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Multiple Myeloma: ASH 2005

Multiple Myeloma: ASH 2005. Steven Coutre , M.D. Associate Professor of Medicine Division of Hematology Stanford University School of Medicine. Quality of Remission Impacts Survival. Alexanian R et al. BMT. 2001;27:1037. Complete Remission Matters.

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Multiple Myeloma: ASH 2005

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  1. Multiple Myeloma: ASH 2005 Steven Coutre, M.D. Associate Professor of Medicine Division of Hematology Stanford University School of Medicine

  2. Quality of Remission Impacts Survival Alexanian R et al. BMT. 2001;27:1037

  3. Complete Remission Matters Alexanian R et al. BMT. 2001;27:1037

  4. IBMTR (EBMT) Criteria for Complete and Partial Response • Complete response requires all of following • No serum/urine M protein by IFE for ≥6 wk • <5% plasma cells in bone marrow aspirate • No increase in size or number of lytic bone lesions • Disappearance of soft tissue plasmacytomas • Partial response requires all of following • 50% reduction in serum M protein 6 wk • 90% reduction in 24-hr urinary light chain excretion • 50% reduction in soft tissue plasmacytomas • No increase in size or number of lytic bone lesions Bladé J et al. Br J Haematol. 1998;102:1115

  5. Thalidomide Plus Melphalan/ Prednisone as First-line MM Therapy • Italian Myeloma Network study: randomized, multicenter, phase III trial Six 4-week cycles Randomization Melphalan 4 mg/m2 Days 1-7 for 6 cycles + Prednisone 40 mg/m2 Days 1-7 for 6 cycles + Thalidomide 100 mg/day*continuously (n = 129) Previously untreated patients with multiple myeloma Median age: 72 years (N = 255) Melphalan 4 mg/m2 Days 1-7 PO for 6 cycles + Prednisone 40 mg/m2 Days 1-7 for 6 cycles (n = 126) Part way through the study, enoxaparin was added to MPT group for 4 months as prophylaxis against clots. *Thalidomide administration continued until relapse or progressive disease. Palumbo A, et al. ASH 2005. Abstract779.

  6. Median event-free survival longer for MPT vs MP 29.2 months vs 13.6 months (P < .001) 36-month OS: 80% vs 64% for MPT vs MP; P = .20 Reduced DVT rates in MPT group for patients receiving vs not receiving prophylactic enoxaparin 3% vs 18.4% (P = .005) More deaths due to adverse events in MPT arm Thalidomide Plus Melphalan/ Prednisone as First-line MM Therapy Response Rates 60% MPT MP 60 45% 40 Percentage of patients P < .001 28% 20 7% 0 PR CR/nCR Palumbo A, et al. ASH 2005. Abstract779.

  7. Thalidomide Plus Melphalan/ Prednisone in Older MM Patients Randomized, multicenter trial IFM 99-06: 3rd interim analysis Standard Melphalan + Prednisone(n = 191) 12 courses every 6 weeks MP Patients with multiple myeloma 65-75 years of age (N = 436) Standard Melphalan + Prednisone + Thalidomide (up to 400 mg/day*) (n = 124) 12 courses every 6 weeks MPT Cyclophosphamide (3 g/m2) + G-CSF VAD: Vincristine + Doxorubicin + Dexamethasone (n = 121) 2 courses Melphalan (100 mg/m2) + Autologous SCT + G-CSF 2 courses MEL100 *Thalidomide administered at maximum tolerated dose. Facon T, et al. ASH 2005. Abstract 780.

  8. Longest OS with MPT MPT vs MP; P = .0008 Median not reached at Month 56 vs 30.3 months MPT vs MEL100; P = .014 Median not reached at month 56 vs 38.6 months Longest PFS with MPT MPT vs MP; P < .0001 Median 29.5 vs 17.2 months MPT vs MEL100; P = .0001 Median 29.5 vs 19.0 months Thalidomide Plus Melphalan/ Prednisone in Older MM Patients 100 100 100 MP MP 81 MPT MPT 80 80 72 MEL100 MEL100 Percentage of Patients 60 60 Patients, % 49 41 41 39 40 40 40 32 17 17 20 20 15 12 11 6.5 7 5 2 0 0 Severe Infection Neutropenia DVT Complete Response ≥ 90% Response ≥ 50% Response Facon T, et al. ASH 2005. Abstract780.

  9. Lenalidomide Plus Dexamethasone for Treatment-Naive Multiple Myeloma • Nonrandomized phase II study (N = 34) • Oral lenalidomide 25 mg/day, Days 1-21 • Dexamethasone 40 mg/day, Days 1-4, 9-12, 17-20; • Days 1-4 only after 4 cycles • Daily prophylaxis with aspirin for deep venous thrombosis • Able to harvest adequate stem cells (> 3 x 106 CD34 cells/kg) in all patients proceeding to ASCT Rajkumar SV, et al. ASH 2005. Abstract781.

  10. Lenalidomide Plus Dexamethasone for Treatment-Naive Multiple Myeloma Rajkumar SV, et al. ASH 2005. Abstract781.

  11. Bortezomib in Patients with Previously Untreated Multiple Myeloma Best Response:(n=60) All AE were grade 1-2, except two grade 4 (fluid overload and meningitis), one grade 3 PN Richardson, P. et al. ASH 2005 abstract # 2548

  12. Bortezomib in Patients with Previously Untreated Multiple Myeloma Treatment-Emergent PN (n = 65) • Reported in 36 pts (55%) • Grade 1: 23 (2 additional pts had grade 1 PN at study entry but remained stable throughout the study) • Grade 2: 12 • Grade 3: 1 • Dose reduction or discontinuation due to PN • 4 pts, grade 1 PN (1.3 to 1.0 mg/m2; 3 had further reduction to 0.7 mg/m2) • 9 pts, grade 2 PN (1.3 to 1.0 mg/m2; 2 had further reduction to 0.7 mg/m2) • 1 pt, grade 3 PN discontinued treatment during cycle 3 Richardson, P. et al. ASH 2005 abstract # 2548

  13. Bortezomib + Melphalan and Prednisone in Elderly Untreated MM Patients Phase II:Expanded up to 60 pts: bortezomib 1.3 mg/m2 Response • Best ORR: 86% (N = 53) following a median of 5 cycles • CR 30%, nCR 13%, PR 43% Best Response 5 cycles V-MP 6 cycles of MP 86% 42% *Hernandez, Br J H, 2004 Mateos, M. et al. ASH 2005, abstract #786

  14. Bortezomib ± Dexamethasone as First-line Multiple Myeloma Treatment • Nonrandomized, prospective phase II trial (N = 50) • Overall response rate with bortezomib + dexamethasone: 90% • Median PFS: 15 months Best Response 100 2% 25% 8% 80 SD/PD 25% MR 60 71% Percentage of Patients PR 40 nCR 40% CR 20 10% 8% 8% 2% 0 Bortezomib ± Dexamethasone Bortezomib Alone at Cycle 2 Jagannath S, et al. ASH 2005. Abstract 783.

  15. Newly Diagnosed Bortezomib +/- Dexamethasone for Previously Untreated Multiple Myeloma • RESPONSE • Response Rates: Bortexomib ± Dex (N=48 evaluable) • CR + nCR + PR = 90%; CR + nCR = 19% • Bortezomib alone: (at cycle 2) • CR + nCR + PR = 50%; CR + nCR = 10% • Survival: • Median PFS = 15 months • OS = Median OS not reached; estimated survival at 12 months 93% Jagannath S, et al. ASH 2005, abstract #783 SLIDE 15

  16. Newly Diagnosed Bortezomib +/- Dexamethasone for Previously Untreated Multiple Myeloma • Addition of Dexamethasone (n = 36) Additional responses observed in 23 of 36 patients (64%) Response improved by 2 levels in 22% (n = 8) SD to PR: 8 Response improved by 1 level in 42% (n =15) SD to MR: 4 MR to PR: 9 PR to nCR: 1 nCR to CR: 1 Jagannath S, et al. ASH 2005, abstract #783 SLIDE 16

  17. Newly Diagnosed Bortezomib +/- Dexamethasone for Previously Untreated Multiple Myeloma • CONCLUSIONS • Bortezomib alone and in combo with Dex is an effective therapy in newly diagnosed MM • Response rate with bortezomib ± dexamethasone was 90% with a CR + nCR rate of 19% • Estimated 1-year survival rate is 93% • Bortezomib is a feasible option for induction therapy • Stem cell harvest was successful and engraftment was prompt • Adverse events were predictable and manageable Jagannath S, et al. ASH 2005, abstract #783 SLIDE 17

  18. Patients: n=20 • Treatment: Induction: four 21 day cycles prior to transplant: • Bortezomib 1.0 mg/m2 days 1,4, 8, 11 • Adriamycin 9 mg/m2 – by infusion or IV push days 1-4 • Dex 40 mg PO - Cycle 1: d 1-4, 8-11, 15-18; Cycle 2 – 4: d 1-4 • PBSC harvested followed by MEL200 and PBSCT Reduced Dose PAD Combination Therapy • Stem cell mobilization was not affected 1Oakervee et al., Br J. Haematol 2005; 129 755-762 Popat R, et al. ASH 2005,Abstract #2554

  19. Reduced Dose PAD Combination Therapy Popat R, et al. ASH 2005, Abstract #2554

  20. First-line Bortezomib, Thalidomide + Dexamethasone in Multiple Myeloma Nonrandomized, single-center, open-label study (N = 38) • Treatment-naive patients • Response compared with previous thalidomide/ dexamethasone study *> 50% reduction in serum myeloma protein and/or > 90% reduction in Bence Jones protein excretion. †> 75% reduction in serum myeloma protein and/or > 99% reduction in Bence Jones protein excretion. ‡ Intensive therapy supported by autologous blood stem cells for patients without serious complications following BTD. Wang M et al. ASH 2005. Abstract 784.

  21. Updated Results of APEX Trial SURVIVAL Overall and 1-Year Survival • Bortezomib continues to demonstrate superior survival despite > 62% of HD dex pts crossing over to bortezomib • Median OS: 29.8 months (95% CI: 23.2, not estimable) vs 23.7 months (95% CI: 18.7, 29.1); hazard ratio = 0.77; P = 0.0272 • 1-year survival rate: 80% vs 67%; P = 0.0002 P=.0272 Richardson P, et al. ASH 2005, abstract 2547

  22. Updated Results of APEX Trial RESPONSE Overall response (CR + PR) improved from 38% to 43% 76/135 responders (56%) - improved response after week 6 (cycle 2) • 20 pts MR or PR to CR • 56 pts MR to PR 100 90 80 70 60 43% Response, % 50 38% 40 34% PR 30 32% PR 20 (7% nCR) (7% nCR) 10 9% CR 6% CR 0 Initial analysis Update *CR + PR Richardson P, et al. ASH 2005, Abstract 2547

  23. Updated Results of APEX Trial Conclusions • Despite rapid initial response, many pts achieve best response after longer duration of therapy • Responders received median of 10 cycles • Best M-protein response occurs > cycle 8 for ~20% of pts responding to bortezomib • Pts receiving bortezomib earlier appear to have longer survival and higher RR • Pts achieving higher quality of response (100% M-protein reduction) have longer response duration Richardson P, et al. ASH 2005, Abstract 2547

  24. Lenalidomide/Dex vs Dex Alone for Relapsed/Refractory MM MM-010: multicenter, phase III trial Dexamethasone 40 mg on Days 1-4, 9-12, 17-20* Lenalidomide 25 mg, Days 1-21 and placebo, Days 22-28 (n = 176) Patients with relapsed/refractory multiple myeloma (N = 351) Dexamethasone 40 mg on Days 1-4, 9-12, 17-20* Placebo on Days 1-28 (n = 175) *After 4 courses, dexamethasone intensity reduced to 40 mg daily on Days 1-4 only. Dimopoulos MA, et al. ASH 2005. Abstract6.

  25. Median time to progression Len/Dex: 11.3 months Dex: 4.7 months Lenalidomide/Dex vs Dex Alone for Relapsed/Refractory MM 1.00 0.75 Lenalidomide/dexamethasone Dexamethasone alone 0.50 % Without Progression P < .001 0.25 0.00 10 20 30 40 50 60 70 80 90 Time to Progression (Weeks) Dimopoulos MA, et al. ASH 2005. Abstract6.

  26. Lenalidomide/Dex vs Dex Alone for Relapsed/Refractory MM • Superior response with addition of lenalidomide • Improved OS with Len/Dex in North American study MM-010 (P < .013) • Hematologic side effects more common for lenalidomide 100 Len/Dex P < .001 80 Dex 59 60 Patients, % 42 40 24 20 17 20 4 0 Overall Partial CR/nCR Response Dimopoulos MA, et al. ASH 2005. Abstract6.

  27. Bortezomib Plus Lenalidomide for Relapsed/Refractory Multiple Myeloma • Phase I study of lenalidomide plus bortezomib (n = 24) • 21-day cycles (maximum of 8) at 8 different dosing schedules • Bortezomib 1.0 or 1.3 mg/m2, Days 1, 4, 8, 11 • Lenalidomide 5-30 mg/day, Days 1-14 • 2 reports of dose-limiting toxicity • No thrombotic events • Little peripheral neuropathy • Total response rate: 67% Response Rates (n = 21) 5% 5% 5% 29% SD PD CR nCR PR MR 43% 14% Richardson PG, et al. ASH 2005. Abstract 365.

  28. Conclusions • Combination regimens for front-line therapy are achieving higher response rates including true CR • No apparent adverse impact on stem cell harvesting • Challenges • What patients benefit from transplant? • Is there a role for maintenance therapy after initial treatment or post-transplant? • Molecular definitions of response

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