A 52-year-old man with newly diagnosed multiple myeloma presents to the oncology clinic. He has a serum creatinine of 2.1 mg/dL (baseline 0.9 mg/dL) and haemoglobin of 8.2 g/dL. His physician initiates induction chemotherapy with melphalan, prednisone, and bortezomib. After the first cycle, the patient develops severe mucositis, diarrhoea, and bone marrow suppression. Laboratory tests reveal WBC 1.8 × 10⁹/L (baseline 7.2 × 10⁹/L) and platelets 45 × 10⁹/L (baseline 220 × 10⁹/L). Which of the following best explains the mechanism of melphalan's toxicity in this patient?

Explanation

## Mechanism of Melphalan (Alkylating Agent) **Key Point:** Melphalan is a nitrogen mustard alkylating agent that forms covalent cross-links between DNA strands, preventing DNA replication and transcription. ### Mechanism of Action Melphalan undergoes activation to form a reactive intermediate that: 1. Binds covalently to guanine residues on opposite DNA strands 2. Creates interstrand and intrastrand cross-links 3. Prevents DNA unwinding and synthesis 4. Triggers apoptosis in cells attempting to replicate damaged DNA ### Why This Patient Developed Toxicity Alkylating agents are **non-cell-cycle-phase-specific** but preferentially affect rapidly dividing cells because: - Bone marrow stem cells and epithelial cells (GI tract, oral mucosa) divide rapidly - These normal tissues accumulate DNA damage and undergo apoptosis - Results in myelosuppression, mucositis, and GI toxicity **High-Yield:** The dose-limiting toxicity of melphalan is **myelosuppression** (WBC and platelet nadirs at 7–14 days post-dose). ### Alkylating Agents Comparison | Agent | Chemical Class | Mechanism | Clinical Use | DLT | |-------|---|---|---|---| | Melphalan | Nitrogen mustard | DNA cross-linking | Multiple myeloma, lymphoma | Myelosuppression | | Cyclophosphamide | Nitrogen mustard | DNA cross-linking | Lymphoma, breast cancer, vasculitis | Myelosuppression, hemorrhagic cystitis | | Nitrosoureas (BCNU, CCNU) | Nitrosourea | DNA cross-linking + carbamoylation | CNS tumours, melanoma | Myelosuppression (delayed) | | Dacarbazine | Triazene | Methylation of DNA | Melanoma, lymphoma | Myelosuppression, hepatotoxicity | **Clinical Pearl:** Melphalan is particularly useful in multiple myeloma because myeloma cells are relatively alkylating-agent-sensitive, and the drug can be given at high doses with stem cell rescue in transplant-eligible patients. **Warning:** ~~Melphalan causes immediate nausea and vomiting~~ — while GI side effects occur, the most clinically significant early toxicity is myelosuppression with infection and bleeding risk. [cite:KD Tripathi 8e Ch 65]