Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Oct 1;4(10):1389-1397.
doi: 10.1001/jamaoncol.2018.2961.

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

Francesca Gay  1 , Graham Jackson  2 , Laura Rosiñol  3 , Sarah A Holstein  4 , Philippe Moreau  5 , Stefano Spada  1 , Faith Davies  6 , Juan José Lahuerta  7 , Xavier Leleu  8 , Sara Bringhen  1 , Andrea Evangelista  9 , Cyrille Hulin  10 , Ugo Panzani  1 , David A Cairns  11 , Francesco Di Raimondo  12 , Margaret Macro  13 , Anna Marina Liberati  14 , Charlotte Pawlyn  15 , Massimo Offidani  16 , Andrew Spencer  17 , Roman Hájek  18 , Evangelos Terpos  19 , Gareth J Morgan  6 , Joan Bladé  3   3 , Pieter Sonneveld  20 , Jesús San-Miguel  21 , Philip L McCarthy  22 , Heinz Ludwig  23 , Mario Boccadoro  1 , Maria-Victoria Mateos  24 , Michel Attal  25
Affiliations

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

Francesca Gay et al. JAMA Oncol. .

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.

PubMed Disclaimer

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.
Figure 1.. PRISMA Flowchart
Figure 2.
Figure 2.. Primary Analysis Network
Thal indicates thalidomide; IFN, interferon; Len, lenalidomide; Bort, bortezomib; Pred, prednisone.
Figure 3.
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.
See this image and copyright information in PMC

References

    1. Palumbo A, Bringhen S, Caravita T, et al. ; Italian Multiple Myeloma Network, GIMEMA . Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet. 2006;367(9513):825-831. doi:10.1016/S0140-6736(06)68338-4 - DOI - PubMed
    1. Waage A, Gimsing P, Fayers P, et al. ; Nordic Myeloma Study Group . Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010;116(9):1405-1412. doi:10.1182/blood-2009-08-237974 - DOI - PubMed
    1. Facon T, Mary JY, Hulin C, et al. ; Intergroupe Francophone du Myélome . Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370(9594):1209-1218. doi:10.1016/S0140-6736(07)61537-2 - DOI - PubMed
    1. Beksac M, Haznedar R, Firatli-Tuglular T, et al. . Addition of thalidomide to oral melphalan/prednisone in patients with multiple myeloma not eligible for transplantation: results of a randomized trial from the Turkish Myeloma Study Group. Eur J Haematol. 2011;86(1):16-22. doi:10.1111/j.1600-0609.2010.01524.x - DOI - PubMed
    1. Wijermans P, Schaafsma M, Termorshuizen F, et al. ; Dutch-Belgium Cooperative Group HOVON . Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010;28(19):3160-3166. doi:10.1200/JCO.2009.26.1610 - DOI - PubMed

Publication types

MeSH terms