1. Optimal Use of Transplant for Myeloma Early-Late-nonablative Koen van Besien, MD, PhD Weill Cornell Medical College

2. Optimal Use of Transplant for Myeloma Transplant Early! Consider Allogeneic Transplant! Koen van Besien, MD, PhD Weill Cornell Medical College

3. Why Transplant Early? It is the standardIt is the standard It is less toxic than alternativesIt is less toxic than alternatives It is curative therapyIt is curative therapy

4. High-Dose Therapy and Autologous SCT Improves PFS and OS in Younger Patients Child JA, et al. N Engl J Med. 2003;348:1875-1883.; Attal M, et al. N Engl J Med. 1996;335:91-97.

5. ASCT vs. Conventional CT Results of Randomized Studies Attal, et al. 1996IFM90 CT Auto Tx Fermand, et al. 2005MAG91 CT Auto Tx Child, et al. 2003MRC7 CT Auto Tx Palumbo, et al. 2004IMMSG CT Auto Tx Blade, et al. 2005PETHEMA CT Auto Tx Barlogie, Kyle, et al. 2006USIG CT Auto Tx 100 96 94 200 201 98 97 83 81 255 261 5 22 18 27 20 36 19 25 a 9 44 20 32 6 25 16 28 11 30 33 42 11 16% at 7 years 17% 44 57 48 42.3 54.1 43 58+ 66 61 38% at 7 years 38%.03 <.001 Patients (n) OS (months) P Value EFS (months) CR (%) CT = chemotherapy; Auto Tx = autologous therapy; IFM = Intergroupe Francais du Myelome; IMMSG = Italian Multiple Myeloma Study Group; MAG = Group Myelome Autographe; MRC = Medical Research Council; USIG = US Intergroup a P =.07

12. Why Transplant Early? It is the standard.It is the standard. It is less toxic than alternativesIt is less toxic than alternatives It is curative therapyIt is curative therapy

13. Months HDT/PSCT: Upfront vs. Rescue Treatment Show Similar OS but Better QOL with Early SCT *Time without symptoms and treatment toxicity Fermand J, et al. Blood. 1998;92:3131-3136 64.6 64.0 39.0 13.0 27.8 22.3 P =.92 n=202

14. 14 Impact of ASCT on QOL of FL patients Andresen et al Leuk & Lymph, 2012; 53: 386

15. Why Transplant Early? It is the standardIt is the standard It induces more remissionsIt induces more remissions It is curative therapyIt is curative therapy

17. Martinez-Lopez et al Blood. 2011;118(3):529-534 CR vs. nCR/VGPR/PR vs. Menos

18. Martinez-Lopez et al Blood. 2011;118(3):529-534 Abstract

19. Why Transplant Early? It is the standardIt is the standard It is less toxic than alternativesIt is less toxic than alternatives Delaying curative therapy until after disease recurrence may result in loss of curabilityDelaying curative therapy until after disease recurrence may result in loss of curability

21. Refractory Myeloma Transient antitumor effect CTX, then TBI, thiotepa with T-cell depleted allograft Progressive disease was documented before day 70 2 nd DLI resulted in complete disappearance of any disease GVHD developed revealing a GVM effect Tricot G. Blood 87;3 1996 1196-1198.

22. Allo Tx Graft vs. MyelomaGraft vs. Myeloma Syngeneic TransplantSyngeneic Transplant

23. Trasplante Syngeneico Bashey et al, BBMT 20089

24. Allo Tx Graft vs. MyelomaGraft vs. Myeloma Syngeneic TransplantSyngeneic Transplant Myeloablative:Myeloablative: Less disease recurrence -AbandonedLess disease recurrence -Abandoned

25. Allo Tx Graft vs. MyelomaGraft vs. Myeloma Syngeneic TransplantSyngeneic Transplant MyeloablativeMyeloablative Non-MyeloablativeNon-Myeloablative

26. Bjorkstrand et al, JCO 29;22: 3016-3022

27. Allo-RIC vs. Auto StudyNEligib TX Cond GVH N Tx AgePFSSurv Hovon260HLA sib2 Gy TBI CSA-MMF 995428%@ 6y 22%@ 6y 55%@ 6y Gimema120HLA sib2Gy TBI6050@ 4y 25@ 4y 60@ 4y 45@4 y CTN700+HLA sib2GyTBI CSA-MMF 15643@ 3y 46 @ 3y 77@ 3y 80@ 3y EBMT- NMAM 375HLA-sibFlu 2 Gy TBI CSA-MMF 10922 @8y 12@8y 49@ 8y 36@ 8y IFM284*HLA SibBU 4 Flu ATG CSA-MTX 655419@5y 22@5y 40@ 5y 45@5y PETHE MA 110**HLA-sibFlu-Mel 140255260%@5y 25%@5y 60%@5y * Only B2M >3 and 13q del** no nCR after Tx1

28. Allo-RIC vs. Auto StudyNEligib TX Cond GVH N Tx AgePFSSurv Hovon260HLA sib2 Gy TBI CSA-MMF 995428%@ 6y 22%@ 6y 55%@ 6y Gimema120HLA sib2Gy TBI6050@ 4y 25@ 4y 60@ 4y 45@4 y CTN700+HLA sib2GyTBI CSA-MMF 15643@ 3y 46 @ 3y 77@ 3y 80@ 3y EBMT- NMAM 375HLA-sibFlu 2 Gy TBI CSA-MMF 10922 @8y 12@8y 49@ 8y 36@ 8y Blood 2012 119, 6219 Blood 2011,;117,6721 Lancet Oncol 2011, 12,1195 Blood 2013, 121, 5055

29. Auto-RIC vs. Auto: Relapse Hovon Gimema EBMT

30. Auto RIC vs. Auto: Survival Gimema Hovon CTN EBMT

31. EBMT: Myeloma with 13q

32. PETHEMA: PFS After Allo vs. 2 nd Auto in <nCR Rossinol Blood 2008

33. OS from the time of first relapse/progression in patients with multiple myeloma treated with auto/RICallo or auto alone. Gahrton G et al. Blood 2013;121:5055-5063 ©2013 by American Society of Hematology Survival after relapse is Superior in patients undergoing Allogeneic Transplant

34. Graft vs. Myeloma Optimized? Tricot G. Blood 87;3 1996 1196-1198. Lenalidomide? Pomalidomide? Vaccines?

35. Conclusions Toxicity of allogeneic Transplant has been reduced in recent years With prolonged follow-up the benefit of allo transplant becomes more apparent. Allogeneic Transplant is particularly attractive for poor prognosis patients. The future: Alternative donors Avoidance of chronic GVHD Early Allogeneic Transplant Incorporation of Maintenance Strategies

36. Case 1 35 YoF35 YoF MM del 17p, IgGMM del 17p, IgG 2012 Auto: PR2012 Auto: PR RelapseRelapse VDT-PACE: PRVDT-PACE: PR Haplo cord:Haplo cord:

37. Case 2 MM IgAMM IgA ETET ChloromaChloroma Cytarabine-Arac + BortezomibCytarabine-Arac + Bortezomib PRPR URD TransplantURD Transplant Tx in 1 st remission Nl cytogenetics

38. Conclusions Autologous transplant remains the standard treatment for myelomaAutologous transplant remains the standard treatment for myeloma It is well tolerated and may lead to superior QOLIt is well tolerated and may lead to superior QOL Cure may be possible in a fraction of patientsCure may be possible in a fraction of patients Allogeneic transplantation should be considered, particularly in patients with adverse prognosisAllogeneic transplantation should be considered, particularly in patients with adverse prognosis