High‐dose idarubicin, cyclophosphamide and melphalan as conditioning for autologous stem cell transplantation increases treatment‐related mortality in patients with multiple myeloma: results of a randomised study

Abstract

SummaryWe conducted a randomised trial comparing an intensified versus a standard conditioning regimen for high-dose chemotherapy followed by autologous stem-cell transplantation in patients with multiple myeloma. In this study, 56 patients were randomly assigned for high-dose therapy with melphalan 200 mg/m 2 or with idarubicin 42 mg/m 2 , melphalan 200 mg/m 2 and cyclophosphamide 120 mg/kg. The primary objective was response rate. Acute toxicity, mainly because of infections, was higher in the intensified treatment arm with a treatment-related mortality of 20% versus 0% in the standard arm. This lead to the early discontinuation of the study. Response rates did not differ significantly between both treatment arms {intensified versus standard: complete response + near complete remission 50% [95% confidence interval (CI) 26-74%] vs. 33% (95% CI 17-55%), partial remission 35% (95% CI 16-61%) vs. 50% (95% CI 30-70%)}. After a followup of 5 years, the median time-to-progression and overall survival were not significantly different between both patient groups. Analysis restricted to patients surviving the first 100 d after transplant showed a better outcome for patients with ‡2 bad prognostic risk factors in the intensified treatment arm, however all treatment-related deaths occurred within this group of patients. In conclusion, intensified conditioning for high-dose therapy had intolerably high toxicity without improving outcome in patients with multiple myeloma.

BU and CY as conditioning regimen for autologous transplant in patients with multiple myeloma

“…24 Dose intensification of conditioning regimen can be potentially dangerous: a study in 56 MM patients added idarubicin and CY to melphalan 200 mg/m 2 , but this was followed by a treatment-related mortality of 20% (vs 0% in the standard arm with melphalan 200 mg/m 2 ), which lead to early discontinuation of the study. 25 Another investigational strategy has been to increase the dose of single-agent melphalan to 4200 mg/m 2 with the concurrent use of the cytoprotective agent amifostine, 26,27 but data are too preliminary to justify the use of this approach in routine clinical practice.…”

Stem cell transplantation for multiple myeloma: current and future status

“…26 Phase I and II trials have combined highdose melphalan with other drugs, including busulfan or idarubicin, with no apparent significant improvements in outcomes. 27,28 More recently, bortezomib was combined with high-dose melphalan followed by ASCT in a phase II study. 29 The regimen was well tolerated and appeared to improve response rates when compared with historical controls (CR rate: 35% versus 11% with high-dose melphalan only; P ¼ 0.001).…”

Novel Preparative Regimens in Hematopoietic Stem Cell Transplantation

“…Likewise, Anagnostopoulos et al [48] showed that a more intense regimen of thiotepa, busulfan and cyclophosphamide was not better than high dose melphalan. Fenk et al [49] showed that the addition of idarubicin and cyclophosphamide to melphalan 200 mg/m 2 increased TRM without improved survival.…”