A 52-year-old man with newly diagnosed multiple myeloma is being counselled about alkylating agent therapy. His oncologist mentions that melphalan and cyclophosphamide are both being considered. Which feature best distinguishes melphalan from cyclophosphamide?

Explanation

## Melphalan vs. Cyclophosphamide: Key Discriminator ### Clinical Distinction **Key Point:** Hemorrhagic cystitis is a dose-limiting and clinically significant toxicity unique to cyclophosphamide among alkylating agents. It is caused by the metabolite acrolein, which is excreted in the urine and damages the bladder urothelium. ### Comparative Toxicity Profile | Toxicity | Melphalan | Cyclophosphamide | | --- | --- | --- | | **Hemorrhagic cystitis** | Absent | Dose-limiting ✓ | | **Acrolein formation** | No | Yes (in urine) | | **Bladder damage** | None | Significant | | **SIADH** | No | Yes (rare) | | **Immunosuppression** | Moderate | Moderate–severe | | **Hepatic activation** | No (direct alkylator) | Yes (prodrug) | | **Oral bioavailability** | Variable, poor | Excellent | | **Route of administration** | IV preferred | IV or oral | ### Mechanism of Cyclophosphamide-Induced Cystitis Cyclophosphamide is a prodrug activated in the liver to phosphoramide mustard (the active alkylator). Acrolein is a toxic metabolite excreted unchanged in the urine. Acrolein binds to bladder mucosa, causing hemorrhage, fibrosis, and increased risk of urothelial carcinoma with prolonged exposure. **Mnemonic:** **CYCLO** = **CY**stitis (Cyclophosphamide causes cystitis due to acrolein). **Clinical Pearl:** Mesna (2-mercaptoethane sulfonate) is co-administered with cyclophosphamide to bind acrolein in the urine and prevent hemorrhagic cystitis. Melphalan does not require mesna. **High-Yield:** Hemorrhagic cystitis is the most clinically relevant distinguishing feature between these two alkylating agents and is a key point in NEET PG pharmacology.