What is the treatment approach for amyloidosis, particularly for patients with systemic involvement?

Treatment Approach for Systemic Amyloidosis

The treatment of amyloidosis must be tailored to the specific amyloid type, with targeted therapy directed at eliminating the precursor protein source being the most effective approach to improve survival and quality of life. 1

Amyloid Typing: Critical First Step

Accurate diagnosis of the amyloid type is essential before initiating treatment:

• Tissue diagnosis: Identification of amyloid deposits through Congo red staining showing characteristic apple-green birefringence under polarized light 1
• Typing methods:
  • Immunohistochemistry (current standard but has limitations)
  • Mass spectrometry (emerging gold standard for challenging cases)
  • Genetic testing for hereditary forms 1

Treatment by Amyloid Type

1. AL (Light Chain) Amyloidosis

AL amyloidosis is the most common type in Western countries and requires targeting the underlying plasma cell clone:

First-line therapy:

• Daratumumab-CyBorD (daratumumab, cyclophosphamide, bortezomib, and dexamethasone) is the preferred first-line regimen and the only FDA-approved therapy for AL amyloidosis 1, 2
• CyBorD (cyclophosphamide, bortezomib, and dexamethasone) alone if daratumumab is unavailable 1

For transplant-eligible patients:

• High-dose melphalan followed by autologous stem cell transplantation (ASCT) in carefully selected patients 1
  • Selection criteria: Limited organ involvement, good performance status, absence of advanced cardiac disease
  • Complete hematologic response occurs in approximately 40% of patients 1

For transplant-ineligible patients:

• Oral melphalan and dexamethasone is well-tolerated with 67% hematologic response rate and 33% complete remission 1
• Bortezomib-based regimens are effective, particularly in patients with cardiac involvement 1

Relapsed/refractory disease:

• Lenalidomide and dexamethasone 1
• Single-agent bortezomib 1
• Venetoclax for patients with t(11;14) translocation (investigational) 2
• CART therapy targeting BCMA (investigational) 2

2. ATTR (Transthyretin) Amyloidosis

For ATTR Cardiomyopathy (wild-type or hereditary):

• Tafamidis (VYNDAQEL/VYNDAMAX) is FDA-approved to reduce cardiovascular mortality and cardiovascular-related hospitalization 3
  • Dosage: Either tafamidis meglumine 80 mg (VYNDAQEL) or tafamidis 61 mg (VYNDAMAX) once daily

For ATTR Polyneuropathy:

• TTR silencers (patisiran, vutrisiran) or TTR stabilizers (diflunisal) 1
  • Note: Diflunisal should be avoided in patients with significant kidney impairment (eGFR <45 mL/min/1.73 m²) 1

3. IgM-Associated Amyloidosis

• Requires a dedicated approach due to distinctive clinical characteristics 1
• Treatment aims at rapid elimination of amyloidogenic light chains
• Monitor free light chains and cardiac biomarkers
• Bortezomib-based therapy in carefully selected patients 1
• ASCT may be considered in selected patients 1

Organ-Specific Supportive Care

Cardiac Involvement:

• Careful diuretic management
• Avoid calcium channel blockers and digoxin (may bind to amyloid fibrils)
• Heart transplantation may be considered in highly selected cases 1

Renal Involvement:

• Dietary sodium restriction
• Loop diuretics (sometimes combined with thiazides like metolazone)
• Avoid NSAIDs and intravenous contrast media 1
• Monitor for nephrotic syndrome

Gastrointestinal Involvement:

• Dietary modifications (small evening meals, longer interval between meals and bedtime)
• Medications for symptom management:
  • Antiemetics (ondansetron, promethazine)
  • Prokinetics (metoclopramide, prucalopride)
  • Anti-diarrheals (loperamide, diphenoxylate/atropine) 1

Neuropathy:

• For IgM-related neuropathy:
  • Plasmapheresis for aggressive/progressing cases (not as permanent therapy)
  • Rituximab-based regimens
  • Symptomatic treatment with gabapentin, pregabalin, or duloxetine 1

Response Assessment

• Hematologic response: Critical determinant of survival in AL amyloidosis 4

  • Monitor serum free light chains
  • Aim for very good partial response (VGPR) or better after 4-6 cycles 2
  • Early response (within first 3 cycles) correlates with better outcomes 4

• Organ response: Typically lags behind hematologic response

  • Cardiac: NT-proBNP, troponin levels, echocardiographic parameters
  • Renal: Proteinuria, eGFR
  • Neurologic: Clinical assessment scales

Common Pitfalls to Avoid

1. Misdiagnosis of amyloid type: Can lead to inappropriate treatment 5

   • Always confirm amyloid type before initiating therapy
   • Don't rely solely on clinical presentation for typing

2. Delayed diagnosis: Nonspecific symptoms often lead to delays 2

   • Maintain high index of suspicion in patients with:
     • Unexplained heart failure with preserved ejection fraction
     • Nephrotic syndrome
     • Peripheral neuropathy with autonomic features

3. Overlooking cardiac toxicity of plasma cell-directed therapies:

   • Monitor for cardiac decompensation, arrhythmias, and thromboembolism 1
   • Corticosteroids can cause fluid retention
   • Proteasome inhibitors may affect cardiac function

4. Inadequate supportive care:

   • Multidisciplinary approach involving hematology, cardiology, nephrology, and neurology is essential
   • Palliative care should be integrated early

The treatment landscape for amyloidosis continues to evolve rapidly with novel agents showing promise, particularly for AL amyloidosis. Clinical trial participation should be considered when available for patients with relapsed/refractory disease 1.