1 / 31

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.

agnes
Download Presentation

Disclosures for Palumbo Antonio, MD

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related