Efficacy and safety of bortezomib maintenance in patients with newly diagnosed multiple myeloma: a meta-analysis

Chun-Yan Sun, Jun-Ying Li, Zhang-Bo Chu, Lu Zhang, Lei Chen, Yu Hu, Chun-Yan Sun, Jun-Ying Li, Zhang-Bo Chu, Lu Zhang, Lei Chen, Yu Hu

Abstract

Multiple myeloma (MM) is a B-cell neoplasm with a high incidence of relapse. Bortezomib has been extensively studied for the maintenance treatment of MM. Here, we carried out a meta-analysis to determine the efficacy and safety of maintenance therapy with bortezomib. We searched for clinical trials in PubMed (Medline), Embase (OVID), and the Cochrane Library. Two randomized controlled trials (RCTs) enrolling a total of 1338 patients were included. Bortezomib maintenance statistically significantly improved both progression-free survival (PFS) (hazard ratio (HR) 0.67, 95% confidence interval (CI) = 0.51 to 0.87, P=0.003) and overall survival (OS) (HR = 0.75 therapy, 95% CI = 0.63 to 0.89, P=0.001) more than did non-bortezomib maintenance therapy. Our analysis revealed higher incidence of neutropenia (risks ratios (RR) = 1.39; 95% CI = 1.08 to 1.79), peripheral neuropathy (PN) (RR = 2.23; 95% CI = 1.38 to 3.61, P=0.001), and cardiologic events (RR = 1.91; 95% CI = 1.12 to 3.28, P=0.02) in patients with bortezomib maintenance therapy. Our meta-analysis demonstrates OS and PFS benefits of bortezomib maintenance therapy in patients with newly diagnosed MM. However, the therapy is associated with increased risk of adverse events. Additionally, more RCTs are needed for better understanding and determination of optimal bortezomib maintenance therapy in MM.

Keywords: bortezomib; maintenance therapy; meta-analysis; multiple myeloma.

Conflict of interest statement

The authors declare that there are no competing interests associated with the manuscript.

© 2017 The Author(s).

Figures

Figure 1. Flow diagram of study selection.
Figure 1. Flow diagram of study selection.
Figure 2. Pooled HRs of PFS comparing…
Figure 2. Pooled HRs of PFS comparing bortezomib maintenance therapy arm with non-borzomib maintenance therapy arm.
Figure 3. Pooled HRs of OS comparing…
Figure 3. Pooled HRs of OS comparing bortezomib maintenance therapy arm with non-borzomib maintenance therapy arm.
Figure 4. Pooled RR of grade 3–4…
Figure 4. Pooled RR of grade 3–4 adverse events comparing bortezomib maintenance therapy arm with non-bortezomib maintenance therapy arm: Different events are separately shown from subparts (a) to (h)
(a) Neutropenia, (b) thrombocytopenia, (c) anemia, (d) infection, (e) deep vein thrombosis, (f) PN, (g) cardiologic events, and (h) GI symptoms.

References

    1. Palumbo A. and Anderson K. (2011) Multiple myeloma. N. Engl. J. Med. 364, 1046–1060
    1. Jemal A., Siegel R., Xu J. and Ward E. (2010) Cancer statistics, 2010. CA Cancer J. Clin. 60, 277–300
    1. Mihelic R., Kaufman J.L. and Lonial S. (2007) Maintenance therapy in multiple myeloma. Leukemia 21, 1150–1157
    1. Ludwig H., Durie B.G., McCarthy P., Palumbo A., San M.J., Barlogie B. et al. (2012) IMWG consensus on maintenance therapy in multiple myeloma. Blood 119, 3003–3015
    1. Nooka A.K., Behera M., Boise L.H., Kaufman J.L., Watson M., Lonial S. (2011) Thalidomide as maintenance therapy in multiple myeloma (MM) improves progression free survival (PFS) and overall survival (OS): a meta-analysis. ASH Annu. Meet. Abstr. 118, 1855
    1. Hahn A., Lilienfeld T.M. and Heteren P. (2011) Improved progression-free and overall survival with thalidomide maintenance therapy after autologous stem cell transplantation in multiple myeloma: a meta-analysis of five randomized trials. Haematologica 96, 884
    1. Morgan G.J., Gregory W.M., Davies F.E., Bell S.E., Szubert A.J. et al. (2012) The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis. Blood 119, 7–15
    1. Palumbo A., Bringhen S., Caravita T., Merla E., Capparella V. et al. (2006) Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet 367, 825–831
    1. Wijermans P., Schaafsma M., Termorshuizen F., Ammerlaan R., Wittebol S. et al. (2010) 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. 28, 3160–3166
    1. Waage A., Gimsing P., Fayers P., Abildgaard N., Ahlberg L. et al. (2010) Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood 116, 1405–1412
    1. Beksac M., Haznedar R., Firatli-Tuglular T., Ozdogu H., Aydogdu I., Konuk N. et al. (2011) 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. 86, 16–22
    1. Yang B., Yu R.L., Chi X.H. and Lu X.C. (2013) Lenalidomide treatment for multiple myeloma: systematic review and meta-analysis of randomized controlled trials. PLoS One 8, e64354.
    1. Palumbo A., Bringhen S., Kumar S.K., Lupparelli G., Usmani S., Waage A. et al. (2014) Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data. Lancet Oncol. 15, 333–342
    1. Adams J. (2004) The proteasome: a suitable antineoplastic target. Nat. Rev. Cancer 4, 349–360
    1. Yang H., Zonder J.A. and Dou Q.P. (2009) Clinical development of novel proteasome inhibitors for cancer treatment. Expert Opin. Investig. Drugs 18, 957–971
    1. Avet-Loiseau H., Leleu X., Roussel M., Moreau P., Guerin C.C., Caillot D. et al. (2010) Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J. Clin. Oncol. 28, 4630–4634
    1. McCarthy P.L., Einsele H., Attal M. and Giralt S (2014) The emerging role of consolidation and maintenance therapy for transplant-eligible multiple myeloma patients. Expert Rev. Hematol. 7, 55–66
    1. Rollig C., Knop S. and Bornhauser M. (2015) Multiple myeloma. Lancet 385, 2197–2208
    1. Schulz K.F., Altman D.G. and Moher D. (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann. Intern. Med. 152, 726–732
    1. Hartling L., Ospina M., Liang Y., Dryden D.M., Hooton N., Krebs-Seida J. et al. (2009) Risk of bias versus quality assessment of randomised controlled trials: cross sectional study. Br. Med. J. 339, b4012.
    1. Higgins J.P., Thompson S.G., Deeks J.J. and Altman D.G. (2003) Measuring inconsistency in meta-analyses. Br. Med. J. 327, 557–560
    1. DerSimonian R. and Laird N (1986) Meta-analysis in clinical trials. Control Clin. Trials 7, 177–188
    1. Palumbo A., Bringhen S., Larocca A., Rossi D., Di Raimondo F., Magarotto V. et al. (2014) 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. 32, 634–640
    1. Sonneveld P., Schmidt-Eolf I.G., van der Holt B., El Jarari J., Bertsch U., Salwender H. et al. (2012) 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. 30, 2946–2955
    1. Sonneveld P., Scheid C., Van Der Holt B., El Jarari J., Bertsch U., Salwender H. et al. (2013) Bortezomib induction and maintenance treatment improves survival in patients with newly diagnosed multiple myeloma: Extended follow-up of the HOVON-65/GMMG-HD4 trial. Blood 21, 122
    1. Rosinnol L., Albert O., Ana I.T., Dolores H., Javier L.J., Javier D.L.R. et al. (2012) Maintenance therapy after stem-cell transplantation for multiple myeloma with bortezomib/thalidomide vs. thalidomide vs. Alfa2b-interferon: Final results of a phase III PETHEMA/GEM randomized trial. Blood (ASH Ann. Meeting Abstr.) 120, Abstract 334
    1. Moreau P., Pylypenko H., Grosicki S., Karamanesht I., Leleu X., Grishunina M. et al. (2011) Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol. 12, 431–440
    1. Niesvizky R., Flinn I.W., Rifkin R.M., Gabrail N.Y., Charu V., Clowney B. et al. (2010) Phase 3b UPFRONT Study: safety and efficacy of weekly bortezomib maintenance therapy after bortezomib-based induction regimens in elderly, newly diagnosed multiple myeloma patients. ASH Ann. Meeting Abstr. 116, 619
    1. Niesvizky R., Flinn I.W., Rifkin R.M., Gabrail N.Y., Charu V., Clowney B. et al. (2011) Patient-reported quality of life (QoL) in elderly, newly diagnosed multiple myeloma (MM) patients receiving bortezomib-based combinations: results from all randomized patients in the community-based, Phase 3b UPFRONT Study. ASH Ann. Meeting Abstr. 118, 1864
    1. Mateos M.V., Oriol A., Martinez-Lopez J., Gutierrez N., Teruel A.I., Lopez De La Guia A. et al. (2012) Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood 120, 2581–2588
    1. Neben K., Lokhorst H.M., Jauch A., Bertsch U., Hielscher T., van der Holt B. et al. (2012) Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood 119, 940–948

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