL amyloidosis requires chemotherapy targeting plasma cells, while ATTR amyloidosis requires TTR stabilizers—these are completely different treatment paradigms. 3, 5

Critical pitfall: Never assume the amyloid type based on clinical presentation alone. Over 10% of patients with monoclonal gammopathy can have ATTR deposits, not AL. 1

Step 3: Complete Monoclonal Protein Screen (for AL Amyloidosis)

If AL amyloidosis is suspected or confirmed, perform all three tests simultaneously—never rely on SPEP/UPEP alone: 2, 4

• Serum free light chain (sFLC) assay 1, 2
• Serum immunofixation electrophoresis (SIFE) 1, 2
• Urine immunofixation electrophoresis (UIFE) 1, 2

SPEP alone misses monoclonal spikes in nearly 50% of AL amyloidosis cases. 1

Step 4: Comprehensive Organ Assessment

Cardiac evaluation (mandatory in all cases): 2

• NT-proBNP or BNP (>332 ng/L has >99% sensitivity for cardiac involvement; disproportionately elevated relative to degree of heart failure) 2, 6
• Troponin T (threshold <0.035 mcg/L for staging) 2
• Echocardiography (look for LV wall thickness ≥12 mm, restrictive physiology) 2
• Cardiac MRI when echocardiography is suggestive but not definitive 2

Renal assessment: 2

• 24-hour urine protein and eGFR 6
• Unexplained proteinuria is a red flag for AL amyloidosis 1, 2

Other organ systems: 1, 2

• Liver function tests (hepatomegaly is a clinical clue) 1
• Neurological evaluation if peripheral neuropathy present 2

Step 5: Risk Stratification

Use cardiac biomarkers for staging (Mayo 2004, Mayo 2012, European 2015, or Boston University models): 2

• Troponin T threshold: <0.035 mcg/L 2
• NT-proBNP threshold: <332 ng/L 2

Cardiac involvement is the main driver of disease prognosis and mortality. 4

Step 6: Initiate Type-Specific Treatment

For AL Amyloidosis:

Daratumumab-CyBorD (daratumumab, cyclophosphamide, bortezomib, dexamethasone) is the current standard of care for both transplant-eligible and ineligible patients. 4, 3 The goal is to eradicate pathological plasma cells and remove affected light chains from circulation. 4

For selected patients (n=394): High-dose melphalan with autologous stem cell transplant resulted in 40% complete hematologic response at 1 year with improved 5-year survival and reversal of amyloid-related disease. 1 This is reserved for eligible patients who do not attain satisfactory response to daratumumab-based therapy. 3

Treatment monitoring: Deep hematologic responses correlate with improved organ function and survival. 4 Response should be assessed using validated criteria with the early goal of profound hematologic response, followed by deepening organ response over time. 3

For ATTR Amyloidosis (Cardiac):

Tafamidis is FDA-approved for ATTR-CM (wild-type or hereditary transthyretin-mediated amyloidosis cardiomyopathy) to reduce cardiovascular mortality and cardiovascular-related hospitalization. 7

Dosing: Either VYNDAQEL 80 mg (four 20-mg tafamidis meglumine capsules) orally once daily OR VYNDAMAX 61 mg (one 61-mg tafamidis capsule) orally once daily. 7 These formulations are not substitutable on a per mg basis. 7

Critical Pitfalls to Avoid

• Never diagnose based on monoclonal gammopathy alone—requires tissue confirmation and typing 4
• Never assume facial droop is stroke—consider soft tissue infiltration with macroglossia or periorbital purpura (pathognomonic for AL amyloidosis) 1, 4
• Never skip amyloid typing—treatment differs fundamentally between AL and ATTR 6, 5
• Never use SPEP/UPEP alone—requires all three tests (sFLC, SIFE, UIFE) simultaneously 2, 4
• Never initiate treatment before confirming the amyloid type—AL requires chemotherapy while ATTR requires TTR stabilizers 3, 5

Supportive Care Considerations

For systemic complications: 1

• Hypercalcemia: hydration, furosemide, bisphosphonates, steroids, and/or calcitonin 1
• Renal dysfunction: maintain hydration, avoid NSAIDs and IV contrast 1
• Infection prevention: consider pneumococcal and influenza vaccines, herpes prophylaxis with bortezomib 1
• Prophylactic anticoagulation if thalidomide-based therapy is used 1

For GI involvement: Management is supportive and not amyloid-specific, but endoscopy with random biopsies (Congo red staining) serves to risk-stratify extracardiac manifestations and exclude other causes. 1 Modified BMI (mBMI = serum albumin × BMI) <600 kg/m²·g/L indicates poor nutritional status and poor prognosis. 1