What are the treatment options for amyloidosis?

Treatment Options for Amyloidosis

Treatment of amyloidosis is fundamentally determined by the type of amyloid protein involved—AL (light chain) amyloidosis requires plasma cell-directed chemotherapy, while ATTR (transthyretin) amyloidosis requires TTR stabilizers or silencers. Accurate typing via mass spectrometry is mandatory before initiating any disease-specific therapy, as these conditions require completely different treatments despite similar clinical presentations 1, 2.

Critical First Step: Accurate Diagnosis and Typing

• Mass spectrometry (LC-MS/MS) of tissue biopsy is the gold standard for amyloid typing, with 88% sensitivity and 96% specificity 1, 3.
• Tissue diagnosis requires biopsy (abdominal fat pad, bone marrow, or affected organ) with Congo Red staining showing characteristic apple-green birefringence under polarized light 4, 1.
• For AL amyloidosis specifically, comprehensive monoclonal protein screening must include all three tests simultaneously: serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) 1.
• Standard protein electrophoresis (SPEP/UPEP) alone is inadequate due to lower sensitivity—it misses monoclonal spikes in nearly 50% of AL cases 4, 1.

Treatment Algorithm for AL (Light Chain) Amyloidosis

First-Line Therapy Selection

Daratumumab-CyBorD (daratumumab plus cyclophosphamide, bortezomib, and dexamethasone) is the preferred first-line treatment for most AL amyloidosis patients, achieving very good partial response or better in 78.5% of patients 1. This applies to both ASCT-eligible and ASCT-ineligible patients 1.

Alternative First-Line Options

• High-dose melphalan followed by autologous stem cell transplantation (ASCT) should be considered for highly selected patients who meet strict eligibility criteria 1:

  • Age <60 years (or 60-65 with extreme caution and reduced melphalan dose to 100 mg/m²) 1
  • ≤2 organs involved without severe cardiac involvement 1
  • Adequate cardiac function and good performance status 1
  • Serum creatinine <2 mg/dL (if 60-65 years old, reduce melphalan dose) 1

• CyBorD alone (cyclophosphamide, bortezomib, and dexamethasone) without daratumumab is an acceptable alternative 1.

• Melphalan 0.22 mg/kg plus high-dose dexamethasone 40 mg orally days 1-4 every 28 days achieves 67% hematologic response and 33% complete remission in ASCT-ineligible patients 4, 1.

Treatment Goal and Monitoring

• The primary goal is to eradicate the pathological plasma cell clone and remove amyloidogenic light chains from circulation 1.
• Deep hematologic responses correlate with improved organ function and survival 1.
• Cardiac involvement is the main driver of disease prognosis and mortality 1.

Important Medication Considerations

• Daratumumab (anti-CD38 antibody) has FDA approval for AL amyloidosis but carries cardiac toxicities: cardiac failure (12%), arrhythmias (8%), and atrial fibrillation (6%) 1.
• Proteasome inhibitors (bortezomib, carfilzomib, ixazomib) risk Grade 3 heart failure, decreased LVEF, and pulmonary hypertension 1.
• Immunomodulatory agents (lenalidomide, pomalidomide, thalidomide) can cause cardiac and renal concerns 1.
• Corticosteroids (dexamethasone, prednisone) require monitoring for peripheral edema, pulmonary edema, and fluid overload 1.

Critical Caveat for AL Amyloidosis

• There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis 1.
• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma alone 1.
• Close monitoring for cardiac decompensation during therapy is essential 1.

Treatment Algorithm for ATTR (Transthyretin) Amyloidosis

Disease-Modifying Therapy

Tafamidis is FDA-approved for treatment of ATTR cardiomyopathy in adults with NYHA Class I-III symptoms to reduce cardiovascular mortality and cardiovascular-related hospitalization 1. This is the only FDA-approved disease-modifying therapy for ATTR cardiac amyloidosis.

TTR Silencers

• Patisiran, inotersen, and vutrisiran are TTR silencers that have shown efficacy in ATTR amyloidosis, particularly for neuropathic manifestations 4, 2.
• These agents work by reducing production of the abnormal transthyretin protein 2.

Important Distinction

• ATTR amyloidosis (both wild-type and hereditary variant) requires completely different targeted therapies than AL amyloidosis 1, 2.
• Wild-type ATTR (age-related) is now recognized as the most common type of amyloidosis due to increased identification 5.
• Hereditary ATTR requires genetic testing to identify specific mutations, especially in African-Americans and patients with peripheral neuropathy 4.

Supportive and Symptom-Directed Management

Cardiac Management

• Judicious diuresis remains the cornerstone of heart failure therapy in cardiac amyloidosis 1.
• Standard heart failure medications (ACE inhibitors, ARBs, beta-blockers) must be used with extreme caution or avoided 1.
• Anticoagulation is reasonable in patients with cardiac amyloidosis and atrial fibrillation to reduce stroke risk, independent of CHA₂DS₂-VASc score 1.

Gastrointestinal Management

Dietary modifications should be the first step for GI symptoms, without waiting for definitive diagnosis 4:

• For reflux and nausea: small evening meal, longer interval between evening meal and lying down 4.
• For malnutrition: calorie-dense supplements and shakes 4.
• For cramping, diarrhea, bloating: low FODMAP diet 4.

Medications for specific GI symptoms 4:

• Nausea/early satiety: Ondansetron 4-8 mg every 4-8 hours, promethazine 12.5-25 mg every 4-6 hours, metoclopramide 10-20 mg every 6-8 hours, or prucalopride 2 mg daily 4.
• Diarrhea: Loperamide 2-4 mg 4 times daily, diphenoxylate/atropine 2.5-5 mg 4 times daily, rifaximin 550 mg 3 times daily for bacterial overgrowth, or octreotide 50-250 mcg 3 times daily subcutaneously 4.
• Constipation: Polyethylene glycol 17 g daily, magnesium-containing products, senna, or linaclotide 145 mg daily 4.

Important GI Caveat

• There is currently no strong evidence that disease-modifying therapies (TTR stabilizers or silencers) impact GI involvement or symptoms 4.

Renal Management

• Avoid NSAIDs and IV contrast to prevent further renal dysfunction 1.
• Supportive care includes blood pressure control and eventually dialysis if needed 1.
• Renal transplantation may be considered in selected patients 1.

Multidisciplinary Care Requirements

Effective management of amyloidosis requires close collaboration between specialists due to the multisystem nature of the disease 1:

• Hematologist: Primary specialist directing anti-plasma cell therapies and coordinating overall care for AL amyloidosis 1.
• Cardiologist: Essential for managing cardiac involvement, which is present in most cases and is the main driver of mortality 1.
• Nephrologist: Manages kidney involvement, proteinuria, and renal dysfunction 1.
• Gastroenterologist: Addresses GI tract involvement, malabsorption, and digestive complications 1.
• Neurologist: Required when peripheral or autonomic nervous system involvement is present 1.
• Transplant specialists: Needed for evaluation of stem cell transplantation in AL amyloidosis or organ transplantation in advanced cases 1.

Common Pitfalls to Avoid

• Delayed diagnosis due to nonspecific symptoms—early specialist referral is critical 1.
• Using standard protein electrophoresis alone—this misses nearly 50% of AL cases 4, 1.
• Overlooking cardiac involvement—heart involvement drives prognosis and must be assessed in all patients 1.
• Fragmented care without coordination between specialists—leads to suboptimal treatment 1.
• Failing to differentiate AL from ATTR amyloidosis—management differs significantly and wrong treatment is ineffective 1, 2.
• Assuming standard heart failure medications are safe—these must be used with extreme caution in cardiac amyloidosis 1.