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Efficacy of MM treatments
of 70 years at diagnosis, the majority of newly diagnosed (ND) MM patients are not transplant eligible (NTE) for stem cell transplant (SCT). Current standards of care for NTE NDMM patients are bortezomib-melphalan-pred- nisone (VMP), lenalidomide-dexamethasone (Rd), and in the USA bortezomib-Rd (Vrd),3 supported by randomized phase III trials.4-6 Recently, better PFS was demonstrated for daratumumab-VMP (DaraVMP) compared to VMP.7
Although randomized clinical trials (RCTs) remain the gold standard to define standards of care, we predict that in the current treatment landscape the role of network meta-analysis (NMA) will become increasingly important. Firstly, today there is more than one standard of care, but a randomized study between two registered standards of care is highly unlikely to be performed because of the reluctance of pharmaceutical industries to support such studies.8 Therefore, head-to-head comparisons of VMP versus Rd or VRd versus VMP are not likely to be initiated.9 NMA can help to discriminate between efficacy of non- head-to-head compared regimens. Secondly, with the increase in the number of treatment modalities, the num- ber of smaller randomized Phase II studies is expected to increase at the cost of Phase III RCTs. NMA provides more solid estimates of treatment effects by combining RCTs that provide direct and indirect evidence for effectiveness and allows competing treatments to be ranked.10 Thirdly, with the high number of studies currently enrolling patients, standard of care arms are expected to change within short time frames.8 This hampers the development of classical phase III trials, as at the end of the study it might appear that the standard arm of the study no longer reflects the reality in the clinic. Finally, the heterogeneous biological characteristics of MM and the clonal evolution of the disease will lead to studies with a smaller sample size that will not allow for randomization, increasing the need for indirect comparisons.
There are currently two systematic literature reviews (SLRs) and NMAs available for first-line NTE NDMM treatments.11,12 Due to the timing of their searches and selection criteria, these reviews did not, however, include all currently available treatments (e.g. VRd, VMPT-VT, DaraVMP) and RCT evidence (e.g. HOVON87 comparing MPT-T and MPR-R13). To support evidence-based decision making in clinical practice, we performed an SLR and an NMA synthesizing all direct and indirect evidence from phase III RCTs that is currently available and compared the outcome of all treatment options for NTE NDMM patients.
Methods
Systematic literature review
An SLR was conducted in the databases EMBASE®, MED- LINE®, MEDLINE®-in-Process and the Cochrane Central Register of Controlled Trials for the period January 1, 1999 to March 1, 2016 to identify relevant studies (Online Supplementary Appendix 1). Studies were included if they described a Phase III RCT among newly diagnosed adult patients with MM. Furthermore, one of the pre-specified treatments (Online Supplementary Appendix 2) had to be part of the regimens of the RCT. After removing duplicates, citations were first screened on the basis of title and abstract and then screened on the contents of their full text. Citations were excluded due to the following reasons: not in English, review, study phase, intervention, dis-
ease, study design, meta-analysis, patient population, economic outcomes, meta-analysis, and other. (For a detailed description of the exclusion categories see Online Supplementary Appendix 2). To incorporate the latest clinical developments, the publication of the pre-specified interim analysis of the phase III ALCYONE RCT comparing DaraVMP to VMP7 was added as additional record.
Data extraction
Data were extracted on trial details (i.e. publication source, trial ID, trial number, research, and comparator treatment(s), number of patients, median age, and primary outcome, and fol- low up) and efficacy outcomes. Efficacy outcomes included PFS and OS. For OS we obtained median survival. For PFS we obtained the median survival, 95% confidence interval (CI) and hazard ratio (HR) and 95%CI of the HR. In cases in which HRs and/or 95%CI for PFS were not reported, we estimated the missing data with the available Kaplan-Meier curves using the methods described by Tierney et al.14 In cases in which multiple sources reported on the same trial, the most recently published PFS data were extracted. Risk of bias in randomized trials was assessed using the Cochrane Collaboration tool15 (Online Supplementary Appendix 3).
Network meta-analysis
A network was made from the identified treatment options in the SLR. It includes the HRs for PFS from the trials for treatments that were compared head-to-head. A comparison between all treatments can be made based on a common comparator (i.e. ref- erence treatment). The choice of the reference treatment does not influence the outcomes of the study and final results can be pre- sented relative to all included treatments. The oldest treatment (i.e. dexamethasone) was selected as a reference treatment from which the relative effectiveness of all treatments was estimated. We performed a similar analysis with MPT as reference treat- ment, given that this regimen was used as (comparator) treatment in several RCTs. Treatments were sorted based on their P-score. This P-score measures the average proportion of treatments worse than the respective treatment where 1 means theoretically the best and 0 means the worst.16
To conduct an NMA for 2- and multi-arm studies, we used the netmeta package v.0.9-7 in R version 3.3.1 (Online Supplementary Appendix 4). We ran a random effects model assuming that the included studies represent a random sample of effect sizes that could have been observed and that the effect can best be estimat- ed by the mean of all available studies. A random effects model was deemed appropriate since there were multiple trials available for some comparisons (e.g. MPT with MP) and sampling error was not considered to be the most plausible explanation for the observed variation. With a random effects model we allow for dif- ferences in the patient population and implementations of inter- ventions.17 The netmeta package uses a frequentist approach based on the graph-theoretical methods routinely applied in elec- trical networks.18,19 In contrast to the Bayesian approach that pro- duces credible intervals, analysis based on the frequentist approach produces 95%CIs and, as all CIs, these should be inter- preted as follows: 95% of the produced CIs would contain the true value if the analysis were repeated many times.20
Face-validity of the NMA results was checked by comparing the computed HRs by the NMA with the HRs reported in the publications of the trials. To validate our outcomes to a previ- ously reported NMA,12 we performed a scenario analysis with different treatment groups (separating MPT and MPT-T) and a scenario with a limited number of studies. In the third scenario analysis, we used a fixed effect model instead of a random
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