What is the initial treatment approach for patients with amyloidosis, particularly those with light-chain amyloidosis?

Initial Treatment Approach for Amyloidosis

For newly diagnosed AL amyloidosis, daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is now the standard of care first-line therapy, achieving unprecedented hematologic response rates of 78.5% (very good partial response or better) compared to 49.2% with CyBorD alone. 1, 2, 3, 4

Diagnostic Confirmation Before Treatment

Before initiating any therapy, accurate diagnosis and typing is mandatory:

• Perform comprehensive 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
• Do not rely on standard protein electrophoresis (SPEP/UPEP) alone due to inadequate sensitivity—nearly 50% of AL amyloidosis cases lack a monoclonal spike on SPEP 1
• Obtain tissue biopsy (abdominal fat pad aspiration or affected organ) with Congo red staining showing apple-green birefringence under polarized light 3, 4
• Confirm amyloid type using mass spectrometry (LC-MS/MS), which is the gold standard with 88% sensitivity and 96% specificity—this is critical because AL and ATTR amyloidosis require completely different treatments 1, 2, 3
• Perform bone marrow biopsy to demonstrate clonal proliferation of lambda or kappa-producing plasma cells 2

Treatment Algorithm Based on Transplant Eligibility

For Transplant-Ineligible Patients (Majority of Cases)

Daratumumab-CyBorD is the preferred first-line regimen for patients who are not candidates for autologous stem cell transplantation (ASCT): 1, 2, 5

• Daratumumab (anti-CD38 monoclonal antibody) is the only FDA-approved agent specifically for AL amyloidosis 1
• This regimen is particularly important for patients with advanced cardiac involvement (NT-proBNP >8,500 pg/mL), who may receive single-agent daratumumab with minimal dexamethasone to minimize cardiotoxicity 1
• Alternative option: CyBorD alone (cyclophosphamide, bortezomib, dexamethasone) if daratumumab is unavailable or contraindicated 1, 2
• Another alternative: Bortezomib-melphalan-dexamethasone, particularly for patients with t(11;14) translocation who may have lower response rates to cyclophosphamide-based regimens 1, 6

For Transplant-Eligible Patients (Approximately 25% of Cases)

Daratumumab-CyBorD may now be considered as first-line therapy even for ASCT-eligible patients, potentially supplanting the traditional approach: 2, 5

• Traditional standard: High-dose melphalan (140-200 mg/m²) followed by autologous stem cell transplantation for selected patients 1, 4
• Eligibility criteria for ASCT: Age <60-65 years, adequate cardiac function (NT-proBNP <8,500 pg/mL), good performance status, ≤2 organs involved, and absence of severe cardiac involvement 1, 7
• For patients aged 60-65 years with serum creatinine ≥2 mg/dL, reduce melphalan dose to 100 mg/m² and proceed with extreme caution 7
• Only ~25% of newly diagnosed AL patients are eligible for SCT due to advanced cardiac and organ involvement 5

Treatment Goals and Monitoring

The primary goal is to eradicate the pathological plasma cell clone and remove amyloidogenic light chains from circulation: 2, 5

Hematologic Response Assessment (3-6 months after treatment initiation):

• Complete response (CR): Negative serum and urine immunofixation with normal FLC ratio 1, 5
• Very good partial response (VGPR): dFLC <40 mg/L 1
• Partial response (PR): dFLC decrease ≥50% 1
• Target depth of response is at least VGPR, with CR being optimal 4

Organ Response Assessment (6-12 months after hematologic response):

• Cardiac response: NT-proBNP decrease >30% and <300 ng/L (if baseline NT-proBNP >650 ng/L) 1, 5
• Renal response: ≥30% decrease in proteinuria or drop below 0.5 g/24 hours without ≥25% decrease in eGFR 1
• Hepatic response: 50% decrease in alkaline phosphatase or ≥2 cm decrease in liver size 1

Critical Cardiotoxicity Considerations

Close cardiac monitoring is essential during treatment, as AL amyloidosis patients are at higher risk for treatment-related toxicity than multiple myeloma patients: 2, 5

• Daratumumab: Cardiac failure in 12% (grade 3-4 in 6%), arrhythmias in 8%, atrial fibrillation in 6% 2, 5
• Bortezomib: Grade 3 heart failure in 6.4%, >10% LVEF decrease in 23%, pulmonary hypertension 2, 5
• Dexamethasone: Peripheral edema, pulmonary edema, fluid overload requiring careful monitoring 2, 5
• Immunomodulatory agents (lenalidomide, pomalidomide, thalidomide): Cardiac and renal concerns, use with extreme caution 1, 2, 5
• No absolute contraindications exist based on ejection fraction or cardiac status—treatment should not be withheld 2

Relapsed or Refractory Disease

For patients whose disease relapses or is refractory to initial therapy: 1, 5

• Daratumumab is generally preferred (if not used first-line) due to lower cardiac and renal toxicity 1, 5
• Immunomodulatory-based regimens: lenalidomide, pomalidomide, thalidomide 1, 5
• Ixazomib (oral proteasome inhibitor) 1
• Venetoclax for patients with t(11;14) translocation 1, 8, 4
• Consider enrollment in clinical trials whenever possible 5

Essential Multidisciplinary Collaboration

Effective management requires close collaboration between hematology, cardiology, and nephrology: 2

• Hematologist directs anti-plasma cell therapies and coordinates overall care 2
• Cardiologist manages cardiac involvement, which is the main driver of disease prognosis and mortality 2, 4
• Nephrologist manages renal dysfunction and interprets serum free light chain concentrations in kidney impairment 2

Common Pitfalls to Avoid

• Delayed diagnosis due to nonspecific symptoms—maintain high index of suspicion for AL amyloidosis in patients with unexplained heart failure with preserved ejection fraction, nephrotic syndrome, or peripheral neuropathy 2, 3, 4
• Failure to differentiate AL from ATTR amyloidosis—management differs completely, and misdiagnosis leads to inappropriate treatment 2, 5
• Using SPEP/UPEP alone for screening—this misses nearly 50% of cases 1
• Avoiding treatment due to cardiac involvement—there are no absolute contraindications based on cardiac status 2
• Inadequate cardiac monitoring during chemotherapy—patients require close surveillance for cardiac decompensation 1, 2, 5