What is the treatment approach for patients diagnosed with amyloidosis?

Treatment Approach for Amyloidosis

The treatment of amyloidosis must be tailored to the specific type of amyloidosis, with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) being the current standard of care for AL amyloidosis, while tafamidis is the first-line treatment for ATTR cardiac amyloidosis. 1

Diagnosis and Classification

Before initiating treatment, proper diagnosis and classification of amyloidosis is essential:

• Diagnosis requires demonstration of amyloid deposits in tissue biopsy (Congo red staining with apple-green birefringence)
• Classification of amyloidosis type is crucial as treatment differs significantly:
  • AL (light chain) amyloidosis: Requires evidence of plasma cell dyscrasia
  • ATTR (transthyretin) amyloidosis: Can be diagnosed non-invasively with bone scintigraphy after excluding AL amyloidosis

Treatment of AL Amyloidosis

First-line Treatment

• Daratumumab-CyBorD is the standard of care for newly diagnosed AL amyloidosis 1, 2
  • Produces very good partial responses or better in 78.5% of patients (vs. 49.2% with CyBorD alone)
  • Only FDA-approved regimen specifically for AL amyloidosis

Alternative First-line Options

• For patients who cannot receive daratumumab:
  • CyBorD alone
  • Bortezomib-melphalan-dexamethasone (BMD)

High-dose Melphalan with Stem Cell Transplantation

• Suitable for highly selected patients (only ~25% of newly diagnosed patients) 1, 3
• Offers possibility of long-lasting remission with median survival >15 years in complete responders
• Eligibility criteria typically exclude patients with:
  • Advanced cardiac involvement (EF <40%)
  • Significant extracardiac manifestations
  • Treatment-related mortality is ~3% in experienced centers

Special Considerations for Cardiac AL Amyloidosis

• Patients with advanced cardiac involvement (NT-proBNP >8,500 pg/mL) may receive single-agent daratumumab with minimal dexamethasone to reduce cardiotoxicity 1
• IgM-associated AL amyloidosis requires a dedicated approach due to its distinctive clinical characteristics 4
  • Treatment should aim at rapid elimination of amyloidogenic light chains
  • Monitor free light chains and cardiac biomarkers
  • Bortezomib-based therapy can be used in carefully selected patients
  • Autologous stem cell transplantation may be considered in selected patients

Treatment of ATTR Amyloidosis

First-line Treatment

• Tafamidis (VYNDAQEL 80 mg or VYNDAMAX 61 mg daily) for ATTR cardiac amyloidosis 1, 5
  • Reduces cardiovascular mortality and cardiovascular-related hospitalization
  • FDA-approved for both wild-type and hereditary ATTR cardiomyopathy

Novel Therapies

• Acoramidis (Attruby) is a novel TTR stabilizer that reduced all-cause mortality by up to 42% and cardiovascular hospitalizations by ~50% 1

Response Assessment and Monitoring

• Hematologic response is usually observed within 3-6 months of treatment initiation 1
• Organ response typically follows hematologic response by 6-12 months
• Monthly monitoring during initial treatment should include:
  • Complete blood count
  • Basic biochemistry
  • NT-proBNP and troponin
  • Serum-free light chain quantification (for AL amyloidosis)
• Echocardiography with strain measurements every 6 months

Supportive Care and Medication Considerations

• Diuretics should be used cautiously to avoid overdiuresis and volume contraction 1
• Avoid medications with potential toxicity in amyloidosis:
  • Digoxin
  • Calcium channel antagonists
• Anticoagulation with warfarin or direct thrombin inhibitors is indicated for patients with atrial fibrillation or history of embolic events

Advanced Therapies

• Heart transplantation may be considered for selected patients with advanced/stage D heart failure 1
• Combined heart and liver transplantation may be considered for selected patients with hereditary ATTR

Prognosis

• Without treatment, AL amyloidosis has poor prognosis with 25% of patients dying within 6 months of diagnosis 6
• 25% of patients with ATTR amyloidosis die within 24 months of diagnosis without treatment 6
• Achievement of a rapid hematologic response to therapy extends survival significantly 3
• Renal response after treatment is associated with improved survival and is an independent marker of treatment success 7

The key to successful management of amyloidosis is early diagnosis, accurate typing, and prompt initiation of appropriate therapy before significant end-organ damage occurs.