What are the treatment options for amyloidosis?

Treatment Options for Amyloidosis

The most effective treatment for amyloidosis depends on the type, with daratumumab-CyBorD being the current standard of care for newly diagnosed AL amyloidosis, while tafamidis or acoramidis are first-line treatments for ATTR cardiac amyloidosis. 1, 2

Types of Amyloidosis and Diagnosis

Accurate typing of amyloidosis is crucial as treatment strategies differ significantly:

• AL (Light Chain) Amyloidosis: Most common, caused by plasma cell dyscrasia producing abnormal light chains
• ATTR Amyloidosis: Caused by misfolded transthyretin protein (either wild-type or hereditary)

Diagnosis requires:

• Tissue biopsy showing amyloid deposits (Congo red staining with apple-green birefringence)
• For AL: Complete monoclonal protein screen (serum free light chains, serum and urine immunofixation)
• For ATTR: Bone scintigraphy and TTR gene sequencing to differentiate hereditary from wild-type

Treatment Options for AL Amyloidosis

1. Autologous Stem Cell Transplantation (ASCT)

• Eligibility: Only ~20-25% of patients qualify due to strict criteria 1
• Approach: High-dose melphalan followed by stem cell transplantation
• Outcomes: 70% achieve very good partial response or better with median survival >15 years in complete responders 1
• Induction: 2-4 cycles of bortezomib-based therapy recommended before ASCT for patients with >10% bone marrow plasma cells 1

2. Non-Transplant Therapies

• First-line therapy: Daratumumab (anti-CD38 monoclonal antibody) plus CyBorD (cyclophosphamide, bortezomib, dexamethasone) 1, 2
  • Produces very good partial responses or better in 78.5% of patients vs. 49.2% with CyBorD alone
  • FDA-approved specifically for AL amyloidosis
• Alternative regimens:
  • CyBorD alone
  • Bortezomib-melphalan-dexamethasone
  • For advanced cardiac involvement: Single-agent daratumumab with minimal dexamethasone 1

Treatment Options for ATTR Amyloidosis

1. TTR Stabilizers

• Tafamidis (VYNDAQEL 80mg or VYNDAMAX 61mg daily): FDA-approved for ATTR cardiomyopathy to reduce cardiovascular mortality and hospitalizations 2, 3
• Acoramidis (Attruby): Novel TTR stabilizer that reduced all-cause mortality by up to 42% and cardiovascular hospitalizations by ~50% 2

2. RNA-Targeting Therapies

• Patisiran: FDA-approved for treatment of polyneuropathy in hereditary ATTR amyloidosis 4

3. Advanced Therapies

• Heart transplantation: For selected patients with advanced heart failure without significant extracardiac manifestations 2
• Combined heart and liver transplantation: May be considered for selected patients with hereditary ATTR 2

Response Assessment

Treatment response is measured by:

1. Hematologic response (for AL amyloidosis):

   • Complete response (CR): Absence of amyloidogenic light chains
   • Very good partial response (VGPR): Difference between involved and uninvolved free light chains <40 mg/L
   • Partial response (PR): ≥50% decrease in difference between involved and uninvolved free light chains 1

2. Organ response:

   • Cardiac: Decrease in NT-proBNP by >30% and <300 ng/L
   • Renal: ≥30% decrease in proteinuria or drop below 0.5g/24h
   • Hepatic: 50% decrease in abnormal alkaline phosphatase or decrease in liver size by ≥2cm 1

Supportive Care

• Cardiac symptoms: Careful diuretic management, avoid calcium channel blockers and digoxin
• GI symptoms: Dietary modifications, antiemetics, prokinetics, or antidiarrheals 2
• Neuropathic pain: Pregabalin, gabapentin, duloxetine (use tricyclics cautiously due to orthostatic hypotension risk) 2
• Orthostatic hypotension: Midodrine, droxidopa, pyridostigmine 2
• Anticoagulation: Recommended for all patients with cardiac amyloidosis and atrial fibrillation regardless of CHA₂DS₂-VASc score 2

Key Considerations

• Early diagnosis before irreversible organ damage is crucial for treatment success 1, 5
• Multidisciplinary care involving hematology, cardiology, nephrology, and neurology is essential
• Regular monitoring for disease progression and treatment response is vital
• Approximately 25% of AL amyloidosis patients die within 6 months of diagnosis, highlighting the importance of early intervention 5