2. Rafael Fonseca MD Mayo Clinic Multiple Myeloma 2012; Update Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Mayo Clinic College of Medicine Mayo Clinic Comprehensive Cancer Center

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

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

5. Importance of progression events 4

6. Renal Metabolism of FLCs

7. 0.1 1 10 100 1000 10000 Light chain concentration (mg/L) SPE CZE IFE Total  & Normal range in serum FLC UPE Analytical sensitivity of laboratory methods for detection of FLCs

8. Katzmann, Clin Chem 2002; 48: 1437 - 1444 sFLCs published normal range 0.1 1 10 100 1000 10000 100000 0.1110100100010000100000 Serum Kappa FLC (mg/L) Serum Lambda FLC (mg/L) Normal sera Renal impairment (non-MG) Bradwell, Lancet 2003; 361: 489-491

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

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

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

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

17. Minimal Residual Disease Ladetto M, et al. ASH 2009. Abstract 960. PFS in PCR-negative patients months

18. Genomics and Precision Medicine

19. Submarine

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

21. CCND12% BRAF4% DIS3 (RPP44)11% FAM46C13% XBP14% LRRK26% IRF6% PRDM16% 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

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

23. Overall survival according to cytogenetic abnormalities Proportion of pts Time in months from 1 st randomization Standard risk: NR High risk: 38m HR: 2.3, 95% IC: 1.4-4.0 p=0.001

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

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

26. No t(4;14) Bortezomib treated t(4;14) Bortezomib treated t(4;14) VAD treated

27. High Risk in Len Treated Patients

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

29. 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

30. Study Design and Treatment Bortezomib-naïve patients (N=129) were enrolled in 2 sequential dose cohorts. –In Cohort 1, patients received carfilzomib 20 mg/m 2 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/m 2 for Cycle 1 followed by carfilzomib 27 mg/m 2 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

31. Significant Responses ‡ in BTZ-naïve Patients *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 Best response (N=127) Cohort 1 20 mg/m 2 (N=59) n (%) Cohort 2 † 20/27 mg/m 2 (N=68) n (%) CR2 (3)0 (0) VGPR8 (14)18 (26) PR15 (25)17 (25) MR10 (17)8 (12) SD13 (22)10 (15) PD7 (12)11 (16) NE4 (7)4 (6) Significant response rates were observed in both cohorts ORR= 42% ORR= 51% CBR= 63% CBR= 59% K Stewart et al ASCO Abstract 8026

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

33. 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

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

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

36. MRC Myeloma IX—Analysis Schematic for ZOL vs CLO 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. N = 1,960 Patients with newly diagnosed MM (stage I, II, III) N = 1,960 Patients with newly diagnosed MM (stage I, II, III) Clodronate (1,600 mg/d PO) + intensive or non-intensive chemotherapy (n = 979) Zoledronic acid (4 mg a IV q 3-4 wk) + intensive or non-intensive chemotherapy (n = 981) Bisphosphonate treatment continued at least until disease progression G Morgan et al ASCO Abstract 8010

37. MRC Myeloma IX—ZOL Significantly  SREs vs CLO in the Overall Population Abbreviations: CLO, clodronate; HR, hazard ratio; SRE, skeletal-related event; ZOL, zoledronic acid. 35.3% 27.0% ZOL reduced the risk of SREs by 26% vs CLO (HR = 0.74; P =.0004) 36423024181260 0 10 20 30 40 CLO ZOL Patients with an SRE, % Time from randomisation, months 138 112 97 74 201 173 284 256 390 337 506 465 663 629 981 979 ZOL CLO Patients at risk, n G Morgan et al ASCO Abstract 8010

38. ZOL Significantly  OS vs CLO in Patients With Bone Disease at Baseline (n = 1,350) 50 60 70 80 90 100 40 30 Survival distribution function estimate OS, % patients 20 10 0 0123456 668 682 544 534 447 437 292 271 165 143 64 53 3 0 Survival, years since initial randomisation Clodronate (n = 682) Zoledronic acid (n = 668) P =.0107 HR: 0.82 (95% CI: 0.70, 0.96) + Censored ZOL CLO Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; ZOL, zoledronic acid. G Morgan et al ASCO Abstract 8010

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

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

41. D-S Stage 1-3, < 70 years > 2 cycles of induction Attained SD or better  1 yr from start of therapy > 2 x 10 6 CD34 cells/kg Placebo Lenalidomide* 10 mg/d with ↑↓ (5–15 mg) Restaging Days 90–100 Registration CALGB 100104 Schema CR PR SD Patient stratification based on diagnostic  -2M level and prior thalidomide and lenalidomide use during Induction Mel 200 ASCT * provided by Celgene Corp, Summit, NJ Randomization

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

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

46. Other Notable Abstracts at ASH J Mikhael et al ASCO Abstract 8067 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

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

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