Disclosures for Palumbo Antonio, MD

Disclosures for Palumbo Antonio, MD Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board o relevant conflicts of interest to declare o relevant conflicts of interest to declare Amgen, Bristol-Myers Squibb, Genmab, Celgene, Janssen, Millennium, Onyx o relevant conflicts of interest to declare o relevant conflicts of interest to declare Amgen, Bristol-Myers Squibb, Genmab, Celgene, Janssen, Millennium, Onyx, ovartis, Sanofi o relevant conflicts of interest to declare Presentation includes discussion of the off-label use of a drug or drugs

To maintain or not to maintain? IMiDs vs PI Yes: IMiDs Antonio Palumbo University of Torino, Italy

MRD sensitivity 1 10-1 10-2 Serum tools 10-3 10-4 10-5 10-6 Immunophenotype RQ- PCR EXT-GEERATIO SEQUECE 10-7 0 cure 1 2 3 4 5

Patients (%) PFS: landmark analyses Maintenance vs. placebo MPR Lenalidomide Maintenance VMPT VT Maintenance Off therapy 100 Median PFS HR (p value) MPR-R 26 months 0.34 (< 0.001) 100 4-year PFS Median PFS HR (p value) VMPT-VT 33% 32 months 0.56 (< 0.0001) MPR 7 months /A VMP 16% 19 months /A 75 75 50 Improvement: 19 months 50 Improvement: 13 months 25 25 0 0 5 10 15 20 25 0 0 10 20 30 40 50 60 70 Time (months) Time (months) Palumbo A, et al. Engl J Med. 2012;366:1759 Palumbo A, et al. J Clin Oncol. 2010;28:5101 M, melphalan; P, prednisone; R, lenalidomide; V, bortezomib; T, thalidomide; PFS, progression-free survival; A, not available

72 wks Patients (%) Continuous vs Fixed-Duration: PFS advantage Rd vs Rd18 vs MPT MPR-R vs MPR vs MP VMPT-VT vs VMP Median Median Median Rd 25.5 mos MPR-R 31 mos VMP-VT 35.3 mos Rd18 20.7 mos MPR 14 mos VMP 28.8 mos MPT 21.2 mos MP 13 mos 100 100 100 80 75 75 60 40 50 50 20 25 25 0 0 6 12 18 24 30 36 42 48 54 60 Time (months) 0 0 10 20 30 40 Time (months) 0 0 10 20 30 40 50 60 70 80 Time (months) Facon T, et al. Blood. 2013;122:abstract 2. Palumbo A, et al. EJM 2012;366:1759 Palumbo A, et al. JCO 2010;28:5101 MPT, melphalan, prednisolone, thalidomide; Rd, lenalidomide plus low-dose dexamethasone; MPR-R, melphalan-prednisone-lenalidomide and lenalidomide maintenance; MPR; melphalan-prednisone-lenalidomide; MP; melphalan-prednisone; VMPT-VT, bortezomib-melphalan-prednisone-thalidomide and bortezomib-thalidomide maintenance; VMP, bortezomib-melphalan-prednisone; PFS, progression-free survival

Thalidomide 1 Continuous vs Fixed-Duration: OS Progression Free Survival Study Maintenance Control Hazard ratio (fixed) 95% CI Hazard ratio (fixed) 95% CI CALGB 100104 231 229 0.48 (0.36, 0.63) MM 015 152 154 0.34 (0.18, 0.64) IFM 2005-02 307 307 0.50 (0.39, 0.64) RV-MM-PI-209 198 204 0.52 (0.40, 0.67) Total (95% CI) 888 894 0.49 (0.41, 0.58) Lenalidomide 2 Bortezomib 3 0.2 0.5 1 2 5 Favors treatment Favors control Overall Survival Study Progression Free Survival Maintenance Control Hazard ratio (fixed) Hazard ratio (fixed) Study Maintenance Control Hazard ratio 95% CI (fixed) Hazard ratio 95% CI (fixed) 95% CI 95% CI CALGB 100104 231 229 0.61 (0.42, 0.88) MM VMPT-VT 015 vs VMP 152 250 154 253 0.79 0.67 (0.53, (0.50, 1.18) 0.90) IFM PAD-V 2005-02 vs VAD-T 307 413 307 414 1.06 0.75 (0.77, (0.62, 1.46) 0.90) RV-MM-PI-209 198 204 0.62 (0.42, 0.92) Total (95% CI) 663 667 0.71 (0.54, 0.87) Total (95% CI) 888 894 0.77 (0.62, 0.95) Overall Survival Study Maintenance Control 0.2 0.5 1 2 5 0.2 0.5 1 2 5 Favors treatment Favors treatment Favors control Favors control Hazard ratio (fixed) Hazard ratio (fixed) 95% CI 95% CI VMPT-VT vs VMP 250 253 0.74 (0.55, 0.99) PAD-V vs VAD-T 413 414 0.73 (0.56, 0.96) Total (95% CI) 663 667 0.73 (0.56, 0.99) 0.2 0.5 1 2 5 Favors treatment Favors control 1. Ludwig H, et al. Blood. 2012; 2. McCarthy PL, et al. Engl J Med 2012; Palumbo A, et al. Engl J Med 2012; Attal M, et al. Engl J Med 2012; Palumbo A, et al. ASCO 2013; 3. Sonneveld P, et al. J Clin Oncol 2012; Palumbo A, et al. J Clin Oncol. 2010

KRd: Fixed-Duration vs Kd: Continuous ASPIRE: KRd vs Rd Progression-Free Survival ITT Population (=792) EDEAVOR: Kd vs Vd Progression-Free Survival ITT Population (=929) 1.0 Median PFS 1.0 Median PFS 0.8 KRd (=396) Rd (=396) 26.3 mos 17.6 mos 0.8 Kd ( = 464) Vd ( = 465) 18.7 mos 9.4 mos 0.6 0.6 0.4 0.4 0.2 KRd Rd 0.0 0.0 0 6 12 18 24 30 36 42 48 0 6 12 18 24 30 Months HR 0.69 P <0.0001 Stewart AK, et al. EJM 2015:372:142 KRd, carfilzomib-lenalidomide-dexamethasone; Rd, lenalidomide-dexamethasone; Kd, carfilzomib-dexamethasone; Vd, bortezomibdexamethasone; ITT, intention-to-treat; PFS, progression-free survival 0.2 Kd Vd Months HR 0.53 P <0.0001 Dimopoulos MA, et al. ASCO 2015; abs 8509

100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 5 37 34 73 VT maintenance GIMEMA MM-03-05 Best response to treatment (n=149) 3 28 37 81 Best response, n (%) All patients, n=149 Overall CR+VGPR+PR 146 (98) CR 81 (54) VGPR 37 (25) PR 28 (19) SD 3 (2) 0% VMPT induction CR VGPR PR SD Overall 17 patients improved their response during VT maintenance: - 5 VGPR improved to CR - 10 PR improved to 8 VGPR and 2 CR - 2 SD improved to 1 PR and 1 CR Palumbo A, et al. J Clin Oncol. 2014; 32:634-40

GIMEMA MM-03-05 Grade 3-4 AEs during VT maintenance neutropenia thrombocytopenia nervous system cardiologic infections vascular metabolic other 0% 1% 2% 3% 4% 5% 6% 7% 8% Patients (%) Palumbo A, et al. J Clin Oncol. 2014; 32:634-40

Car-Len maintenance UITO-MM-01/FORTE study IDUCTIO COSOL. MAIT. R A D O M I Z A T I O CCyD (4 28-d cycles) C: 20 mg/m2 IV d 1-2 cycle 1; 36 mg/m2 IV once daily d 8-9,15-16 cycle 1;for all subsequent doses 36 mg/m2 IV once daily d 1-2,8-9,15-16 Cy: 300 mg/m2 PO d 1,8,15 D: 20 mg PO d 1,2,8,9,15,16,22,23 CRD (4 28-d cycles) C: 20 mg/m2 IV d 1-2 cycle 1; 36 mg/m2 IV once daily d 8-9,15-16 cycle 1; for all subsequent doses 36 mg/m2 IV once daily d 1-2,8-9,15-16 R: 25 mg PO daily d 1-21 D: 20 mg PO d 1,2,8,9,15,16,22,23 CCyD (4 28-d cycles) C: 36 mg/m2 IV once daily d 1-2,8-9,15-16 Cy: 300 mg/m2 PO d 1,8,15 D: 20 mg orally d 1,2,8,9,15,16,22,23 CRD (4 28-d cycles) C: 36 mg/m2 IV once daily d 1-2,8-9,15-16 R: 25 mg PO daily on days 1-21 D: 20 mg orally d 1,2,8,9,15,16,22,23 CRD (12 28-d cycles) C: 20 mg/m2 IV d 1-2 cycle 1; 36 mg/m2 IV once daily d 8-9,15-16 cycle 1; for all subsequent doses 36 mg/m2 IV once daily d 1-2,8-9,15-16 R: 25 mg PO daily on days 1-21 D: 20 mg PO d 1,2,8,9,15,16,22,23 T R A S P L A T R A D O M I Z A T I O R (until PD) R: 10 mg PO daily d1-21 CR (until PD) C: 36 mg/m2 IV once daily d 1-2,15-16 R: 10 mg PO daily d1-21 C, carfilzomib; Cy, cyclophosphamide; D, dexamethasone; R, lenalidomide; PO, orally; IV, intravenously; d, day; PD, progressive disease Clinicaltrials.gov number CT02203643

Oral Proteasome inhibitor: Ixazomib Antitumor activity in preclinical xenograft models Four global phase 3 trials are ongoing: TOURMALIE MM1 (C16010): Ixazomib plus lenalidomide and dexamethasone in relapsed and/or refractory multiple myeloma TOURMALIE MM2 (C16014): Ixazomib plus lenalidomide and dexamethasone in newly diagnosed multiple myeloma TOURMALIE-AL1 (C16011): Ixazomib or physician s choice of treatment in relapsed or refractory AL amyloidosis TOURMALIE-MM3: Ixazomib maintenance therapy following autologous stem cell transplant in multiple myeloma

Ixaxomib Maintenance Best Response To Treatment In Phase 2 Patients 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 19 33 9 10 29 scr CR ncr VGPR PR MR SD Best response, (%) All patients, n=21 To maintenance CR+sCR+nCR 61 CR 33 scr 19 ncr 9 VGPR 10 CR+VGPR 71 PR 29 MR 0 0% Best response overall SD 0 10 (48%) patients improved their response during maintenance: 2 VGPR to ncr, 5 VGPR to CR, 1 VGPR to scr, and 2 CR to scr Kumar SK et al. Proc ASH 2014; Abstract 82.

Ixaxomib Maintenance Most common drug-related AEs During maintenance Any AE Skin and SC tissue disorders Diarrhea Fatigue ausea Peripheral neuropathies EC Constipation Insomnia Vomiting Dysgeusia Abdominal distension Malaise Muscle spasms Anemia Thrombocytopenia Hypokalemia Pain in extremity Headache During 0 10 20 30 40 50 60 70 80 90 100 Patients, % EC, not elsewhere classified

C16019 (TOURMALIE MM-3): Phase 3 Study of Maintenance Post-ASCT Arm A: Ixazomib Cycles 1-4: Ixazomib (3.0 mg) po days 1, 8, 15 Cycles 5-26: Ixazomib (3.0 or 4.0 mg) po days 1, 8, 15 Randomization 652 patients 28-day cycles Arm B: Placebo Cycles 1-4: Matching placebo (3.0 mg) po days 1, 8, 15 Cycles 5-26: Matching placebo (3.0 or 4.0 mg) po days 1, 8, 15 28-day cycles Inclusion Criteria: Symptomatic MM; Received standard of care induction therapy followed by single SCT within 12 months of diagnosis, w/o consolidation therapy; Documented response ( PR) to SCT, with no relapse; ECOG performance status 0-2 C16021 (TOURMALIE MM-4): Phase 3 Study of Oral Ixazomib Maintenance in Patients ot ASCT Eligible Arm A: Ixazomib Cycles 1-4: Ixazomib (3.0 mg) po days 1, 8, 15 Cycles 5-26: Ixazomib (3.0 or 4.0 mg) po days 1, 8, 15 Randomization 28-day cycles up to 26 cycles Inclusion Criteria: Symptomatic MM; Initial treatment for 6-12 months (± 2 wks) to best resp PR; ECOG performance status 0-2 Select Endpoints: Primary: PFS; Secondary: OS, ORR, TTP, 2 nd PFS Arm B: Placebo Cycles 1-4: Placebo (3.0 mg) po days 1, 8, 15 Cycles 5-26: Placebo (3.0 or 4.0 mg) po days 1, 8, 15 28-day cycles up to 26 cycles

100% Lenalidomide maintenance RV-MM-PI-209 Best response to treatment (n=115) 2 2 90% 80% 70% 60% 50% 40% 37 50 24 43 All patients, n=115 Best response, n (%) Overall CR+VGPR+PR 113 (98) CR 46 (40) VGPR 43 (37) PR 24 (21) 30% SD 2 (2) 20% 46 10% 26 0% Induction Overall CR VGPR PR SD 25 patients improved their response during lenalidomide maintenance: - 12 VGPR improved to CR - 13 PR improved to 5 VGPR and 8 CR Palumbo A, et al. Engl J Med. 2014 Sep 4;371:895-905

Lenalidomide maintenance RV-MM-PI-209 Grade 3-4 AEs during lenalidomide maintenance neutropenia thrombocytopenia anemia dermatologic infections endocrinologic 0% 5% 10% 15% 20% 25% Patients (%) Palumbo A, et al. Engl J Med. 2014 Sep 4;371:895-905

Continuous vs Fixed-Duration: PFS MRC Myeloma IX RVMM 209 Thalidomide maintenance: PFS Lenalidomide maintenance: PFS 1.00 0.75 Median 41.9 months Median 15 months Median 23 months Morgan GJ, et al. Blood 2012;119:7 IFM 05-02 Lenalidomide maintenance: PFS 0.50 0.25 0.00 Median 21.6 months Len. maintenance o maintenance 0 6 12 18 24 30 36 42 48 54 60 Palumbo A, et al. EJM. 2014;371:895 CALGB 100104 Lenalidomide maintenance: TTP HR 0.47; P<0.001 Median 41 months Median 53 months Median 23 months Median 26 months P<0.001 Attal M, et al. EJM 2012;366:1782 Holstein S, et al. ASCO 2015:8523

% of patients = 1218 Continuous vs Fixed-Duration Meta-analysis of 3 studies: 1218 patients 1-year Landmark analysis O S P F S P F S PFS1 PFS2 Ind. Maintenance Ind. Maintenance Median 100 100 CT 32 mos CT Median 55 mos 2 1 75 FDT 16 mos 75 FDT 40 mos 50 50 = 687 2 nd P F S 25 0 25 HR 0.47, 95% CI 0.40-0.56, P <.001 0 HR 0.61, 95% CI 0.50-0.75, P <.001 0 12 24 36 48 60 0 12 24 36 48 60 Months Months CT, continuous therapy; FDT, fixed duration of therapy; PFS, progression-free survival; mos, months. Palumbo A, et al. JCO 2015 in Press

Conclusion Lenalidomide extensive efficacy/safety evidence Ixaxomib is under evaluation Limited value for IV drugs Monthly exposure with MoAb in the future