What are the treatment options for amyloidosis?

Treatment Options for Amyloidosis

For amyloidosis treatment, daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line therapy for light-chain (AL) amyloidosis, while tafamidis (VYNDAQEL 80 mg or VYNDAMAX 61 mg daily) is the recommended first-line therapy for ATTR cardiac amyloidosis. 1

Classification-Based Treatment Approach

Light-Chain (AL) Amyloidosis Treatment

AL amyloidosis treatment targets the underlying plasma cell disorder to eradicate pathological plasma cells and remove affected light chains from circulation:

1. First-line therapy:

   • Daratumumab-CyBorD (preferred): Combination of daratumumab with cyclophosphamide, bortezomib, and dexamethasone 2, 1
   • CyBorD: Alternative if daratumumab is unavailable 2

2. Autologous Stem Cell Transplantation (ASCT):

   • Consider for eligible patients (approximately 25% of newly diagnosed cases) 1
   • Patient selection criteria:
     • Age typically under 65 years
     • Limited organ damage
     • Good cardiac function (EF >40%)
     • Low treatment-related mortality risk 2

3. Alternative regimens:

   • Bortezomib-based combinations: High response rates with 81.4% overall hematologic response and 41.9% complete response 3
   • Ixazomib-based therapy: Oral proteasome inhibitor option with 63% overall hematologic response 4

ATTR Amyloidosis Treatment

For transthyretin amyloidosis (ATTR), treatment focuses on stabilizing TTR protein:

1. First-line therapy:

   • Tafamidis: 80 mg VYNDAQEL or 61 mg VYNDAMAX daily 1
   • Reduces cardiovascular mortality and hospitalization

2. Newer options:

   • Acoramidis (Attruby): Novel TTR stabilizer that reduced all-cause mortality by up to 42% 1

3. Transplantation options:

   • Liver transplantation: Potentially curative for hereditary ATTR 1
   • Combined heart and liver transplantation: For selected hereditary ATTR patients 1
   • Heart transplantation: For advanced heart failure without significant extracardiac manifestations 1

Treatment Selection Algorithm

1. Confirm amyloidosis type:

   • AL amyloidosis: Tissue biopsy + evidence of plasma cell dyscrasia
   • ATTR amyloidosis: Bone scintigraphy + TTR gene sequencing

2. For AL amyloidosis:

   • Assess transplant eligibility:
     • If eligible → Consider high-dose melphalan + ASCT
     • If ineligible → Dara-CyBorD (preferred) or CyBorD

3. For ATTR amyloidosis:

   • Cardiac involvement:
     • Tafamidis (first-line)
     • Consider acoramidis as newer option

Monitoring Treatment Response

• Hematologic response (AL amyloidosis):

  • Assess within 3-6 months
  • Complete response: Absence of amyloidogenic light chains by immunofixation with normalized FLC ratio 1

• Organ response:

  • Assess 6-12 months after hematologic response
  • Cardiac response: Decrease in NT-proBNP by >30% and <300 ng/L (if baseline >650 ng/L) 1

Managing Treatment Toxicities

• Bortezomib:

  • Monitor for peripheral neuropathy (grade 2 in 20% of patients) 5
  • Cardiac toxicity: Grade 3 heart failure in 6.4%, LVEF reduction in 23% 2

• Daratumumab:

  • Cardiac failure in 12% (grade 3-4 in 6%)
  • Cardiac arrhythmia in 8% (grade 3-4 in 2%)
  • Atrial fibrillation in 6% (grade 3-4 in 2%) 2

• Immunomodulatory agents:

  • Lenalidomide: Paradoxical increase in cardiac biomarkers, kidney dysfunction 2
  • Thalidomide: Bradycardia 2

Important Considerations

• Multidisciplinary approach is essential: Involve hematologists, cardiologists, nephrologists, neurologists, and palliative care specialists 1

• Special populations:

  • Advanced cardiac involvement (NT-proBNP >8,500 pg/mL): Consider single-agent daratumumab with minimal dexamethasone 1
  • Pre-existing neuropathy: Avoid bortezomib or use attenuated dosing 1

• Medications to avoid with cardiac involvement:

  • Digoxin and calcium channel blockers (can bind to amyloid fibrils) 1

• Anticoagulation for atrial fibrillation:

  • Warfarin (target INR 2-3) or direct oral anticoagulants 1

• Diuretics: Use cautiously to prevent overdiuresis and volume contraction 1

The treatment landscape for amyloidosis continues to evolve, with newer agents like daratumumab-CyBorD showing superior outcomes compared to previous standards of care. Early diagnosis and prompt treatment initiation are crucial to prevent irreversible organ damage.