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Treatment of Multiple Myeloma with Stem Cell Transplantation (SCT)

Treatment of Multiple Myeloma with Stem Cell Transplantation (SCT). Görgün Akpek, MD, MHS Director , SCT and Cellular Therapy Program Adjunct Associate Professor of Medicine University of Texas MD Anderson Cancer Center GAkpek@mdanderson.org. MULTIPLE MYELOMA A plasma cell neoplasm.

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Treatment of Multiple Myeloma with Stem Cell Transplantation (SCT)

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  1. Treatment of Multiple Myeloma with Stem Cell Transplantation (SCT) Görgün Akpek, MD, MHS Director, SCT and Cellular Therapy Program Adjunct Associate Professor of Medicine University of Texas MD Anderson Cancer Center GAkpek@mdanderson.org

  2. MULTIPLE MYELOMAA plasma cell neoplasm Malignant plasma cell proliferation in the BM Monoclonal Immunoglobulin (or light chain) in serum +urine

  3. Multiple MyelomaPresenting Features 98% >40 years old 61% Males 79% Skeletal X-ray abnormalities 68% Bone pain 62% Anemia 55% Renal Insufficiency 30% Hypercalcemia 88% Proteinuria 49% Bence Jones Proteinuria 21% Hepatomegaly 5% Splenomegaly Kyle RA, Mayo ClinProc 1975:50:29

  4. Life expectancyis doubled in myeloma • Now, average 7 years after diagnosis Kumar S K et al. Blood 2008;111:2516-20 4 years • Longer survival is directly related to depth of response to therapy • Complete response (CR): No detectable disease • Partial response (PR): Still detectable disease • No response: Poor outcome 2.5 years 5 years

  5. Improvement in survival of patients with myeloma is multifactorial • Initial (Induction) Therapy (2-4 months) • Stem Cell Transplantation (Highest CR rate) • Post-transplant Consolidation and Maintenance (Some additional benefit) • Supportive Care (Critical) • Treatment of Relapsed Disease (Clinical trials)

  6. Hematopoietic Stem Cell (CD34+ cells)

  7. Stem Cell Donor Selection • Autologous (from patients) • Matched Sibling/Related Donor (MRD) • Matched Unrelated Donor (MUD) • Cord Blood Unit (>4/6 match with adequate cell dose) • Mismatched Related/Unrelated (MMURD) • Haploidentical (parent or child) • Source of Stem Cells • Peripheral Blood Stem cells • Shorter time to engraftment • Bone Marrow Stem Cells • Less chronic GVH

  8. How do we perform Stem Cell Transplantation? • Patients are initially treated to reduce myeloma cells in BM • Stem cells are • mobilized from bone marrow into blood • collected by apheresis • processed & frozen in vaporized liquid nitrogen containers (-200 C) • Patients are treated with high dose Melphalan chemotherapy • Stem cells are thawed at the bedside and infused like a blood transfusion (Day 0) • Stem cells grow in the empty marrow and produce new blood cells within 2 weeks • Patients are discharged home and followed in the clinic

  9. History of Hematopoietic Stem Cell Transplantation Appelbaum F. N Engl J Med 2007;357:1472-1475

  10. 5,500 Allogeneic (Total N=7,012) 5,000 Autologous (Total N=9,778) 4,500 4,000 3,500 3,000 2,500 2,000 1,500 1,000 500 0 Multiple NHL AML HD ALL MDS/MPD Aplastic CML Other Non- Other Myeloma Anemia Leuk Malig Cancer Disease Indications for Hematopoietic Stem Cell Transplants in the United States, 2009 Number of Transplants

  11. <65 Stem cell transplant adds one more year to patient survival Blood 2005

  12. Why Stem Cell Transplant in the Era of Novel Therapy? Safer than before Deaths due to transplant 1-2% (was 3-5%) Improves outcome when combined with newer agents Doubles CR rate 30-35% (Harousseau J, JCO 2010, CavoM, Lancet 2010) More durable responses (remission of disease) Probably still longer overall survivalwith SCT Longer duration of remission and better Quality of Life with upfront (early) Stem Cell Transplant Cumulative cost of SCT is similar to novel agents x 6 mos

  13. Why early SCT is recommended? Chemotherapy or Novel agent therapy alone (No transplant) R R R R Early transplant 65% R R R R 35% R R R = Recurrence of Myeloma

  14. How can we further improve transplant outcomes? • Planned Tandem (double) transplants • Select cases • Consolidation therapy after initial transplant • Controversial • Maintenance therapy • Cost/benefit ratio is high • Reduced intensity allogeneic transplantation • Benefit in select cases • New Preparative Regimens • Needed

  15. 4643 Higher CR rate and longer EFS with double transplant but survival benefit is less clear

  16. The study was not statistically powered to evaluate this difference We probably don’t need to do second transplant in all patients

  17. Post-transplant Consolidation Therapy • Short-term multiagent treatment after auto-HCT to improve the depth of response • It is associated with • Improvement in CR • Improvement in PFS • Cavo M et al. Blood 2012 • Consider in select high risk cases who have less than CR after auto-SCT and not eligible to undergo tandem SCT (Medicare patients).

  18. Maintenance Therapy after Transplant Thalidomide Attal et al. Blood 2006 (597 patients) Observation vs. Pamidronate vs. Thalidomide 3-year EFS: 38, 39 and 51% 4-year OS: 77, 74 and 87% Spencer et al. JCO 2009(269 patients) Prednisolone vs. Thalidomide + Prednisolone 3-year PFS: 23 vs. 42% 3-year OS: 75 vs. 86% 1 trial (MRC IX) showed improvement in PFS but not OS Morgan GI et al. Blood 2012

  19. Maintenance Therapy after Transplant Lenalidomidevs. Placebo Attal et al. IFM Trial. NEJM 2012 614 patients Median EFS: 40 vs. 23 months No survival benefit McCarthy et al. CALGB trial. NEJM 2012 568 patients Median TTP: 46 vs. 27 months OS: p=0.03 Lenalidomide was associated with: Neutropenia Blood clots Increased second cancers?

  20. The Improved Outcome in Myeloma is Not Seen in High-Risk Patients Life expectancy: • Standard Risk Disease : 8-9 years • High Risk Disease: 2-3 years

  21. Investigations for Risk Stratification • Conventional studies • Conventional Karyotyping (Cytogenetics) • Fluorescent in-situ hybridization (FISH) • Newer Studies • Comparative Genomic Hybridization (CGH) Array • Single Nucleotide Polymorphism (SNP) array • Gene expression profiling (GEP) • Positron Emission Tomography (PET) • >3 FDG-avid lesions  Poor • Magnetic Resonance Imaging (MRI) • CR on MRI correlates with superior outcome

  22. Risk Stratification of Myeloma(IMWG) • High-Risk • By conventional karyotyping • del 13 or 13q • t(4;14) • del 17p • By FISH • t(4;14) • t(14;16) • Del 17p • Standard-Risk • All others

  23. Risk Stratification of Myeloma(Mayo Clinic)

  24. Treatment Goal in High-Risk MM • Achievement and maintenance of CR with more intense treatment strategies • Rajkumar SV AJH 2012; Haessler J, Clin Cancer Res 2007 • Bortezomib should be part of treatment in all phases in patients with t(4;14) • Thalidomide or Lenalidomidedo not improve outcome in t (4;14) or del 17p

  25. Multiple myeloma: Update on diagnosis, risk‐stratification, and management Blood 2011; 87: 78-88

  26. Advances in Cellular Therapy in Myeloma University of Texas MD Anderson Cancer Center Randomized Phase II Trial Of CD3/CD28 Activated Id-KLH Primed Autologous Lymphocytes In Patients With Myeloma Undergoing Autologous TransplantPhase II Study of the combination of MLN 9708 with Lenalidomideas Maintenance Therapy post Autologous Stem Cell Transplant in Patients with Multiple MyelomaAllogeneic Hematopoietic Stem Cell Transplantation for High-Risk Myeloma

  27. Idiotype Vaccine Preparation

  28. Activated T Cell Production Ex Vivo 1. Leukapheresis, enrich, deplete, or isolate cells of interest Reinfuse cells 5. Quality Control 4. Remove beads, wash and concentrate cells 3. Large scale cell expansion 2. Stimulate cells with aAPC

  29. Artificial APC: Bead Anti-CD3 Anti-CD28 TcR/CD4 CD28 CTLA4 Signal 1 Signal 2 Growth Activated T Cell Production with Artificial APCs Cellular and Vaccine Production Facility CVPF J Immunol 1997; 159: 5921 Science 1997; 276: 273 Immunol. Rev. 1997; 160: 43 Mol. Ther. 2004; 9; 902 Exp. Opin. Biol. Ther. 2008; 8: 475

  30. MLN9708 (Ixazomib) • Second generation small molecule proteosome inhibitor. • Orally bioavailable. • Longer survival time in mice vs. bortezomib. • Less risk of neuropathy. • Several trials have demonstrated efficacy in relapsed/refractory myeloma. Chauhan et al. CCR 2011

  31. Allogeneic SCT for Multiple Myeloma • Only therapy with a potential to cure the disease • Graft-versus-myeloma effect • Usually associated with GVHD • Not effective in extramedullary myeloma • Treatment-related mortality remains a major obstacle • GVHD, regimen related toxicity, and infection.

  32. Allogeneic SCT is potentially curative in myeloma Barlogie et al. JCO 2006

  33. TRM has decreased with RIC regimens Crawley et al. Blood 2007

  34. FM100 vs. FM140(Protocol # ID01-518) 41 vs. 24% @ 2-yr P=0.12 63 vs. 45% @ 2-yr P=0.38 Bashir et al MDACC. Submitted 2013

  35. Bortezomib With Tacrolimus And Methotrexate Reduces The Risk Of GVHD In Mismatched Transplantation Koreth et al. JCO 2012

  36. Conclusions • Patients with standard-risk myeloma highly benefit from stem cell transplantation and incorporation of novel agents in their treatment plans • High-risk myeloma has significantly worse outcome even in the era of novel agents and tandem transplants • New anti-myeloma agents and novel cellular therapies targeting common myeloma antigens are likely to change the poor outlook in high-risk myeloma.

  37. Stem Cell Transplantation Program Jan 14, 2014 (First year)

  38. Additional Slides

  39. Adoptive T Cell Therapy • Adoptive transfer comprises of the infusion of immunocompetent cells for the treatment of cancer or infectious disease • Adoptively transferred T cells can persist for at least a decade in humans • T cells produce effector and central memory subsets that have extensive replicative capacity and stem cell like qualities • Dr. June’s laboratory has developed a novel “prime-and-boost” strategy by collecting T lymphocytes from patients that have been vaccine-primed in vivo • These cells are activated and expanded ex vivo with anti-CD3/CD28 coated magnetic beads (artificial antigen -presenting cells), and reinfused after lymphocytotoxic chemotherapy • Adoptive T-cell transfer can facilitate both humoral and cellular immune responses to vaccination despite cytotoxic therapy

  40. Cancer Vaccine T cell expansion ex vivo Combining Active and Passive Immunotherapy 100 10 1 0.1 0.01 Hypothesis “Threshold for cure” % Tumor specific T cells in vivo

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