What is the recommended chemotherapy regimen for light-chain amyloidosis?

Chemotherapy Regimens for Light-Chain Amyloidosis

Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the standard first-line therapy for light-chain (AL) amyloidosis based on the landmark ANDROMEDA trial, which demonstrated unprecedented deep hematologic responses compared to CyBorD alone. 1, 2

Treatment Algorithm Based on Transplant Eligibility

Transplant-Eligible Patients (~25% of newly diagnosed cases)

1. First-line option:

   • Induction with bortezomib-based regimen (particularly if BMPC >10% or foreseeable delay >1 month in ASCT) 1
   • Followed by high-dose melphalan with autologous stem cell transplantation (HDM/ASCT)
   • Consider Dara-CyBorD as induction therapy before HDM/ASCT 1

2. Stem cell collection:

   • Use G-CSF (10-16 μg/kg/day) without cyclophosphamide
   • Split dose recommended to minimize toxicity 1
   • Target: at least 5 × 10^6 CD34+ cells/kg
   • Plerixafor can be used as adjuvant if mobilization fails 1

Transplant-Ineligible Patients (majority of cases)

1. Standard first-line therapy:

   • Daratumumab-CyBorD (FDA-approved) 1, 2, 3
   • Demonstrated 78.5% very good partial response (VGPR) or better vs. 49.2% with CyBorD alone 1

2. Alternative regimens (if daratumumab unavailable/contraindicated):

   • CyBorD (cyclophosphamide, bortezomib, dexamethasone) 1
   • BMDex (bortezomib, melphalan, dexamethasone) 1, 4
   • MDex (melphalan, dexamethasone) - when bortezomib is contraindicated 1

3. Special considerations:

   • For advanced cardiac involvement (NT-proBNP >8,500 pg/mL): Consider single-agent daratumumab with minimal dexamethasone 1
   • For patients with pre-existing neuropathy: Avoid bortezomib or use attenuated dosing 1

Dosing and Administration Considerations

1. Bortezomib administration:

   • Use subcutaneous administration
   • Weekly dosing preferred (twice-weekly not recommended)
   • Start at lower dose (0.7-1.0 mg/m²) for patients with cardiac involvement and uptitrate as tolerated 1

2. Dexamethasone dosing:

   • Consider lower dose (20 mg on days 1-4) for elderly patients or those with severe renal/cardiac involvement 1

3. Melphalan-dexamethasone regimen:

   • Melphalan 0.22 mg/kg plus dexamethasone 40 mg/day on days 1-4 in a 28-day cycle 1

Response Assessment and Monitoring

1. Hematologic response (typically within 3-6 months):

   • Complete response (CR): Absence of amyloidogenic light chains by SIFE and UIFE, with normalized FLC ratio
   • Very good partial response (VGPR): dFLC <40 mg/L
   • Partial response (PR): dFLC decrease ≥50% 1

2. Organ response (typically 6-12 months after hematologic response):

   • Cardiac: Decrease in NT-proBNP by >30% and <300 ng/L (if baseline >650 ng/L)
   • Renal: ≥30% decrease in proteinuria or drop below 0.5 g/24h
   • Hepatic: 50% decrease in abnormal alkaline phosphatase or decrease in liver size by ≥2 cm 1

3. Monitoring schedule:

   • Monthly: CBC, basic biochemistry, NT-proBNP, troponin, serum-free light chain quantification
   • Every 6 months: Echocardiography with strain measurements, Holter ECG 2

Common Pitfalls and Caveats

1. Do not expect immediate organ response - organ response typically follows hematologic response by several months 2

2. Continue treatment despite initial worsening of cardiac biomarkers, which can occur transiently 2

3. Bortezomib toxicity management:

   • Monitor for neuropathy and adjust dose accordingly
   • Watch for cardiotoxicity, especially in patients with cardiac involvement
   • Regular monitoring of cardiac biomarkers is essential 1

4. Recognize that diagnosis and treatment are time-sensitive - delays can lead to irreversible organ damage 1

5. Daratumumab-CyBorD is superior to CyBorD alone and should be preferred when available 1, 3

The treatment landscape for AL amyloidosis continues to evolve, with promising investigational therapies including venetoclax for patients with t(11;14) translocation and BCMA-targeted CAR-T cell therapy for relapsed/refractory disease 3.