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

Initial Treatment Approach for Primary (AL) Amyloidosis

Daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line therapy for patients with primary (AL) amyloidosis. 1, 2

Diagnosis Confirmation Before Treatment

Before initiating treatment, proper diagnosis and classification are essential:

1. Tissue diagnosis and typing:

   • Abdominal fat aspiration is preferred initial biopsy site (sensitivity: 84% for AL-CM) 1
   • Congo red staining showing apple-green birefringence under polarized microscopy 1
   • Immunohistochemistry with antibodies against amyloid A, κ- and λ-light chains 1
   • Mass spectrometry is the gold standard for typing amyloidosis 1

2. Cardiac assessment:

   • Echocardiography for ventricular wall thickening, diastolic dysfunction 1
   • Cardiac biomarkers: BNP/NT-proBNP, Troponin 1
   • Nuclear imaging with Technetium Tc 99m dicarboxypropane diphosphonate 1

Treatment Algorithm

First-line Treatment Options:

1. Preferred regimen: Daratumumab-CyBorD 1, 3, 2

   • Highly effective with superior hematologic response rates
   • Lower toxicity profile compared to other regimens
   • Targets CD38 on plasma cells while having minimal organ toxicity

2. Alternative if daratumumab unavailable: CyBorD (cyclophosphamide, bortezomib, dexamethasone) 1, 3

   • Effective but with lower response rates than daratumumab-containing regimens
   • Consider for patients who cannot tolerate daratumumab

3. Special considerations:

   • Autologous stem cell transplantation for eligible patients who don't achieve adequate response to Dara-CyBorD 2
   • Patients should be referred to specialized centers whenever possible 2

Monitoring Treatment Response

Monthly monitoring should include:

• Complete blood count
• Basic biochemistry
• NT-proBNP, troponin
• Serum-free light chain quantification 1

Goal of treatment:

• Achieve very good partial response or better hematologic response 1
• Monitor for cardiac toxicities which are common with many treatments 1

Every 6 months:

• Echocardiography with strain measurements
• Holter ECG 1

Treatment for Relapsed/Refractory Disease

For relapsed disease, consider:

1. Depth and duration of initial response
2. Use of agents from a different class than previously used
3. Patient fitness/frailty and end-organ damage 3

Immunomodulatory drugs are the cornerstone of rescue therapy, while daratumumab combinations are often used if not previously administered 2.

Common Pitfalls and Caveats

1. Delayed diagnosis: AL amyloidosis is often diagnosed late due to nonspecific symptoms like asthenia and dyspnea 4. Early referral to specialized centers is crucial.

2. Cardiac management challenges:

   • Standard heart failure medications may be ineffective or dangerous
   • Avoid β-blockers (cardiac output is heart rate dependent)
   • Avoid digoxin and calcium channel blockers (bind to amyloid fibrils)
   • Use ACE inhibitors/ARBs with caution
   • Use diuretics judiciously 1

3. Treatment toxicity: Patients with AL amyloidosis often have impaired organ function and may not tolerate standard dosing of chemotherapy agents. Dose modifications may be necessary based on organ involvement.

4. Importance of multidisciplinary care: Management requires collaboration between hematologists, cardiologists, nephrologists, neurologists, and palliative care specialists 1.

Emerging Approaches

Monoclonal antibodies targeting both plasma cells and amyloid deposits are under investigation:

• Daratumumab targets plasma cells
• Agents like CAEL-101 target and potentially eliminate amyloid from organs 5

This dual-targeting approach may revolutionize treatment outcomes in AL amyloidosis 5.