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Multiple Myeloma: Current Therapy Issues and The Spanish PETHEMA Approach

Multiple Myeloma: Current Therapy Issues and The Spanish PETHEMA Approach. Seminars in Haematological Oncology: An International Educational Forum Ashkelon Academic College, Israel, April 6 Joan Bladé, Barcelona. History of Myeloma Treatment. 1960s : - Melphalan / Cyclophosphamide

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Multiple Myeloma: Current Therapy Issues and The Spanish PETHEMA Approach

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  1. Multiple Myeloma: Current Therapy Issues and The Spanish PETHEMA Approach Seminars in Haematological Oncology: An International Educational Forum Ashkelon Academic College, Israel, April 6 Joan Bladé, Barcelona

  2. History of Myeloma Treatment • 1960s: - Melphalan / Cyclophosphamide - Prednisone • 1980s: - Dexamethasone - Combination chemotherapy - HDT / SCT • 2000s: - Thalidomide / IMiDs - Bortezomib - Novel targets

  3. Multiple Myeloma Treatment

  4. MAIN GOALS IN CANCER TREATMENT • Complete remission • Prolonged EFS and OS • Quality of life • Cure

  5. MM. CRITERIA FOR COMPLETE REMISSION(EBMT, IBMTR, ABMTR)* • Negative immunofixation *Br J Haematol 1998; 102:1115-1123.

  6. HEMATOPOIETIC STEM CELLTRANSPLANT IN MULTIPLE MYELOMAPossible Approaches • Autologous • Syngeneic • Allogeneic

  7. Autologous Transplantation in Multiple Myeloma

  8. Autologous Transplantation in Multiple Myeloma

  9. Autologous Transplantation in Multiple Myeloma

  10. MM. HDT/ASCT vs “CONVENTIONAL” TREATMENT Randomized Trials

  11. MM. FACTORS ASSOCIATED WITH CR AFTER HDT/ASCT • Speed of response to initial chemotherapy • Pretransplant M-protein size (<10 g/L) Alexanian et al, Bone Marrow Transplant 2001; 27: 1037-1043 Nadal et al, Bone Marrow Transplant 2004; 33: 61-64

  12. MM. CR after HDT According to Tumor Burden Pretransplant *Alexanian et al, BMT 2001; 27: 1037-1043 ** Nadal et al, BMT 2004; 33: 61-64

  13. Autologous Transplantation in Multiple Myeloma

  14. Overall Survival After DOUBLE “Auto-SCT” Attal et al. N Engl J Med 2003;3349:2495–502.

  15. MM. SYNGENEIC TRANSPLANT“Treatment of Choice” • Bensinger et al, BMT 1996 • Gahrton et al, BMT 1999

  16. MM. ALLOGENEIC TRANSPLANT: Conventional Conditioning Pros • No contaminated graft • Graft versus myeloma effect Cons • Donor availability • Transplant-related mortality (decreased from 1994 -EBMT-) • Relapse rate

  17. MM. ALLOGENEIC TRANSPLANT: Newer Approaches • Peripheral blood progenitor cells • T-cell depletion • Dose-reduced intensity conditioning

  18. MM. ALLOGENEIC TRANSPLANT With Dose-reduced Intensity Conditioning • Conditioning: MEL/FLUDA ± ATG or Campath-1H • TRM: ≈ 20% (11- 40%) • CR rate: 22-73% • aGVHD: ≈ 40% • cGVHD: 20-45% • PFS/OS: longer follow-up required

  19. MM. Donor Lymphocyte Infusion (DLI) • GVM effect associated to GVHD • aGVHD: ≈ 60% • cGVHD: ≈ 50% • Response rate: 45-61% (20-30% CR) (responses lasting >1 yr: 20%) • Benefit from DLI: • Duration of response vs. complications from GVHD

  20. MULTIPLE MYELOMANew Drugs

  21. Angiogenesis in Multiple Myeloma

  22. Thal/IMiDs Target MM Cells in the BM Microenvironment C. Thalidomide/IMiD MM cells IL-6 TNF IL-1 B.Thalidomide /IMiD Bone Marrow Stromal Cells A.Thalidomide /IMiD ICAM-1 Bone Marrow Vessels VEGF bFGF IL-2 IFN PBMC D. Thalidomide /IMiD E. Thalidomide /IMiD CD8+ T Cells NK Cells Hideshima et al. Blood 96: 2943, 2000 Davies et al. Blood 98: 210, 2001 Gupta et al. Leukemia 15: 1950, 2001 Mitsiades et al. Blood 99: 4525, 2002 Lentzsch et al Cancer Res 62: 2300, 2002

  23. THALIDOMIDE in Multiple Myeloma

  24. THALIDOMIDE in Multiple Myeloma • Lack of response of soft-tissue plasmacytomas Bladé et al. Br J Haematol, 2001 • Extramedullary progression despite good bone marrow response Avigdor et al. Leuk and Lymph; 2001 • Extramedullary progression in patients with myeloma treated with thalidomide-based regimens Dimopoulos et al. Leuk and Lymph, 2004

  25. Response to Thalidomide According to the Presence of EMP *EMP: Extramedullary Plasmacytomas Rosiñol et al, Haematologica 2004

  26. Thal/IMiDs Target MM Cells in the BM Microenvironment C. Thalidomide/IMiD MM cells IL-6 TNF IL-1 B.Thalidomide /IMiD Bone Marrow Stromal Cells A.Thalidomide /IMiD ICAM-1 Bone Marrow Vessels VEGF bFGF IL-2 IFN PBMC D. Thalidomide /IMiD E. Thalidomide /IMiD CD8+ T Cells NK Cells Hideshima et al. Blood 96: 2943, 2000 Davies et al. Blood 98: 210, 2001 Gupta et al. Leukemia 15: 1950, 2001 Mitsiades et al. Blood 99: 4525, 2002 Lentzsch et al Cancer Res 62: 2300, 2002

  27. CC-5013 (Revlimid) in Relapsed / Refractory Myeloma • No. evaluable patients: 83 • Phase II trial • Setting: refractory / relapsed MM • Response rate: 6% CR, 18% PR, 14% MR • Toxicity*: myelosupression *Fatigue, muscle weakness

  28. 61.2%* 57.9% 34.7% 22.8%* 21.7% 44.3% 18.7% 17.7% 26.5% 13.6% 4.0% 4.1% MM-009/010: Response1 80 PR + CR PR (>50%) CR (IF-) 60 *P<0.001 Response Rate (%) 40 20 0 Len/dex Len/dex Dex Dex 009 010 009 010 1Blade criteria IF, immunofixation

  29. 1.0 009 Len/Dex 010 Len/Dex 010 Dex alone 009 Dex alone 0.9 0.8 0.7 0.6 P < 0.000001 Proportion of Patients 0.5 0.4 010 0.3 009 0.2 0.1 010 009 0.0 0 2.5 5 7.5 10 12.5 15 17.5 20 22.5 Time to Tumor Progression (in Months) MM- 009/010 Time to Progression

  30. MM. CC-4047 (Actimid) in Relapsed / Refractory Disease • No. patients: 24 • Phase I (dose-escalating study) • MTD: 2 mg/day • DVT: 16% • Response rate: 54% PR (16% CR) • T cell co-estimulation

  31. VELCADE™ (bortezomib) Dipeptidyl boronic acid Millennium Pharmaceuticals, Inc., 2003.

  32. BORTEZOMIB. SUMMIT Trial (Study Design) • Open-label, multicenter phase II trial • Setting: refractory MM • No. Patients: 202 • Dose schedule: 1.3 mg/m2 on days 1,4,8 and 11 every 3 weeks • Primary endpoint: response rate (CR + PR+ MR) • Secondary endpoints: safety, QoL, clinicalbenefit

  33. Previous Therapies 100% 90% • Median lines of prior therapy = 6 (range 2-15) • 91% were refractory to last therapy 80% 70% 60% 50% 40% 30% 20% 10% 0% SCT Steroids Alkylators Thalidomide Anthracyclines

  34. SUMMIT – Response Rates Bortezomib (VELCADE™)Alone 35% • 193 evaluable pts • 35% overall response (CR+PR+MR) • 27% CR+PR • 24% SD • 59% of pts SD or better • Assessed by IRC CR Near CR PR MR SD Adapted from data in Richardson P et al. N Engl J Med 2003;348:2609-17

  35. 100 90 80 70 60 50 40 30 20 10 0 0 2 4 6 8 10 12 14 16 18 SUMMIT – Overall Survival Percent Overall Survival Over Time (N=202) Median overall survival = 16 months*; now at 17.8 months with longer-term follow-up Percent Months *As of October 2002. Richardson P et al. N Engl J Med 2003;348:2609-17. Berenson J et al. Proc ASCO 2003. Abstract 2337. Presented at Poster Discussion.

  36. Bortezomib. CREST Trial • Randomized phase II trial • Setting: refractory MM • Dose schedule: 1.0 mg/m2 vs 1.3 mg/m2 • No. patients: 54 • Overall response rate: 50% in 1.3 mg/m2 vs 33% in 1.0 mg/m2 • Possible dose response • Lower toxicity in the 1.0 mg/m2 arm

  37. APEX Phase III trialBORTEZOMIB VS HIGH-DOSE DEXAMETHASONE FOR RELAPSED MULTIPLE MYELOMA * • Nº patients: 669 • Setting: relapsed / refractory disease 3 lines • Bortezomib superior to dexamethasone: • RR (CR + PR): 38% vs 18% (p<0.001) • CR or nCR rate: 13% vs 2% (p<0.001) • TTP: 6.2 vs 3.5 mos (p<0.001) • One-year OS: 80% vs 66% (p=0.003) * Richardson PG, Sonneveld P, Schuster MW, et al. N Engl J Med 2005; 352: 2487-98.

  38. Front-line Trials with THALIDOMIDE • DEX / THAL  58 to 76% PR (10-15% CR) (replacing VAD as pre-transplant induction regimen) • MP / THAL  76 to 84% PR (~25% CR)

  39. Front-line Phase II Trials with BORTEZOMIB *17% nCR. **11% nCR.

  40. THALIDOMIDECharacteristics of Response • Slow response • Independent of previous regimens • Lack of activity in extramedullary plasmacytomas

  41. BORTEZOMIBCharacteristics of Response • Quick response (1 or 2 cycles) • Independent of previous regimens (including thalidomide) • Active on extramedullary plasmacytomas* * Rosiñol L, Cibeira MT, Uriburu C, et al.Eur J Haematol 2006 (in press).

  42. 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 0 20 40 60 80 100 120 140 160 180 200 SUMMIT: Time to Best Response Bortezomib Alone CR Proportion of Patients PR MR Range 30 – 127 Days Days Median Time to Response = 38 Days Richardson et al, New Engl J Med. 2003;348:2609

  43. MM. THALIDOMIDE TOXICITY • Constitutional symptoms • Limit the initial dose • Peripheral neuropathy • Limits treatment duration • Deep vein thrombosis (when associated with Dex or Chemotherapy) • Prophylactic anticoagulation

  44. MM. BORTEZOMIB TOXICITY • Constitutional symptoms • Gastrointestinal toxicity • Peripheral neuropathy / neuropathic pain • Thrombocytopenia • Postural hypotension • Skin lesions • Unusual toxicities

  45. Unusual Toxicities of BORTEZOMIB • Tumor lysis syndrome • Terpos et al. J Cancer Res Clin Oncol 2004; 130:623-5. • Jaskiewicz et al. Pharmacotherapy 2005; 25:1820-5. • Bortezomib-induced Hepatitis • Rosiñol et al. Arch Intern Med 2005; 165:464-5. • Bortezomib-induced Rhabdomyolysis • Cibeira et al. Acta Haematol 2006 (in press).

  46. Treatment of Relapsed / Refractory MMGeneral Considerations • COMPONENTS OF INITIAL THERAPY • Alkylating-based • Dexamethasone-based • HDT/SCS • EFFICACY OF INITIAL THERAPY • Degree of response • Timing of relapse • PATIENT STATUS AND CIRCUMSTANCES OF RELAPSE • Age, PS • Aggressive vs “non-aggressive” relapse

  47. Treatment of Relapsed / Refractory MMPossible Options • Alkylating-based • Dexamethasone-based (VAD, VBAD) • Bortezomib-based • Thalidomide / IMiDs-based • HDT / SCS “rescue” • Investigational agents • Palliation (supportive care / cyclo-pred)

  48. Update on Transplant Trialsfrom the PETHEMA/SPANISH MYELOMA GROUP

  49. Transplant PETHEMA/GEM Myeloma Trials • PETHEMA-94 • HDT intensification vs conventional chemotherapy • PETHEMA-2000 • Tandem transplant • PETHEMA-2005 • Induction & maintenance with new agents

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