1. in partnership with 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 Abstract presented at the 54th ASH ® Annual Meeting and Exposition Atlanta, December 8-11 2012 1 Haemato-Oncology Research Unit, Division of Molecular Pathology, The Institute of Cancer Research, London, UK; 2 Seràgnoli Institute of Hematology, Bologna University School of Medicine, Italy; 3 Wessex Regional Genetics Laboratory, University of Southampton, Salisbury, UK; 4 Clinical Trials Research Unit, University of Leeds, Leeds, UK; 5 St James's University Hospital, Leeds, UK; 6 Haematology Department, University of Newcastle, Newcastle-upon-Tyne, UK UKMF Spring Day UKMF Spring Day 13 th March 2013

2. Study Background Maintenance therapy can modify residual disease behaviour delaying or preventing relapses decreasing post relapse survival 10 9 10 8 10 7 10 6 10 5 10 4 10 3 10 2 10 Presentation PR VGPR CR sCR Cure Tumour bulk Relapse Time to progression Induction Maintenance Clonal extinction and cure Relapse Time Time to progression

3. 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 behaviours 1, 2 The presence of co-segregating adverse FISH lesion defines a group of patients with more aggressive disease 3 1.Avet-Loiseau H, et al. J Clin Oncol. 2012;30(16):1949-52. 2.Fonseca R, et al. Leukemia 2009;23(12):2210-21 3.Boyd K, et al. Leukemia 2012;26(2):349-55 PFSOS Study Background

4. Thalidomide maintenance Studies have shown conflicting results: improvement of tumor response 1-3 vs no improvement 4 improvement of progression-free survival (PFS) 1-2,5-6 vs no change 3 survival benefit 1,6-7 vs no advantage 3,5 higher benefit in lower 2,4 vs higher risk biological groups 9 impaired quality of life 10 6.Barlogie B, et al. N Engl J Med. 2006;354:1021-30 7.Brinker BT, et al. Cancer. 2006;106:2171-80 8.Barlogie B, et al. J Clin Oncol. 2010;28:1209-14 9.Barlogie B,et al. Blood 2008; 112:3115-3121 10.Hicks LK, et al. Cancer Treat Rev. 2008;34:442-52. 1.Spencer A, et al. J Clin Oncol. 2009;27:1788-93. 2.Attal M, et al. Blood. 2006;108:3289-94 3.Sahebi F, et al. Bone Marrow Transplant. 2006;37:825-9 4.Morgan GJ, et al. Blood 2012: 119:7-15 5.Lockhorst HM, et al. Blood. 2010;115:1113-20 Evaluate the impact of thalidomide maintenance on biological risk groups defined by co-segregating FISH lesion

5. Study Design MP CTDa No Maintenance Thalidomide Maintenance Randomization Induction 1-3 Older, less fit Thalidomide maintenance = 50 mg/day × 4 weeks, increasing thereafter to 100 mg/day if well tolerated, until disease progression CVAD CTD Younger, fitter HDM 200 mg/m 2 1.Morgan GJ, et al. Lancet. 2010;376:1989-99. 2.Morgan GJ, et al. Haematologica. 2012: 97(3):442-50. 3.Morgan GJ, et al. Blood. 2011;118:1231-8. 4. Morgan GJ, et al. Blood. 2012: 119:7-15. CTD, cyclophosphamide, thalidomide and dexamethasone; CTDa, CTD attenuated (low-intensity); CVAD, vincristine, doxorubicin, dexamethasone and cyclophosphamide; HDM, high-dose melphalan; MP, melphalan and prednisone. Maintenance 4 Median time on maintenance treatment: 7 months MRC Myeloma IX trial

6. Study accrual2003-2007 N° pts enrolled N° entered maintenance N° ® thalidomide N° ® no maintenance 1960 818 408 410 Cutoff dateFebruary 2012 Median follow-up -from beginning of therapy -from beginning of maintenance 5.9 years 5.4 years Thalidomide maintenance vs no maintenance

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

8. Evaluable patients 881 patients entered maintenance 369 patients with complete:  IgH@  del 17(p13)  +1(q32) 182 thalidomide maintenance 182 thalidomide maintenance 187 no maintenance 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 each maintenance arm had received Zoledronic acid 60% of patients in each maintenance arm had received ASCT 50% of patients in each maintenance 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 p=0.004 Months from maintenance randomization survival Thal maintenance No maintenance Standard risk FISH p=0.475 survival Months from maintenance randomization Thal maintenance No maintenance p=0.840 survival Months from maintenance randomization Thal maintenance No maintenance High risk FISH Ultra-high risk FISH Median PFS: 29.6 m vs 20.3 m Median PFS: 11.3 m vs 13.4 m Median PFS: 6.5 m vs 6.3 m Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

13. Months from maintenance randomization survival p=0.431 Thal maintenance No maintenance Months from maintenance randomization survival p=0.039 Thal maintenance No maintenance Months from maintenance randomization p=0.975 survival Thal maintenance No maintenance FISH based risk groups OS Standard risk FISH High risk FISH Ultra-high risk FISH Median OS: NR in both arms Median OS: 23.5 m vs 42.4 m Median PFS: 34.7 m vs NR 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 No maintenance p=0.069 p=0.280 p=0.813 Thal maintenance No maintenance Thal maintenance No maintenance No t(11;14) t(11;14)t(11;14)+1 p=0.163 p=0.455 p=0.362 Thal maintenance No maintenance Thal maintenance No maintenance Thal maintenance No maintenance Months from maintenance randomization survival Months from maintenance randomization 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 Median PFS: 22.1 m vs 14.7 m Median PFS: 18.9 m vs 18.8 m Median PFS: 11.7 m vs 12.1 m Brioli A. et al, Leuk Lymphoma 2013 [Epub ahead of print]

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

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

17. Hyperdiploidy defined risk groups OS Months from maintenance randomization survival p=0.958 Thal maintenance No maintenance Hyperdiploidy alone Months from maintenance randomization survival p=0.258 Thal maintenance No maintenance Months from maintenance randomization survival Thal maintenance No maintenance Hyperdiploidy+1 No Hyperdiploidy p=0.056 Median OS: 48.8 m vs NR Median OS: NR in both arm Median OS: 30.0 m vs 54.7 m 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 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 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 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

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