What is the treatment regimen for amyloidosis (ATTR amyloidosis)?

Treatment Regimen for ATTR Amyloidosis

For ATTR amyloidosis, the standard first-line treatment is daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD), which has demonstrated superior outcomes compared to other regimens. 1

Treatment Algorithm Based on Transplant Eligibility

For Transplant-Eligible Patients:

• Consider high-dose melphalan followed by autologous stem cell transplantation (HDM/SCT) for eligible patients 1, 2
• Eligibility criteria for SCT include:
  • Ejection fraction >40% (EF <40% is a contraindication) 1
  • Ability to tolerate fluid shifts and potential infections 1
  • Limited organ involvement 1
• Only about 25% of newly diagnosed AL amyloidosis patients are eligible for this intensive treatment 1
• Prior to SCT, 2-4 cycles of a bortezomib-based regimen is recommended for induction in patients with bone marrow plasma cell percentages >10% 1
• Treatment-related mortality with HDM/SCT is approximately 3% in experienced centers 1

For Transplant-Ineligible Patients:

• Daratumumab-CyBorD is the preferred first-line regimen 1, 2
  • The ANDROMEDA trial demonstrated very good partial responses or better in 78.5% of patients receiving daratumumab plus CyBorD vs 49.2% with CyBorD alone 1
  • Daratumumab is FDA-approved for treatment of newly-diagnosed AL amyloidosis 1
• Alternative regimens include:
  • CyBorD (cyclophosphamide, bortezomib, and dexamethasone) 1, 3
  • Bortezomib-melphalan-dexamethasone (BMDex) 1
• For patients with advanced cardiac involvement (NT-proBNP >8,500 pg/mL), consider single-agent daratumumab with minimal dexamethasone to minimize cardiotoxicity 1

Medication Considerations and Toxicities

Daratumumab (Anti-CD38 Monoclonal Antibody):

• Potential cardiac toxicities include:
  • Cardiac failure in 12% (grade 3-4 in 6%) 1
  • Cardiac arrhythmia in 8% (grade 3-4 in 2%) 1
  • Atrial fibrillation in 6% (grade 3-4 in 2%) 1

Proteasome Inhibitors:

• Bortezomib: Grade 3 heart failure in 6.4%, >10% decrease in LVEF in 23% 1
• Carfilzomib: Dyspnea, LVEF reduction, pulmonary hypertension in 36% 1
• Ixazomib: Grade 3 fatigue, dyspnea, skin rash in 15%, Grade 3 heart failure in 10% 1, 4

Other Agents:

• Corticosteroids (dexamethasone, prednisone): Monitor for peripheral edema, pulmonary edema, and fluid overload 1
• Immunomodulatory agents (lenalidomide, pomalidomide): Can cause paradoxical increase in cardiac biomarkers and kidney dysfunction 1
• Cyclophosphamide: Risk of myocarditis, pericardial effusion, arrhythmias, and heart failure 1

Response Assessment and Monitoring

Hematologic Response Criteria:

• Complete response (CR): Absence of amyloidogenic light chains and normalized free light chain ratio 1
• Very good partial response (VGPR): dFLC <40 mg/L 1
• Partial response (PR): dFLC decrease ≥50% 1
• No response (NR): dFLC decrease <50% 1

Organ Response Criteria:

• Cardiac response: Decrease in NT-proBNP by >30% and <300 ng/L (if baseline NT-proBNP >650 ng/L) 1
• Renal response: At least 30% decrease in proteinuria or drop below 0.5 g/24h, without kidney progression 1
• Hepatic response: 50% decrease in abnormal alkaline phosphatase or decrease in radiographic liver size by ≥2 cm 1

Monitoring Schedule:

• Hematologic response typically observed within 3-6 months of treatment initiation 1
• Organ-specific response generally observed 6-12 months after hematologic response 1
• Regular monitoring should include:
  • Serum free light chains 2
  • Cardiac biomarkers (troponin, NT-proBNP) 1
  • Renal function and proteinuria 1
  • Liver enzymes 1
  • Electrocardiography and echocardiography 1

Important Clinical Considerations

• Cardiac involvement is the main driver of disease prognosis and mortality 2
• Multidisciplinary care involving hematologists, cardiologists, and nephrologists is crucial 2
• Differentiation between AL amyloidosis and transthyretin (TTR) amyloidosis is essential as management differs significantly 2
• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma 2
• Close monitoring for cardiac decompensation during therapy is essential 2

Common Pitfalls to Avoid

• Delaying treatment initiation - early intervention is critical for preventing further organ damage 2
• Using standard protein electrophoresis (SPEP/UPEP) alone for diagnosis - serum free light chain assay, SIFE, and UIFE are required 2
• Overlooking cardiac involvement - heart involvement drives prognosis 2
• Fragmented care without coordination between specialists 2
• Failing to adjust treatment based on organ involvement - patients with advanced cardiac disease may require modified regimens 1