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Multiple Myeloma in the Non-transplant Setting

Multiple Myeloma in the Non-transplant Setting. Antonio Palumbo, MD University of Torino, Torino, I, EU. Standard of Care for Elderly Patients. Meta-Analysis: MPT vs MP.

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Multiple Myeloma in the Non-transplant Setting

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  1. Multiple Myeloma in the Non-transplant Setting Antonio Palumbo, MD University of Torino, Torino, I, EU

  2. Standard of Care for Elderly Patients

  3. Meta-Analysis: MPT vs MP • Meta-analysis of randomized clinical trials (GIMEMA, IFM, HOVON, NMSG and TMSG)N = 1,682 (MP, n = 868 vs MPT, n = 814) • Median overall survival (OS), 32.7 mo vs 39.3 mo Overall hazard ratio for OS = 0.82 • Median progression-free survival (PFS), 14.9 mo vs 20.4 mo Overall hazard ratio for PFS = 0.67 • Test of heterogeneity between studies was statistically significant for OS (p = 0.26) and for PFS (p = 0.23). MPT: melphalan-prednisone-thalidomide; MP: melphalan-prednisone Waage A et al. EHA 2010. Abstract 0567.

  4. LMWH vs Warfarin vs Aspirinfor Lenalidomide and Thalidomide StandardRisk of VTE Lenalidomide Thalidomide LMWH WAR ASA 0 1 2 3 4 5 6 7 8 Patients (%) HighRisk of VTE • Previous VTE, infection, immobilization, CVC, doxorubicin • LMWH is suggested ASA: Acetylsalicylic acid; LMWH: low molecular weight heparin; VTE: venous thromboembolism; CVC: central venous catheter; PE: pulmonary embolism Palumbo A et al. EHA 2009. Abstract 0214.

  5. VMP (Bortezomib/Melphalan/Prednisone) –Current Standard of Care • ~52% reduced risk of progression • ~36% reduced risk of death Progression-free survival 3-year overall survival* * Median follow-up 25.9 months, median OS not reached San Miguel JF et al. ASH 2008. Abstract 650.

  6. Bortezomib: Once Weekly Bringhen S et al. Blood 2010;116(23):4745-53.

  7. New Treatment Options

  8. Bortezomib-Melphalan-Prednisone-ThalidomideVMPT-VT vs VMP R A N D O M I Z E VMP Cycles 1-9 Bortezomib 1.3 mg/m2 IV Days 1,8,15,22* Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4 NO MAINTENANCE 9 x 5-week cycles in both arms Until relapse VMPT Cycles 1-9 Bortezomib 1.3 mg/m2 IV Days 1,8,15,22* Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4 Thalidomide 50 mg/day continuously MAINTENANCE Bortezomib 1.3 mg/m2 IV Days 1,15 Thalidomide 50 mg/day continuously • 511 patients (older than 65 years) randomized from 61 Italian centers • Patients: Symptomatic multiple myeloma/end-organ damage with measurable disease • ≥ 65 yrs or < 65 yrs and not transplant-eligible; creatinine < 2.5 mg/dL *66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of bortezomib Palumbo A et al. J Clin Oncol 2010;28(34):5101-9.

  9. Bortezomib-Melphalan-Prednisone-ThalidomideTime to First Response and Time to CR VMP VMPT  VT 100 80 60 40 20 0 PR: VMPTVT PR: VMP % of patients CR: VMPTVT CR: VMP 0 5 10 15 20 25 30 Months Palumbo A et al. Proc ASH 2010;Abstract 620.

  10. 3-year TNT Median TTNT VMPT 70% Not reached VMP 51% 37.6 months Bortezomib-Melphalan-Prednisone-Thalidomide Median follow-up 32 months Progression-free survival 41% Reduced Risk of Progression Time to next therapy 48% Reduced Risk of Progression 3-year PFS Median PFS VMPT 51% 37.2 months 32% 27.4 months VMP HR 0.52 p < 0.0001 HR 0.59 p < 0.0001 Palumbo A et al. J Clin Oncol 2010;28(34):5101-9.

  11. 1.00 0.75 Patients (%) 0.50 0.25 0.00 0 10 20 30 40 50 60 Time (months) 1.00 0.75 0.50 0.25 0.00 0 10 20 30 40 50 60 Prognostic FactorsPFS According to ISS and Cytogenetics ISS 1 or 2 Absence of t(4;14) or t(14;16) or del17 1.00 0.75 VMPT-VT VMPT-VT Patients (%) 0.50 VMP VMP 0.25 P=0.003 P<0.0001 0.00 0 10 20 30 40 50 60 Time (months) ISS 3 Presence of t(4;14) or t(14;16) or del17 1.00 0.75 VMPT-VT VMPT-VT Patients (%) Patients (%) 0.50 VMP VMP 0.25 P=0.51 P=0.49 0.00 0 10 20 30 40 50 60 Time (months) Time (months) Palumbo A et al. Proc ASH 2010;Abstract 620.

  12. Melphalan-Prednisone-Lenalidomide Double-Blind Treatment Phase Open-Label Extension Phase N = 459, 82 centers in Europe, Australia, and Israel Cycles 10+ Cycles (28-day) 1-9 Continuous lenalidomidetreatment RANDOMIZATION MPR-R M: 0.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 R: 10 mg/day po Days 1-21 10 mg/daydays 1-21 Lenalidomide (25 mg/day) ± Dexamethasone MPR M: 0.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 R: 10 mg/day po Days 1-21 DiseaseProgression Placebo MP M: 0.18 mg/kg Days 1-4 P: 2 mg/kg Days 1-4 PBO: Days 1-21 Placebo Stratified by age (≤ 75 vs > 75 years) and stage (ISS I/II vs III) M, melphalan; P, prednisone; R, lenalidomide; PBO, placebo; po, orally; ISS, International Staging System Palumbo A et al. EHA 2010. Abstract 0566.

  13. Melphalan-Prednisone-LenalidomideProgression-Free Survival 100 75 50 25 0 0 5 10 15 20 25 30 35 40 58% Reduced Risk of Progression 65-75 Years of Age 2 2 - - Year PFS Year PFS Median PFS Median PFS 2 2 - - Year PFS Year PFS Median PFS Median PFS 100 100 100 100 100 61% 61% Not reached Not reached MPR MPR - - R R MPR MPR - - R R 55% 55% Not reached Not reached MPR MPR 27% 27% 14.7 months 14.7 months 75 75 75 75 75 10% 10% 12.4 months 12.4 months MP MP 16% 16% 13.0 months 13.0 months MP MP HR 0.315 HR 0.423 Log rank < .001 P 50 50 50 50 50 Log rank P < .001 Patients (%) Patients (%) Patients (%) Patients (%) 25 25 25 25 25 HR 0.675 Log rank = .031 P 0 0 0 0 0 0 0 5 5 10 10 15 15 20 20 25 25 30 30 35 35 40 40 0 0 0 5 5 5 10 10 10 15 15 15 20 20 20 25 25 25 30 30 30 35 35 35 40 40 40 Time (months) Time (months) MPR-R: melphalan-prednisone-lenalidomide/lenalidomide continuous treatment; MPR: melphalan-prednisone-lenalidomide; MP: melphalan-prednisone Palumbo A et al. EHA 2010. Abstract 0566.

  14. 100 75 Patients (%) 50 25 0 0 5 10 15 20 25 30 Time (months) Melphalan-Prednisone-LenalidomideLandmark Analysis 69% Reduced Risk of Progression MPR Lenalidomide Continuous Therapy HR 0.314 Log rank P < .001 MPR-R: melphalan-prednisone-lenalidomide/lenalidomide continuous treatment; MPR: melphalan-prednisone-lenalidomide Palumbo A et al. EHA 2010. Abstract 0566.

  15. Age-Adjusted Therapies

  16. Impact of AEs on Outcome Safety meta-analysis of 6 MPT trials1 Median OS, MP vs MPT: 32.7 mo vs 39.3 mo HR = 0.83 p = 0.004 Median PFS, MP vs MPT: 14.9 mo vs 20.3 mo Estimated HR = 0.68 p < 0.0001 – In practice, clinicians would vary the actual dose according to patient's status, evidence of response or relapse and occurrence of side effects or toxicity. – A substantial proportion of patients in all studies either stopped thalidomide prematurely or dose reduced. MPT, melphalan-prednisone-thalidomide; AE, adverse event 1 Fayers P et al Blood 2011, in press

  17. Frail Patients: Treatment Algorithm Go-go Moderate-go Slow-go Palumbo personal communication

  18. Frail Patients: Treatment Algorithm Dose Reductions Wk, week; d, day; qod, every other day Palumbo & Anderson, New Engl J Med 2011

  19. For how many patients with MM have you used subcutaneous (SQ) bortezomib?

  20. What Clinicians Want to KnowA Live CME Event Addressing the Most Common Questions and Controversies in the Current Clinical Management of Select Hematologic CancersSunday, June 5, 20117:00 PM – 9:30 PMChicago, Illinois Moderator Neil Love, MD Faculty Sergio Giralt, MDJohn P Leonard, MD Lauren C Pinter-Brown, MD Antonio Palumbo, MDSusan M O’Brien, MDProfessor Michael Hallek

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