The data were obtained by searching databases for published, unpublished, and ongoing trials. The databases included PubMed, Embase, the Cochrane Library and the Science Citation Index, and other relevant websites (eg, http://www.controlledtrials.com/, http://www.clinicaltrials.gov/ct). Data from conference proceedings of the American Society of Hematology (2000–2014), the American Society of Clinical Oncology (2000–2014), and European Hematology Association was also collected. The key words utilized were “multiple myeloma OR plasmacytoma”, “ASCT OR autologous stem-cell transplantation OR BMT OR bone marrow transplantation”, “maintenance OR consolidation”, and “bortezomib OR velcade”. Additional potentially relevant studies in the reference lists of the trials were identified and other published systemic reviews and practice guidelines were examined as well.
We reviewed all the titles and abstracts obtained from the results of our search strategy to select potential articles. After all full-text papers were reviewed independently by two review authors, the eligibility of these articles was further verified to ensure that they met the inclusion criteria: 1) the studies were RCTs; 2) the participants were patients with newly diagnosed MM of any stage and who had been treated with induction chemotherapies followed by ASCT; 3) intervention was bortezomib-containing regimens; 4) the corresponding control was a placebo or other non-bortezomib-containing regimens; 5) the outcomes reported should include PFS/EFS (event-free survival), OS as well as response rate of CR/nCR, VGPR (very good partial response), and PR (partial response). Multiple reports of the same trial were considered as one study. According to the Jadad scale that includes the reporting of the randomization method, blinding scores, and completeness of follow-up, the maximal score for an included study was 5 and studies were classified on the basis of quality as high (score: 3–5) vs low (score: 0–2).14
The aim of this meta-analysis is to evaluate the effect of bortezomib as post-ASCT therapy on the survival of newly diagnosed MM patients. The key end points for this review are OS (calculated from the date of randomization until death from any cause), PFS (measured from the date of randomization to the time of disease progression, relapse, or death), and efficacy index (ie, CR/nCR).
Relevant studies were investigated through full-text review, and only those that met all the inclusion criteria were included in the final analysis. A predesigned data extraction form involving baseline characteristics, outcomes, and numbers of events was utilized in the data extraction process which was conducted by Xiaoping Liu and Xiangyu Meng independently. Any discrepancies between the two investigators at the screening or data extraction stage were resolved by discussion.
We used meta-package in R 3.1.1 software for all meta-analyses. As to the end points of PFS and OS, the hazard ratio (HR) and 95% confidence interval (95% CI) were applied to evaluate the effect of bortezomib. With respect to comparison of response rates between patients receiving bortezomib-based and non-bortezomib-based consolidation or maintenance therapy, the Cochran–Mantel–Haenszel test was conducted and odds ratios (OR) and 95% CI were calculated; P-values were determined using the chi-square test. In order to show individual study and each cumulative step ratio, traditional meta-analysis and cumulative meta-analysis were performed simultaneously. The I2statistic was used to quantify heterogeneity among the studies. Any value of I2 less than 25%, 25%–50%, and greater than 50% was defined as low, moderate, and high heterogeneity, respectively. When high heterogeneity was detected, a random-effects model and sensitivity analysis were used for explanation and solution. The publication biases were examined by Egger’s test with which the “trim and fill” method15,16 was used to add several hypothetical studies to the primary meta-analysis to make it unbiased upon detection of bias.