Maintenance Treatment and Survival in Patients With Myeloma: A Systematic Review and Network Meta-analysis

Abstract

Importance: Several trials demonstrated the impact of novel agent-based maintenance in newly diagnosed multiple myeloma (NDMM), but there is no current evidence demonstrating the superiority of one regimen over the other, owing to the lack of direct/indirect comparisons.

Objective: To analyze and compare the effectiveness of different maintenance regimens in NDMM via a network meta-analysis.

Data sources: We performed 2 independent searches in PubMed and Cochrane databases, and then we identified all the records registered after 1999 and on or before November 20, 2017.

Study selection: By blinded review, we identified prospective phase 3 randomized trials evaluating novel agent-based maintenance in patients with NDMM; the included studies compared at least 2 maintenance approaches; comparators included placebo and no maintenance. From 364 screened records, 11 studies were included.

Data extraction and synthesis: We followed (independent extraction) the guidelines provided by the PRISMA Report and the EQUATOR Network. The evidence was synthesized using a network meta-analysis (NMA). To allow comparison of all treatments, no maintenance was selected as common comparator and the effect of placebo was assumed to be the same as no treatment. The best option was identified by a Bayesian consistency model based on hazard ratio (HR), 95% credible interval (CrI), probability of being the best treatment (PbBT), and median ranking distribution (MedR).

Main outcomes and measures: Outcomes of interest were progression-free survival (PFS) and overall survival (OS).

Results: Eleven trials and 8 treatments including a total of 5073 participants were included. By PFS analysis, lenalidomide-based regimens (lenalidomide-prednisone, lenalidomide alone) were identified as the most effective options (HR, 0.39 [95% CrI, 0.28-0.53] and 0.47 [95% CrI, 0.39-0.55], respectively; MedR, 1 and 2; overall PbBT, 74%). Four treatments (thalidomide-interferon, thalidomide-bortezomib, bortezomib-prednisone, thalidomide alone) showed an HR in favor of maintenance. By OS analysis, lenalidomide alone was identified as the best option (HR, 0.76; 95% CrI, 0.51-1.16; MedR, 2; PbBT, 38%), followed by bortezomib-thalidomide and bortezomib-prednisone. Similar features were noticed in the restricted network including transplant trials, in the sensitivity analysis, and in most of the prognostic subgroups.

Conclusions and relevance: Based on PFS and OS results of this NMA, lenalidomide maintenance appears to be the best treatment option, by synthesizing the available evidence of novel agent-based maintenance in the past 20 years.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Gay has received honoraria from Takeda, Amgen, Celgene, Janssen, and BMS and has served on the advisory boards for Takeda, Seattle Genetics, Celgene, and Roche. Mr Jackson has received honoraria and served on the speakers’ bureau for Celgene, Janssen, Amgen, and Takeda and has received research funding from Celgene, Takeda, and Amgen. Dr Rosiñol has received honoraria from Janssen, Celgene, and Amgen. Dr Holstein has served on advisory committees for Celgene, Takeda, and Amgen and has received consulting fees from Celgene. Dr Moreau has served on the advisory boards for and received honoraria from Celgene, Janssen, Takeda, Amgen, and Novartis. Dr Davies has undertaken consultancy for and received honoraria from Takeda, Janssen, Celgene, AbbVie, and Amgen and has received research funding from Janssen. Dr Lahuerta has undertaken consultancy or acted in an advisory role for Celgene, Janssen, Amgen, and Takeda. Dr Leleu has received honoraria from Celgene, Janssen, Sanofi, Merck, Bms, Amgen, AbbVie, Roche, Gilead, Novartis, and Takeda. Dr Bringhen has received honoraria from BMS, Celgene, Amgen and Janssen; has served on the advisory boards for Amgen and Janssen; and has undertaken consultancy for Takeda. Dr Hulin has received honoraria from Celgene, Janssen, Amgen, Takeda, and Novartis. Dr Cairns has received research funding to his institution from Celgene, Amgen, and Merck Sharpe and Dohme. Dr Di Raimondo has received honoraria from Celgene and Janssen. Dr Macro has received honoraria from Amgen and Sanofi; has served on the advisory boards for Amgen, Celgene, Janssen, Novartis, and Takeda; and has participated in international congresses with the support of Amgen, Celgene, Janssen, Novartis, and Takeda. Dr Pawlyn has undertaken consultancy for Takeda Oncology, Celgene, and Amgen and has received honoraria from Celgene and Janssen and travel support from Amgen, Takeda Oncology, Janssen, and Celgene. Dr Offidani has received honoraria from Celgene. Dr Hájek has received research grants from Celgene, Amgen, Takeda, Janssen, and Novartis and consulting fees from Janssen, Amgen, Celgene, BMS, and Takeda. Dr Terpos has received honoraria from Amgen, Celgene, Janssen, Takeda, and BMS; research support from Amgen, Celgene, and Janssen. Dr Morgan has undertaken consultancy for and received honoraria from Janssen, Bristol-Myers Squibb, Takeda, Celgene, and Amgen and has received research funding from Celgene. Dr Bladé has received honoraria for lectures from Janssen, Celgene, Amgen, and Takeda and grant support from Janssen and Celgene. Dr Sonneveld has received research support from Amgen, Celgene, Janssen, and Karyopharm and has served in the advisory boards for and received honoraria from BMS, Amgen, Celgene, and Janssen. Dr San-Miguel served on an advisory board for Takeda, Celgene, Novartis, Amgen, Janssen-Cilag, BMS, and MSD. Dr McCarthy has received honoraria from Celgene, Bristol-Myers Squibb, Sanofi, Takeda, The Binding Site, and Karyopharm Therapeutics; has acted in a consulting or advisory role for Celgene, Janssen, Bristol-Myers Squibb, Sanofi, and Karyopharm Therapeutics; has received research funding from Celgene, both individually and to his institution. Dr Ludwig has received research funding from Takeda and Amgen and has served on the speakers’ bureau for Takeda, Amgen, Janssen-Cilag, Bristol-Myers Squibb, and Celgene. Dr Boccadoro has received honoraria from Sanofi, Celgene, Amgen, Janssen, Novartis, AbbVie, and BMS and research funding from Celgene, Janssen, Amgen, BMS, Mundipharma, Novartis, and Sanofi. Dr Mateos has received honoraria from lectures and served on the advisory boards for Janssen, Celgene, Takeda, Amgen, and AbbVie. No other conflicts are reported.

Figures

Figure 1.. PRISMA Flowchart

Figure 2.. Primary Analysis Network

Thal indicates thalidomide; IFN, interferon; Len, lenalidomide; Bort, bortezomib; Pred, prednisone.

Figure 3.. Forest Plot of Network Meta-analysis Results (Primary Analysis)

Thal indicates thalidomide; IFN, interferon; Len, lenalidomide; Bort, bortezomib; Pred, prednisone; PFS, progression-free survival; OS, overall survival; PbBT, probability of being the best treatment; MedR, median value of the ranking distribution for all the simulations. A, PFS results. B, OS results.