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The Impact of Thalidomide Maintenance Therapy Varies According to Biological Risk Grouping

The Impact of Thalidomide Maintenance Therapy Varies According to Biological Risk Grouping. Annamaria Brioli. Fiona M Ross 3 , Martin Kaiser 1 , Charlotte Pawlyn 1 , Ping Wu 1 , Walter M Gregory 4 , Roger Owen 5 , Graham H Jackson 6 , Michele Cavo 2 , Faith E Davies 1 , Gareth J Morgan 1.

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The Impact of Thalidomide Maintenance Therapy Varies According to Biological Risk Grouping

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  1. The Impact of Thalidomide Maintenance Therapy Varies According to Biological Risk Grouping Annamaria Brioli Fiona M Ross3, Martin Kaiser1, Charlotte Pawlyn1, Ping Wu1, Walter M Gregory4, Roger Owen5, Graham H Jackson6, Michele Cavo2, Faith E Davies1, Gareth J Morgan1 1Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK; 2Seràgnoli Institute of Hematology, Bologna University School of Medicine, Italy; 3Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, UK; 4Clinical Trials Research Unit, University of Leeds, Leeds, UK; 5St James's University Hospital, Leeds, UK; 6Haematology Department, University of Newcastle, Newcastle-upon-Tyne, UK UKMF Spring Day 13th March 2013 Abstract presented at the 54th ASH® Annual Meeting and Exposition Atlanta, December 8-11 2012

  2. Study Background • Maintenance therapy can modify residual disease behaviour • delaying or preventing relapses • decreasing post relapse survival Induction Maintenance 109 Presentation PR Relapse VGPR CR 108 107 Relapse 106 Time to progression 105 Tumour bulk Time to progression sCR 104 Relapse 103 102 Relapse 10 Cure Clonal extinction and cure Time

  3. Study Background • The impact of maintenance may vary according to the underlying biology of the disease • Genetic alterations, such as t(4;14), del(17p) and +1q, can be used to define different biological behaviours1, 2 • The presence of co-segregating adverse FISH lesion defines a group of patients with more aggressive disease3 PFS OS • Avet-Loiseau H, et al. J ClinOncol. 2012;30(16):1949-52. • Fonseca R, et al. Leukemia 2009;23(12):2210-21 • Boyd K, et al. Leukemia 2012;26(2):349-55

  4. Study Background Thalidomide maintenance • Studies have shown conflicting results: • improvement of tumor response1-3 vs no improvement4 • improvement of progression-free survival (PFS)1-2,5-6vs no change3 • survival benefit1,6-7vs no advantage3,5 • higher benefit in lower2,4vs higher risk biological groups9 • impaired quality of life10 Evaluate the impact of thalidomide maintenance on biological risk groups defined by co-segregating FISH lesion • Spencer A, et al. J Clin Oncol. 2009;27:1788-93. • Attal M, et al. Blood. 2006;108:3289-94 • Sahebi F, et al. Bone Marrow Transplant. 2006;37:825-9 • Morgan GJ, et al. Blood 2012: 119:7-15 • Lockhorst HM, et al. Blood. 2010;115:1113-20 Barlogie B, et al. N Engl J Med. 2006;354:1021-30 Brinker BT, et al. Cancer. 2006;106:2171-80 Barlogie B, et al. J Clin Oncol. 2010;28:1209-14 Barlogie B,et al. Blood 2008; 112:3115-3121 Hicks LK, et al. Cancer Treat Rev. 2008;34:442-52.

  5. MRC Myeloma IX trial Study Design Induction1-3 Maintenance4 CTDa Thalidomide Maintenance Older, less fit MP Median time on maintenance treatment: 7 months Randomization CTD No Maintenance HDM 200mg/m2 Younger, fitter CVAD • Thalidomide maintenance = 50 mg/day × 4 weeks, increasing thereafter to • 100 mg/day if well tolerated, until disease progression CTD, cyclophosphamide, thalidomide and dexamethasone; CTDa, CTD attenuated (low-intensity); CVAD, vincristine, doxorubicin, dexamethasone and cyclophosphamide; HDM, high-dose melphalan; MP, melphalan and prednisone. Morgan GJ, et al. Lancet. 2010;376:1989-99. Morgan GJ, et al. Haematologica. 2012: 97(3):442-50. Morgan GJ, et al. Blood. 2011;118:1231-8. Morgan GJ, et al. Blood. 2012: 119:7-15.

  6. MRC Myeloma IX trial Thalidomide maintenance vs no maintenance

  7. PFS and OS according to maintenance randomization MRC Myeloma IX trial PFS OS Thal maintenance Thal maintenance Median PFS: 23.0 m vs 15.3 m Median OS: 59.1 m vs 57.6 m No maintenance No maintenance p=0.397 p<0.001 survival survival Months from maintenance randomization Months from maintenance randomization

  8. Evaluable patients 881 patientsenteredmaintenance • 369 patients with complete: • IgH@ • del 17(p13) • +1(q32) 182 thalidomidemaintenance 187 no maintenance Median time from initiation of trial to maintenance randomization: 8.3 months Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

  9. Patients’ characteristics Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

  10. Response rate pre maintenance randomization • 60% of patients in each maintenance arm had received ASCT • 50% of patients in eachmaintenance arm had received Zoledronic acid Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

  11. Presence of genetic alterations SR HR UHR Each lesion was considered whether present in isolation or plus an additional adverse lesion (+(1)(q21) and del(17)(p13) for IGH translocations, +(1)(q21), del(17)(p13) and t(4;14) for hyperdiploidy). • FISH based risk groups: • Standard risk: no adverse FISH lesion • High risk: presence of one of t(4;14), t(14;16), t(14;20), del17(p13), +1(q32) • Ultra high risk: presence of two or more between t(4;14), t(14;16), t(14;20), del17(p13), +1(q32) Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

  12. FISH based risk groups PFS Thal maintenance Thal maintenance No maintenance No maintenance p=0.004 Thal maintenance High risk FISH Standard risk FISH p=0.840 No maintenance survival survival Median PFS: 11.3 m vs 13.4 m Median PFS: 29.6 m vs 20.3 m p=0.475 survival Months from maintenance randomization Months from maintenance randomization Ultra-high risk FISH Months from maintenance randomization Median PFS: 6.5 m vs 6.3 m Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

  13. FISH based risk groups OS Thal maintenance Thal maintenance No maintenance No maintenance Thal maintenance p=0.039 p=0.431 High risk FISH p=0.975 Standard risk FISH No maintenance Median PFS: 34.7 m vs NR Median OS: NR in botharms survival survival survival Months from maintenance randomization Months from maintenance randomization Months from maintenance randomization Ultra-high risk FISH Median OS: 23.5 m vs 42.4 m Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

  14. Translocation defined risk groups PFS No t(4;14) t(4;14) t(4;14)+1 Thal maintenance Thal maintenance Thal maintenance Median PFS: 22.1 m vs 16.1 m Median PFS: 24.6 m vs 7.1 m Median PFS: 5.3 m vs 6.0 m No maintenance No maintenance No maintenance p=0.069 p=0.280 p=0.813 survival survival survival Months from maintenance randomization Months from maintenance randomization Months from maintenance randomization No t(11;14) t(11;14) t(11;14)+1 Thal maintenance Thal maintenance Thal maintenance Median PFS: 18.9 m vs 18.8 m Median PFS: 22.1 m vs 14.7 m Median PFS: 11.7 m vs 12.1 m No maintenance No maintenance No maintenance p=0.163 p=0.362 p=0.455 survival survival survival Months from maintenance randomization Months from maintenance randomization Months from maintenance randomization Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

  15. Translocation defined risk groups OS t(4;14) t(4;14)+1 No t(4;14) Thal maintenance Thal maintenance Thal maintenance Median OS: NR vs 36.1 m Median OS: 54.6 m vs NR Median OS: 31.1 m vs 42.4 m No maintenance No maintenance No maintenance p=0.987 p=0.762 survival survival survival p=0.106 Months from maintenance randomization Months from maintenance randomization Months from maintenance randomization t(11;14)+1 t(11;14) No t(11;14) Thal maintenance Thal maintenance Thal maintenance Median OS: 29..6 m vs NR Median OS: 54.6 m vs NR Median OS: NR in botharm No maintenance No maintenance No maintenance p=0.128 survival survival survival p=0.940 p=0.182 Months from maintenance randomization Months from maintenance randomization Months from maintenance randomization

  16. Hyperdiploidy defined risk groups PFS Thal maintenance No maintenance Hyperdiploidy alone No Hyperdiploidy p=0.003 Median PFS: 14.0 m vs 13.3 m Thal maintenance Median PFS: 36.7 m vs 22.7 m survival No maintenance p=0.417 survival Months from maintenance randomization Hyperdiploidy+1 Months from maintenance randomization Thal maintenance Median PFS: 8.7 m vs 11.1 m No maintenance p=0.142 survival Months from maintenance randomization Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

  17. Hyperdiploidy defined risk groups OS Thal maintenance No maintenance Hyperdiploidy alone No Hyperdiploidy Thal maintenance Median OS: 48.8 m vs NR Median OS: NR in botharm No maintenance survival p=0.958 survival p=0.258 Months from maintenance randomization Months from maintenance randomization Hyperdiploidy+1 Median OS: 30.0 m vs 54.7 m Thal maintenance p=0.056 No maintenance survival Months from maintenance randomization Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

  18. Conclusions • The association of multiple FISH adverse genetic lesions has an additive effect • Maintenance thalidomide: • prolongs PFS of both transplant eligible and non eligible patients • prolongs PFS in patients with low biological risk disease (hyperdiploidy and standard risk FISH)

  19. Aknowledgments Chief Investigators JA Child GJ Morgan GH Jackson CTRU, Leeds K Cocks W Gregory A Szubert S Bell N Navarro Coy F Heatley P Best J Carder M Matouk D Emsell A Davies D Phillips MRC Leukaemia Trial Steering Committee MRC Leukaemia Data Monitoring and Ethics Committee NCRI Haematological Oncology Clinical Studies Group UK Myeloma Forum Clinical Trials Committee Myeloma UK Funding Medical Research Council Pharmion Novartis Chugai Pharma Bayer Schering Pharma OrthoBiotech Celgene Kay Kendall Leukaemia Fund University of Birmingham MT Drayson K Walker A Adkins N Newnham Wessex Regional Genetics Laboratory, Salisbury F Ross L Chieccio LTHT, Leeds G Cook S Feyler D Bowen HMDS, Leeds RG Owen AC Rawstron R de Tute M Dewar S Denman ICR, London FE Davies M Jenner B Walker D Johnson D Gonzalez N Dickens K Boyd P Leone L Brito A Avridromou C Pawlyn M Kaiser L Melchor Everyone else from the Morgan and Davies Teams

  20. Aknowledgments Patients and staff from 121 participating institutions in the UK

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