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H.M. Blommestein et al.
analysis and by Kuhr et al.,11 is, however, more appropri- ate, as this model allows for the between study-hetero- geneity in the additional studies.
One might argue that while our NMA provides addi- tional evidence in different circumstances, we had to make assumptions in order to conduct the analysis, and that this introduces a level of uncertainty. Firstly, we grouped MPT and MPT-T studies together since we could not make an unambiguous distinction between them. For example, thalidomide was prescribed until disease pro- gression in the HOVON49 and GIMEMA trial but pre- scribed “continuously” for up to a maximum of 12 months in the TMSG trial. In the NMSG trial, it was even recom- mended to continue thalidomide maintenance until sec- ond relapse. However, most investigators discontinued thalidomide at first relapse. Prescription of thalidomide was also not consistent within a trial.38 Sacchi et al.38 described that, although planned, maintenance was only provided to 18% of the patients and in a limited number of centers. Their results, however, showed that there was no difference in PFS between maintenance and no-mainte- nance approaches.42 Therefore, we believe that it is appro- priate to combine these trials, as performed previously,11,43 and the results of our sensitivity analysis confirm this assumption (see Online Supplementary Appendix 7).
Secondly, the validity of the outcomes of NMA depends on the comparability between studies. Our analysis focused on treatments for NTE NDMM patients studied in phase III RCTs. Although it is possible to include non-randomized evidence in NMA,45 and this could have provided additional information regarding effectiveness in clinical practice46-48 or treatments not analyzed in a phase III RCT (e.g. borte- zomib-cyclophosphamide-dexamethasone, VCD49), we believe that limiting our analysis to the relative effective- ness of RCT evidence reduces the risk of bias and system- atic errors.44 Further research to improve methodologies for conducting, evaluating and interpreting non-randomized evidence is recommended.44 We focused on NTE NDMM treatment to increase homogeneity between the patient populations in the study. We observed between-study het- erogeneity comparable to the proportions previously
reported by Kuhr et al.11 We allow for this heterogeneity by using a random effects instead of a fixed effect model. However, the consequence of this is larger 95%CIs.
A potential limitation of our search strategy is that we only included English language publications. To the best of our knowledge, this does not, however, lead to the exclusion of relevant studies or treatments. Furthermore, our NMA was limited to the intermediate outcome PFS and did not include other outcomes of interest such as OS, adverse events, quality of life, cost, and cost-effectiveness. While OS may even be the most important subject of investigation for patients and health care decision makers, we believe a comparison of OS for first-line therapies with the currently available data is prone to bias due to cross- over, heterogenous and limited follow up (e.g. especially for DaraVMP: median OS was not reached at 16.5 months follow up), and different subsequent treatment lines.50,51 In the context of increasing health care expenditures, cost- effectiveness is also another relevant and important out- come, and this remains a subject for further research. Several treatment options showed comparable effective- ness outcomes, but costs could very well differ due to drug prices, treatment duration, and route of administra- tion. Our study facilitates cost-effectiveness research on first-line NTE treatments.
The treatment armamentarium is rapidly increasing and evolving for NTE NDMM patients, and NMAs will, there- fore, become increasingly important. We illustrate the additional value and evidence that can be provided. NMAs support evidence-based decision making and may help optimize treatment and outcomes of NTE NDMM patients in clinical practice.
Funding
This work was supported by a grant from ZonMw, the Netherlands Organisation for Health Research and Development, project number 152001020, project title “Treatment Sequencing in Multiple Myeloma: modeling the dis- ease and evaluating cost-efficacy vs. cost-effectiveness”. The funding source had no role in writing the manuscript or decision to submit for publication.
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