New Findings in Hematology: Independent Conference Coverage* of ASH 2015, December 5-8, 2015, Orlando, Florida ARRAY : Phase II Trial of Carfilzomib With or Without Filanesib 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, Incyte, Merck, Seattle Genetics, and Takeda Oncology.

ARRAY : Background  Filanesib: targeted kinesin spindle protein inhibitor –Leads to cell death by disrupting spindle formation during cell division –Targets MCL-1 dependent cells, including in MM  Novel agent for treatment of MM pts with poor prognosis –Preclinical evidence of synergistic antitumor activity with filanesib and bortezomib [1]  Phase II ARRAY trial evaluated efficacy of carfilzomib alone and with filanesib in pretreated R/R MM [2] 1. Woessner R, et al. AACR Abstract Zonder JA, et al. ASH Abstract 728. Slide credit: clinicaloptions.comclinicaloptions.com

 Randomized, open-label, multicenter phase II trial  Primary endpoint: PFS within each treatment arm (no comparison)  Secondary endpoint: serum AAG level as predictor of response Carfilzomib 20/27 mg/m 2 IV Days 1,2,8,9,15,16 (n = 25) ARRAY : Study Design R/R MM pts with ≥ 2 prior treatments, including bortezomib and IMiD, but no prior carfilzomib (N = 77) Carfilzomib 20/27 mg/m 2 IV Days 1,2,8,9,15,16 Filanesib* 1.25 mg/m 2 IV Days 1,2,15,16 G-CSF (n = 52) † Stratified by bortezomib refractory (yes vs no) *Initial dose 1.5 mg/m 2 reduced due to myelosuppression. † 9 pts originally on 1.5 mg/m 2 excluded; analysis for combo arm n = 43. Zonder JA, et al. ASH Abstract 728. ClinicalTrials.gov. NCT day cycles for 18 mos Pts with PD allowed to crossover to combo (n = 7) Slide credit: clinicaloptions.comclinicaloptions.com

Zonder JA, et al. ASH Abstract 728. Characteristic Carfilzomib (n = 25) Carfilzomib + Filanesib (n = 43) Age, median yrs (range)64 (48-82)65 (48-80) Male, %4840 Light chain only disease, %823 High-risk cytogenetics,* %4447 Yrs since Dx, median (range)4.0 ( )5.0 ( ) Prior therapies, median n (range)3 (2-6)3 (2-10) Refractory, %  Bortezomib  Lenalidomide  Pomalidomide  Bortezomib + IMiD Prior anthracyclines, %2419 Prior transplant, %72 ARRAY : Baseline Characteristics *t(4;14), t(14;16), del(17p;13) by cytogenetics/FISH or del(13q;14) by cytogenetics. Slide credit: clinicaloptions.comclinicaloptions.com

ARRAY : Response Efficacy  Low serum AAG (< 1.1 g/L) associated with higher ORR, PFS in both arms –PFS with carfilzomib: 1.8 mos vs 5.2 mos with high vs low AAG –PFS with carfilzomib + filanesib: 2.8 mos vs 8.5 mos with high vs low AAG Zonder JA, et al. ASH Abstract 728. Outcome Carfilzomib (n = 25*) Carfilzomib + Filanesib (n = 43*) PFS, median mos (95% CI) 3.7 ( )8.5 (3.7-NR) ORR (≥ PR), n (%)  VGPR  PR 6 (24) 0 6 (24) 12 (28) 3 (7) 9 (21) CBR (≥ MR), n (%) 7 (28)14 (33) Response in dual refractory, † n (%)  ORR (≥ PR)  CBR (≥ MR) 5 ‡ (33) 6 ‡ (40) 9 § (33) 10 § (37) *1 pt never treated due to ineligibility. † Bortezomib + IMiD. ‡ n = 15. § n = 27. Slide credit: clinicaloptions.comclinicaloptions.com

ARRAY : Duration of Response  Pts remaining on treatment: –16% with carfilzomib –30% with carfilzomib + filanesib Zonder JA, et al. ASH Abstract 728. Duration of Response, Mos (Range) Carfilzomib (n = 25*) Carfilzomib + Filanesib (n = 43*) Pts with ≥ PRNR ( )11.2 ( ) Pts with clinical benefit (≥ MR) 6.5 ( )11.2 ( ) Pts with disease control (≥ SD for 8+ wks) 12.1 ( )12.1 ( ) In dual refractory †  Pts with ≥ PR  Pts with clinical benefit (≥ MR) NR ( ) ‡ 6.5 ( ) ‡ 11.2 ( ) § *1 pt never treated due to ineligibility. † Bortezomib + IMiD. ‡ n = 15. § n = 27. Slide credit: clinicaloptions.comclinicaloptions.com

ARRAY : Safety and Tolerability  Treatment discontinuation –Due to PD: 48% carfilzomib; 28% carfilzomib + filanesib –Due to AE: 4% carfilzomib; 12% carfilzomib + filanesib Zonder JA, et al. ASH Abstract 728. AEs in ≥ 20% of Pts Regardless of Causality, % Carfilzomib (n = 25)Carfilzomib + Filanesib (n = 43) Any GradeGrade 3/4Any GradeGrade 3/4 Hematologic  Neutropenia  Thrombocytopenia Nonhematologic  Fatigue  Diarrhea  Nausea  Dyspnea  Vomiting  Headache Slide credit: clinicaloptions.comclinicaloptions.com

 Among pts with pretreated R/R MM, carfilzomib + filanesib shows promising efficacy compared to single-agent carfilzomib –Longer median PFS (no statistical analysis comparison) –Potentially longer DoR in pts achieving clinical benefit –However, ORR similar in both arms and in dual-refractory pts compared with overall population  Combination overall well tolerated with filanesib 1.25 mg/m 2 dose and G-CSF support –Investigators suggested that hematologic events were not cumulative and generally reversible  Investigators conclude that pts with high serum AAG levels may be less responsive to either drug ARRAY : Conclusions Zonder JA, et al. ASH Abstract 728. Slide credit: clinicaloptions.comclinicaloptions.com

Go Online for More CCO Coverage of ASH 2015! Short slideset summaries of all the key data Additional CME-certified analyses with expert faculty commentary on all the key studies in:  Acute leukemias/chronic leukemias  Myeloma/plasma cell disorders  Lymphomas  MDS and myeloproliferative neoplasms clinicaloptions.com/oncology