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Efficacy of MM treatments
Prednisone-Thalidomide and Bortezomib-Thalidomide (VMPT- VT), 15) Cyclophosphamide-Prednisone-Lenalidomide (CPR), 16) Lenalidomide-Dexamethasone (Rd), 17) 18 cycles Lenalidomide- Dexamethasone (Rd18), 18) Melphalan-Prednisone-Lenalidomide (MPR), 19) Melphalan-Prednisone-Lenalidomide and Lenalidomide maintenance (MPR-R), 20) Bortezomib- Lenalidomide-Dexamethasone (VRd), 21) Daratumumab- Bortezomib-Melphalan-Prednisone (DaraVMP).
Data extraction
Table 1 provides the details, and extracted and calculated data of the included trials. Most trials (21 out of 24) investigated iMID- based regimens (thalidomide or lenalidomide). Since MP has been the standard treatment for decades,25 MP was the comparator in 12 trials. PFS was the primary end point for 13 trials. The median age of the patient population was reported by most trials and ranged from 64 to 79 years. While some trials included patients aged <65 years, either because of choosing broader age limits or because of including patients who were not eligible for SCT inde- pendent of age, most trials only included patients aged ≥65 years. The IFM99-0626 and IFM01/0127 only focused on patients aged ≥70 and ≥75, respectively.
Network meta-analysis network
All identified RCTs (n=24) and treatments (n=21) were incorpo- rated within one network (Figure 2). We combined MPT and MPT-T. The duration of induction therapy with thalidomide var-
ied leading to a clear overlap in planned thalidomide use between protocols with and without maintenance, preventing a clear dis- crimination between MPT with and without thalidomide mainte- nance.
Figure 2 presents the obtained HR(s) from the trial(s) and the HR obtained from the NMA for each of the connections (i.e. treatment comparisons) in our network. In order to validate our data, we compared the HR from treatments for which only direct evidence from a single RCT was available. The HR obtained from the NMA should be equal to the HR obtained from the RCT. The HR from the NMA was indeed similar to the HR from the trials for six comparisons5-7,28-30 [i.e. CTD(a) vs. MP, VMP vs. MP, DaraVMP vs. VMP, VRd vs. Rd, VMPT-VT vs. VMP and VMP vs. VTP] (Online Supplementary Appendix 5). In addition, our network includes sev- eral treatments for which both direct and indirect evidence were available. Online Supplementary Appendix 5 presents the HRs based on direct and indirect evidence and shows that none of the P-val- ues for disagreement was lower than 0.05.
The percentage of the variability in effect estimates due to het- erogeneity rather than sampling error (=I2) was 72% indicating substantial between-study heterogeneity (i.e. within the 50-90% range can be quantified as substantial heterogeneity24). We allowed for between-study heterogeneity by using the random effects model. Heterogeneity could be reduced by excluding some of the trials; however, because of a lack of valid reasons (e.g. patients' characteristics, treatment dosing or follow up) for exclud- ing trials, we decided not to perform analyses of this kind.
Figure 2. Network of the studies included in the network meta-analysis (NMA). White boxes represent treatments and reference numbers using the following abbre- viations. 1) Dexamethasone (D); 2) Dexamethasone-Interferon alpha (DI); 3) Melphalan 100 (M100); 4) Melphalan-Dexamethasone (MD); 5) Melphalan-Prednisone (MP); 6) Thalidomide-Dexamethasone (TD); 7) Cyclophosphamide-Thalidomide-Dexamethasone (CTD); 8) Cyclophosphamide-Thalidomide-Dexamethasone (attenuat- ed) [CTD(a)]; 9) Melphalan-Prednisone-Thalidomide / Melphalan-Prednisone-Thalidomide and Thalidomide maintenance (MPT/MPT-T); 10) Bortezomib- Dexamethasone (VD); 11) Bortezomib-Thalidomide-Dexamethasone (VTD); 12) Bortezomib-Melphalan-Prednisone (VMP); 13) VTP: Bortezomib-Thalidomide- Prednisone (VTP); 14) Bortezomib-Melphalan-Prednisone-Thalidomide and Bortezomib-Thalidomide (VMPT-VT); 15) Cyclophosphamide-Prednisone-Lenalidomide (CPR); 16) Lenalidomide-Dexamethasone (Rd); 17) 18 cycles Lenalidomide-Dexamethasone (Rd18); 18) Melphalan-Prednisone-Lenalidomide (MPR); 19) Melphalan- Prednisone-Lenalidomide and Lenalidomide maintenance (MPR-R); 20) Bortezomib-Lenalidomide-Dexamethasone (VRd); 21) Daratumumab-Bortezomib-Melphalan- Prednisone (DaraVMP). Black box represents the reference treatment in the network meta-analysis. Gray boxes include the trial reference and hazard ratio (HR) for progression-free survival on the top row(s). Bottom row shows HR according to the NMA. *HR not statistically significant at 5%.
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