What is the treatment for primary amyloidosis?

Treatment of Primary Amyloidosis (AL Amyloidosis)

Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line treatment for most patients with primary (AL) amyloidosis, achieving very good partial response or better in 78.5% of patients. 1, 2

Initial Diagnostic Requirements Before Treatment

Before initiating therapy, confirm the diagnosis and complete essential workup:

• Obtain histopathologic confirmation with Congo red staining showing apple-green birefringence under polarized light 1
• Type the amyloid protein using mass spectrometry (gold standard with 88% sensitivity and 96% specificity) to differentiate AL from ATTR amyloidosis, as treatments differ completely 2
• Perform comprehensive monoclonal protein screening with all three tests: serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) 2
• Obtain bone marrow biopsy to demonstrate clonal proliferation of lambda or kappa-producing plasma cells 2

Treatment Algorithm Based on Transplant Eligibility

For Transplant-Eligible Patients (approximately 25% of newly diagnosed cases):

• Consider high-dose melphalan followed by autologous stem cell transplantation (HDM/SCT) for patients meeting eligibility criteria 2, 3
• Eligibility criteria include: ejection fraction >40%, ability to tolerate fluid shifts and potential infections, limited organ involvement, age typically <60 years with ≤2 organs involved without severe cardiac involvement 2, 3
• Treatment-related mortality is approximately 3% in experienced centers 1, 3
• Administer 2-4 cycles of bortezomib-based induction therapy prior to SCT in patients with bone marrow plasma cell percentages >10% 3
• Alternatively, Daratumumab-CyBorD may be considered as first-line therapy even for transplant-eligible patients based on recent evidence 2

For Transplant-Ineligible Patients (approximately 75% of cases):

• Daratumumab-CyBorD is the preferred first-line regimen, with the ANDROMEDA trial demonstrating superiority over CyBorD alone (78.5% vs 49.2% achieving very good partial response or better) 2, 3
• Alternative option: CyBorD (cyclophosphamide, bortezomib, and dexamethasone) alone if daratumumab is unavailable or contraindicated 2

Treatment Goal and Mechanism

• The primary goal is to eradicate pathological plasma cells and remove amyloidogenic light chains from circulation 2
• Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor light chain is eliminated 4, 5

Critical Monitoring for Cardiac Toxicities

Close monitoring for cardiac decompensation during therapy is essential, as patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma 2:

• Daratumumab cardiac toxicities: 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%) 2, 3
• Bortezomib toxicities: grade 3 heart failure in 6.4%, >10% decrease in LVEF in 23% of patients 3
• Corticosteroids require monitoring for peripheral edema, pulmonary edema, and fluid overload 2

Response Assessment Timeline and Criteria

Hematologic Response (assessed at 3-6 months):

• Complete response (CR): absence of amyloidogenic light chains and normalized free light chain ratio 3
• Very good partial response (VGPR): dFLC <40 mg/L 3
• Partial response (PR): dFLC decrease ≥50% 3
• No response (NR): dFLC decrease <50% 3

Organ-Specific Response (assessed at 6-12 months after hematologic response):

• Cardiac response: decrease in NT-proBNP by >30% and <300 ng/L (if baseline NT-proBNP >650 ng/L) 3
• Organ function improvement typically follows hematologic response by 6-12 months 1, 3

Essential Multidisciplinary Collaboration

• Collaboration between hematologists, cardiologists, and nephrologists is crucial for effective treatment 2
• Cardiac involvement is the main driver of disease prognosis and mortality 2, 3
• There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis 2

Common Pitfalls to Avoid

• Do not confuse AL amyloidosis with ATTR (transthyretin) amyloidosis, as management differs significantly—ATTR requires tafamidis, not plasma cell-directed therapy 2, 3
• Do not use standard protein electrophoresis (SPEP/UPEP) alone due to lower sensitivity; always include serum free light chain assay 2
• Do not delay treatment in patients with advanced cardiac involvement, as early intervention is critical despite higher treatment-related risks 2
• Recognize that approximately 10-15% of multiple myeloma patients also have AL amyloidosis; evaluate for amyloidosis in myeloma patients presenting with restrictive cardiomyopathy, unexplained proteinuria, macroglossia, periorbital purpura, or peripheral neuropathy with autonomic features 2