Efficacy of first-line treatments for multiple myeloma patients not eligible for stem cell transplantation: a network meta-analysis

Abstract

Decision making for patients with multiple myeloma (MM) not transplant eligible (NTE) is complicated by a lack of head-to-head comparisons of standards of care, the increase in the choice of treatment modalities, and the promising results that are rapidly evolving from studies with novel regimens. To support evidence-based decision making, we performed a network meta-analysis for NTE MM patients that synthesizes direct and indirect evidence and enables a comparison of all treatments. Relevant randomized clinical trials were identified by a systematic literature review in EMBASE®, MEDLINE®, MEDLINE®-in-Process and the Cochrane Central Register of Controlled Trials for January 1999 to March 2016. Efficacy outcomes [i.e. the hazard ratio (HR) and 95% confidence interval (95%CI) for progression-free survival] were extracted and synthesized in a random effects network-meta analysis. In total, 24 studies were identified including 21 treatments. According to the network-meta analysis, the HR for progression-free survival was favorable for all NTE MM treatments compared to dexamethasone (HR: 0.19-0.90). Daratumumab-bortezomib-melphalan-prednisone and bortezomib-melphalan-prednisone-thalidomide with bortezomib-thalidomide maintenance were identified as the most effective treatments (HR: 0.19, 95%CI: 0.08-0.45 and HR: 0.22, 95%CI: 0.10-0.51, respectively). HR and 95%CI for currently recommended treatments, bortezomib-lenalidomide-dexamethasone, bortezomib-melphalan-prednisone, and lenalidomide-dexamethasone compared to dexamethasone, were 0.31 (0.16-0.59), 0.39 (0.20-0.75), and 0.44 (0.29-0.65), respectively. In addition to identifying the most effective treatment options, we illustrate the additional value and evidence of network meta-analysis in clinical practice. In the current treatment landscape, the results of network meta-analysis may support evidence-based decisions and ultimately help to optimize treatment and outcomes of NTE MM patients.

Figure 1.

PRISMA 2009 flow diagram: transplant not eligible multiple myeloma (TNEMM) Phase III randomized controlled trials (RCTs). n: number. From Moher et al. 2009.

Figure 2.

Network of the studies included in the network meta-analysis (NMA). White boxes represent treatments and reference numbers using the following abbreviations. 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 (attenuated) [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%.

Figure 3.

Results of the network meta-analysis in which dexamethasone was used as comparator. HR: hazard ratio; CI: confidence interval. For abbreviations for treatments, see Figure 2.