New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida TOURMALINE-MM1: Improved PFS With Ixazomib + Len/Dex in R/R MM *CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs. This program is supported by educational grants from Amgen, Celgene Corporation, Merck, Incyte, Seattle Genetics, and Takeda Oncology.

TOURMALINE-MM1: Background  Feasible long-term therapy options needed for MM because of significant improvements in pt survival with PI- and IMiD-based treatment regimens  All-oral combination of PI ixazomib with lenalidomide/dexamethasone (Rd) showed promising efficacy and tolerability in newly diagnosed MM [1] –Safety profile encouraging for long-term use  Phase III TOURMALINE-MM1 trial: first interim analysis (with final PFS) reported here [2] 1. Kumar SK, et al. Lancet Oncol. 2014;15: Moreau P, et al. ASH Abstract 727. Slide credit: clinicaloptions.comclinicaloptions.com

TOURMALINE-MM1: Study Design  Randomized, double-blind, placebo-controlled phase III trial [1]  Primary endpoint: PFS by IRC per IMWG criteria [2]  Secondary endpoints (data not yet mature): OS, OS in del(17p) pts 1. Moreau P, et al. ASH Abstract Rajkumar SV, et al. Blood. 2011;117: Ixazomib 4 mg PO D1,8,15 + Lenalidomide 25 mg* D Dexamethasone 40 mg D1,8,15,22 (n = 360) R/R MM pts with measurable disease; 1-3 prior treatments; CrCl ≥ 30 mL/min; not refractory to PIs or lenalidomide (N = 722) Placebo D1,8,15 + Lenalidomide 25 mg* D Dexamethasone 40 mg D1,8,15,22 (n = 362) 28-day cycles until PD or unacceptable toxicity Stratified by prior therapy (1 vs 2-3), ISS stage (I-II vs III), and prior PI exposure (yes vs no) *10 mg for pts with CrCl ≤ 60 or ≤ 50 mL/min. Slide credit: clinicaloptions.comclinicaloptions.com

Characteristic Ixazomib + Rd (n = 360) Placebo + Rd (n = 362) Median age, yrs (range)66 (38-91)66 (30-89) Male, %5856 Stratification factors, %  ISS stage I or II/III  Lines of prior tx, 0-1 or 2  PI exposed 87/13 59/ /12 59/41 70 High-risk cytogenetics,* %2117 Prior regimen, %  Bortezomib  Thalidomide  Lenalidomide  Carfilzomib  Melphalan  Stem cell transplantation < TOURMALINE-MM1: Baseline Characteristics *t(4;14), t(14;16), del(17p). Moreau P, et al. ASH Abstract 727. Slide credit: clinicaloptions.comclinicaloptions.com

TOURMALINE-MM1: PFS Moreau P, et al. ASH Abstract 727. Slide credit: clinicaloptions.comclinicaloptions.com  Addition of ixazomib to Rd resulted in 35% improvement in PFS vs Rd alone  PFS benefit with ixazomib seen in all prespecified subgroups, including cytogenetic high risk, PI and IMiD exposed Log-rank P =.012 HR (95% CI): ( ) Number of events: IRD 129; placebo-Rd 157 Median PFS: IRd: 20.6 mos Placebo-Rd: 14.7 mos Time from randomization (mos) Probability of PFS (%)

TOURMALINE-MM1: Response Moreau P, et al. ASH Abstract 727. Characteristic Ixazomib + Rd (n = 360) Placebo + Rd (n = 362) P Value ORR, %  CR  VGPR  PR Median time to response, mos Median DoR, mos Median TTP, mos * *HR: Slide credit: clinicaloptions.comclinicaloptions.com

TOURMALINE-MM1: Safety Moreau P, et al. ASH Abstract 727. AE, % Ixazomib + Rd (n = 361)Placebo + Rd (n = 359) Any gradeGrade 3-4Any gradeGrade 3-4 AEs attributed to ixazomib and/or lenalidomide  Diarrhea  Constipation  Nausea  Vomiting  Rash  Back pain  Upper respiratory infection  Thrombocytopenia < < < 1 0 < AEs attributed to ixazomib  Peripheral neuropathy  Peripheral edema AEs attributed to lenalidomide  Thromboembolism  Neutropenia 8 33 < < 4 24 Slide credit: clinicaloptions.comclinicaloptions.com

TOURMALINE-MM1: Safety  Median number of treatment cycles: ixazomib + Rd, 17 (range: 1-34); Rd, 15 (range: 1-34)  Other infrequent AEs included cardiac, renal, liver, and lung impairment but no safety concerns were identified  Similar QoL (EORTC-QLQ-C30 health score) in each arm Moreau P, et al. ASH Abstract 727. AE, % Ixazomib + Rd (n = 361) Placebo + Rd (n = 359) Any AE9899 Any grade ≥ 3 AE7469 Serious AEs4749 Discontinuation due to AEs1714 On-study* death46 *Death ≤ 30 days from last dose. Slide credit: clinicaloptions.comclinicaloptions.com

 Addition of ixazomib to Rd improved clinical outcomes with fast/durable responses in R/R MM –Significantly prolonged PFS vs placebo, including del(17p) pts –Significantly improved TTP and response rates vs placebo  Ixazomib plus Rd has tolerable safety profile with limited additional toxicity over Rd alone –Quality of life preserved vs placebo  Study investigators conclude that this all-oral triplet combination regimen could represent new standard of care for R/R MM pts [1] –Ixazomib approved by FDA on November 20, 2015, for use in previously treated MM [2] TOURMALINE-MM1: Conclusions 1. Moreau P, et al. ASH Abstract FDA.gov. Accessed December 8, Slide credit: clinicaloptions.comclinicaloptions.com

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