What is the management of amyloidosis?

Management of Amyloidosis

The management of amyloidosis requires a type-specific approach, with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) as the preferred first-line therapy for AL amyloidosis, and tafamidis for ATTR cardiac amyloidosis. 1, 2

Classification and Diagnosis

Before initiating treatment, proper classification of amyloidosis is essential:

• AL amyloidosis: Requires tissue biopsy showing amyloid deposits and evidence of plasma cell dyscrasia
• ATTR amyloidosis: Requires bone scintigraphy and TTR gene sequencing to differentiate hereditary from wild-type 2

Diagnostic confirmation requires:

• Tissue biopsy with Congo red staining showing 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 2

Treatment by Amyloidosis Type

AL Amyloidosis Management

1. First-line therapy:

   • Dara-CyBorD (daratumumab plus cyclophosphamide, bortezomib, and dexamethasone) is the preferred regimen 1, 2
   • CyBorD alone is an alternative if daratumumab is unavailable 1

2. Stem cell transplantation:

   • High-dose melphalan followed by autologous stem cell transplantation (HDM/SCT) for eligible patients (approximately 25% of newly diagnosed cases) 2
   • Consider induction with bortezomib-based regimen if bone marrow plasma cell percentage >10% or if there's a delay in transplantation 2

3. For refractory disease:

   • IMiD-based strategies (lenalidomide + melphalan + dexamethasone) with escalating dosage 1

4. For advanced cardiac involvement (NT-proBNP >8,500 pg/mL):

   • Single-agent daratumumab with minimal dexamethasone 2

ATTR Amyloidosis Management

1. First-line therapy:

   • Tafamidis (VYNDAQEL 80 mg or VYNDAMAX 61 mg daily) - reduces cardiovascular mortality and hospitalizations 2, 3
   • Acoramidis (Attruby) - a novel TTR stabilizer that reduced all-cause mortality by up to 42% and cardiovascular hospitalizations by ~50% 2

2. For hereditary ATTR with polyneuropathy:

   • Patisiran - indicated for polyneuropathy of hereditary ATTR 4

3. Transplantation options:

   • Liver transplantation for hereditary ATTR (5-year survival 50-80%) 2
   • Combined heart and liver transplantation for selected patients with hereditary ATTR 2

Cardiac Amyloidosis-Specific Management

1. Heart failure management:

   • Diuretics (use cautiously to prevent volume contraction)
   • Avoid medications that can cause toxicity (digoxin, calcium channel blockers) 2

2. Anticoagulation:

   • Warfarin (target INR 2-3) or direct oral anticoagulants for atrial fibrillation 2

3. Heart transplantation:

   • Consider for select patients with advanced/stage D heart failure
   • Contraindicated with significant extracardiac manifestations
   • For AL amyloidosis, generally not recommended due to high risk of recurrence (5-year survival only 20-30%) unless followed by bone marrow transplantation (improves 5-year survival to 35-55%) 2

Gastrointestinal Amyloidosis Management

1. Dietary modifications:

   • Small evening meal
   • Longer interval between evening meal and lying down
   • Calorie-dense supplements for malnutrition
   • FODMAP diet for cramping, diarrhea, bloating 1

2. Medications:

   • Antiemetics (ondansetron, promethazine)
   • Prokinetics (metoclopramide, prucalopride)
   • Opioid receptor agonists (loperamide, diphenoxylate/atropine)
   • Antibiotics for small intestine bacterial overgrowth
   • Bile acid sequestrants
   • Octreotide
   • Laxatives (polyethylene glycol, magnesium products, senna)
   • Linaclotide, prucalopride 1

Monitoring and Response Assessment

1. Monthly monitoring:

   • Complete blood count
   • Basic biochemistry
   • NT-proBNP, troponin
   • Serum-free light chain quantification 2

2. Every 6 months:

   • Echocardiography with strain measurements
   • Holter ECG 2

3. Response assessment:

   • Assess cardiac response 6-12 months after hematologic response
   • Positive response: Decrease in NT-proBNP by >30% and <300 ng/L (if baseline >650 ng/L) 2

Multidisciplinary Approach

A collaborative approach involving hematologists, cardiologists, nephrologists, neurologists, and palliative care specialists is essential for optimal management 2. Early integration of palliative care is recommended for symptom management and quality of life improvement 2.

Pitfalls and Caveats

1. Delayed diagnosis: Early recognition and treatment initiation before irreversible organ damage is critical 1
2. Mistyping: Ensure proper typing of amyloidosis as treatment differs significantly between AL and ATTR 1
3. Medication toxicity: Monitor for bortezomib toxicity (neuropathy) and adjust dose accordingly 2
4. Overdiuresis: Can worsen hemodynamics in cardiac amyloidosis 2
5. Overlooking extracardiac manifestations: These can affect transplantation eligibility 1

The hallmark of successful management is early recognition and prompt initiation of appropriate type-specific therapy before irreversible organ damage occurs 1, 5.