A phase i study of high-dose melphalan + topotecan + VP-16 phosphate (Mtv) Followed by autologous stem cell rescue in multiple myeloma

Abstract

We conducted a dose-escalation trial of topotecan (TPT) given in combination with melphalan & VP-16. In this HDC protocol in multiple myeloma the drugs were given as melphalan (150 mg/m2, total dose)→TPT (0 to 27 mg/m2, total dose)→VP-16 phosphate (2400 mg/m2, etoposide equivalent total dose). Thirty-five patients have been enrolled in this study. Ten patients were enrolled in the first dose level (melphalan and VP-16 phosphate only), while TPT was dose-escalated from 10 mg/m2 to 27 mg/m2 (total dose over 3 days) in dose levels 2–5. The MTD of high-dose topotecan is 20 mg/m2, with a DLT or grade 3/4 mucositis and enteritis. The 100 day non-relapse mortality is 5.7%. There have been two regimen-related deaths; one patient died of cardiotoxicity and the other of sepsis/ARDS after being intubated for severe mucositis. The median day to an ANC >500/μl is day +10, while the median day to a platelet count >50,000/μl is day +17.5. The overall response in 31 evaluable patients is 52% (10 CR + 6 PR) while another 42% demonstrated stable disease. The event free survival and overall survival at 6 months are 77% ± 8% and 96% ± 3.5%, respectively. The PK of TPT in this study have been found to be similar to those found in a recent phase I study of ifosfamide→TPT→ etoposide, TIME regimen. The results of confocal microscopy analyses of malignant plasma cells obtained from MTV patients demonstrate that the subcellular distribution of topo I and IIα may be critical in determining the sensitivity of these cells to inhibitors of these enzymes.