What is the initial treatment approach for patients with amyloidosis, specifically primary amyloidosis (AL amyloidosis)?

Initial Treatment Approach for Primary (AL) Amyloidosis

The initial treatment of choice for patients with primary (AL) amyloidosis is daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD), which is currently the preferred first-line therapy. 1, 2

Disease Overview and Diagnosis

AL amyloidosis results from a clonal plasma cell disorder that produces misfolded light chain proteins that deposit in tissues and organs, causing progressive dysfunction. Before initiating treatment:

• Confirm diagnosis with tissue biopsy showing Congo red staining with characteristic green birefringence
• Determine amyloid type using mass spectrometry (gold standard) or immunohistochemistry
• Assess extent of organ involvement, particularly cardiac and renal systems
• Evaluate patient's eligibility for various treatment options

Treatment Algorithm

Step 1: Risk Stratification and Treatment Selection

1. Evaluate eligibility for stem cell transplantation (SCT):

   • Consider cardiac biomarkers, age, performance status, and organ function
   • Cardiac involvement is a major determinant of transplant eligibility

2. Treatment options based on eligibility:

   • For all patients: Dara-CyBorD is the preferred first-line therapy 1, 2, 3
   • For SCT-eligible patients: High-dose melphalan followed by autologous SCT may be considered, though this approach may be supplanted by Dara-CyBorD 1

Step 2: Treatment Administration and Monitoring

• Monitor for treatment response using serum free light chain assays
• Assess for hematologic response (goal: very good partial response or better)
• Monitor for cardiac toxicities, which are common with many treatments 1

Evidence-Based Rationale

The 2023 American College of Cardiology consensus pathway strongly recommends Dara-CyBorD as the preferred treatment for AL amyloidosis 1. This is supported by the European Society of Haematology and International Society of Amyloidosis guidelines, which also recommend Dara-VCD (same as Dara-CyBorD) for most untreated patients 4.

Previously, high-dose melphalan with autologous stem cell transplantation (HDM/SCT) was the standard of care for eligible patients. However, recent evidence suggests that Dara-CyBorD may be supplanting this approach as first-line therapy even for transplant-eligible patients 1, 3.

Important Considerations and Potential Pitfalls

• Cardiac toxicity: Many treatments for AL amyloidosis can cause cardiac complications. Monitor closely, especially with proteasome inhibitors and immunomodulatory agents 1

• Treatment-related mortality: HDM/SCT carries approximately 3% treatment-related mortality even in experienced centers 1

• Patient selection: Careful patient selection is crucial, particularly for more intensive therapies like HDM/SCT

• Multidisciplinary approach: Collaboration between hematologists, cardiologists, nephrologists, and other specialists is essential for optimal management 2

• Response assessment: Regular monitoring of hematologic and organ responses is critical to guide treatment decisions

Alternative Approaches

For patients who cannot tolerate Dara-CyBorD or in settings where daratumumab is unavailable:

• CyBorD (cyclophosphamide, bortezomib, dexamethasone) alone 1, 4
• VMDex (bortezomib, melphalan, dexamethasone) 4
• Oral cyclic melphalan and dexamethasone for frail patients 5

For relapsed/refractory disease, treatment selection depends on prior therapy exposure, depth and duration of initial response, and patient fitness 4, 6, 3.