Rafael Fonseca MD Mayo Clinic Multiple Myeloma 2012; Update

1. Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Rafael Fonseca MDMayo ClinicMultiple Myeloma 2012;Update Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center

2. Disclosures • Consulting: AMGEN, Genzyme, BMS, Otsuka, Celgene, Medtronic, Lilly, Onyx. • Millennium • Speakers Bureaus: None • Research: Cylene, Proteolix • Patent for FISH based prognostication in MM

3. Clinical Features • Calcium elevation • Renal disease • Anemia • Bone disease • …and other constitutional Smith. Br J Haematol. 2005;132:410.

4. Importance of progression events

5. Renal Metabolism of FLCs

6. Analytical sensitivity of laboratory methods for detection of FLCs 10000 1000 Total k & l SPE CZE 100 IFE Light chain concentration (mg/L) Normal range in serum 10 UPE 1 FLC 0.1

7. sFLCs published normal range 100000 10000 1000 Normal sera Renal impairment (non-MG) 100 Serum Lambda FLC (mg/L) 10 1 0.1 0.1 1 10 100 1000 10000 100000 Serum Kappa FLC (mg/L) Bradwell, Lancet 2003; 361: 489-491 Katzmann, Clin Chem 2002; 48: 1437 - 1444

8. sFLCs in LCMM and NSMM Normal sera Kappa LCMM Lambda LCMM NSMM Drayson Blood 2001; 97: 2900 – 2902

9. Treatment of Myeloma 2008 MP era 42% at 3 years 93% at 3 years Menon S. Cancer 112:1522-1528 MTCG. J Clin Oncol 1998; 16:3832

10. Spanish Long Term Blood 2011 blood-2011-01-332320

11. Transplant Outcomes Reeder et al, Leukemia 2009, 23:1337-41

16. MinimalResidualDisease PFS in PCR-negative patients months Ladetto M, et al. ASH 2009. Abstract 960.

17. Genomics and Precision Medicine

18. Submarine

19. REAL TIME REPORT GENERATED FOR PATIENT AND TREATING PHYSICIAN N OF 1

20. CCND1 2% • BRAF 4% • DIS3 (RPP44) 11% • FAM46C 13% • XBP1 4% • LRRK2 6% • IRF 6% • PRDM1 6% • Known; ras (50%), NF-kB (37%), p53 (8%) • Protein translation 42% • Histone modifying enzymes (lead HOXA9) • Fibrin clot formation 16% Nature 24 March 2011, 471:467

21. Study population stratified according to cytogenetic abnormalities 232 pts Standard-risk High-risk no cytogeneticabnormalities + del (13q) + t(11;14)188 pts(80%) t(4;14) ± t(14;16) + del(17p) 44 pts(19%) t(14;16)3 (1%) t(4;14)±del(13q)17 (7%) del(17p)±del(13q)21(9%) both3 (1%)

22. 1.0 0.8 0.6 0.4 0.2 0.0 0 5 10 15 20 25 30 35 40 45 50 Overall survival according to cytogenetic abnormalities Standard risk: NR Proportion of pts High risk: 38m p=0.001 HR: 2.3, 95% IC: 1.4-4.0 Time in months from 1st randomization

23. EFS and OS; t(4;14) VD (n = 106) vsVAD (n = 98) Avet-Loiseau H et al. JCO 2010;28:4630-4634

24. EFS and OS; VD Treated t(4;14) (n = 106) vs not (n = 401) Avet-Loiseau H et al. JCO 2010;28:4630-4634

25. No t(4;14) Bortezomib treated t(4;14) Bortezomib treated t(4;14) VAD treated Avet-Loiseau H et al. JCO 2010;28:4630-4634

26. High Risk in Len Treated Patients

27. Lenalidomide maintenance on PFS of t(4;14) del13 p<.0001 p<.001 IFM 2005-02 trial: general results for PFS PFS for patients with del(13) del17p t(4;14) p<.02 p<.04 PFS for patients with del(17p) > 60% PFS for patients wit t(4;14) Avet-Loiseau ASH 2010

28. Carfilzomib and PX-171-004 • Carfilzomib is a selective tetrapeptide epoxyketone proteasome inhibitor that displays potent and sustained proteasome inhibition. • The high degree of selectivity of carfilzomib may account for its improved tolerability profile: • In early clinical studies, carfilzomib has not been associated with dose-limiting peripheral neuropathy (PN). • PX-171-004 is an ongoing multicenter, non-randomized, open-label, single-arm phase 2 trial of single-agent carfilzomib in patients with R/R MM who have received 1–3 prior lines of therapy. K Stewart et al ASCO Abstract 8026

29. Study Design and Treatment • Bortezomib-naïve patients (N=129) were enrolled in 2 sequential dose cohorts. • In Cohort 1, patients received carfilzomib 20 mg/m2 IV on Days 1, 2, 8, 9, 15, and 16 every 28 days, for up to 12 cycles. • In Cohort 2, patients received a stepped-up, dose-escalating regimen of carfilzomib 20 mg/m2 for Cycle 1 followed by carfilzomib 27 mg/m2 for all subsequent treatment cycles. • Dexamethasone 4 mg was administered prior to carfilzomib in Cycle 1 only to ameliorate a potential “first dose” effect (including fever, chills, rigors, and dyspnea). • Patients completing all 12 cycles were eligible to enroll in an extension study (PX-171-010). K Stewart et al ASCO Abstract 8026

30. Significant Responses‡in BTZ-naïve Patients • Significant response rates were observed in both cohorts *Data cut-off date 9 February 2011 †2 patients (3%) in Cohort 2 were excluded on the basis of missing baseline or post-baseline disease assessments. ‡Responses confirmed by Independent Review Committee ORR= 42% ORR= 51% CBR= 59% CBR= 63% K Stewart et al ASCO Abstract 8026

31. Substantial Duration of Response Observed for Cohorts 1 and 2* K Stewart et al ASCO Abstract 8026 *Data cut-off date 9 February 2011

32. Similar Incidence and Severity of AEs Between Cohorts • There were no discontinuations of treatment due to peripheral neuropathy. • In no case were any toxicities (any grades) >2% higher in Cohort 2 than in Cohort 1; in general they were either similar or lower • cumulative toxicities has been observed in patients continuing on extended carfilzomib treatment (PX-171-010). K Stewart et al ASCO Abstract 8026

33. Pomalidomide in Len Treated Patients Patient Characteristics J Mikhael et al ASCO Abstract 8067

34. Response rate on Pomalidomide Despite Prior Treatment with Lenalidomide J Mikhael et al ASCO Abstract 8067

35. MRC Myeloma IX—Analysis Schematic for ZOL vs CLO Zoledronic acid (4 mga IV q 3-4 wk) + intensive or non-intensive chemotherapy(n = 981) RANDOMISATION N = 1,960 Patients with newly diagnosed MM (stage I, II, III) Bisphosphonate treatment continued at least until disease progression Clodronate (1,600 mg/d PO) + intensive or non-intensive chemotherapy (n = 979) Endpoints (ZOL vs CLO) Primary: PFS, OS, and Response Secondary: SREs (time to first SRE, SRE incidence) and Safety SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions, or the appearance of new osteolytic bone lesions. G Morgan et al ASCO Abstract 8010

36. MRC Myeloma IX—ZOL Significantly  SREs vs CLO in the Overall Population • ZOL reduced the risk of SREs by 26% vs CLO (HR = 0.74; P = .0004) 40 35.3% CLO 30 27.0% ZOL Patients with an SRE, % 20 10 0 0 6 12 18 24 30 36 42 Time from randomisation, months Patients at risk, n ZOL CLO 981 979 663 629 506 465 390 337 284 256 201 173 138 112 97 74 Abbreviations: CLO, clodronate; HR, hazard ratio; SRE, skeletal-related event; ZOL, zoledronic acid. G Morgan et al ASCO Abstract 8010

37. ZOL Significantly  OS vs CLO in Patients With Bone Disease at Baseline (n = 1,350) 100 + Censored 90 P = .0107 HR: 0.82 (95% CI: 0.70, 0.96) 80 70 60 Survival distribution function estimateOS, % patients 50 40 30 20 Clodronate (n = 682) 10 Zoledronic acid (n = 668) 0 0 1 2 3 4 5 6 Survival, years since initial randomisation ZOL 668 544 447 292 165 64 3 CLO 682 534 437 271 143 53 0 Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; ZOL, zoledronic acid. G Morgan et al ASCO Abstract 8010

38. Phase III IFM 2005-02: Lenalidomide as Consolidation/Maintenance Post-ASCT Maintenance Consolidation Lenalidomide: 25 mg/d Days 1–21/month 2 months Lenalidomide: 10–15 mg/d until relapse N = 614 First-line ASCT < 65 years ≤ 6 months No PD Lenalidomide: 25 mg/d Days 1–21/month 2 months Placebo until relapse Primary end point: PFS Attal et al, 2009.

39. Lenalidomide maintenance on PFS of t(4;14) del13 p<.0001 p<.001 PFS for patients with del(13) IFM 2005-02 trial: general results for PFS del17p t(4;14) p<.02 p<.04 PFS for patients with del(17p) > 60% PFS for patients wit t(4;14) Avet-Loiseau ASH 2010

40. CALGB 100104 Schema Registration Restaging Days 90–100 Randomization Mel 200 ASCT Placebo D-S Stage 1-3, < 70 years > 2 cycles of induction Attained SD or better  1 yr from start of therapy > 2 x 106 CD34 cells/kg CR PR SD Lenalidomide* 10 mg/d with ↑↓ (5–15 mg) * provided by Celgene Corp, Summit, NJ Patient stratification based on diagnostic -2M level and prior thalidomide and lenalidomide use during Induction

41. Median TTP: 39.6 mo Median TTP: 21.9 mo CALGB 100104, follow up to study un-blinding ITT Analysis with a Median Follow-up from transplant of 18 months P < 0.0001

42. 23 deaths in the lenalidomide arm and 39 deaths in the placebo arm CALGB 100104, follow up to 04/17/2011 Median follow-up of 28 months P = 0.018

45. Other Notable Abstracts at ASH • MLN9708, the oral proteasome inhibitor • Marizomib (NPI-0052) • BT062 the antibody-drug conjugate • Phase 2 study of elotuzumab-lenalidomide and low dose Dex • Vorinostat plus bortezomib as Salvage therapy J Mikhael et al ASCO Abstract 8067

46. Standard Risk MM SCT Minimize gap between Rx end and SCT Len maintenance (+/- Dex at start) Start at day 100 16 weeks of weekly CyBORD with supportive care SC collection and SCT Bisphosphonate per Mayo; RNE responsibility Bisphosphonate per Mayo; RNE responsibility High Risk MM SCT Minimize gap between Rx end and SCT Len maintenance (+/- Dex at start) Start after CyBORD 16 weeks of weekly RVD with supportive care SC collection and SCT 16 weeks of CyBORD consolidation

47. Sequencing of Treatments Maintenance approach Biochemical relapse approach Clinical relapse approach