What is the recommended diagnostic workup and treatment algorithm for AL amyloidosis, including first‑line options for patients under 70 with good performance status and limited cardiac involvement versus transplant‑ineligible patients, and appropriate second‑line therapies?

AL Amyloidosis: Diagnostic Workup and Treatment Algorithm

Diagnostic Workup

When you suspect AL amyloidosis based on unexplained restrictive cardiomyopathy, nephrotic-range proteinuria, peripheral neuropathy with autonomic features, macroglossia, or periorbital purpura, immediately pursue simultaneous tissue biopsy and comprehensive monoclonal protein screening. 1

Tissue Diagnosis Strategy

• First-line approach: Perform abdominal fat pad aspiration (84% sensitivity) and bone marrow biopsy (69% sensitivity) concurrently—this combination negates the need for organ biopsy in most patients 1, 2
• If fat pad and bone marrow are Congo red negative but clinical suspicion remains high, proceed directly to biopsy of the clinically involved organ (heart, kidney, liver, etc.) 3, 1
• Critical typing requirement: After confirming Congo red positivity with apple-green birefringence under polarized light, send tissue for mass spectrometry (LC-MS/MS) to definitively identify the amyloid precursor protein (88% sensitivity, 96% specificity) 1
• Avoid the ATTR misdiagnosis trap: 10-40% of patients with ATTR cardiac amyloidosis have concurrent monoclonal gammopathy of uncertain significance—immunohistochemistry alone will misclassify these as AL amyloidosis, so mass spectrometry is mandatory 3, 1

Monoclonal Protein Assessment

• Obtain serum and urine immunofixation electrophoresis plus serum free light chain (FLC) assay to identify the amyloidogenic light chain (lambda in 75-80% of cases) 3
• Bone marrow biopsy demonstrates the clonal plasma cell population; if plasma cells exceed 10% of marrow cellularity, consider concurrent multiple myeloma rather than isolated AL amyloidosis 1

Organ Involvement Assessment

• Cardiac evaluation: Obtain NT-proBNP (>332 ng/L has >99% sensitivity for cardiac involvement), troponin T, ECG (look for low voltage despite wall thickening, pseudoinfarct pattern), and echocardiography showing increased wall thickness with restrictive physiology 3
• Renal evaluation: 24-hour urine protein collection (two-thirds present with heavy proteinuria), serum creatinine (but recognize this underestimates dysfunction due to muscle wasting—use cystatin C-based eGFR or 24-hour creatinine clearance instead) 3, 4
• Hepatic screening: If alkaline phosphatase is elevated, obtain abdominal CT or ultrasound to evaluate hepatomegaly 3
• Neurologic assessment: Evaluate for peripheral neuropathy with autonomic features, bilateral carpal tunnel syndrome 3

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Treatment Algorithm

For Transplant-Eligible Patients (Age <70, Good Performance Status, Limited Cardiac Involvement)

Autologous stem cell transplantation (ASCT) remains the standard of care for carefully selected patients, achieving hematologic response rates exceeding 70% and median overall survival of 7.6 years, with 55% of complete responders alive at 14 years. 3

ASCT Eligibility Criteria

• Cardiac biomarker thresholds: Troponin T ≤0.06 ng/mL and NT-proBNP ≤5000 ng/L (exceeding these cutoffs predicts prohibitively high transplant-related mortality) 3
• Absence of severe renal impairment with hypoalbuminemia (treatment-related mortality is excessive in this setting) 4
• Age typically <70 years with adequate performance status 3

ASCT Treatment Sequence

• Consider bortezomib-based induction (e.g., CyBorD) before ASCT, particularly in patients with suboptimal disease burden 3
• Proceed to high-dose melphalan (typically 200 mg/m²) with autologous stem cell rescue 3
• For patients failing to achieve complete response post-ASCT, add bortezomib consolidation to increase complete response rate to nearly 60% 3

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For Transplant-Ineligible Patients

Daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (dara-CyBorD) is the current standard of care, achieving very good partial response or better in 78.5% of patients. 4, 5

First-Line Regimen Selection

• Preferred regimen: Dara-CyBorD (daratumumab + cyclophosphamide + bortezomib + dexamethasone) has emerged as the standard with the addition of daratumumab to bortezomib-based therapy 3, 4
• Alternative bortezomib-based options: VCD (bortezomib + cyclophosphamide + dexamethasone) or BMDex (bortezomib + melphalan + dexamethasone) if daratumumab is unavailable, achieving hematologic response rates of 76-90% 3
• Historical option: Melphalan plus dexamethasone (MDex) achieves 76% hematologic response and 7-year overall survival of 7.3 years, with 80% of complete responders alive at 7 years—outcomes comparable to ASCT in landmark analyses 3

Critical Dosing Adjustments

• In severe renal impairment or end-stage renal disease requiring dialysis, reduce ixazomib starting dose to 3 mg 4
• Use full-dose dexamethasone cautiously; cardiac amyloidosis patients tolerate hemodynamic fluctuations poorly 3

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Second-Line Therapies for Relapsed/Refractory Disease

For patients relapsing after or refractory to first-line therapy, immunomodulatory drugs (lenalidomide, pomalidomide) form the cornerstone of rescue therapy, while novel immunotherapies targeting BCMA and BCL-2 inhibitors represent promising alternatives. 5

Relapse Treatment Options

• Daratumumab-based regimens: If not used in first-line, daratumumab combinations are highly effective in relapsed disease 5
• Immunomodulatory drug combinations: Lenalidomide or pomalidomide with dexamethasone, often combined with proteasome inhibitors 5
• Emerging therapies: BCMA-targeted immunotherapy and venetoclax (BCL-2 inhibitor) are under investigation for daratumumab-exposed patients 3, 5
• Repeat ASCT: May be considered if initial response lasted ≥2 years 3

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Supportive Care Essentials

Cardiac Management

• Diuretics are the mainstay: Use torsemide or bumetanide over oral furosemide for better bioavailability in patients with bowel wall edema 4
• Avoid standard heart failure medications: ACE inhibitors, ARBs, β-blockers, and calcium channel blockers cause exaggerated hypotension and negative inotropy due to amyloid fibril binding—use with extreme caution or avoid entirely 3
• Anticoagulation: Indicated for atrial fibrillation and consider even in sinus rhythm due to high risk of atrial mechanical standstill and thrombus formation 3
• Arrhythmia management: Use amiodarone for rhythm control; consider pacemaker for conduction abnormalities 3

Renal Management

• Dietary sodium restriction plus loop diuretics for nephrotic syndrome 4
• ACE inhibitors/ARBs may be used for anti-proteinuric effects only if blood pressure tolerates (most patients have prohibitively low blood pressure) 4
• For end-stage kidney disease, peritoneal dialysis or extended hemodialysis schedules (short daily or long nocturnal) are better tolerated hemodynamically than conventional thrice-weekly hemodialysis 4

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Response Monitoring

• Hematologic response: Serial serum free light chain measurements every 2-4 weeks initially; aim for complete response (normal FLC ratio and negative immunofixation) or very good partial response (≥90% reduction in involved FLC) 3
• Organ response: NT-proBNP for cardiac response (typically lags hematologic response by months); proteinuria for renal response (decreases progressively over months to years, with renal response in ~60% of patients) 4
• Expected outcomes: GFR usually stabilizes rather than improves even with successful hematologic response; proteinuria can resolve fully if sustained deep hematologic response is achieved 4

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Critical Prognostic Factors

• Cardiac involvement is the dominant prognostic driver: Median survival is 13 months overall but drops to 4 months once heart failure symptoms develop 3
• Cardiac staging systems based on troponin and NT-proBNP levels guide treatment intensity and predict early mortality 3
• Early diagnosis before irreversible organ damage is the single most important factor for improving outcomes—69% of patients already have multi-organ involvement at diagnosis 3