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Dr Mark Cook Consultant Haematologist University Hospital Birmingham Slide 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 Slide 3 Slide 4 IMW 2011 Paris The Haematologist Who Suggested Allogeneic Transplant is Useful in Myeloma Slide 5 Data on allograft in myeloma is generally a dogs breakfast Slide 6 Slide 7 Inter-trial comparison is understandably fraught with difficulties, but is generally all we have Slide 8 Data on allograft in myeloma is generally a dogs breakfast Inter-trial comparison is understandably fraught with difficulties, but is generally all we have Opinion is just that- an individuals perspective on the data betrays their underlying instincts and biases Slide 9 Slide 10 Tricot et al Blood 1996 Slide 11 Perez-Simon, BJH, 2003, 121; 104-8 Slide 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 Slide 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 Slide 14 . Corradini P et al. Blood 2003;102:1927-1929 2003 by American Society of Hematology Slide 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 Slide 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% Slide 17 The lure of GvM raises the prospect of cure TRM rates decreasing Prospects are better of post-transplant options Slide 18 Kumar et al Blood 2011 Slide 19 Slide 20 Roos-Weil et al Haematologica 2011 Slide 21 Nishihori et al Cancer Control 2011 Slide 22 Presented by Giralt IMW 2011 Slide 23 Roos-Weil et al Haematologica 2011 Slide 24 Lokhorst et al Blood 2004 Slide 25 Slide 26 Slide 27 . El-Cheikh J et al. Haematologica 2008;93:455-458 2008 by Ferrata Storti Foundation Slide 28 Kroger et al Blood 2004 Slide 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 Slide 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 Slide 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 Slide 32 LenaRIC Slide 33 Slide 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 Slide 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 Slide 36 Presented by Einsele IMW 2011 Slide 37 Clarify the group that will benefit Slide 38 Overhaul conditioning Slide 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 Slide 40 Clarify the group that will benefit Overhaul conditioning Look at the graft Slide 41 Gabriel et al Blood 2010Benson et al prePub Blood October 2011 Slide 42 Towards Personalised Medicine Population Efficacy Toxicity + Efficacy Toxicity - Efficacy + Toxicity + Efficacy + Toxicity - Treatment e.g. Transplant Slide 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