First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies

Abstract

Several clinical studies have compared single with tandem (also called double) autologous stem cell transplantation (ASCT) as first-line treatment in patients with symptomatic multiple myeloma (MM), one of the leading indications for ASCT worldwide. The present Cochrane Review compares tandem autologous stem cell transplantation (TASCT) with single autologous stem cell transplantation (SASCT) as first-line treatment in patients with symptomatic MM with respect to overall survival (OS), event-free survival (EFS), quality of life (QoL) and treatment- or transplantation-related mortality. We systematically identified controlled trials published between January 1995 and May 2011 in two bibliographic databases (MEDLINE and CENTRAL) and in clinical trial registries. One researcher screened references for controlled trials to determine eligibility for the systematic review (SR) according to pre-specified inclusion and exclusion criteria, reflecting characteristics of disease and the interventions. We required a minimal set of details to be reported for observational studies for the studies to be included. We critically evaluated eligible trials with respect to quality of design and actual performance. One researcher extracted individual trial results, which were checked by another researcher. We recapitulated the results of the individual trials in a standardised way for the SR in order to allow a systematic assessment of potential sources of bias. Overall, we identified 14 controlled studies. One registered randomised controlled trial (RCT) is still recruiting patients at the time of this review and no clinical results have been published. Two registered RCTs have remained unpublished despite their termination. Publications on one RCT had been retracted. We excluded five observational studies since neither patients nor treatment regimens were sufficiently characterised to allow an assessment of potential confounding by indication. We conducted a SR of study designs, definition of endpoints, treatment regimens and baseline characteristics of patients in the five included RCTs (two full-text publications, three conference presentations) enrolling1506 patients in total. Because we identified substantial clinical and methodological heterogeneity, we refrained from conducting a formal meta-analysis.While we included only previously untreated, symptomatic patients with MM the treatment regimens differed notably with respect to acute toxicity, between trials and also between study arms. Compared to state of the art treatment standards, the treatment regimens applied in all trials have to be considered as below standard from a contemporary perspective in at least one component.Three trials were likely to have the potential of being highly biased while two RCTs had a moderate potential for bias. The observed treatment effects in the set of included trials may have been influenced by a steep decrease in compliance with the second ASCT and the concomitant selection of patients. In addition, OS data were confounded by the treatment subsequent to first-line therapy.OS was statistically significantly improved in one trial only. While EFS was prolonged in four of the five trials, the median prolongation ranged between three to 12 months, with an uncertain direction of bias in the individual trials. QoL was not reported in any study. Results concerning treatment- or transplantation-related mortality could not be adequately assessed due to substantial differences in definitions between trials and low reporting quality. We did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question single versus tandem ASCT in view of inherent biases. In addition, none of the trials integrated the so-called "novel agents" which are now considered standard treatment for MM. To improve the quality of future studies, sample size calculations should consider the potentially steep decrease in compliance with the second ASCT. Reporting of results of treatment- or transplantation-related mortality should clearly specify the type and number of events (the numerator) in a well-defined population (the denominator).