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.

Blood and Marrow Transplant Program Department of Medicine Roswell Park Comprehensive Cancer Center State University at Buffalo Buffalo New York

Clinica di Ematologia AOU Ospedali Riuniti di Ancona Ancona Italy

Clínica Universidad de Navarra CIMA IDISNA CIBERONC Pamplona Spain

Clinical Trials Research Unit Leeds Institute of Clinical Trials Research University of Leeds Leeds United Kingdom

Department of Clinical Therapeutics National and Kapodistrian University of Athens School of Medicine Athens Greece

Department of Haematology Alfred Health Monash University Melbourne Australia

Department of Haematooncology University Hospital Ostrava Czech Republic and Faculty of Medicine University of Ostrava Czech Republic

Department of Hematology Erasmus Medical Center Rotterdam the Netherlands

Department of Hematology Institut Universitaire du Cancer Toulouse Oncopole Toulouse France

Department of Internal Medicine University of Nebraska Medical Center Omaha

Division of Hematology AOU Policlinico OVE University of Catania Catania Italy

Hématologie and Inserm CIC 1082 Poitiers France

Hematology Department IDIBAPS Hospital Clinic Barcelona Spain

Hematology Department University Hospital Hôtel Dieu Nantes France

Hospital Universitario 12 de Octubre Madrid Spain PETHEMA Grupo Español de Mieloma

Institut d'Hématologie de Basse Normandie University Hospital of Caen Côte de Nacre 14033 Caen Cedex 9 France

Myeloma Unit Division of Hematology University of Torino Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino Torino Italy

Newcastle upon Tyne Hospitals Trust United Kingdom

Service d'Hématologie Hôpital Haut Lévêque CHU Bordeaux 33600 Pessac France

The Institute of Cancer Research London United Kingdom

The Myeloma Institute University of Arkansas for Medical Sciences Little Rock

Unit of Clinical Epidemiology Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino and CPO Piemonte Torino Italy

Università degli Studi di Perugia Struttura Complessa Universitaria Oncoematologia Azienda Ospedaliera Santa Maria di Terni Italy

University Hospital of Salamanca Instituto de Investigación Biomédica de Salamanca Salamanca Spain

Wilhelminen Cancer Research Institute Vienna Austria

Zobrazit více v PubMed

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

Hulin C, Facon T, Rodon P, et al. . Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27(22):3664-3670. doi:10.1200/JCO.2008.21.0948 PubMed DOI

Barlogie B, Pineda-Roman M, van Rhee F, et al. . Thalidomide arm of Total Therapy 2 improves complete remission duration and survival in myeloma patients with metaphase cytogenetic abnormalities. Blood. 2008;112(8):3115-3121. doi:10.1182/blood-2008-03-145235 PubMed DOI PMC

Spencer A, Prince HM, Roberts AW, et al. . Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol. 2009;27(11):1788-1793. doi:10.1200/JCO.2008.18.8573 PubMed DOI

Stewart AK, Trudel S, Bahlis NJ, et al. . A randomized phase 3 trial of thalidomide and prednisone as maintenance therapy after ASCT in patients with MM with a quality-of-life assessment: the National Cancer Institute of Canada Clinicals Trials Group Myeloma 10 Trial. Blood. 2013;121(9):1517-1523. doi:10.1182/blood-2012-09-451872 PubMed DOI PMC

Attal M, Harousseau J-L, Leyvraz S, et al. ; Inter-Groupe Francophone du Myélome (IFM) . Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108(10):3289-3294. doi:10.1182/blood-2006-05-022962 PubMed DOI

Sonneveld P, Schmidt-Wolf IGH, van der Holt B, et al. . Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol. 2012;30(24):2946-2955. doi:10.1200/JCO.2011.39.6820 PubMed DOI

Goldschmidt H, Lokhorst HM, Mai EK, et al. . Bortezomib before and after high-dose therapy in myeloma: long-term results from the phase III HOVON-65/GMMG-HD4 trial. Leukemia. 2018;32(2):383-390. doi:10.1038/leu.2017.211 PubMed DOI

Rosiñol L, Oriol A, Teruel AI, et al. . Bortezomib and thalidomide maintenance after stem cell transplantation for multiple myeloma: a PETHEMA/GEM trial. Leukemia. 2017;31(9):1922-1927. doi:10.1038/leu.2017.35 PubMed DOI

Palumbo A, Bringhen S, Larocca A, et al. . Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014;32(7):634-640. doi:10.1200/JCO.2013.52.0023 PubMed DOI

Palumbo A, Bringhen S, Rossi D, et al. . Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010;28(34):5101-5109. doi:10.1200/JCO.2010.29.8216 PubMed DOI

Mateos M-V, Oriol A, Martínez-López J, et al. . Bortezomib, melphalan, and prednisone versus bortezomib, thalidomide, and prednisone as induction therapy followed by maintenance treatment with bortezomib and thalidomide versus bortezomib and prednisone in elderly patients with untreated multiple myeloma: a randomised trial. Lancet Oncol. 2010;11(10):934-941. doi:10.1016/S1470-2045(10)70187-X PubMed DOI

Mateos M-V, Oriol A, Martínez-López J, et al. . GEM2005 trial update comparing VMP/VTP as induction in elderly multiple myeloma patients: do we still need alkylators? Blood. 2014;124(12):1887-1893. doi:10.1182/blood-2014-05-573733 PubMed DOI

McCarthy PL, Holstein SA, Petrucci MT, et al. . Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis. J Clin Oncol. 2017;35(29):3279-3289. doi:10.1200/JCO.2017.72.6679 PubMed DOI PMC

Jackson G, Davies FE, Pawlyn C, et al. . Lenalidomide maintenance significantly improves outcomes compared to observation irrespective of cytogenetic risk: results of the Myeloma XI trial. Blood. 2017;130(Suppl_1):Abstract #436 [ASH 2017 59th Meeting].

Greipp PR, San Miguel J, Durie BGM, et al. . International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412-3420. doi:10.1200/JCO.2005.04.242 PubMed DOI

Munshi NC, Anderson KC, Bergsagel PL, et al. ; International Myeloma Workshop Consensus Panel 2 . Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011;117(18):4696-4700. doi:10.1182/blood-2010-10-300970 PubMed DOI PMC

Hutton B, Salanti G, Caldwell DM, et al. . The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777-784. doi:10.7326/M14-2385 PubMed DOI

Systematic reviews/Meta-analyses/HTA | Study Designs | The EQUATOR Network. UK EQUATOR Centre, Centre for Statistics in Medicine, NDORMS, University of Oxford. https://www.equator-network.org/?post_type=eq_guidelines&eq_guidelines_study_design=systematic-reviews-and-meta-analyses&eq_guidelines_clinical_specialty=0&eq_guidelines_report_section=0&s=. Accessed February 23, 2018.

Higgins JPT, Altman DG, Gøtzsche PC, et al. ; Cochrane Bias Methods Group; Cochrane Statistical Methods Group . The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi:10.1136/bmj.d5928 PubMed DOI PMC

Altman DG, Bland JM. How to obtain the P value from a confidence interval. BMJ. 2011;343:d2304. doi:10.1136/bmj.d2304 PubMed DOI

Higgins JPT, Jackson D, Barrett JK, Lu G, Ades AE, White IR. Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods. 2012;3(2):98-110. doi:10.1002/jrsm.1044 PubMed DOI PMC

Ludwig H, Adam Z, Tóthová E, et al. . Thalidomide maintenance treatment increases progression-free but not overall survival in elderly patients with myeloma. Haematologica. 2010;95(9):1548-1554. doi:10.3324/haematol.2009.020586 PubMed DOI PMC

Morgan GJ, Gregory WM, Davies FE, et al. ; National Cancer Research Institute Haematological Oncology Clinical Studies Group . The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood. 2012;119(1):7-15. doi:10.1182/blood-2011-06-357038 PubMed DOI

Morgan GJ, Davies FE, Gregory WM, et al. . Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res. 2013;19(21):6030-6038. doi:10.1158/1078-0432.CCR-12-3211 PubMed DOI

Palumbo A, Hajek R, Delforge M, et al. ; MM-015 Investigators . Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366(19):1759-1769. doi:10.1056/NEJMoa1112704 PubMed DOI

Holstein SA, Jung S-H, Richardson PG, et al. . Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial. Lancet Haematol. 2017;4(9):e431-e442. doi:10.1016/S2352-3026(17)30140-0 PubMed DOI PMC

McCarthy PL, Owzar K, Hofmeister CC, et al. . Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1770-1781. doi:10.1056/NEJMoa1114083 PubMed DOI PMC

Attal M, Lauwers-Cances V, Marit G, et al. ; IFM Investigators . Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782-1791. doi:10.1056/NEJMoa1114138 PubMed DOI

Palumbo A, Cavallo F, Gay F, et al. . Autologous transplantation and maintenance therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905. doi:10.1056/NEJMoa1402888 PubMed DOI

Gay F, Oliva S, Petrucci MT, et al. . Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 2015;16(16):1617-1629. doi:10.1016/S1470-2045(15)00389-7 PubMed DOI

Bringhen S, Offidani M, Musto P, et al. . Long term outcome of lenalidomide-dexamethasone (Rd) vs melphalan-lenalidomide-prednisone (MPR) vs cyclophosphamide-prednisone-lenalidomide (CPR) as induction followed by lenalidomide-prednisone (RP) vs lenalidomide (R) as maintenance in a community-based newly diagnosed myeloma population. Blood. 2017;130(Suppl_1):Abstract #901 [ASH 2017 59th Meeting].

Magarotto V, Bringhen S, Offidani M, et al. . Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016;127(9):1102-1108. doi:10.1182/blood-2015-08-662627 PubMed DOI

Ludwig H, Durie BGM, McCarthy P, et al. ; International Myeloma Working Group . IMWG consensus on maintenance therapy in multiple myeloma. Blood. 2012;119(13):3003-3015. doi:10.1182/blood-2011-11-374249 PubMed DOI PMC

Reece DE. Posttransplantation maintenance therapy and optimal frontline therapy in myeloma. Hematology Am Soc Hematol Educ Program. 2011;2011(1):197-204. doi:10.1182/asheducation-2011.1.197 PubMed DOI

Attal M, Lauwers-Cances V, Hulin C, et al. ; IFM 2009 Study . Lenalidomide, Bortezomib, and Dexamethasone with Transplantation for Myeloma. N Engl J Med. 2017;376(14):1311-1320. doi:10.1056/NEJMoa1611750 PubMed DOI PMC

Jackson GH, Davies FE, Pawlyn C, et al. . Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages; results of the phase III Myeloma XI Study. Blood. 2016;128(22):Abstract #1143.

Mandelli F, Avvisati G, Amadori S, et al. . Maintenance treatment with recombinant interferon alfa-2b in patients with multiple myeloma responding to conventional induction chemotherapy. N Engl J Med. 1990;322(20):1430-1434. doi:10.1056/NEJM199005173222005 PubMed DOI

Cunningham D, Powles R, Malpas J, et al. . A randomized trial of maintenance interferon following high-dose chemotherapy in multiple myeloma: long-term follow-up results. Br J Haematol. 1998;102(2):495-502. doi:10.1046/j.1365-2141.1998.00795.x PubMed DOI

Fritz E, Ludwig H. Interferon-alpha treatment in multiple myeloma: meta-analysis of 30 randomised trials among 3948 patients. Ann Oncol Off J Eur Soc Med Oncol. 2000;11(11):1427-1436. PubMed

Cavo M, Tacchetti P, Patriarca F, et al. ; GIMEMA Italian Myeloma Network . Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet. 2010;376(9758):2075-2085. doi:10.1016/S0140-6736(10)61424-9 PubMed DOI

Larocca A, Offidani M, Musto P, et al. . Impact of bortezomib- or lenalidomide-based induction treatment on high risk cytogenetic transplant-ineligible patients with newly diagnosed multiple myeloma enrolled in the Gimema-MM-03-05 and EMN01 trials. Blood. 2017;130(Suppl_1):Abstract #744 [ASH 2017 59th Meeting].

Nooka AK, Kaufman JL, Muppidi S, et al. . Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014;28(3):690-693. doi:10.1038/leu.2013.335 PubMed DOI

Yakoub-Agha I, Hulin C, Doyen C, et al. . A multicenter prospective randomized study testing non-inferiority of thalidomide 100 mg/day as compared with 400 mg/day in patients with refractory/relapsed multiple myeloma: first results of the final analysis of the IFM 01-02 study. Blood. 2005;106(11):Abstract #364.

Weisel K, Doyen C, Dimopoulos M, et al. . A systematic literature review and network meta-analysis of treatments for patients with untreated multiple myeloma not eligible for stem cell transplantation. Leuk Lymphoma. 2017;58(1):153-161. doi:10.1080/10428194.2016.1177772 PubMed DOI

Liu X, Chen J, He YA, et al. . Comparing efficacy and survivals of initial treatments for elderly patients with newly diagnosed multiple myeloma: a network meta-analysis of randomized controlled trials. Onco Targets Ther. 2016;10:121-128. doi:10.2147/OTT.S123680 PubMed DOI PMC

Durie BGM, Hoering A, Abidi MH, et al. . Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519-527. doi:10.1016/S0140-6736(16)31594-X PubMed DOI PMC

Lokhorst HM, Schmidt-Wolf I, Sonneveld P, et al. ; Dutch-Belgian HOVON; German GMMG . Thalidomide in induction treatment increases the very good partial response rate before and after high-dose therapy in previously untreated multiple myeloma. Haematologica. 2008;93(1):124-127. doi:10.3324/haematol.11644 PubMed DOI

Abonour R, Durie BGM, Jagannath S, et al. . Health-related quality of life of patients with newly diagnosed multiple myeloma receiving any or lenalidomide maintenance after autologous stem cell transplant in the Connect MM disease registry. Blood. 2016;128(22):Abstract #537.

Palumbo A, Bringhen S, Kumar SK, et al. . Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. Lancet Oncol. 2014;15(3):333-342. doi:10.1016/S1470-2045(13)70609-0 PubMed DOI

Ixazomib as Postinduction Maintenance for Patients With Newly Diagnosed Multiple Myeloma Not Undergoing Autologous Stem Cell Transplantation: The Phase III TOURMALINE-MM4 Trial

Lenalidomide Maintenance with or without Prednisone in Newly Diagnosed Myeloma Patients: A Pooled Analysis