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MULTIPLE MYELOMA

MULTIPLE MYELOMA . ASH 2006 UPDATE Jeffrey Wolf, MD Director, Myeloma Program UCSF. Myeloma ASH Review. Abstracts to be covered Abstract 795: Thal/Dex vs Dex frontline Abstract 57: Thal/Dex vs VAD frontline Abstract 796: Velcade/Dex frontline Abstract 56: Velcade/Dex vs VAD

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MULTIPLE MYELOMA

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  1. MULTIPLE MYELOMA ASH 2006 UPDATE Jeffrey Wolf, MD Director, Myeloma Program UCSF

  2. Myeloma ASH Review Abstracts to be covered • Abstract 795: Thal/Dex vs Dex frontline • Abstract 57: Thal/Dex vs VAD frontline • Abstract 796: Velcade/Dex frontline • Abstract 56: Velcade/Dex vs VAD • Abstract 798: Revlimid/Dex frontline • Abstract 800: R-MP frontline • Abstract 799: Revlimid/Dex (high dose) vs Revlimid/Dex (lower dose) frontline • Abstract 407: VMPT for relapse • Abstract 404: Velcade/Doxil for relapse

  3. WHAT SHOULD WE BE LEARNING? • Does the type of induction matter? • Does CR matter? • Does transplant matter? • What do we do for the non-transplant patient?

  4. Thalidomide/Dex vs. Dex Abstract #795

  5. A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study Thalidomide Plus Dexamethasone Versus Dexamethasone Alone As Initial Therapy For Newly Diagnosed Multiple Myeloma (MM 003) S. Vincent Rajkumar, Mohamad Hussein, John Catalano, Wieslaw Jedrzejczak, Svetlana Sirkovich, Marta Olesnyckyj, Zhinuan Yu, Robert Knight, Jerry Zeldis, and Joan Bladé Mayo Clinic, Rochester, MN; Cleveland Clinic, Cleveland, Ohio; Frankston Hospital, Frankston, Australia; Medical Academy of Warsaw, Warsaw, Poland; Kiev Institution of Oncology of the UAMS, Kiev, Ukraine; Celgene Corporation, Summit, NJ, and Hospital Clinic, Barcelona, Spain. Rajkumar et al. ASH 2006, abstract # 795

  6. Trial Design Thalidomide 50→200* mg d 1-28 TTP Dex 40 mg, d 1-4, 9-12, 17-20 OS Same except Dex d 1-4 RR X 4 COURSES Continue until PD Safety Placebo d 1-28 Dex 40 mg, d 1-4, 9-12, 17-20 * Thalidomide dose escalated in all patients, over 4 weeks, to improve tolerability Rajkumar et al. ASH 2006, abstract # 795

  7. Response (RRC/IMWG) PR+VGPR+CR 80 VGPR PR 69.4%* CR 60 51.1%* 25.5% * p=0.001 Response Rate (%) 40 35.3% * CR+VGPR p<0.0001 20 35.7% * 12.8% * 3.0% * 8.1% * 0 Thalidomide/ Dex Placebo/ Dex Rajkumar et al. ASH 2006, abstract # 795

  8. Grade 1-2 Grade 1-2 Thal/Dex Dex Grade 3-4 Grade 3-4 Common Non-Hematological Toxicities Constipation Edema Insomnia Asthenia Tremor Neuropathy Percent Rajkumar et al. ASH 2006, abstract # 795

  9. 0 10 20 30 40 50 Major Grade 3/4 Toxicities Thal/Dex (n=234) Dex (n=232) DVT/PE Pneumonia Hyperglycemia Atrial Fibrillation Myocardial Ischemia Cerebrovascular Ischemia Any Grade 4 Percent Rajkumar et al. ASH 2006, abstract # 795

  10. Time to Progression HR (95% CI) 0.43 (0.32, 0.58) Thalidomide/dex median time to progression: 22.4 months Placebo/dex median time to progression: 6.5 months P<0.0001 Rajkumar et al. ASH 2006, abstract # 795

  11. Overall Survival HR (95% CI) 0.82 (0.57, 1.16) Thalidomide/Dex median overall survival: Not reached Placebo/Dex median overall survival: 32 months Rajkumar et al. ASH 2006, abstract # 795

  12. Thalidomide/Dex vs. VAD Abstract #57

  13. A randomized study ofThalidomide + Dexamethasone (Thal/Dex) compared with Vincristine, Adriamycine and Dexamethasone(VAD)as a pre-transplant treatment in newly diagnosed Multiple Myeloma (MM) M. Macro, M.Diviné, S.Chevret, J.P.Fermand & all members of the “Myélome-autogreffe” group Paris, Amiens, Caen, Créteil, Limoges, Strasbourg FRANCE Macro et al. ASH 2006, abstract # 57

  14. Stage II-III MM, <65 years HD steroids Randomization Infusional VAD Oral Thal/Dex Thal + Dex 3 mths VAD 3 mthly courses Cytoxan (4g/m2) + G-CSF PBSC Collection MLP 200 mg/m2 + autologous PBSC transplantation Macro et al. ASH 2006, abstract # 57

  15. Thal/Dex vs VAD as Induction: Response R Thal/Dex 3 mths VAD 3 mthly courses VGPR RR (≥50%) VAD 7.3% VAD 47% TD 24.7% TD 65% Before PBSC mobilization CTX + G-CSF CTX + G-CSF (p=.0027) (p=.01) VGPR RR (≥50%) VAD 12.6% VAD 52% TD 34.7% TD 66% MLP 200 mg/m2 MLP 200 mg/m2 Before high-dose MLP (p=.002) (p=.04) VGPR RR (≥50%) VAD 41.7% VAD 62% TD 44.4% TD 68% At 6 mths post-transplant (p=.87) (p=.38) Macro et al. ASH 2006, abstract # 57

  16. Venous thrombosis and pulmonary embolism (no proph) Any grade ≥ 2 side effect 7.5% (p=.004)22.8% 27% (p=.07) 39% 12.9% (p=.42) 17.4 % Symptomatic peripheral neuropathy Thal/Dex vs VAD as a pre-transplant treatment in MM Toxicity VAD 3 mthly courses Thal/Dex 3 mths Thal/Dex 3 mths Macro et al. ASH 2006, abstract # 57

  17. Velcade +/- Dex Abstract #796

  18. Long-term follow-up of a phase 2 trial of bortezomib alone and in combination with dexamethasone for the frontline treatment of multiple myeloma S. Jagannath1, B. Durie1, J. Wolf1, E. Camacho1, D. Irwin1, J. Lutzky1, M. McKinley,1 E. Gabayan1, A. Mazumder1, J. Crowley2, R. Vescio1 1Aptium Oncology Research Network, CA; 2Cancer Research and Biostatistics, WA Jagannath et al. ASH 2006, abstract # 796

  19. Bortezomib  dexamethasone Bortezomib 88 78 49 Cumulative Best Response (N = 49) • Median time to response: 1.9 months • Responses assessed by EBMTR criteria with the addition of VGPR Jagannath et al. ASH 2006, abstract # 796

  20. OS In All Patients (N = 49) 100% 80% 60% 40% 20% 0% 12-month Deaths/N estimate Bortezomib (Velcade) 7/49 92% (83,100) 0 12 24 36 48 Months after registration • Median follow-up 26.7 months • Estimated 1- and 2-year survival rates: 92% and 85% Jagannath et al. ASH 2006, abstract # 796

  21. Velcade/Dex vs VAD Abstract #56

  22. 56VELCADE/Dexamethasone (Vel/Dex) Versus VAD as Induction Treatment Prior to Autologous StemCell Transplantation (ASCT) in Newly Diagnosed Multiple Myeloma (MM): An Interim Analysis ofthe IFM 2005-01 Randomized Multicenter Phase III Trial. Jean-Luc Harousseau,1 Gerald Marit,2 Denis Caillot,3 Philippe Casassus,4 Thierry Facon,5 Mohamad Mohty,6 Frederic Maloisel,7Herve Maisonneuve,8 Carine Chaleteix,9 Lofti Benboubker,10 Dixie-Lee Esseltine,11 Michel Attal.12 1Hematology, Hôpital Hotel-Dieu, Nantes, France; 2CHU Bordeaux, Pessac, Bordeaux, France; 3Hematology Unit, Hôpital Bocage, Dijon, France; 4Hôpital Avicenne, Bobigny, Paris, France; 5Hôpital Claude-Huriez, Lille, France; 6Institute Paoli-Calmettes, Marseille, France; 7Hôpital Civil, Strasbourg, France; 8CHD La Roche Sur Yon, La Roche Sur Yon, Vendee, France; 9CHU Clermont-Ferrand, Clermont-Ferrand, Auvergne, France; 10Hematology and Cell Therapy Unit, CHRU Tours, Tours, France; 11Millennium Pharmaceuticals Inc, Cambridge, MA, USA; 12Hôpital Purpan, Toulouse, France.

  23. Randomization Stratification for β2 microglobulin and Ch 13 abnormalities A B Arm A1: VAD Arm A2: VAD + DCEP Induction ± Consolidation Arm B1: Vel/Dex Arm B2: Vel/Dex + DCEP ASCT Transplant 1 ASCT Second ASCT or RIC allo if <VGPR Vel/Dex vs. VAD Induction in Newly Diagnosed MM: Preliminary Analysis of IFM 2005-01 Trial • Treatment Scheme: Harousseau et al. ASH 2006, abstract # 56

  24. Vel/Dex vs. VAD Induction in Newly Diagnosed MM: Preliminary Analysis of IFM 2005-01 Trial • Response: by investigator assessment; evaluated by modified EBMT criteria Harousseau et al. ASH 2006, abstract # 56

  25. Vel/Dex vs. VAD Induction in Newly Diagnosed MM: Preliminary Analysis of IFM 2005-01 Trial • Efficacy: Impact of baseline characteristics on post-induction response (preliminary analysis) Harousseau et al. ASH 2006, abstract # 56

  26. Vel/Dex vs. VAD Induction in Newly Diagnosed MM: Preliminary Analysis of IFM 2005-01 Trial • Stem Cell Transplant: Preliminary data Harousseau et al. ASH 2006, abstract # 56

  27. Vel/Dex vs. VAD Induction in Newly Diagnosed MM: Preliminary Analysis of IFM 2005-01 Trial • Safety: No sig difference between 2 arms Harousseau et al. ASH 2006, abstract # 56

  28. What have We Learned? • The use of Vel/Dex over VAD results in fewer patients needing a 2nd transplant • The use of TD is more toxic than VAD (DVT’s and VTE’s) and results in similar outcomes post transplant

  29. Revlimid/DecadronFrontline Abstract # 798

  30. Results: Response to TherapyAll 34 pts assessed prior to transplant or any other therapy Lacy et al. ASH 2006, abstract # 798

  31. fatigue (21%) neutropenia (21%) anxiety (6%) pneumonitis (6%) muscle weakness (6%) rash (6%) pulmonary embolism (3%) with ASA prophylaxis Toxicity > Grade 3 Lacy et al. ASH 2006, abstract # 798

  32. Progression Free Survival 83% 59% 2 yr PFS rate Lacy et al. ASH 2006, abstract # 798

  33. Overall Survival 92% 90% 2 yr OS rate Lacy et al. ASH 2006, abstract # 798

  34. OS for 2 Novel agents in Newly Diagnosed MM in Combo with Dex: No Transplant Rev/Dex: Lacy et al Vel/Dex: Jagannath et al

  35. Revlimid/Melphalan/PrednisoneNewly Diagnosed Abstract #800

  36. day 1 2 3 4 21 Mel 0.18–0.25 mg/Kg Prednisone 2 mg/Kg Revlimid® 5–10 mg daily Every 4–6 weeks for a maximum of 9 cycles Melphalan mg/Kg/d Revlimid® mg/d Patients Cohort 1 0.18 5 6 Cohort 2 0.25 5 6 Cohort 3 0.18 10 6+15 Cohort 4 0.25 10 6+15 6 patients in each cohort with additional 15 pts in cohort 3 and 4 RMP: Treatment Schedule Palumbo et al. ASH 2006, abstract # 800

  37. DLT at Cycle 1 Cohort 10.18–5 Cohort 20.25–5 Cohort 30.18–10 Cohort 40.25–10 Severe Neutropenia 1/6 Neutropenic fever 1/6 Delay at cycle 2 2/6 Cutaneous GR 3 Thrombosis GR 4 Metabolic GR 3 1/6 1/6 1/6 Pts with DLT 0/6 0/6 1/6 3/6 Dose Limiting Toxicity Palumbo et al. ASH 2006, abstract # 800

  38. R-MP vs MPT: Response Rates R-MP Cohort 3 (0.18-10) Best Response n=21 MPT Best Response n=129* 48% 37% Proportion of patients Proportion of patients *Historical control – Palumbo et al, Lancet 2006 5.4% of response not available Palumbo et al. ASH 2006, abstract # 800

  39. p=0.046 R-MP vs MPT: EFS and OS R-MP: median follow-up 14.6 months (10.8-21.8) [N=53] MPT: median follow-up 17.6 months (0.23-44.3) [N=129]* OS EFS p=0.053 Palumbo et al. ASH 2006, abstract # 800 *Historical control – Palumbo et al, Lancet 2006

  40. MPT Superior to MP Previous Studies

  41. Melphalan/Velcade/Prednisone (MVP) Previous Study

  42. Newly Diagnosed Melphalan + Velcade + Prednisone(MVP) Response to Therapy * Modified EBMT criteria • 12 of 16 CR patients tested for minimal residual disease; 6/12 (50%) achieved an immunophenotypic remission • Historical response with MP: 42% nCR + PRHernandez, BJH, 2004 • No DLTs observed in Phase I Phase II: 20% G4 myelosuppression • Phase II trial accruing, goal of 60 pts, dose will be 1.3 mg/m2 Mateos et al. Blood, June, 2006

  43. Revlimid/High Dose Dex vsRevlimid/Lower Dose Dex Abstract #799

  44. A Randomized Phase III Trial of Lenalidomide Plus High-Dose Dexamethasone Versus Lenalidomide Plus Low-Dose Dexamethasone in Newly Diagnosed Multiple Myeloma (E4A03): A Trial Coordinated by the Eastern Cooperative Oncology Group S. Vincent Rajkumar, Susanna Jacobus, Natalie Callander, Rafael Fonseca, David Vesole, Philip Greipp Mayo Clinic, Rochester, MN; Dana Farber Cancer Institute, Boston, MA; University of Wisconsin, Madison, WI; Mayo Clinic Arizona, Scottsdale, AZ; St. Vincents Hospital, New York, NY

  45. Schema 445 pts RANDOMIZATION Len + Dex x4 cycles (40 mg d1-4, 9-12, 17-20) @ 4 months Pts eligible for SCT proceed to SCT* CR/PR Len + Low dose Dex x 4 cycles (40 mg wkly D1,8,15,22) Thal + Dex x 4 cycles Less than PR CR/PR/Stable Rajkumar et al. ASH 2006, abstract # 799

  46. Serious adverse events Rajkumar et al. ASH 2006, abstract # 799

  47. Bortezomib (Velcade®), Melphalan, Prednisone and Thalidomide (VMPT) in Advanced Multiple Myeloma Results of a Multicenter Phase I/II Study Abstract 407 Antonio Palumbo Div. Hematology, University of Torino

  48. V-MPT at 1° RelapseMPT at Diagnosis V-MPT (N=14) MPT (N=129)^ 1° Relapse Diagnosis 45 50 57% 39% 45 40 40 35 36% 36% 35 30 30 25 21% % % 25 21% 21% 21% 20 20 15% 13% 15 15 10 10 5% 5 5 0% 0 0 CR- VGPR PR MR SD-PD CR- VGPR PR MR SD-PD ^Palumbo et al,Lancet 2006;367:825

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