Page 187 - 2019_05-HaematologicaMondo-web

Efficacy of MM treatments
Discussion
Current clinical decision making in MM is complicated by a lack of head-to-head comparisons of standards of care, an increasing number of treatment modalities, and rapidly evolving promising results of studies with novel regimens (among smaller subpopulations). In this treat- ment landscape, we believe the role of NMA will become increasingly important, although it cannot replace RCTs, and these will still represent the gold standard.
Firstly, NMAs are able to provide data where head-to- head comparisons are lacking.20,24 For NTE NDMM, there have been no head-to-head comparisons between the cur- rent three standard of care regimens (i.e. VRd, VMP and Rd). Only VRd has been compared head-to-head with Rd, and there are no studies comparing VMP with VRd or Rd. With our NMA, we show that the HR of VRd was lower than VMP and Rd, and VRd also had the highest P-score. We present similar HRs and P-scores for VMP and Rd. However, we also show considerable overlap of the 95%CIs of VRd, Rd and VMP. Our NMA does not support the use of one over the other regimens, thus leaving three valuable options for clinical practice. The choice of thera- py will be guided by the patient's characteristics. For example, a proteasome inhibitor (PI)-based regimen in high-risk cytogenetic disease, and a preference for lenalidomide without bortezomib in patients with neu- ropathy.31-34
According to the ranking based on their P-scores and comparative effectiveness estimates, DaraVMP and VMPT-VT were identified as the most effective treat- ments. Although there is one RCT already showing better PFS and OS28 for VMPT-VT when compared with VMP, we now add data showing comparable efficacy to DaraVMP, which is expected to become an important standard of care. This finding is important given the pro- nounced differences in global access to expensive treat- ment regimens. As all drugs in the VMPT-VT regimen will soon be available as generic compounds, this regimen is a valuable option in clinical practice as well. In addition, the pronounced efficacy of VMPT-VT highlights the use of maintenance therapy following PI-based induction regi- mens. In addition, in a non-head-to-head comparison with VMP, the study of the PETHEMA group showed that maintenance therapy did result in a substantially longer PFS.35 We now add further evidence for maintenance ther- apy with PIs by showing high efficacy of VMPT-VT as compared to VMP. This is important because the European Medicines Agency has still not approved main- tenance therapy with bortezomib, given that no head-to- head comparisons of maintenance versus no maintenance therapy have been made.
Secondly, NMAs provide more solid and precise effec- tiveness estimates when head-to-head data from multiple RCTs are available.20,24 Our network included several trials investigating MPT/MPT-T versus MP. Some of these trials showed superiority of MPT/MPT-T over MP,26,27,36 while other trials found no difference.37-40 NMA enables this evi- dence to be synthesized and, according to our analysis, MPT/MPT-T was superior over MP (HR 0.67, 95%CI: 0.55-0.81).
Thirdly, NMA calculates effectiveness estimates includ- ing direct and indirect evidence from RCTs providing additional evidence when head-to-head data are only available from one single RCT. Due to the rapid evolution
of the treatment armamentarium, efficacy evidence is increasingly based on a single RCT, and this is often from only one institute or region in the world. There is increas- ing evidence of RCTs investigating a similar treatment comparison providing contradictory results41 and this may increase the interest in indirect evidence. Indirect evidence may confirm or alter the results from a single RCT, as we have shown for MPR-R compared to MPT. Although there was no statistically significant difference between MPR-R and MPT-T based on direct evidence from two RCTs, syn- thesizing direct and indirect evidence resulted in a statisti- cally significant HR for MPR-R compared to MPT/MPT-T. Favorable indirect evidence for MPR-R compared to MPT- T was obtained through the comparison with MP. MPR-R compared more favorably to MP (according to the MM-15 HR MPR-R vs. MP 0.4) than MPT (HR MPT vs. MP 0.67 according to multiple trials). However, it should be noted that the direct evidence for MPR-R compared to MP was based on a single RCT while MPT/MPT-T versus MP was studied in seven RCTs, and therefore the evidence for the latter comparison is believed to be more solid.24,41 Indirect evidence is not always available, for example, for the com- parison between VRd and Rd there is only direct evidence from a single study.6 While a fixed effect NMA will pro- duce similar results to the trial (HR 0.71, 95%CI: 0.57-0.9), a random effects NMA obtains larger 95%CIs (HR 0.71, 95%CI: 0.43-1.17), as it includes two levels of uncertainty: within and between study variances.17 Therefore, there is less likelihood of significant differences between treat- ments.
Two other NMAs are available for newly diagnosed NTE NDMM patients. Our results align with the results from Kuhr et al.11 in that VMP and MPT are more effective than MP. Our results also confirm the conclusion from Weisel et al.12 that Rd is more favorable than MP [HR 0.63, 95%CI: 0.44-0.89 (Online Supplementary Appendix 5)]. However, in contrast to their findings, we found that Rd and VMP have comparable effectiveness outcomes (i.e. small difference in HR for PFS compared to D but largely overlapping CIs). The primary analysis of Weisel et al. included a limited number of treatments (i.e. VMP, MP, MPT and Rd) and RCTs (i.e. VISTA, IFM01/01, IFM 99/06, Sacchi, FIRST) as Phase III trials not using dosing schemes in line with the summary of product characteristics (SmPC) were excluded. There are several arguments against this restriction. Firstly, although dosing schemes in line with the SmPC might be recommended in the select- ed trials by Weisel et al., it is debatable whether this ensures treatments are identical within a network, espe- cially because of variation in clinical practice due to either physician's preference or patient-related factors such as age, co-morbidities and toxicities. For example, the trial of Sacchi et al. 2011 was grouped with MPT studies while maintenance was only provided in a limited number of centers. Furthermore, the administered and planned dose may differ, as, for example, illustrated by the HOVON87 in which relative dose intensity varied between 0.54- 0.96.13 Since there is no evidence on the impact of dosing schemes, we believe that a more comprehensive network (e.g. our network, including 19 additional trials) provides more solid evidence. The reason Weisel et al.12 did not find an overlap between VMP and Rd in their sensitivity analy- ses including six and twelve additional studies, is most likely because they used a fixed effect model for their analysis. A random effects model, like that used in our
haematologica | 2019; 104(5)
1033