A 72-year-old man with newly diagnosed AL (light-chain) amyloidosis affecting the heart and kidneys is being considered for chemotherapy. Which of the following is the preferred first-line chemotherapy regimen for systemic AL amyloidosis?

Explanation

## First-Line Chemotherapy for AL Amyloidosis **Key Point:** Bortezomib-based regimens (VCD: bortezomib, cyclophosphamide, dexamethasone) are now the preferred first-line treatment for systemic AL amyloidosis, replacing traditional melphalan-based regimens due to superior hematologic response rates and organ response. ### Evolution of AL Amyloidosis Treatment **High-Yield:** The shift from melphalan-prednisone (MP) to proteasome inhibitor-based regimens (VCD) represents a major paradigm change in AL amyloidosis management, driven by improved outcomes in clinical trials. ### Mechanism and Efficacy of VCD 1. **Bortezomib (proteasome inhibitor)** - Targets plasma cells producing misfolded light chains - Induces apoptosis of clonal plasma cells - Achieves hematologic response in 60–70% of patients 2. **Cyclophosphamide** - Synergistic anti-plasma cell activity - Reduces burden of amyloidogenic clones 3. **Dexamethasone** - Immunomodulatory effect - Enhances plasma cell death ### Comparison of Chemotherapy Regimens | Regimen | Hematologic Response | Organ Response | Toxicity | Current Role | |---------|---------------------|----------------|----------|---------------| | **VCD (Bortezomib-based)** | 60–70% | 40–50% | Manageable; neuropathy | **First-line** | | MP (Melphalan-prednisone) | 30–40% | 15–25% | Myelosuppression | Elderly, frail patients | | Lenalidomide + dexamethasone | 50–60% | 30–40% | Thrombosis risk | Second-line alternative | | Thalidomide monotherapy | 20–30% | <15% | Neuropathy, thrombosis | Rarely used | **Clinical Pearl:** Bortezomib-based regimens achieve organ response (improvement in cardiac or renal function) in 40–50% of patients, compared to <25% with melphalan-prednisone — a critical outcome in AL amyloidosis where organ dysfunction drives mortality. ### Why VCD Is Preferred 1. Rapid hematologic response (weeks to months vs. months to years) 2. Higher rates of complete hematologic response 3. Organ response and stabilization of amyloid-related dysfunction 4. Better outcomes in younger, fit patients 5. Manageable toxicity profile with appropriate monitoring **Warning:** Bortezomib can cause peripheral neuropathy; baseline and serial neurologic assessment is mandatory. Lenalidomide carries thrombosis risk and is reserved for second-line use or bortezomib-intolerant patients.