What is the initial treatment for AL (Amyloid Light-chain) amyloidosis?

Initial Treatment for AL Amyloidosis

Daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line treatment for newly diagnosed AL amyloidosis, regardless of stem cell transplant eligibility. 1, 2

Treatment Selection Algorithm

For All Newly Diagnosed Patients

First-line therapy should be Dara-CyBorD, which achieved unprecedented deep hematologic responses with very good partial response or better in 78.5% of patients compared to 49.2% with CyBorD alone in the landmark ANDROMEDA trial. 1, 2 This regimen is the only FDA-approved treatment specifically for AL amyloidosis and has emerged as the standard of care. 1

Stem Cell Transplant Eligibility Assessment

After initiating Dara-CyBorD, assess candidacy for high-dose melphalan with autologous stem cell transplantation (HDM/SCT) based on: 1

• Cardiac function: Ejection fraction <40% is generally a contraindication due to risk of hemodynamic decompensation during fluid shifts and potential infections 1
• Age and performance status: Typically reserved for highly selected patients who can tolerate intensive treatment 1
• Organ involvement severity: Advanced cardiac involvement (NT-proBNP >8,500 pg/mL) or multiple severely affected organs reduce eligibility 1

Only approximately 25% of newly diagnosed AL amyloidosis patients are eligible for HDM/SCT due to advanced cardiac and other organ involvement. 1

For Transplant-Eligible Patients

• Dara-CyBorD may be used as induction therapy (2-4 cycles of bortezomib-based regimen for patients with bone marrow plasma cells >10%) before proceeding to HDM/SCT 1, 2
• HDM/SCT offers treatment-related mortality of approximately 3% in experienced centers, with very good partial hematologic response or better in 70% of patients and median survival exceeding 15 years in complete responders 1

For Transplant-Ineligible Patients

Continue Dara-CyBorD as definitive therapy for the majority of patients who cannot undergo SCT. 1, 2

Special Consideration: Advanced Cardiac Involvement

For patients with severe cardiac involvement (NT-proBNP >8,500 pg/mL), consider single-agent daratumumab with minimal dexamethasone to minimize cardiotoxicity risk while maintaining anti-plasma cell activity. 1

Treatment Goal and Mechanism

The primary objective is to eradicate pathological plasma cells and remove amyloidogenic light chains from circulation, thereby limiting further organ damage and allowing regression of tissue amyloid deposits. 1, 2 AL amyloidosis results from clonal plasma cell disorders, making chemotherapy and immunotherapy targeting aberrant plasma cells the cornerstone of management. 1

Alternative First-Line Options (When Dara-CyBorD Unavailable)

If daratumumab is not accessible, CyBorD alone (cyclophosphamide, bortezomib, dexamethasone) remains highly effective: 1

• Overall hematologic response rate of 81-94% 3, 4
• Complete response in 42-71% of patients 3, 4
• Rapid response within 2 months 4
• Two-year overall survival of 97.7% (94.4% even in Mayo Stage III patients) 3

Bortezomib-melphalan-dexamethasone (BMDex) is another alternative bortezomib-based regimen. 1

Critical Monitoring During Treatment

Cardiotoxicity Surveillance

Close collaboration between hematology and cardiology is mandatory to monitor for treatment-related cardiac complications: 1, 2

• Daratumumab: Cardiac failure (12%, grade 3-4 in 6%), cardiac arrhythmia (8%, grade 3-4 in 2%), atrial fibrillation (6%, grade 3-4 in 2%) 1
• Bortezomib: Grade 3 heart failure in 6.4%, >10% decrease in LVEF in 23% 1
• Cyclophosphamide: Myocarditis, pericardial effusion, cardiac tamponade, supraventricular and ventricular arrhythmias, particularly with high doses or advanced age 1
• Corticosteroids (dexamethasone): Peripheral edema, pulmonary edema, fluid overload 1

Response Assessment Timeline

Hematologic response is typically observed within 3-6 months of treatment initiation, measured by magnitude of light chain reduction. 1 Organ-specific response generally follows 6-12 months after achieving hematologic response. 1

Monitor with: 1, 2

• Serum free light chain assay (sFLC) with difference between involved/uninvolved chains (dFLC)
• NT-proBNP and troponin for cardiac response
• 24-hour urine protein and creatinine for renal response
• Echocardiography and electrocardiography

Common Pitfalls to Avoid

Do not use standard protein electrophoresis (SPEP/UPEP) alone for diagnosis or monitoring, as it has lower sensitivity than the required triad of serum free light chain assay, serum immunofixation electrophoresis, and urine immunofixation electrophoresis. 2

There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis—treatment should be initiated even in advanced cardiac disease, with appropriate monitoring and dose modifications. 2

Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma due to multiorgan involvement and fragility, requiring more cautious dosing and closer monitoring. 2

Avoid immunomodulatory agents (lenalidomide, pomalidomide) as first-line therapy due to paradoxical increases in cardiac biomarkers (BNP elevation in 86-88.8% of patients), significant renal dysfunction (26-66% of patients), and potential need for renal replacement therapy (10% with lenalidomide). 1 These agents are reserved for relapsed/refractory disease.