What is the front line treatment approach for a patient with systemic amyloidosis?

Front-Line Treatment for Systemic Amyloidosis

For AL (light chain) amyloidosis, daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line treatment for most patients, while for ATTR (transthyretin) amyloidosis, tafamidis is the FDA-approved disease-modifying therapy. 1, 2

Critical First Step: Accurate Amyloid Typing

Before initiating any therapy, you must definitively determine the amyloid type, as AL and ATTR amyloidosis require completely different treatments. 1, 2

• For AL amyloidosis diagnosis: Perform 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. 1
• Mass spectrometry (LC-MS/MS) of tissue biopsy is the gold standard for amyloid typing with 88% sensitivity and 96% specificity. 1, 2
• Bone marrow biopsy is necessary to demonstrate clonal proliferation of lambda or kappa-producing plasma cells in AL amyloidosis. 1

AL Amyloidosis Treatment Algorithm

For Transplant-Ineligible Patients (Majority of Cases)

Daratumumab-CyBorD is the standard of care, achieving very good partial responses or better in 78.5% of patients versus 49.2% with CyBorD alone. 1, 2, 3

• Daratumumab is the only FDA-approved agent specifically for AL amyloidosis treatment. 1, 3
• This regimen is preferred for ASCT-ineligible patients regardless of cardiac involvement. 1
• For patients with severe cardiac involvement (stage 3b, NYHA ≥3): Use single-agent daratumumab with minimal dexamethasone to minimize cardiotoxicity. 1, 2, 3

Alternative regimen: CyBorD (cyclophosphamide, bortezomib, dexamethasone) alone can be used if daratumumab is unavailable. 1

For Transplant-Eligible Patients (Highly Selected)

High-dose melphalan (200 mg/m²) followed by autologous stem cell transplantation (ASCT) should be considered for eligible patients. 4, 1, 2

Eligibility criteria include: 4, 1, 3

• Mayo stage 1-2

• Age <65 years

• Performance status 0-2

• eGFR >50 ml/min/1.74 m²

• NYHA class <3

• Ejection fraction >40-45%

• Systolic blood pressure >90 mmHg (standing)

• DLCO >50%

• Bone marrow plasma cells >10%

• Only approximately 25% of newly diagnosed AL amyloidosis patients meet these strict criteria. 3

• Consider 2-4 cycles of bortezomib-based induction therapy prior to ASCT if bone marrow plasma cell infiltration is >10%. 4, 3

• Treatment-related mortality with HDM/SCT is approximately 3% in experienced centers. 3

• Median survival exceeds 15 years in complete responders. 2

Risk-Stratified Approach for Intermediate Risk Patients

For patients with specific features, tailor the regimen: 4

• Patients with t(11;14): Melphalan-dexamethasone (MDex) or bendamustine-melphalan-dexamethasone (BMDex)
• Patients with neuropathy: MDex
• Patients with 1q21 amplification or renal failure: VCD (bortezomib, cyclophosphamide, dexamethasone)

ATTR Amyloidosis Treatment

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, 5

• Dosing: Either tafamidis meglumine 80 mg orally once daily OR tafamidis 61 mg orally once daily. 5
• VYNDAMAX and VYNDAQEL are not substitutable on a per mg basis. 5
• This is a transthyretin stabilizer that prevents amyloid fibril formation. 5, 6

Critical Monitoring and Response Assessment

Hematologic Response Criteria (AL Amyloidosis)

Monitor serum free light chains and define response as: 1, 3

• Complete response (CR): Absence of amyloidogenic light chains and normalized free light chain ratio
• Very good partial response (VGPR): dFLC <40 mg/L
• Partial response (PR): dFLC decrease ≥50%
• No response (NR): dFLC decrease <50%

Organ Response Criteria

Cardiac response: Decrease in NT-proBNP by >30% AND <300 ng/L (if baseline NT-proBNP >650 ng/L). 1, 3

• Hematologic response typically occurs within 3-6 months of treatment initiation. 3
• Organ-specific response generally occurs 6-12 months after hematologic response. 3
• Serial NT-proBNP, troponin, echocardiography, and serum free light chains are used to assess treatment response. 2

Important Cardiotoxicity Considerations

Daratumumab cardiac toxicities include: 1, 3

• 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%)

Bortezomib toxicities include: 1, 3

• Grade 3 heart failure in 6.4%

• 10% decrease in LVEF in 23%

• Pulmonary hypertension

Close monitoring for cardiac decompensation during therapy is essential, particularly in patients with pre-existing cardiac involvement. 1, 3

Essential Supportive Care Measures

While treating the underlying plasma cell disorder, implement these supportive measures: 4

• Salt restriction and daily weight monitoring
• Diuretics (but avoid reducing intravascular volume excessively)
• ACE inhibitors at lowest dose with caution due to hypotension risk
• Elastic compression stockings for orthostatic hypotension
• Midodrine for refractory hypotension
• Amiodarone as antiarrhythmic (avoid digoxin due to binding to amyloid fibrils)
• Nutritional support
• Octreotide for diarrhea
• Gabapentin or pregabalin for neuropathic pain

Common Pitfalls to Avoid

• Never initiate treatment without definitive amyloid typing - AL and ATTR require completely different therapies. 1, 2
• Avoid digoxin - it binds to amyloid fibrils causing toxicity even at normal serum levels. 2
• Avoid calcium channel blockers - they bind to amyloid fibrils causing exaggerated hypotension and negative inotropy. 2
• Avoid NSAIDs and IV contrast in patients with renal involvement to prevent further renal dysfunction. 4
• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma. 1, 3
• There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis. 1

Multidisciplinary Care Requirements

Effective management requires close collaboration between: 1, 3

• Hematologist (directs anti-plasma cell therapies and coordinates overall care)
• Cardiologist (manages cardiac involvement, the main driver of mortality)
• Nephrologist (manages kidney involvement and proteinuria)

Cardiac involvement is the main driver of disease prognosis and mortality in systemic amyloidosis. 1, 3