High-Dose Topotecan, Melphalan and Cyclophosphamide (TMC) with Autologous Stem Cell Support for Multiple Myeloma

Introduction High dose chemotherapy and autologous stem cell transplantation (auto SCT) was associated with prolonged event-free (EFS) and overall survival (OS) in selected patients with multiple myeloma (MM) in at least two randomized controlled trials. High-dose melphalan at 200 mg/m2 is considered the standard regimen, but the complete remission (CR) rate at best is 30–40% and the EFS approximately 2 years. Novel preparative regimens are being evaluated to improve the efficacy without increasing the toxicity. We evaluated the safety and efficacy of a new regimen, Topotecan, Melphalan and Cyclophosphamide (TMC) in patients undergoing auto SCT for MM.

Methods The primary objectives were to determine the safety and to evaluate if TMC could increase the CR rate in MM patients undergoing auto SCT. Patients received cyclophosphamide at the dose of 1 g/m2 intravenously over 2 h on days -6, -5, -4; melphalan at the dose of 70 mg/m2 intravenously over 30 min on days -3 and -2 and topotecan at a dose of 3.5 mg/m2 over 30 min for 5 total doses on days -6 to -2.

Results 44 patients (26 males, 18 females) with primary refractory disease or in first remission received the TMC regimen followed by auto SCT between August 2002 and March 2004. The median age of patients at auto SCT was 55 years (range 40–67) and the median interval between the diagnosis and auto SCT was 6.3 month (range 2.2– 42 months). Twelve patients (27%) had chromosomal abnormalities on conventional cytogenetic studies. Median follow-up in surviving patients was 47.8 months. Median time to neutrophil engraftment (ANC > 500/dl) and platelet engraftment (>20,000/dl) were 10 (range 7–11 days) and 9 days (range 6–9 days), respectively. Thirty seven patients (84%) were transplanted for consolidation of first remission and 7 for primary refractory disease (16%). Most common adverse events were: grade 1& 2 nausea (59%), grade 1 & 2 diarrhea (41%) and dysphagia (34%). Non-hematologic grade 3 & 4 toxicities were seen in 9 patients (20%) and included infectious complications (2 patients), congestive heart failure exacerbation (2 patients), electrolyte abnormalities including hypocalcemia and hypokalemia (1 patient each), GI complications like dysphagia and vomiting (1 patient each) and cardiac arrhythmia (1 patient). Febrile neutropenia occurred in 8 patients (18%). Thirty-three patients (75%) had a complete or partial response, 9 patients (21 %) had a minimal response or stable disease, while 2 patients had progressed within 3 months of auto SCT. At the time of this analysis, 31 patients are alive, 13 of whom in remission. Four-year EFS was 23.5%, and 4-year OS was 63%. Patients with chromosomal abnormalities had a shorter time to progression (13.9 vs. 19.7 months, p=0.18) that was not statistically significant. These results were similar to those reported by our group in 89 patients who received high-dose mephalan (200 mg/m2) only: complete + partial response rate of 66%; 4-year Kaplan-Meier estimates of EFS and OS 20% and 57%, respectively. (Anagnostoupoulos et al. Cancer 2004).

Conclusion TMC is a safe preparative regimen for auto SCT for MM. There is no major advantage over high-dose melphalan alone in terms of CR rate or EFS in patients in first remission or primary refractory disease.