What are the treatment options for amyloidosis?

Treatment of Amyloidosis

Treatment of amyloidosis is fundamentally determined by accurate typing of the amyloid protein, as AL and ATTR amyloidosis require completely different therapeutic approaches that directly impact mortality and quality of life. 1, 2

Mandatory Diagnostic Confirmation Before Treatment

Before initiating any therapy, you must:

• Obtain tissue biopsy with Congo red staining showing characteristic apple-green birefringence under polarized light 1, 3
• Perform mass spectrometry (LC-MS/MS) as the gold standard for amyloid typing with 88% sensitivity and 96% specificity 1, 2
• Complete monoclonal protein screening with all three tests simultaneously: serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) 1, 2
• Never rely on standard protein electrophoresis (SPEP/UPEP) alone due to inadequate sensitivity, as it misses monoclonal spikes in nearly 50% of cases 1, 2

Treatment Algorithm for AL Amyloidosis

First-Line Therapy Selection

For both ASCT-eligible and ASCT-ineligible patients, Daratumumab-CyBorD (daratumumab plus cyclophosphamide, bortezomib, and dexamethasone) is the preferred first-line treatment, achieving very good partial response or better in 78.5% of patients 2. This represents the most recent high-quality evidence prioritizing mortality outcomes.

ASCT-Eligible Patients (Age <60, ≤2 organs involved, adequate cardiac function)

• Primary option: Daratumumab-CyBorD as first-line therapy 2
• Alternative: High-dose melphalan (140-200 mg/m²) followed by autologous stem cell transplantation for highly selected patients, which achieved 40% complete hematologic remission and improved 5-year survival in 394 patients 1, 2
• Critical caveat: For patients aged 60-65 years with serum creatinine ≥2 mg/dL, reduce melphalan dose to 100 mg/m² and proceed with extreme caution 2

ASCT-Ineligible Patients

• Preferred: Daratumumab-CyBorD as first-line option 2
• Alternative: CyBorD alone (cyclophosphamide, bortezomib, dexamethasone) if daratumumab is contraindicated 2
• Alternative: Melphalan 0.22 mg/kg plus high-dose dexamethasone 40 mg orally days 1-4 every 28 days, achieving 67% hematologic response and 33% complete remission 1, 2

Relapsed/Refractory Disease

For patients whose disease relapses or is refractory to initial therapy:

• Daratumumab is generally preferred (if not used first-line) given potential cardiac and kidney toxicity of alternatives 1
• Immunomodulatory-based regimens: lenalidomide, pomalidomide, or thalidomide 1
• Ixazomib (oral proteasome inhibitor) for relapsed disease 1
• Venetoclax for patients with t(11;14) cytogenetic alteration, providing high hematologic response in relapsed/refractory disease 1
• Enroll in clinical trials whenever possible 1

Critical Medication Toxicities to Monitor

Daratumumab (anti-CD38 antibody):

• Cardiac failure (12%), arrhythmias (8%), atrial fibrillation (6%) 2
• FDA-approved specifically for AL amyloidosis 2

Proteasome inhibitors (bortezomib, carfilzomib, ixazomib):

• Grade 3 heart failure, decreased LVEF, pulmonary hypertension 2

Immunomodulatory agents (lenalidomide, pomalidomide, thalidomide):

• Cardiac and renal toxicity concerns 2

Corticosteroids (dexamethasone, prednisone):

• Monitor for peripheral edema, pulmonary edema, fluid overload 2

Treatment Algorithm for ATTR Amyloidosis

Wild-Type or Hereditary ATTR Cardiomyopathy

Tafamidis (VYNDAQEL/VYNDAMAX) is FDA-approved and indicated for treatment of ATTR cardiomyopathy in adults with NYHA Class I-III symptoms to reduce cardiovascular mortality and cardiovascular-related hospitalization 4, 2. This is the only disease-modifying therapy with proven mortality benefit in ATTR cardiac amyloidosis.

Hereditary ATTR with Polyneuropathy

Patisiran (ONPATTRO) is FDA-approved for treatment of polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults 5.

Monitoring Treatment Response

Hematologic Response (AL Amyloidosis)

Response is assessed at 3-6 months using difference between involved and uninvolved free light chains (dFLC) 1:

• Complete response (CR): Negative SIFE and UIFE, plus normal FLC ratio 1
• Very good partial response (VGPR): dFLC <40 mg/L 1
• Partial response (PR): dFLC decrease ≥50% 1
• No response (NR): dFLC decrease <50% 1

Organ Response

Organ-specific response is generally observed 6-12 months after hematologic response 1:

• Cardiac: NT-proBNP decrease >30% and <300 ng/L (if baseline >650 ng/L) 1
• Renal: ≥30% decrease in proteinuria or drop below 0.5 g/24 h without ≥25% decrease in eGFR 1
• Hepatic: 50% decrease in alkaline phosphatase or ≥2 cm decrease in liver size 1

Multidisciplinary Management Requirements

Effective treatment requires mandatory collaboration between:

• Hematologist as primary specialist directing anti-plasma cell therapies 2
• Cardiologist for managing cardiac involvement, the main driver of mortality 2
• Nephrologist for kidney involvement and proteinuria management 2
• Gastroenterologist for GI tract involvement and malabsorption 2
• Neurologist when peripheral or autonomic nervous system involvement is present 2
• Transplant specialists for evaluation of stem cell or organ transplantation 2

Critical Pitfalls to Avoid

Common diagnostic errors:

• Delayed diagnosis due to nonspecific symptoms (asthenia, dyspnea) 3, 6
• Assuming facial droop is stroke rather than soft tissue infiltration from amyloidosis 7
• Missing cardiac involvement, which drives prognosis and mortality 2

Treatment errors:

• Using standard heart failure medications (calcium channel blockers, β-blockers, ACE inhibitors) in amyloid heart disease—these are inefficient or dangerous 3
• Failing to achieve deep hematologic responses, which correlate with improved organ function and survival 2
• Not monitoring closely for cardiac decompensation during therapy 2

There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis 2, but close monitoring is essential.

Prognosis and Treatment Goals

The primary goal is to eradicate pathological plasma cells and remove amyloidogenic light chains from circulation 2. Cardiac involvement is the main driver of disease prognosis and mortality 2, with 25% of AL amyloidosis patients dying within 6 months of diagnosis and 25% of ATTR patients dying within 24 months 6. Deep hematologic responses directly correlate with improved organ function and survival 2.