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Disclosures for Palumbo Antonio, MD

Disclosures for Palumbo Antonio, MD. Research Support/P.I. No relevant conflicts of interest to declare. Employee. No relevant conflicts of interest to declare. Consultant. Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx. Major Stockholder.

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Disclosures for Palumbo Antonio, MD

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  1. Disclosures for Palumbo Antonio, MD Research Support/P.I. No relevant conflicts of interest to declare Employee No relevant conflicts of interest to declare Consultant Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx Major Stockholder No relevant conflicts of interest to declare No relevant conflicts of interest to declare Speakers Bureau Honoraria Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx No relevant conflicts of interest to declare Scientific Advisory Board Presentation includes discussion of the off-label use of a drug or drugs

  2. Case presentation

  3. History • 48 year-old man • Newly diagnosed myeloma • Haemoglobin 123 g/l • IgG-λ M-protein peak 38 g/l • 14% bone marrow plasma cells • No chromosomal abnormalities • Several bone lytic lesions • Induction: 4 courses of VTD  MEL200 and ASCT • After ASCT: Immunofixation negative CR VTD = bortezomib, thalidomide, dexamethasone.

  4. Question 1 Which is the best therapeutic option? • 1. No treatment • 2. Maintenance with thalidomide • 3. Maintenance with lenalidomide • 4. Maintenance with bortezomib

  5. Question 2 Which is the optimal duration? • 1. Maintenance for 1 year • 2. Maintenance for 2 years • 3. Maintenance until progression or intolerance • 4. No maintenance

  6. Improving Outcomes in Myeloma Case 4: Patient who has responded well to induction therapy – should maintenance therapy be recommended, and if so, what strategy? Antonio Palumbo University of Torino, Italy, EU 25min 20 min

  7. Maintenance

  8. Thalidomide Maintenance35% reduced risk of progression 16% reduced risk of death Ludwig H, et al. Blood. 2012

  9. LenalidomideMaintenance 51% reduced risk of progression 23% reduced risk of death McCarthy PL, et al. N Engl J Med 2012; Palumbo A, et al. N Emgl J Med 2012; Attal M, et al. N Emgl J Med 2012; Palumbo A, et al. ASCO 2013.

  10. BortezomibMaintenance 31% reduced risk of progression 27% reduced risk of death VMP, bortezomib-melphalan-prednisone; VMPT-VT, VMP plus thalidomide followed by bortezomib-thalidomide; VAD-T, vincristine-adriamycin-dexamethasone followed by thalidomide; PAD-V, bortezomib-adriamycin-dexamethasone followed by bortezomib. Sonneveld P, et al. J Clin Oncol 2012; Palumbo A, et al. J Clin Oncol. 2010.

  11. Early vs. Late ASCT

  12. 100 100 MEL200-R 75 MPR-R 75 MEL200 50 MPR 50 MEL200-R MEL200 25 25 MPR-R MPR 0 0 0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 Months Early vs. Late ASCT vs. Maintenance vs. Placebo MPR vs. MEL 200 MPR six 28-day courses M: 0.18 mg/Kg/d, days 1-4 P: 2 mg/Kg/d, days 1-4 R: 10 mg/d, days 1-21 NO MAINTENANCE Rd four 28-day courses R: 25 mg/d, days 1-21 d: 40 mg/d, days 1,8,15,22 1° R 2° R MEL200 two courses M: 200 mg/m2 day -2 Stem cell support day 0 R MAINTENANCE 28-day courses until relapse R: 10 mg/day, days 1-21 Progression-free survival Overall survival Months MPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; R, lenalidomide maintenance

  13. Rationale - Continuous treatment

  14. Progression-free Survival According to Quality of Response +12 m maint Pre maint +3 m maint +6 m maint +18 m maint Dia +12 m maint Pre maint +3 m maint +6 m maint +18 m maint Dia MRD - CR- Progression-free survival 100 MRD - CR - 80 60 Percent survival MRD+ CR- 40 MRD + CR - 20 0 0 10 20 30 40 50 Months MRD, minimal residual disease; CR complete response

  15. Tumor Load During Maintenance

  16. Resistant Relapse

  17. BiologicalEvents Clinical Phase Normal Pregerminal B cells Precursordisease Multiple myeloma Extramedullarymyeloma Primary IgH translocations Hyperdiploidy Cyclin D gene dysregulation Deletion of chromosome 13 NRAS mutation KRAS and FGFR3 mutations MYC up-regulation MYC rearrangement p18, p53 and Rb gene inactivation Karyotypic and epigenetic adnormalities NFkB-activating mutations Secondary IgH translocations • BONE MARROW MICROENVIRONMENT CHANGES • Osteoclast activation • Osteoblast inhibition • Increased angiogenesis • Altered expression of cytokines, growth factors, and adhesion molecules Korde N, et al. Blood. 2011;117: 5573-81.

  18. ClonalEvolution 1.00 1.00 Spontaneousclonalevolution 0.75 0.75 Patients (%) 0.50 0.50 0.25 0.25 Drug-relatedclonalevolution 0.00 0.00 0 0 5 5 10 10 15 15 20 20 25 25 Time

  19. 100 75 R maint. 100 50 75 50 No maint. 25 25 0 0 10 20 30 40 50 60 70 0 HR 0.82, 95% CI 0.55-1.22, P =.32 0 10 20 30 40 50 60 Months R Maintenance vs. No Maintenance OS from relapse PFS from diagnosis Chemoresistant relapse Delayed clonal evolution R maint. Chemosensitive relapse Faster clonal evolution No maint. HR 0.52, 95% CI 0.40-0.67, P <.0001 Months R, lenalidomide

  20. 100 100 Chemoresistantrelapse Delayedclonalevolution 75 75 50 50 VMPT-VT VMPT-VT Chemoresistant relapse 25 Faster clonal evolution 25 VMP HR 0.92, 95% CI, 0.66-1.28, p =.63 0 HR 0.58, 95% CI, 0.47-0.71, P < 0.0001 0 10 20 30 40 50 60 0 0 10 20 30 40 50 60 70 80 VT Maintenance vs. No Maintenance OS from relapse PFS from diagnosis VMP Months Months VMP, bortezomib-melphalan-prednisone; VMPT, bortezomib-melphalan-prednisone-thalidomide; VT, bortezomib-thalidomide maintenance

  21. Until progression?

  22. 100 75 50 25 0 PFS: Landmark AnalysesMaintenance vs. Placebo MPR Lenalidomide Maintenance Patients (%) 0 5 10 15 20 25 Time (months) Palumbo A, et al. N Engl J Med. 2012 M, melphalan; P, prednisone; R, lenalidomide; V, bortezomib; T, thalidomide; PFS, progression-free survival; NA, not available

  23. Progression-free SurvivalLandmark Analysis VMPT VT Maintenance Off therapy 1.00 4-years PFS MedianPFS VMPT-VT 33% 31.5 months 0.75 VMP 16% 17.8 months Patients (%) 0.50 0.25 HR 0.56, 95% CI, 0.44-0.71, p<0.0001 0.00 0 10 20 30 40 50 60 70 Time (months)

  24. Overall Survival (OS)30% Reduced Risk of Death 5-years OS MedianOS VMPT-VT 61% Notreached VMP 51% 60.6 months VMPT VT Maintenance Off therapy 1.00 0.75 0.50 Patients (%) 0.25 0.00 HR 0.70, 95% CI, 0.52-0.92, P = 0.01 0 10 20 30 40 50 60 70 80 90 Time (months)

  25. Whatisnew?

  26. Carfilzomib, Cyclophosphamide, Dexamethasone (CCyd) MAINTENANCE CCyd Cycles 1-9 C: 20 mg/m2 d 1,2 followed by 36 mg/m2 d 8,9,15,16,22 (cycle 1); 36 mg/m2 d 1,2,8,9,15,16,22 (cycle 2-9); Cy: 300 mg/m2 d 1,8,15 d: 40 mg d 1,8,15,22 C Until progression/intolerance C: 36 mg/m2 d 1,2,15,16 sCR sCR/nCR/CR ≥VGPR ≥PR 96 94 100 89 100 76 80 72 64 63 75 60 46 41 50 40 24 15 13 20 25 1-year rate 86% 0 0 Cycle 2 Cycle 6 Cycle 9 0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0 • 58 newly diagnosed elderly MM patients enrolled at 10 Italian centers Progression-free survival Best response Patients (%) Patients (%) Time (months) CCyd, cyclophosphamide-cyclophosphamide-dexamethasone; C, carfilzomib; PR, partial response; VGPR, very good partial response; CR, complete response; sCR, stringent complete response; nCR, near complete response.

  27. Carfilzomib, Lenalidomide, Dexamethasone (CRd) MAINTENANCE RECOMMENDED CRd Cycles 1-8 C: 20/27/36 mg/m2, d 1,2,8,9,15,16 R: 25 mg/m2, d 1-21 d: 40 mg (cycles 1-4) 20 mg (cycles 5-8), d 1,8,15,22 CRd Cycles 9-24 C: 20/27/36 mg/m2, d 1,2, 15,16 R: 25 mg/m2, d 1-21 d: 20 mg, d 1,8,15,22 R (off protocol) Cycles 25+ L: 25 mg/day on days 1-21 For ASCT eligible: Stem cell collection after cycle 4 • 53 newly diagnosed transplant eligible and ineligible MM patients enrolled at 4 US centers Progression-free survival Median follow-up 13 months (range 1-20) Best response Median 12 cycles (range 1-25) ≥PR ≥VGPR ≥nCR sCR 100 98 80 81 60 62 Patients (%) 40 42 1-year rate 97% 2-year rate 92% 20 0 CRd, cyclophosphamide-lenalidomide-dexamethasone; R, lenalidomide; ASCT, autologous stem cell transplantation; PR, partial response; VGPR, very good partial response; CR, complete response; sCR, stringent complete response. Jakubowiak AJ, et al. Blood 2012.

  28. Dose-Escalation Study of Oprozomib (ONX0912) Maintenance Induction: up to 12 x 28-day treatment cycles 1 8 15 28 22 • Administered on days 1-5 of a 14-day cycle MLN9708 maintenance Days 1, 8, 15 28-day cycles MLN9708 MLN9708 MLN9708 Dex 40 mg Dex 40 mg Dex 40 mg Dex 40 mg Lenalidomide 25 mg, days 1–21 Ixazomib-lenalidomide-dexamethasone in previously untreated MM Savona MR, et al. ASH 2012: Abstract 203; Kumar, et al. ASH 2012: Abstract 332

  29. Ixazomib-Lenalidomide-Dexamethasone in Previously Untreated MM Maintenance Induction: up to 12 x 28-day treatment cycles 1 8 15 28 22 MLN9708 maintenance Days 1, 8, 15 28-day cycles MLN9708 MLN9708 MLN9708 Dex 40 mg Dex 40 mg Dex 40 mg Dex 40 mg Lenalidomide 25 mg, days 1–21 Response rates MM, multiple myeloma; ORR, overall response rate; VGPR, very good partial response; CR, complete response; nCR, near complete response; Dex, dexamethasone. Kumar, et al. ASH 2012: Abstract 332

  30. Conclusions • Untilprogression • IF alltoxicitieswithingrade 1 • Thalidomide Cost • Lenalidomide  Oral, PN • Bortezomib Injection, SPM

  31. Thank You

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