AL Amyloidosis: Diagnostic Work-Up and First-Line Therapy
Immediate Diagnostic Approach
In adults presenting with unexplained restrictive cardiomyopathy, nephrotic-range proteinuria, peripheral neuropathy, or macroglossia, you must simultaneously obtain comprehensive monoclonal protein screening and pursue tissue biopsy to confirm AL amyloidosis. 1, 2
Step 1: Monoclonal Protein Screening (Order All Three Tests Simultaneously)
- Serum free light chain assay (sFLC) with kappa/lambda ratio 2, 3
- Serum immunofixation electrophoresis (SIFE) 2, 3
- Urine immunofixation electrophoresis (UIFE) 2, 3
Critical pitfall: Do NOT use standard protein electrophoresis (SPEP/UPEP) alone—it misses monoclonal spikes in nearly 50% of AL amyloidosis cases. 2, 3
Step 2: Tissue Biopsy Strategy
You have two acceptable approaches for tissue diagnosis 1:
Option A (Less Invasive First):
- Perform abdominal fat pad aspiration (84% sensitivity for AL-CM) AND bone marrow biopsy (69% sensitivity for systemic AL) 1
- If Congo red staining is negative, proceed immediately to biopsy of the affected organ 1
Option B (Direct Approach):
- Biopsy the affected organ directly (heart, kidney, etc.) 1
Mandatory next step after positive Congo red staining: Send tissue for mass spectrometry (LC-MS/MS) to identify the amyloid precursor protein—this is the gold standard with 88% sensitivity and 96% specificity. 1, 2, 3 Immunohistochemistry alone is insufficient, particularly because over 10% of patients with monoclonal gammopathy can have ATTR deposits. 1
Step 3: Bone Marrow Evaluation
- Bone marrow biopsy is necessary to demonstrate clonal proliferation of lambda (75-80% of cases) or kappa-producing plasma cells 1, 2
- This distinguishes AL amyloidosis from multiple myeloma (which has higher plasma cell burden, typically >10%) 1
Step 4: Organ Involvement Assessment
Cardiac evaluation (most critical for prognosis): 3
- NT-proBNP and troponin T levels
- Echocardiography
- Cardiac MRI
Renal evaluation: 3
- 24-hour urine protein collection
- Serum creatinine and BUN
Additional assessments based on clinical presentation: Hepatic function tests (alkaline phosphatase elevation with normal transaminases suggests hepatic involvement), peripheral nerve conduction studies if neuropathy present 4
First-Line Therapy
Treatment Selection Algorithm
For ASCT-eligible patients (highly selected): 2, 3
Consider high-dose melphalan followed by autologous stem cell transplantation (ASCT) ONLY if ALL criteria met:
- Age <60 years (age 60-65 requires dose reduction to 100 mg/m² and extreme caution) 2
- ≤2 organs involved 2, 3
- Mayo stage 1-2 2
- Performance status 0-2 2
- eGFR >50 mL/min/1.73 m² 2
- NYHA class <3 2
- Ejection fraction >40-45% 2
- Systolic blood pressure >90 mmHg 2
- DLCO >50% 2
For all other patients (the majority):
Daratumumab-CyBorD (daratumumab plus cyclophosphamide, bortezomib, and dexamethasone) is the preferred first-line treatment, achieving very good partial response or better in 78.5% of patients. 2, 3 This regimen is FDA-approved and represents the current standard of care. 2
Alternative option if Daratumumab-CyBorD unavailable:
- CyBorD alone (cyclophosphamide, bortezomib, and dexamethasone) 2
Critical Treatment Considerations and Monitoring
Cardiotoxicity Monitoring (Essential)
Close collaboration between hematology and cardiology is mandatory because cardiac involvement drives mortality—approximately 30% of patients die within the first year due to advanced cardiac involvement. 2, 3
Specific cardiac toxicities to monitor: 2
- Daratumumab: cardiac failure (12%), arrhythmias (8%), atrial fibrillation (6%)
- Proteasome inhibitors (bortezomib, carfilzomib): Grade 3 heart failure, decreased LVEF, pulmonary hypertension
- Immunomodulatory agents: cardiac and renal concerns
- Corticosteroids: peripheral edema, pulmonary edema, fluid overload
Important principle: There are NO absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis. 2 However, patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma. 2
Treatment Goals and Response Assessment
Primary goal: Eradicate pathological plasma cells and remove amyloidogenic light chains from circulation. 2, 3 Deep hematologic responses directly correlate with improved organ function and survival. 3
Response assessment at 3-6 months: 3
- Measure difference between involved and uninvolved free light chains (dFLC)
- Monitor organ-specific responses (NT-proBNP for cardiac, proteinuria for renal)
Supportive Care Essentials
Cardiac management: 2
- Judicious diuresis (cornerstone of heart failure therapy)
- Use standard heart failure medications with extreme caution
- Consider anticoagulation for atrial fibrillation regardless of CHA₂DS₂-VASc score
Renal protection: 2
- Avoid NSAIDs and IV contrast to prevent further renal dysfunction
Symptom management: 2
- Salt restriction and daily weight monitoring
- Elastic compression stockings for orthostatic symptoms
- Midodrine for refractory hypotension
- Gabapentin or pregabalin for neuropathic pain
- Octreotide for diarrhea
Common Pitfalls to Avoid
Delayed diagnosis: The constellation of seemingly disparate symptoms (restrictive cardiomyopathy + proteinuria + neuropathy + macroglossia) should immediately trigger AL amyloidosis evaluation. 1
Confusing AL with ATTR amyloidosis: Approximately 10-40% of ATTR-CM patients have concomitant monoclonal gammopathy of uncertain significance (MGUS), which can be mistaken for AL amyloidosis. 1 Always confirm with tissue typing by mass spectrometry. 1
Missing the 10-15% overlap with multiple myeloma: Patients with both conditions are more fragile and require modified treatment approaches. 2
Underestimating cardiac involvement: Cardiac involvement is the main driver of disease prognosis and mortality, not hepatic or renal failure. 4, 3