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Meta-Analysis
. 2016 Apr 20;4(4):CD010816.
doi: 10.1002/14651858.CD010816.pub2.

Bortezomib for the treatment of multiple myeloma

Kathleen Scott  1 , Patrick J Hayden, Andrea Will, Keith Wheatley, Imelda Coyne
Affiliations
Meta-Analysis

Bortezomib for the treatment of multiple myeloma

Kathleen Scott et al. Cochrane Database Syst Rev. .

Abstract

Background: Multiple myeloma is a malignancy of plasma cells accounting for approximately 1% of cancers and 12% of haematological malignancies. The first-in-class proteasome inhibitor, bortezomib, is commonly used to treat newly diagnosed as well as relapsed/refractory myeloma, either as single agent or combined with other therapies.

Objectives: We conducted a systematic review and meta-analysis to assess the effects of bortezomib on overall survival (OS), progression-free survival (PFS), response rate (RR), health-related quality of life (HRQoL), adverse events (AEs) and treatment-related death (TRD).

Search methods: We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE (till 27 January 2016) as well as conference proceedings and clinical trial registries for randomised controlled trials (RCTs).

Selection criteria: We included randomised controlled trials (RCTs) that compared i) bortezomib versus no bortezomib with the same background therapy in each arm; ii) bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s) and iii) bortezomib dose comparisons and comparisons of different treatment administrations and schedules.

Data collection and analysis: Two review authors independently extracted outcomes data and assessed risk of bias. We extracted hazard ratios (HR) and their confidence intervals for OS and PFS and odds ratios (OR) for response rates, AEs and TRD. We contacted trial authors to provide summary statistics if missing. We estimated Logrank statistics which were not available. We extracted HRQoL data, where available.

Main results: We screened a total of 3667 records, identifying 16 relevant RCTs involving 5626 patients and included 12 trials in the meta-analyses. All trials were randomised and open-label studies. Two trials were published in abstract form and therefore we were unable to assess potential risk of bias in full.There is moderate-quality evidence that bortezomib prolongs OS (four studies, 1586 patients; Peto OR 0.77, 95% CI 0.65 to 0.92) and PFS (five studies, 1855 patients; Peto OR 0.65, 95% CI 0.57 to 0.74) from analysing trials of bortezomib versus no bortezomib with the same background therapy in each arm.There is high-quality evidence that bortezomib prolongs OS (five studies, 2532 patients; Peto OR 0.76, 95% CI 0.67 to 0.88) but low-quality evidence for PFS (four studies, 2489 patients; Peto OR 0.67, 95% CI 0.61 to 0.75) from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s).Four trials (N = 716) examined different doses, methods of administrations and treatment schedules and were reviewed qualitatively only.We identified four trials in the meta-analysis that measured time to progression (TTP) and were able to extract and analyse PFS data for three of the studies, while in the case of one study, we included TTP data as PFS data were not available. We therefore did not analyse TTP separately in this review.Patients treated with bortezomib have increased risk of thrombocytopenia, neutropenia, gastro-intestinal toxicities, peripheral neuropathy, infection and fatigue with the quality of evidence highly variable. There is high-quality evidence for increased risk of cardiac disorders from analysing trials of bortezomib versus no bortezomib with different background therapy in each arm or versus other agents. The risk of TRD in either comparison group analysed is uncertain due to the low quality of the evidence.Only four trials analysed HRQoL and the data could not be meta-analysed.Subgroup analyses by disease setting revealed improvements in all outcomes, whereas for therapy setting, an improved benefit for bortezomib was observed in all outcomes and subgroups except for OS following consolidation therapy.

Authors' conclusions: This meta-analysis found that myeloma patients receiving bortezomib benefited in terms of OS, PFS and response rate compared to those who did not receive bortezomib. This benefit was observed in trials of bortezomib versus no bortezomib with the same background therapy and in trials of bortezomib versus no bortezomib with different background therapy in each arm or compared to other agent(s). Further evaluation of newer proteasome inhibitors is required to ascertain whether these agents offer an improved risk-benefit profile, while more studies of HRQoL are also required.

PubMed Disclaimer

Conflict of interest statement

Kathleen Scott: None known.

Andrea Will: None known.

Keith Wheatley: None known.

Patrick J Hayden: Received payment for talks given at educational meetings from Janssen Cilag, Celgene, Sanofi; received payment for participation in advisory board meetings from Janssen Cilag, Celgene.

Imelda Coyne: None known.

Figures

1
1
Study flow diagram.
2
2
'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 3 All studies, outcome: 3.1 Overall Survival.
5
5
Forest plot of comparison: 3 All studies, outcome: 3.2 Progression Free Survival.
6
6
Forest plot of comparison: 3 All studies, outcome: 3.3 Complete Response Rate.
7
7
Forest plot of comparison: 3 All studies, outcome: 3.4 Overall Response Rate.
1.1
1.1. Analysis
Comparison 1 All Studies, Outcome 1 Overall Survival.
1.2
1.2. Analysis
Comparison 1 All Studies, Outcome 2 Progression‐Free Survival.
1.3
1.3. Analysis
Comparison 1 All Studies, Outcome 3 Complete Response Rate.
1.4
1.4. Analysis
Comparison 1 All Studies, Outcome 4 Overall Response Rate.
1.5
1.5. Analysis
Comparison 1 All Studies, Outcome 5 Treatment‐related death.
1.6
1.6. Analysis
Comparison 1 All Studies, Outcome 6 Adverse Events: Thrombocytopenia.
1.7
1.7. Analysis
Comparison 1 All Studies, Outcome 7 Adverse Events: Neutropenia.
1.8
1.8. Analysis
Comparison 1 All Studies, Outcome 8 Adverse Events: Anaemia.
1.9
1.9. Analysis
Comparison 1 All Studies, Outcome 9 Adverse Events: Nausea/Vomiting.
1.10
1.10. Analysis
Comparison 1 All Studies, Outcome 10 Adverse Events: Diarrhoea.
1.11
1.11. Analysis
Comparison 1 All Studies, Outcome 11 Adverse Events: Constipation.
1.12
1.12. Analysis
Comparison 1 All Studies, Outcome 12 Adverse Events: Peripheral Neuropathy.
1.13
1.13. Analysis
Comparison 1 All Studies, Outcome 13 Adverse Events: Infections (All).
1.14
1.14. Analysis
Comparison 1 All Studies, Outcome 14 Adverse Events: Herpes Zoster infection.
1.15
1.15. Analysis
Comparison 1 All Studies, Outcome 15 Adverse Events: Cardiac Disorders.
1.16
1.16. Analysis
Comparison 1 All Studies, Outcome 16 Adverse Events: Fatigue.
2.1
2.1. Analysis
Comparison 2 Subgroup Analyses ‐ Disease Setting, Outcome 1 Overall Survival.
2.2
2.2. Analysis
Comparison 2 Subgroup Analyses ‐ Disease Setting, Outcome 2 Progression Free Survival.
2.3
2.3. Analysis
Comparison 2 Subgroup Analyses ‐ Disease Setting, Outcome 3 Complete Response Rate.
2.4
2.4. Analysis
Comparison 2 Subgroup Analyses ‐ Disease Setting, Outcome 4 Overall Response Rate.
3.1
3.1. Analysis
Comparison 3 Subgroup Analyses ‐ Therapy Setting, Outcome 1 Overall Survival.
3.2
3.2. Analysis
Comparison 3 Subgroup Analyses ‐ Therapy Setting, Outcome 2 Progression Free Survival.
3.3
3.3. Analysis
Comparison 3 Subgroup Analyses ‐ Therapy Setting, Outcome 3 Complete Response Rate.
3.4
3.4. Analysis
Comparison 3 Subgroup Analyses ‐ Therapy Setting, Outcome 4 Overall Response Rate.
See this image and copyright information in PMC

Update of

References

References to studies included in this review

All India Institute Study {published data only}
    1. Sahai S, Kumar L, Raina V, Sharma A, Gupta R, Mahajan S, et al. Multiple myeloma with light chain‐induced acute renal failure ‐ role of bortezomib‐dexamethasone & cyclophosphamide‐thalidomide & dexamethasone: a prospective randomized study (Abstract 3648). Proceedings of the European Cancer Congress. Amsterdam, 27 Sep ‐ 01 Oct 2013.
APEX Study {published data only}
    1. Chanan‐Khan A, Sonneveld P, Schuster MW, Stadtmauer EA, Facon T, Harousseau JL, et al. Analysis of herpes zoster events among bortezomib‐treated patients in the phase III APEX study. Journal of Clinical Oncology 2008;26(29):4784‐90. - PubMed
    1. Lee SJ, Richardson PG, Sonneveld P, Schuster MW, Irwin D, San Miguel JF, et al. Bortezomib is associated with better health‐related quality of life than high‐dose dexamethasone in patients with relapsed multiple myeloma: results from the APEX study. British Journal of Haematology 2008;143(4):511‐9. - PubMed
    1. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high‐dose dexamethasone for relapsed multiple myeloma. New England Journal of Medicine 2005;352(24):2487‐98. - PubMed
    1. Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer EA, Facon T, et al. Extended follow‐up of a phase 3 trial in relapsed multiple myeloma: final time‐to‐event results of the APEX trial. Blood 2007;110(10):3557‐60. - PubMed
CREST Study {published data only}
    1. Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, et al. A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. British Journal of Haematology 2004;127(2):165‐72. - PubMed
    1. Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Richardson PG, et al. Updated survival analyses after prolonged follow‐up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. British Journal of Haematology 2008;143(4):537‐40. - PubMed
GEM05MENOS65 Study {published data only}
    1. Rosinol L, Oriol A, Teruel AI, Hernandez D, Lopez‐Jiminez J, Rubia J, et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood 2012;120(8):1589‐96. - PubMed
    1. Rosinol L, Oriol A, Teruel AL, Hernandez D, Lopez‐Jimenez J, Rubia J, et al. 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 Annual Meeting Abstracts) Abstract 334. 2012; Vol. 120, issue 21.
GEM2010MAS65 Study {published data only}
    1. Mateos MV, Martinez‐Lopez J, Hernandez MT, Martinez R, Rosinnol L, Ocio EM, et al. Comparison of sequential vs alternating administration of bortezomib, melphalan and prednisone (VMP) and lenalidomide plus dexamethasone (Rd) in elderly patients with newly diagnosed multiple myeloma (MM) patients: GEM2010MAS65 trial. Blood (ASH Annual Meeting Abstracts) Abstract 178. 2014; Vol. 124.
    1. Mateos MV, Martinez‐Lopez J, Hernandez MT, Martinez R, Rosinnol L, Ocio EM, et al. Comparison of sequential vs alternating administration of bortezomib, melphalan and prednisone (VMP) and lenalidomide plus dexamethasone (Rd) in elderly patients with newly diagnosed multiple myeloma (MM) patients: GEM2010MAS65 trial. Blood (ASH Annual Meeting Abstracts) Abstract 403. 2013; Vol. 122, issue 21.
GIMEMA‐MM‐03‐05 Study {published data only}
    1. Palumbo A, Bringhen S, Paoli L, Cotzia E, Ria R, Gentili S, et al. Bortezomib‐melphalan‐prednisone‐thalidomide followed by continuous bortezomib thalidomide (VMPT‐VT) improved survival. Clinical Lymphoma, Myeloma and Leukemia 2013;13:S106‐107.
    1. Palumbo A, Bringhen S, Larocca A, Rossi D, Raimondo F, Magarotto V, 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. Journal of Clinical Oncology 2014;32(7):634‐40. - PubMed
    1. Palumbo A, Bringhen S, Rossi D, Cavalli M, Larocca A, Ria R, 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. Journal of Clinical Oncology 2010;28(34):5101‐9. - PubMed
GIMEMA‐MMY‐3006 Study {published data only}
    1. Cavo M, Galli M, Pantani L, Raimondo F, Crippa C, Offidani M, et al. Bortezomib‐thalidomide‐dexamethasone incorporated into autotransplantation is associated with more favorable outcomes after relapse in comparison with thalidomide‐dexamethasone plus autotransplantation in multiple myeloma. Blood (ASH Annual Meeting Abstracts) Abstract 4210. 2012; Vol. 120.
    1. Cavo M, Galli M, Pezzi A, Raimondo F, Crippa C, Offidani M, et al. Persistent improvement in clinical outcomes with bortezomib‐thalidomide‐dexamethasone vs thalidomide‐dexamethasone incorporated into double autologous transplantation for multiple myeloma: an updated analysis of phase 3 Gimema‐MMY‐3006 study. Blood (ASH Annual Meeting Abstracts) Abstract 2090. 2013; Vol. 122, issue 21.
    1. Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, et al. Bortezomib‐thalidomide‐dexamethasone is superior to thalidomide‐dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Blood 2012;120(1):9‐19. - PubMed
    1. Cavo M, Tacchetti P, Patriarca F, Petrucci MT, Pantani L, Galli M, et al. 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):2075‐85. - PubMed
HOVON‐65/GMMG‐HD4 Study {published data only}
    1. Sonneveld P, Scheid C, Holt B, Jarari L, Bertsch U, Salwender H, et al. 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 (ASH Annual Meeting Abstracts) Abstract 404. 2013; Vol. 122, issue 21.
    1. Sonneveld P, Schmidt‐Wolf IGH, Holt B, Jarari L, Bertsch U, Salwender H, 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. Journal of Clinical Oncology 2012;30(24):2946‐55. - PubMed
IFM 2005‐01 Study {published data only}
    1. Harousseau JL, Attal M, Avet‐Loiseau H, Marit G, Caillot D, Mohty M, et al. Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem‐cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005‐01 phase III trial. Journal of Clinical Oncology 2010;28(30):4621‐9. - PubMed
IFM 2007‐02 Study {published data only}
    1. Moreau P, Avet‐Loiseau H, Facon T, Attal M, Tiab M, Hulin C, et al. Bortezomib plus dexamethasone versus reduced‐dose bortezomib, thalidomide plus dexamethasone as induction treatment before autologous stem cell transplantation in newly diagnosed multiple myeloma. Blood 2011;118(22):5752‐8. - PubMed
MD Anderson Study {published data only}
    1. Sharma M, Khan H, Thall PF, Orlowski RZ, Bassett Jr RL, Shah N, et al. A randomized phase 2 trial of a preparative regimen of bortezomib, high‐dose melphalan, arsenic trioxide, and ascorbic acid. Cancer 2012;118(9):2507‐15. - PMC - PubMed
MMVAR/IFM 2005‐04 Study {published data only}
    1. Garderet L, Iacobelli S, Moreau P, Mamoun D, Lafon I, Niederwieser D, et al. Superiority of the triple combination of bortezomib‐thalidomide‐dexamethasone over the dual combination of thalidomide‐dexamethasone in patients with multiple myeloma progressing or relapsing after autologous transplantation: the MMVAR/IFM 2005‐04 Randomized Phase III Trial from the Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Journal of Clinical Oncology 2012;30(20):2475‐82. - PubMed
MMY‐3021 Study {published data only}
    1. Arnulf B, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Velde H, et al. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica 2012;97(12):1925‐8. - PMC - PubMed
    1. Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non‐inferiority study. Lancet Oncology 2011;12(5):431‐40. - PubMed
NMSG 15/05 Study {published data only}
    1. Mellqvist UH, Gimsing P, Hjertner O, Lenhoff S, Laane E, Remes K, et al. Bortezomib consolidation after autologous stem cell transplantation in multiple myeloma: a Nordic Myeloma Study Group randomized phase 3 trial. Blood 2013;121(23):4647‐54. - PMC - PubMed
NMSG 17/07 Study {published data only}
    1. Hjorth M, Hjertner O, Knudsen LM, Gulbrandsen N, Homberg E, Pedersen PT, et al. Thalidomide and dexamethasone vs. bortezomib and dexamethasone for melphalan refractory myeloma: a randomized study. European Journal of Haematology 2012;88(6):485‐96. - PMC - PubMed
VISTA Study {published data only}
    1. Delforge M, Dhawan R, Robinson D Jr, Meunier J, Regnault A, Esseltine DL, et al. Health‐related quality of life in elderly, newly diagnosed multiple myeloma patients treated with VMP vs. MP: results from the VISTA trial. European Journal of Haematology 2012;89(1):16‐27. - PubMed
    1. Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow‐up and impact of subsequent therapy in the phase III VISTA trial. Journal of Clinical Oncology 2010;28(13):2259‐66. - PubMed
    1. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. New England Journal of Medicine 2008;359(9):906‐17. - PubMed
    1. San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib‐melphalan‐prednisone versus melphalan‐prednisone in patients with previously untreated multiple myeloma. Journal of Clinical Oncology 2013;31(4):448‐55. - PubMed
    1. Spicka I, Mateos MV, Redman K, Dimopoulos MA, Richardson PG. An overview of the VISTA trial: newly diagnosed, untreated patients with multiple myeloma ineligible for stem cell transplantation. Immunotherapy 2011;3(9):1033‐40. - PubMed

References to studies excluded from this review

Chen 2011b {published data only}
    1. Chen RA, Tu Y, Cao Y, Liu L, Liang Y. Bortezomib‐dexamethasone or vincristine‐doxorubicin‐dexamethasone as induction therapy followed by thalidomide as maintenance therapy in untreated multiple myeloma patients. Journal of International Medical Research 2011;39(5):1975‐84. - PubMed
Goldschmidt 2012 {published data only}
    1. Goldschmidt H, Salwender H, Bertsch U, et al. GMMG MM5 trial in newly diagnosed multiple myeloma to evaluate PAD vs VCD induction prior to HDT followed by lenalidomide consolidation and maintenance ‐ first interim analysis on induction. Haematologica 2012;97(115):Abstract 285.
Kumar 2012 {published data only}
    1. Kumar S, Flinn I, Richardson PG, Hari P, Callander N, Noga SJ, et al. Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma. Blood 2012;119(19):4375‐82. - PubMed
Mateos 2010 {published data only}
    1. Mateos MV, Oriol A, Martínez‐López J, Gutiérrez N, Teruel AI, Paz R, 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 Oncology 2010;11(10):934‐41. - PubMed
Niesvisky 2010 {published data only}
    1. Niesvizky R, Flinn IW, Rifkin RM, Gabrail NY, Charu V, et al. Phase 3b UPFRONT study: safety and efficacy of weekly bortezomib maintenance therapy after bortezomib‐based induction regimens in elderly, newly diagnosed multiple myeloma patients. American Society of Hematology. 2010.
Orlowski 2007 {published data only}
    1. Orlowski R, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. Journal of Clinical Oncology 2007;25(25):3892‐901. - PubMed

References to studies awaiting assessment

References to ongoing studies

CLARION Study {unpublished data only}
    1. CLARION Study. Ongoing study 2013.
Consolidation (61‐75 years) Study {unpublished data only}
    1. CR006127 Study. Ongoing study 2006.
Consolidation (less than 60 years) Study {unpublished data only}
    1. CR006124 Study. Ongoing study 2006.
E1A11 Study {unpublished data only}
    1. ECOG E1A11 Study. Ongoing study 2013.
ENDEAVOR Study {unpublished data only}
    1. ENDEAVOR Study. Ongoing study 2012.
Hackensack University Study {unpublished data only}
    1. PRO# 1307 Study. Ongoing study 2010.
HOVON 95 Study {unpublished data only}
    1. HOVON 95 Study. Ongoing study 2011.
King Fasail Hospital Study {unpublished data only}
    1. 2081‐113 Study. Ongoing study 2009.
Optimized Retreatment Study {unpublished data only}
    1. CR018796 Study. Ongoing study 2013.
Subcutaneous Bortezomib Maintenance Study {unpublished data only}
    1. Subcutaneous bortezomib maintenance Study. Ongoing study 2013.
SWOG‐S0777 Study {unpublished data only}
    1. SWOG‐S0777 Study. Ongoing study 2008.
VCAT Study {unpublished data only}
    1. CR018751 Study. Ongoing study 2012.
Wuerzburg University Hospital Study {unpublished data only}
    1. DSMM XIV Study. Ongoing study 2012.

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