1. Dr Mark Cook Consultant Haematologist University Hospital Birmingham

2.  Demonstrate there is a role for allogeneic stem cell transplant in myeloma and evaluate some of the composite elements of the transplant process  Review the evidence to understand the current state of play  Discuss how allogeneic transplant needs to evolve to be more commonly considered as an option

4. IMW 2011 Paris The Haematologist Who Suggested Allogeneic Transplant is Useful in Myeloma

5.  Data on allograft in myeloma is generally a dog’s breakfast

7.  Inter-trial comparison is understandably fraught with difficulties, but is generally all we have

8.  Data on allograft in myeloma is generally a dog’s breakfast  Inter-trial comparison is understandably fraught with difficulties, but is generally all we have  Opinion is just that- an individual’s perspective on the data betrays their underlying instincts and biases

10. Tricot et al Blood 1996

11. Perez-Simon, BJH, 2003, 121; 104-8

12. Copyright ©2005 American Society of Hematology. Copyright restrictions may apply. Crawley, C. et al. Blood 2005;105:4532-4539 Figure 4. Overall survival with respect to the presence of chronic graft-versus-host disease

13. Copyright ©2005 American Society of Hematology. Copyright restrictions may apply. Crawley, C. et al. Blood 2005;105:4532-4539 Effect of alemtuzumab on progression

14. . Corradini P et al. Blood 2003;102:1927-1929 ©2003 by American Society of Hematology

15.  Thus graft versus myeloma is evidenced by: Response to DLI Link with GVHD (esp chronic GVHD) Increased relapse with T-cell depletion  And If you can get a deep response, you can get a durable response  So why is use not more widespread? Age Comorbidities Performance status

16. Years 026 13 45 Probability of Survival, % HLA-matched sibling, Allo (N=878) autologous transplant (N=22,254) Unrelated, Allo (N=143) 0 20 40 60 80 100 10 30 50 70 90 0 20 40 60 80 100 10 30 50 70 90 P < 0.0001 68% 47% 28%

17.  The lure of GvM raises the prospect of cure  TRM rates decreasing  Prospects are better of post-transplant options

18. Kumar et al Blood 2011

20. Roos-Weil et al Haematologica 2011

21. Nishihori et al Cancer Control 2011

22. Presented by Giralt IMW 2011

23. Roos-Weil et al Haematologica 2011

24. Lokhorst et al Blood 2004

27. . El-Cheikh J et al. Haematologica 2008;93:455-458 ©2008 by Ferrata Storti Foundation

28. Kroger et al Blood 2004

29.  13/24 patients given pre-emptive DLI after partial T-depleted allograft  4/13 developed GVHD grade II or above Levenga et al Bone Marrow transplant 2007

30.  38 patients treated with RIC allo (2Gy TBI) 2-6 months post auto  Lenalidomide 10mg daily for 21/28 days started 1-6 months post transplant  14 patients (47% of those evaluable) stopped lenalidomide by the end of the 2 nd cycle, primarily due to GVHD

31.  Utilising the following: RIC approach rather than myeloablative to increase the potential treatment population and reduce toxicity Combined Auto- RIC allo to optimise pre allo disease status If T-depleting, then a strategy to minimise risk of relapse post-transplant Pre-emptive DLI

32. LenaRIC

34.  Primary endpoint: Progression free survival at 2 years post-transplant  Secondary endpoints: Donor engraftment Day +100 and 1 year post-transplant non-relapse mortality Graft versus host disease Disease free survival at 1 and 2 years post-transplant Overall survival at 1 and 2 years post-transplant  Exploratory endpoints: Immune reconstitution samples NK receptor genetics and transplant outcome Flow cytometry assessment for minimal residual disease LenaRIC

35.  (1) use a prior debulky autologous Transplantation  (2) limit the procedure to patients with sensitive disease  (3) use the best conditioning with fludarabine/melphalan or low-dose TBI with or without fludarabine and with no T- cell depletion  (4) optimize DLI (ie, with low-dose thalidomide) for suboptimal responses

36. Presented by Einsele IMW 2011

37.  Clarify the group that will benefit

38.  Overhaul conditioning

39.  Radioimmunotherapy (RIT) with anti-CD66 promising in autologous transplant  ?potential role in allogeneic transplant Buchmann et al Eur J Nucl Med Mol Imaging 2009

40.  Clarify the group that will benefit  Overhaul conditioning  Look at the graft

41. Gabriel et al Blood 2010Benson et al prePub Blood October 2011

42. Towards Personalised Medicine Population Efficacy – Toxicity + Efficacy – Toxicity - Efficacy + Toxicity + Efficacy + Toxicity - Treatment e.g. Transplant

43.  To conclude:  Whilst trying to ignore my own biases, allografting offers the prospect of cure/long-term immune mediated control  However, effective delivery remains hampered by toxicity which is especially high in the non- myeloablative context  RIC allografting reduces toxicity but thereby diminishes efficacy  The challenge is to transform how RIC allos are delivered, to reduce toxicity further and to increase efficacy  There remain opportunities in the peri and post transplant period to effect further progress