How do you treat Amyloidosis, specifically light-chain (AL) amyloidosis?

Treatment of Light-Chain (AL) Amyloidosis

The preferred first-line treatment for AL amyloidosis is daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD), with autologous stem cell transplantation (ASCT) considered for eligible patients. 1, 2

Diagnostic Confirmation

Before initiating treatment, proper diagnosis is essential:

• Tissue biopsy with Congo Red staining showing characteristic apple-green birefringence under polarized light is required 2
• Accurate monoclonal protein screening requires serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) 1
• Standard protein electrophoresis (SPEP/UPEP) should not be used alone due to lower sensitivity 1
• Bone marrow biopsy to demonstrate clonal proliferation of lambda or kappa-producing plasma cells 1

Treatment Algorithm

Step 1: Assess ASCT Eligibility

Eligibility criteria for ASCT include:

• Adequate cardiac function 2
• Good performance status 2
• Limited organ involvement 2

Step 2: Choose Treatment Regimen

For ASCT-eligible patients:

• Consider high-dose melphalan followed by autologous stem cell transplantation 1, 2
• Daratumumab-CyBorD may supplant ASCT as first-line therapy based on recent evidence 1

For ASCT-ineligible patients:

• Daratumumab-CyBorD (preferred first-line option) 1, 2
• Alternative: CyBorD (cyclophosphamide, bortezomib, and dexamethasone) 1

Step 3: Monitor Treatment Response

• Assess hematologic response regularly 1, 2
• Monitor for cardiac decompensation, including heart failure, atrial arrhythmias, or thromboembolism 1
• Evaluate organ function improvement 2

Medication Details and Considerations

Daratumumab (anti-CD38 antibody):

• Recently FDA-approved for AL amyloidosis 1
• Potential cardiac toxicities: cardiac failure (12%), arrhythmias (8%), atrial fibrillation (6%) 1

Proteasome Inhibitors:

• Bortezomib: Risk of Grade 3 heart failure (6.4%), decreased LVEF (23%) 1
• Carfilzomib: Higher risk of dyspnea, LVEF reduction, pulmonary hypertension (36%) 1
• Ixazomib: Grade 3 fatigue, dyspnea, skin rash (15%), Grade 3 heart failure (10%) 1

Immunomodulatory Agents (for refractory/relapsed disease):

• Lenalidomide: Can cause paradoxical increase in cardiac biomarkers and kidney dysfunction 1
• Pomalidomide: Similar cardiac and renal concerns as lenalidomide 1
• Thalidomide: Associated with bradycardia 1

Corticosteroids:

• Dexamethasone/prednisone: Monitor for peripheral edema, pulmonary edema, and fluid overload 1

Important Clinical Considerations

• The goal of treatment is to eradicate pathological plasma cells and remove affected light chains from circulation 1, 2
• Cardiac involvement is the main driver of disease prognosis and mortality 1, 2
• Treatment responses can be rapid (median 0.9 months for hematologic response) 3
• Organ response may take longer (median 4 months) 3
• Collaboration between hematologists, cardiologists, and nephrologists is crucial 1

Common Pitfalls and Caveats

• No absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis, unlike other cardiotoxic chemotherapies 1
• Dose adjustments may be necessary based on organ involvement and treatment toxicities 3
• Differentiate AL amyloidosis from transthyretin (TTR) amyloidosis, as management differs significantly 1, 2
• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma 1
• Close monitoring for cardiac decompensation during therapy is essential 1

Emerging Therapies

• Fibril-directed therapies using antibodies that bind to amyloid protein in organs show early efficacy in clinical trials 4
• These newer approaches may help reverse light chain deposits in organs, which current therapies cannot achieve 4