Orlowski mm rel_ref_celgene
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  • 1. Therapy for Relapsed/ Refractory Multiple Myeloma Robert Z. Orlowski, Ph.D., M.D. Director, Myeloma Section Professor, Departments of Lymphoma/Myeloma & Experimental Therapeutics Principal Investigator, M. D. Anderson SPORE in Multiple Myeloma Chair, Southwest Oncology Group Myeloma Committee
  • 2. Clinical Scenario • 59 yo F with IgG κ multiple myeloma • Hgb 9.2 and lytic lesions, so symptomatic • Albumin 3.8 and β2m 5.8, so ISS stage III • FISH and cytogenetics normal • What induction regimen would you recommend?
  • 3. Induction Options • 1: Bortezomib/dexamethasone • 2: Lenalidomide/dexamethasone • 3: Bortezomib/thalidomide/dexamethasone • 4: Bortezomib/doxorubicin/dexamethasone • 5: Bortezomib/cyclophosphamide/dexamethasone • 6: Bortezomib/lenalidomide/dexamethasone • 7: Thalidomide/dexamethasone • 8: Vincristine/doxorubicin/dexamethasone (VAD) • 9: Dexamethasone
  • 4. Alternate Clinical Scenario 1 • 59 yo F with IgG κ multiple myeloma • Hgb 9.2 and lytic lesions, so symptomatic • Albumin 3.8 and β2m 5.8, so ISS stage III • FISH shows del 17p, cytogenetics are normal • What induction regimen would you recommend?
  • 5. Induction Options • 1: Bortezomib/dexamethasone • 2: Lenalidomide/dexamethasone • 3: Bortezomib/thalidomide/dexamethasone • 4: Bortezomib/doxorubicin/dexamethasone • 5: Bortezomib/cyclophosphamide/dexamethasone • 6: Bortezomib/lenalidomide/dexamethasone • 7: Thalidomide/dexamethasone • 8: Vincristine/doxorubicin/dexamethasone (VAD) • 9: Dexamethasone
  • 6. Alternate Clinical Scenario 2 • 59 yo F with IgG κ multiple myeloma • Hgb 9.2 and lytic lesions, so symptomatic • Albumin 3.8 and β2m 5.8, so ISS stage III • FISH and cytogenetics are normal • Serum creatinine 5.0 (vs. prior baseline of 1.0) • What induction regimen would you recommend?
  • 7. Induction Options • 1: Bortezomib/dexamethasone • 2: Lenalidomide/dexamethasone • 3: Bortezomib/thalidomide/dexamethasone • 4: Bortezomib/doxorubicin/dexamethasone • 5: Bortezomib/cyclophosphamide/dexamethasone • 6: Bortezomib/lenalidomide/dexamethasone • 7: Thalidomide/dexamethasone • 8: Vincristine/doxorubicin/dexamethasone (VAD) • 9: Dexamethasone
  • 8. Clinical Scenario Resumed • 59 yo F with IgG κ multiple myeloma • Hgb 9.2 and lytic lesions, so symptomatic • Albumin 3.8 and β2m 5.8, so ISS stage III • FISH and cytogenetics normal • The patient receives thalidomide + dexamethasone induction, and after 6 cycles is in a VGPR • She then undergoes autologous stem cell transplantation, and receives thalidomide maintenance, which produces a CR
  • 9. Second Line Options • While on thalidomide maintenance, the patient develops new bony pain and anemia • Laboratory studies show a recurrent monoclonal protein, and the creatinine has risen to 2.0 • Your choice for second line therapy at this point would be
  • 10. Induction Options • 1: Bortezomib/dexamethasone • 2: Lenalidomide/dexamethasone • 3: Bortezomib/liposomal doxorubicin/dexamethasone • 4: Bortezomib/cyclophosphamide/dexamethasone • 5: Bortezomib/lenalidomide/dexamethasone • 6: Thalidomide/dexamethasone • 7: Vincristine/doxorubicin/dexamethasone (VAD) • 8: Dexamethasone
  • 11. Definitions of Relapse • Relapse from CR – Reappearance of serum and/or urine M-protein • Confirm with repeat study; not oligoclonal banding – ≥5% clonal plasma cells on aspirate or biopsy – New or increased lytic bone lesion(s) or plasmacytoma(s) – Hypercalcemia not attributable to other factor • Relapse from less than a CR – Confirmed >25% increase in serum M-protein of 0.5 g/dL≥ – Confirmed >25% increase in BJP of 200 mg/24 hrs≥ – >25% increase in marrow plasmacytosis ( 10% increase)≥ – Criterion 3 or 4 from above
  • 12. Definitions of Refractory • Progressing on current treatment • Progression within 60 days of completing a previous treatment • Most recent treatment did not induce at least a minor response (25% reduction in disease burden)
  • 13. Biochemical vs. Symptomatic Relapse • Not all patients who suffer a biochemical relapse have disease that requires immediate salvage therapy • Patients who have asymptomatic disease progression may be candidates for a watchful waiting approach, or “window” trials of novel agents/approaches
  • 14. Types of Relapse Alegre, A et al. Haematologica. 87:609, 2004.
  • 15. Major Treatment Goals • Achieve disease response • Reduce active symptom burden • Prevent any additional morbidity • Prolong the patient’s overall survival • Ultimately, to cure multiple myeloma altogether
  • 16. What Disease Response is Best ? Depth of response Time to progression MR PR VGPR nCR CR sCR Treatment initiation Time iCR • Depth of response is related to TTP Adapted from: Niesvizky, R et al. Br J Haematol. 143:46, 2008. Harousseau, J-L et al. Blood 114:3139, 2009. Chanan-Khan, AA et al. J Clin Oncol. 28: 2612, 2010.
  • 17. Other Treatment Goals • Target rational pathway – Multiple key downstream targets to pathobiology • Maximize the quality of life – Enhance TTNT, TFI • Minimize the toxicities of therapy – Use agents with predictable and manageable side effects • Exploit the potential of synergistic interactions – Ability to reuse and recombine regimens • Administer medically- & cost-effective therapies – Don’t break the bank while breaking multiple myeloma
  • 18. 2013 NCCN Guidelines in Relapse • Bortezomib (Category 1) • Bortezomib/liposomal doxorubicin (1) • Lenalidomide/dex (1) • Bendamustine • Repeat primary therapy (if relapse at > 6 mos.) • Bortezomib/dex • Bortezomib/lenalidomide/dex • Cyclophosphamide + VD or + Rd • Thalidomide/dex • Dex, or DCEP, or DT-PACE ± Bortezomib
  • 19. APEX : Bortezomib vs. Dex 78% improvement in median time-to-progression Time (days) P = .0001 Proportionofpatients 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 Median TTP Bortezomib Dexamethasone Bortezomib Dexamethasone 0 All Pts Post-1st relapse 6.2 mos 3.5 mos 7.0 mos 5.6 mos Richardson, PG et al. N. Engl. J. Med. 352:2487, 2005.
  • 20. Bortezomib : Early vs. Late Relapse Sonneveld, G et al. Haematologica 90:146, 2005. Bortezomib 1 prior therapy n = 132 > 1 prior therapy n = 200 Median TTP (months) 7.0 4.9 CR (%) 10%* 7%† CR + PR (%) 51%* 37%† Median Duration of Response (months) 8.1 7.8 1-year Survival 89% 73%
  • 21. SC Bortezomib Moreau, P et al. Lancet Oncol. 12:431, 2011. Response rate, % Bortezomib IV ± dex (N=73) Bortezomib SC ± dex (N=145) ORR (CR + PR) 52 52 CR* 12 10 PR 40 42 nCR 10 10 VGPR 3 5 ≥VGPR (CR + nCR + VGPR) 25 25 Response improvement (cycle 4 → 8) in patients who received dex, n/N (%) n=39 n=82 PR → CR 2/15 (13%) 4/31 (13%) <PR → PR 7/23 (30%) 14/47 (30%)
  • 22. TTP of SC vs. IV Vd Moreau, P et al. Lancet Oncol. 12:431, 2011. 100 90 80 70 60 50 40 30 20 10 0 PatientswithoutPD(%) IV : 9.4 months SC: 10.4 months (0.839 HR; P-value 0.38657) Days from randomization 74 60 56 50 36 24 16 10 7 5 4 3 1 148 126 109 93 72 51 32 18 13 8 5 2 1 No. patients at risk IV SC 0 50 100 150 200 250 300 350 400 450 500 550 600 ORR identical after 4 cycles
  • 23. Bortezomib/PLD vs. Bortezomib PLD + Bortezomib 9.3 months Bortezomib 6.5 months Statistical analysis: HR (95% CI) 1.82 (1.41-2.35) p = 0.000004 PercentofPatientsProgression-Free 0 100 200 300 400 500 020406080100 Orlowski, RZ et al. J. Clin. Oncol. 25:3892, 2007.
  • 24. Other Bortezomib Combinations Kaufman, J et al. Curr Hematol Malignant Rep. 4:99, 2009. Author/Year N Regimen Overall Response Rate (%) CR/nCR Rate (%) Median PFS (mos) Median OS (mos) Pineda-Romané/2008 85 BTD 63 22 – 22 Jakubowiak/2005 20 BD + PLD 56 33 – – Biehn/2007 22 B + PLD 63 36 9.3 (TTP) 38.3 Popat/2005 22 B + Iv Mel +/- D 43 5 6.8 (TTP) – Palumbo/2007 30 V Mel PT 67 17 61% (1 yr) 84% (1 yr) Reece/2008 37 B + Cy + P 95 54 >12 >12
  • 25. Len/Dex vs. Dex Weber, DM et al. N. Engl. J. Med. 357:2133, 2007.
  • 26. Lenalidomide-based Combinations Schey S et al. ASH 2008 Annual Meeting. Abstract 3707; Knop S et al. Blood. 2009;113:4137-4143; Reece DE et al. ASH 2009 Annual Meeting. Abstract 1874; Baz R et al. Ann Oncol. 2006;17:1766-1771; Richardson PG et al. J Clin Oncol. 2009;27:5713-5719; Anderson KC et al. 2009 ASCO Annual Meeting. Abstract 8536. Author/Year N Regimen Overall Response Rate (%) CR/nCR Rate (%) Median PFS Median OS Schey/2009 31 LCD 81 36 (VGPR) – – Knop/2009 66 LDoD 73 15 40 weeks 88% (1 year) Reece/2009 15 LCP 74 45 (VGPR) – – Baz/2006 52 L PLD ViD 75 29 (nCR) 1 year 84% (1 year) Richardson/2009 35 LBV+/- D 60 >MR 8 7.7 months 37 months Anderson/2009 62 LBVD 69 26 12 months 29 months
  • 27. Thal/Dex Lonial, S & Richardson, PG. Clin Cancer Res. 17:1264, 2011.
  • 28. RV ± d in Relapsed Disease Richardson, PG et al. J Clin Oncol. 27:5713, 2009. • 61% MR or better
  • 29. V ± T ± d Pineda-Roman, M et al. Leukemia 22:1419, 2008. • Excellent regimen in salvage setting even after heavy prior treatment
  • 30. VMPT Palumbo, A et al. Blood 109:2767, 2007. • VMPT is one option to consider • Response rate of ~80% as second line therapy
  • 31. Single Agents or Combinations? Garderet, L et al. J Clin Oncol.30:2475, 2012. • Better salvage therapy results in better long-term outcomes
  • 32. Response and Prior Lines Kumar, SK et al. Mayo Clin Proc. 79:867, 2004. • 578 patients; median age 65 years • Follow-up 55 months • Overall survival • One year 72% • Two years 55% • Three years 22% • 84% died in 5 years Figure 3. Duration of response to each treatment 0 2 4 6 8 10 12 1 2 3 4 5 6 Treatment number Medianresponse duration(months)
  • 33. Overall Survival and Prior Lines Kumar, SK et al. Mayo Clin Proc. 79:867, 2004. 00.20.40.60.81.0 0 2 4 6 8 10 CumulativeProbability(%) Years From Start of Regimen Regimen 1 Regimen 2 Regimen 3 Regimen 4 Regimen 5 Regimen 6
  • 34. Carfilzomib : Approved in July, 2012 Siegel, DS et al. Blood 120:2817, 2012. • Results from PX- 171-003-A1 study of carfilzomib in patients with relapsed and refractory myeloma
  • 35. Long-term Outcomes Siegel, DS et al. Blood 120:2817, 2012.
  • 36. Toxicities Siegel, DS et al. Blood 120:2817, 2012. • Most notable for the lower risk of peripheral neuropathy overall, and especially for the low rates of grade 3 or 4 events in this category
  • 37. Activity in Bortezomib-naïve Cohort Vij, R et al. Blood 119:5661, 2012. • Response rate with carfilzomib for patients who received 20 mg/m2 was 42.4% • ORR increased to 52.2% if the dose was escalated to 27 mg/m2
  • 38. Infusional Carfilzomib Lendvai, N et al. ASH Abstract 947, 2012. Continue single-agent CFZ POD ≥ PR after 2 cycles Single arm, open-label, Ph II Continue CFZ + low-dose DEX ≥ SD Add low-dose DEX (20 mg) < PR after 2 cycles Relapsed or refractory symptomatic MM Previous therapy with BTZ & IMiD Single-agent infusional CFZ (28-day cycle)* Cycle 1 • 20 mg/m2 on Days 1, 2 • 56 mg/m2 on Days 8, 9, 15 & 16 Cycles 2≥ • 56 mg/m2 as tolerated
  • 39. Best Response Rate N=38* Best response, n CR 1 (3%) VGPR 9 (24%) PR 10 (26%) MR 1 (3%) SD 11 (29%) POD 6 (16%) ORR 53% Lendvai, N et al. ASH Abstract 947, 2012.
  • 40. Response Durability Progression-free Survival 6mo: 57% (42–75%) 12mo: 44% (29–67%) Median: 7.6 mo (2.8–NR) Duration of response Median 95% CI 10.0 mo (5.8–NR) Overall Survival 6mo: 64% (50–82%) 12mo: 50% (36–71%) Median: Not reached (NR) Lendvai, N et al. ASH Abstract 947, 2012.
  • 41. Grade 3 or 4 Adverse Events N=41 Hematologic Anemia 8 (20%) Thrombocytopenia 14 (37%) Non-hematologic Hypertension 8 (20%) Pneumonia 6 (15%) Pulmonary edema/CHF 4 (10%) Sepsis 3 (7%) LV systolic dysfunction 2 (5%) Dyspnea/hypoxia 2 (5%) Fatigue 2 (5%) Lendvai, N et al. ASH Abstract 947, 2012.
  • 42. Pomalidomide : Approved in February, 2013 Vij, R et al. ASCO Abstract 8016, 2012. • Approval based on the results of the MM-002 study
  • 43. Response Rates Vij, R et al. ASCO Abstract 8016, 2012. • Outcomes shown in dual-refractory patients
  • 44. Responses by Prior Therapies Vij, R et al. ASCO Abstract 8016, 2012.
  • 45. Progression-free Survival Vij, R et al. ASCO Abstract 8016, 2012.
  • 46. Overall Survival Vij, R et al. ASCO Abstract 8016, 2012.
  • 47. Grade 3 and 4 Adverse Events Vij, R et al. ASCO Abstract 8016, 2012.
  • 48. Data from the MM-003 Study Dimopoulos, MA et al. ASH Abstract LBA-6, 2012. (n = 302) POM: 4 mg/day D1-21 + LoDEX: 40 mg ( 75 yrs)≤ 20 mg (> 75 yrs) D1, 8, 15, 22 Follow-Up for OS and SPM Until 5 Years Post Enrollment (n = 153) HiDEX: 40 mg ( 75 yrs)≤ 20 mg (> 75 yrs) D1-4, 9-12, 17-20 28-day cycles PD* or intolerable AE PD* Companion trial MM-003C POM 21/28 days Thromboprophylaxis was indicated for those receiving POM or with DVT history
  • 49. Prior Therapies Dimopoulos, MA et al. ASH Abstract LBA-6, 2012. POM + LoDEX (n = 302) HiDEX (n = 153) Median number, n (range) 5 (1-14) 5 (2-17) Prior DEX, % 97 99 Prior THAL, % 57 61 Prior SCT, % 71 69 Prior LEN, % 100 100 Prior BORT, % 100 100 LEN-refractory, % 93 90 BORT-refractory, % 78 77 LEN- and BORT-refractory, % 73 71
  • 50. Progression-free Survival Dimopoulos, MA et al. ASH Abstract LBA-6, 2012. 0 4 8 12 16 0.0 0.2 0.4 0.6 0.8 1.0 Progression-Free Survival (months) ProportionofPatients Median PFS POM + LoDEX (n = 302) 3.6 months HiDEX (n = 153) 1.8 months HR = 0.45 P < .001
  • 51. PFS in Dual Refractory Patients Dimopoulos, MA et al. ASH Abstract LBA-6, 2012. ProportionofPatients 0.0 0.2 0.4 0.6 0.8 1.0 0 4 8 12 16 HR = 0.48 P < .001 Progression-Free Survival (months) Median PFS POM + LoDEX (n = 221) 3.2 months HiDEX (n = 108) 1.7 months
  • 52. Overall Survival Dimopoulos, MA et al. ASH Abstract LBA-6, 2012. Overall Survival (months) 0.0 0.2 0.4 0.6 0.8 1.0 0 4 8 12 16 ProportionofPatients Median OS (95% CI) POM + LoDEX (n = 302) Not Reached (11.1-NE) HiDEX (n = 153) 7.8 months (5.4-9.2) HR = 0.53 P < .001
  • 53. OS in Dual Refractory Patients Dimopoulos, MA et al. ASH Abstract LBA-6, 2012. 0.0 0.2 0.4 0.6 0.8 1.0 Overall Survival (months) 0 4 8 12 16 ProportionofPatients HR = 0.56 P = .003 Median OS (95% CI) POM + LoDEX (n = 221) Not Reached (8.5-NE) HiDEX (n = 108) 7.4 months (4.3-9.2)
  • 54. Adverse Events Dimopoulos, MA et al. ASH Abstract LBA-6, 2012. 7% of POM + LoDEX and 6% of HiDEX patients discontinued due to AEs HiDEX POM+LoDEX All grades % of patients experiencing ≥ grade 3 adverse event Neutropenia Febrile neutropenia Anemia Thrombocytopenia Infection Pneumonia Hemorrhage Glucose intolerance Fatigue VTE* PN* * 0 10 20 30 40 50
  • 55. Carfilzomib/Pomalidomide Shah, JJ et al. ASH Abstract 74, 2012. 1 2 8 9 15 16 1 8 15 22 1 21 Carfilzomib Pomalidomide Dexamethasone •Cycle 1-6: 28 day cycle
  • 56. Hematologic AEs G 1 G 2 G 3 G 4 Total Anemia 1 7 11 1 20 Thrombocytopenia 5 4 7 2 18 Neutropenia 1 8 13 5 27 Febrile neutropenia 0 0 2 0 2 Shah, JJ et al. ASH Abstract 74, 2012.
  • 57. Non-Hematologic AEs G 1 G 2 G 3 G 4 total Diarrhea 8 2 0 0 10 (31%) Fatigue 9 8 1 0 18 (56%) Dyspnea 9 0 0 0 9 (28%) Skin, Rash, Pruritis 5 1 1 0 7 (21%) Creatinine elevated 5 2 1 0 8 (26%) Hypocalcemia 7 4 0 0 11 (34%) Shah, JJ et al. ASH Abstract 74, 2012.
  • 58. Response Rates N = 30 Overall Response Rate ( ≥ PR) 15 (50%) VGPR 4 (13%) PR 11 (37%) MR 5 (17%) SD 7 (23%) PD 3 (10%) Shah, JJ et al. ASH Abstract 74, 2012.
  • 59. Progression-free Survival Outcome Car-Pom-d (N = 32) Response rates (n = 30), %  ORR 50 • ≥ VGPR 13 • PR 37  Minor response 17  SD 23  PD 10 Median PFS, mos 7.4 1-yr OS, % 90 PFS(%) Time in Study (Mos) Car-Pom-d PFS (N = 32) 95% CI Median PFS: 7.4 mos 0 3 6 9 12 100 90 80 70 60 50 40 30 20 10 0 Shah, JJ et al. ASH Abstract 74, 2012.
  • 60. Pomalidomide/Bortezomib/Dex Richardson, PG et al. ASH Abstract 727, 2012. 3 + 3 Design (21-day cycles) Evaluation Every 21 Days (± 3 Days) Follow-Up for OS and SPM Until 5 Years Post-enrollment Cohort POM (D1-14) BORT (D1, 4, 8, 11*) LoDEX (D1-2, 4-5, 8-9, 11-12† ) 1 (n = 3) 1 mg/day 1 mg/m2 20 mg‡ 2 (n = 3) 2 mg/day 1 mg/m2 20 mg‡ 3 (n = 3) 3 mg/day 1 mg/m2 20 mg‡ 4 (n = 3) 4 mg/day 1 mg/m2 20 mg‡ 5 (n = 3) 4 mg/day 1.3 mg/m2 20 mg‡ Expansion cohort (n = 6) at MTD/MPD *For cycles 1-8, then D1, 8 for cycles 9+; † For cycles 1-8, then D1-2, 8-9 for cycles 9+; ‡ 10 mg for pts aged > 75 yrs
  • 61. DLTs Cohort Dose-Limiting Toxicity Cohort 1 (n = 3) None Cohort 2 (n = 3) None Cohort 3 (n = 3) None Cohort 4 (n = 3) None Cohort 5 (n = 3) None Richardson, PG et al. ASH Abstract 727, 2012.
  • 62. Adverse Events Patients (%) Richardson, PG et al. ASH Abstract 727, 2012.
  • 63. Response Summary • ORR (≥ PR): 73%; VGPR: 27%; SD: 27% • Median time to response: 1 cycle (range 1-2) • Most responses are ongoing Cohort Best Response Cohort 1 (n = 3) 1 VGPR, 1 PR, 1 SD Cohort 2 (n = 3) 1 PR, 2 SD Cohort 3 (n = 3) 2 VGPR, 1 PR Cohort 4 (n = 3) 1 VGPR, 2 PR Cohort 5 (n = 3) 2 PR, 1 SD Richardson, PG et al. ASH Abstract 727, 2012.
  • 64. Response Duration VGPR PR SD Ongoing Cohort 1 Cohort 2 Cohort 3 Cohort 4 Cohort 5 Discontinued PD 2 3 4 5 6 7 8 9 10 Discontinued PD PD Completed Treatment 11 * * Richardson, PG et al. ASH Abstract 727, 2012.
  • 65. Novel Agents : Elotuzumab + Len/Dex Elotuzumab 10 mg/kg Elotuzumab 20 mg/kg Total Pts, n 31 32 63 ≥ PR, n (%) 28 (90) 23 (72) 51 (81) Stringent CR, n (%) 1 (3) 1 (3) 2 (3) CR, n (%) 2 (7) 1 (3) 3 (5) VGPR, n (%) 10 (32) 8 (25) 18 (29) PR, n (%) 15 (48) 13 (41) 28 (44) SD, n (%) 3 (10) 7 (22) 10 (16) PD, n (%) 0 (0) 0 (0) 0 (0) Not evaluable, n (%) 0 (0) 2 (6) 2 (3) Richardson, PG et al. 2010 ASH Abstract 986.
  • 66. Other Antibodies : Daratumumab Plesner, T et al. ASH Abstract 73, 2012. Expansion cohort Dose- escalation cohorts Part 2 Open label, single arm, i.v. infusion weekly: 8 weeks every other week: 16 weeks every fourth week: up to 96 weeks 8 mg/kg, 16 patients Part 1 Open label, weekly i.v. infusion, 8 weeks Dose-escalation: 3+3 scheme* 0.005→0.05→0.1→0.5→1.0 →2.0→4.0→8.0→16.0 →24.0 mg/kg
  • 67. Paraprotein Responses 9 2 5 1 20 19 10 12 31 16 29 8 13 4 26 15 3 7 11 17 14 33 27 21 6 30 18 34 23 32 22 28 -100 -50 0 50 100 Reletivechangeinparaproteinefrombaseline(%) Patientnumber A AA A AA A AA A AA AA AA AA AAB B B B C A C C C CC C 2 mg/kg2 mg/kg 4 mg/kg4 mg/kg 8 mg/kg8 mg/kg 16 mg/kg16 mg/kg 24 mg/kg24 mg/kg< 1 mg/kg Plesner, T et al. ASH Abstract 73, 2012.
  • 68. PFS vs. Drug Exposure Plesner, T et al. ASH Abstract 73, 2012.
  • 69. Other Novel Agents : ARRY520 Shah, JJ et al. ASH Abstract 449, 2012.
  • 70. Toxicities Shah, JJ et al. ASH Abstract 449, 2012. Adverse Events, % ARRY-520 (n = 32) ARRY + Dexamethasone (n = 21) Grade 3 Grade 4 Grade 3 Grade 4 Nonhematologic  Pneumonia -- -- 10 10  Fatigue 12 3 10 --  Arthralgia -- -- 5 --  Back pain 6 -- -- --  Hypokalemia 3 3 5 --  Upper respiratory tract infection -- -- 5 -- Hematologic  Neutropenia 19 28 24 38  Thrombocytopenia 22 25 38 19  Anemia 31 6 43 5  Febrile neutropenia 3 -- 5 --
  • 71. Outcomes Shah, JJ et al. ASH Abstract 449, 2012. Outcome ARRY-520 (n = 32) ARRY-520 + Dexamethasone (n = 18) Overall best response, %  PR 16 22 • MR + PR 19 33  SD 44 28  PD 34 28  Not evaluable 3 11 Median duration of response (≥ PR), mos (range) 8.6 (1.4-20.0) 5.4 (2.5-9.0)
  • 72. Len/Thal/Dex Shah, JJ et al. ASH Abstract 75, 2012.
  • 73. Study Design 1 8 15 22 1 21 Lenalidomide Dexamethasone Cycle 1-8: 28 day cycle Dexamethasone dosing for cycle 1-2: 40 mg days 1-4, 9-12, and 17-20; all subsequent cycles weekly dosing Last cohort of 10 patients with Lenalidomide refractory disease: weekly dosing started with cycle 1 Thalidomide 1 28 Shah, JJ et al. ASH Abstract 75, 2012.
  • 74. DLTs/RP2D Patients DLT Cohort 1 (len15 / thal 100) 3 0 Cohort 2 (len25 / thal 100) 6 1 Cohort 3 (len25 / thal 200) 9 2 DLT in cohort 2: Steroid induced toxicity, requiring reduction in dex dosing in cycle 1 DLT in cohort 3: G3 rash; asymptomatic G2 atrial fibrillation G3 hypertensive crisis and volume overload due to dexamethasone MRD : Lenalidomide 25 mg / Thalidomide 100 mg / Dex Shah, JJ et al. ASH Abstract 75, 2012.
  • 75. Response Rates N = 61 Overall Response Rate ( ≥ PR) 31 (51%) Stable Disease 15 (25%) Minimal Response 8 (13%) Partial Response 19 (31%) VGPR 4 (7%) nCR/CR 8 (13%) Progressive Disease 7 (11%) Clinical Benefit Ratio (≥ MR) of 64% Shah, JJ et al. ASH Abstract 75, 2012.
  • 76. Outcomes in Len Refractory Disease N = 41* Overall Response 13 (34%) Stable Disease 12 (29%) Minimal Response 8 (20%) Partial Response 11 (27%) VGPR 1 (2%) CR / nCR 2 (5%) Progressive Disease 7 (17%) Lenalidomide Refractory: Clinical Benefit Ratio ( MR) of 51%≥ Lenalidomide Naïve: Overall Response (≥ PR) of 14/16 (88%) Shah, JJ et al. ASH Abstract 75, 2012.
  • 77. Progression-free Survival Median PFS 8.0 months Shah, JJ et al. ASH Abstract 75, 2012.
  • 78. Overall Survival Median OS 29 months Shah, JJ et al. ASH Abstract 75, 2012.
  • 79. Outcomes in Del 17p Shah, JJ et al. ASH Abstract 75, 2012. Progression Free Survival Overall Survival Not Del 17p Del 17p Not Del 17p Del 17p
  • 80. Second Autologous Transplant AHCT2 AHCT1 AHCT2 Response at 1 year (%) - CR - PR 82 43 39 68 25 43 - Relapse at 3 years (%) 80 82 - Median time to relapse (months) 18 12 Saad, A et al. ASH Abstract 504, 2011.
  • 81. Overall Survival ProbabilityofOS,% Years 0 2 4 986 100 0 20 40 60 80 90 10 30 50 70 0 100 20 40 60 80 90 10 30 50 70 N = 187 1 3 75 Survival (95% CI): @ 1 yr: 83% (77-89) @ 3 yrs: 46% (37-54) @ 5 yrs: 29% (21-38) Saad, A et al. ASH Abstract 504, 2011.
  • 82. Non-relapse Mortality Incidence,% Years 0 2 4 986 100 0 20 40 60 80 90 10 30 50 70 0 100 20 40 60 80 90 10 30 50 70 1 3 75 NRM (95% CI): @ 1 yr: 2% (1-5) @ 3 yrs: 4% (2-8)) Saad, A et al. ASH Abstract 504, 2011.
  • 83. Multivariate Analysis Reference group * NRM Relapse/PD Treatment Failure/ PFS Mortality/OS HR P HR P HR P Time from AHCT1 to relapse : <36 mo vs. >36 mo NO significant covariates 1.58 0.036 1.52 0.04 1.91 0.02 Year of AHCT2 (after vs. before 2004) - - - - 0.61 0.026 Saad, A et al. ASH Abstract 504, 2011.
  • 84. OS and Time to First Relapse ProbabilityofOS,% Years 0 2 4 986 100 0 20 40 60 80 90 10 30 50 70 0 100 20 40 60 80 90 10 30 50 70 <36 months (N = 151) 1 3 75 ≥36 months (N )= 38 (HR 1.91, P = 0.02) Saad, A et al. ASH Abstract 504, 2011.
  • 85. Clinical Scenario Resumed • 59 yo F with IgG κ multiple myeloma • Hgb 9.2 and lytic lesions, so symptomatic • Albumin 3.8 and β2m 5.8, so ISS stage III • FISH and cytogenetics normal • The patient receives thalidomide + dexamethasone induction, and after 6 cycles is in a VGPR • She then undergoes autologous stem cell transplantation, and receives thalidomide maintenance, which produces a CR
  • 86. Second Line Options • While on thalidomide maintenance, the patient develops new bony pain and anemia • Laboratory studies show a recurrent monoclonal protein, and the creatinine has risen to 2.0 • Your choice for second line therapy at this point would be
  • 87. Induction Options • 1: Bortezomib/dexamethasone • 2: Lenalidomide/dexamethasone • 3: Bortezomib/liposomal doxorubicin/dexamethasone • 4: Bortezomib/cyclophosphamide/dexamethasone • 5: Bortezomib/lenalidomide/dexamethasone • 6: Thalidomide/dexamethasone • 7: Vincristine/doxorubicin/dexamethasone (VAD) • 8: Dexamethasone
  • 88. Other Factors That Influence Choice DISEASE-DISEASE- RELATEDRELATED DOR to initial therapyDOR to initial therapy FISH / cytogeneticsFISH / cytogenetics REGIMEN-REGIMEN- RELATEDRELATED Prior drug exposurePrior drug exposure Toxicity of regimenToxicity of regimen Mode of administrationMode of administration Previous SCTPrevious SCT PATIENT-PATIENT- RELATEDRELATED Pre-existing toxicityPre-existing toxicity Co-morbiditiesCo-morbidities AgeAge Performance statusPerformance status Stage generally does not influence salvage therapy choice. Lonial, SL. ASH Educational Book, 303, 2010.
  • 89. Conclusions • 2nd generation PI carfilzomib & 3rd generation IMiD pomalidomide approved • Studies of rationally designed combination regimens are underway and showing promise • Mabs such as elotuzumab and daratumumab bring new approach into play against myeloma • Novel agents with new mechanisms of action such as ARRY-520 and dinaciclib are entering the fray
  • 90. MDACC Lymphoma & Myeloma Center • Clinical faculty – Dr. Raymond Alexanian – Dr. Robert Orlowski • rorlowsk@mdanderson.org • Twitter: @Myeloma_Doc • http://bit.ly/bM3sqS – Dr. Jatin Shah – Dr. Sheeba Thomas – Dr. Michael Wang – Dr. Donna Weber