PowerPoint Presentation

Focus on the Role of Proteasome Inhibitors in the Management of Multiple Myeloma

Sagar Lonial, MDEditor-In-Chief for Multiple Myeloma @Point of CareProfessor, Vice Chair of Clinical AffairsDepartment of Hematology and Medical OncologyWinship Cancer Institute, Emory UniversityAtlanta, Georgia

Kenneth C. Anderson, MDKraft Family Professor of Medicine, Harvard Medical SchoolDirector, Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer InstituteBoston, Massachusetts2196219831986199619992000+Oral melphalan14 and prednisone15High-dose dexamethasone12Proteasome inhibitors4-6Other immuno-modulatory agents7-9Historical Perspective of Multiple Myeloma Therapies1Thalidomide131. Kyle RA, Rajkumar SV. Blood. 2008;111:2962-2972. 2. McElwain TJ, Powles RL, Lancet. 1983;2:822-824. 3. Barlogie B, et al. Blood. 987;70:869-872. 4. Richardson PG, et al. N Engl J Med. 2003;348:2609-2617. 5. Richardson PG, et al. N Engl J Med. 2005;352:2487-2498. 6. Siegel DS, et al. Blood. 2012;120:2817-2825. 7. Dimopoulos M, et al. N Engl J Med. 2007;357: 2123-2132. 8. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 9. Richardson PG, et al. Blood. 2014;123: 1826-1832. 10. Barlogie B, et al. N Engl J Med. 1984;310:1353-1356. 11. Berenson JR, et al. N Engl J Med. 1996;334:488-493. 12. Alexanian R, et al. Ann Intern Med. 1986;105:8-11. 13. Singhal S, et al. N Engl J Med. 1999;341:1565-157 14. Bergsagel DE, et al. Cancer Chemother Rep. 1962;21:87-99. 15. Mass RE. Cancer Chemother Rep. 1962;16:257-259. Slide courtesy of Dr. Anderson.1987High-dose therapy with autologous stem cell support3ABMT22High-dose melphalan2 Bisphosphonates111984VAD533Targeting Growth, Survival, and Drug Resistance of MM in Bone Marrow Microenvironment Anderson KC.J Clin Oncol. 2012;30:445-452. Reprinted with permission. 2012 American Society of Clinical Oncology. All rights reserved.VCAM-1FibronectinICAM-1LFA-1MUC-1VLA-4CytokinesIL-6, VEGFIGF-1, SDF-1BAFF, APRILBSF-3TNFTGFVEGFNF-BNF-BBMSCadhesion moleculesNF-BSmad, ERK JAK/STAT3MEK/ERKPI3-KGSK-3FKHRCaspase-9NF-BmTORBadPKCBcl-xLMcl-1MEK/ERKp27Kip1NF-BBcl-xLIAPCyclin-DMMSurvivalAnti-apoptosisCell cycleSurvivalAnti-apoptosisCell cycleproliferationSurvivalAnti-apoptosisAktmigrationProliferationAnti-apoptosiscytokinesRafFGFR3AdhesionSCCD40CS1BAFF-RCell surfacetargetsVEGFRProteasomePresent and Future TherapiesAnderson KC. J Clin Oncol. 2012;30:445-452. Bortezomib: 1st proteasome inhibitor2nd generation proteasome inhibitors moving from bench to bedsideCarfilzomibIxazomibMarizomibCan block ubiquitin proteasome cascade upstream of the proteasome Deubiquitylating enzyme inhibitorsNovel Agents for Frontline Multiple Myeloma: A New Era of Efficacy5Review of Proteasome Inhibitors (PIs)Currently Approved PIs andPIs in Phase III Development6Currently approved PIsBortezomibCarfilzomibPIs in developmentIxazomib citrate phase IIIMarizomib phase II/IIIReview of Proteasome Inhibitors (PIs)7BortezomibThe First Approved Proteasome InhibitorA covalent, reversible inhibitor of proteasome chymotryptic activity1,2Induces apoptosis in solid tumors and hematologic cancers, including multiple myeloma3Alters the bone marrow microenvironment to reduce tumor cell growth3Efficacy in both previously untreated and relapsed multiple myeloma1

1. Bortezomib Prescribing Information. 2. Adams J, et al. Cancer Res. 1999;59:2615-2622. 3. Adams J. Cancer Cell. 2004;5:417-421.8JNK; Caspases & PARP cleavage; ROS; m Cyto-c & Smac release; IAPs; Mitochondrial Ca+2 influx; Bid cleavage, Fas & FasL, BH-3 only proteins: Bim, Bik, & NOXAApoptosis Migration, VEGF,Proangiogenic MMP-9, &Caveolin-1; Osteoclastogenesis viaMIP1, BAFF Osteoblast formation Antiangiogenic &Antiosteoclastic ActivityCaspase-12 cleavage; phospo-PERK; GADD-153, ATF4, GRP 78, & XBP-1 splicing ER-Stress InductionCdk inhibitors: P21 & p27, p53Cyclins: D1, E1, A, B.Cell-Cycle MM-BMSCs interaction; ICAM, VCAM, V3 IGF-1, IL-6, BAFF,RANKLMicroenvironment NF-B, MAPK,JAK/STAT IGF-1/IL-6 PI3K-AktGrowth & Survival Heat shock proteins-27, -70, 90; DNA-PK Heat Shock Proteins& DNA RepairChymotrypsin- and caspase-likeproteasome activities;Mono-ubiquitination;26S Proteasome subunitsProteasomeMechanisms Mediating Anti-MM Activityof BortezomibSlide courtesy of Dr. Anderson.Bortezomib9

CarfilzomibA Novel Proteasome (Chymotryptic) InhibitorNovel chemical class with highly selective and irreversible proteasome binding1Improved antitumor activity with consecutive day dosing1No neurotoxicity in animals223.7% responses lasting 7.8 months with survival 15.6 months in relapsed and relapsed/refractory MM3Mechanisms of action1Induction of apoptosisCell cycle arrestActivation of stress response pathways (hsp27, hsp70)1. Demo SD, et al. Cancer Res. 2007; 67:6383-6391. 2. Kirk CJ, et al, Blood. 2008;112:abstract 2765. 3. Siegel DS, et al. Blood 2012:120:2817-2825.

EpoxyketoneTetrapeptideIxazomibOral Chymotryptic InhibitorIn in vivo studies, ixazomib1 Decreased MM cell viability Overcame resistance to bortezomibBlocked MM cell growth more potently than bortezomib

Currently in phase I/II studies for relapsed/refractory and newly diagnosed multiple myeloma2

1. Chauhan D, et al. Clin Cancer Res. 2011;17:5311-5321.2. ClinicalTrials.gov. Accessed 5/29/14. 11Isolated from Salinispora tropica, a marine bacterium1,2Inhibits chymotrypsin-like, trypsin-like, and caspase-like proteasome activity in MM cells3Lack of cross-resistance with other proteasome inhibitors1,2Cytotoxic mechanisms include caspse-8-dependent apoptosis and oxidative stress1-3Currently in phase I/II studies for relapsed/refractory multiple myeloma4Marizomib (NPI-0052)Moreau P, et al. Blood. 2012;120:947-959. Allegra A, et al. Leuk Res. 2014;38:1-9. Chauhan D, et al. Cancer Cell. 2005;8:407-419. ClinicalTrials.gov. Accessed 5/5/14. 12Response Criteria and Clinical Trial Results for PI Therapy in MMRoute of Administration, Efficacy, Safety13Currently approved PisBortezomib SC, IVCarfilzomib IV PIs in phase III developmentIxazomib citrate oralMarizomib IV

PI Therapy in MMRoute of Administration14

SUMMIT1(Phase II)

CREST2(Phase II)

APEX3(Phase III)Pegylated LiposomalDoxorubicin + Bortezomib(Phase III)Patient populationRelapsed/refractoryRelapsed/refractory (1 prior therapy)Relapsed/refractory(1-3 prior therapies)Relapsed/refractory(1 prior therapy)N19354669646Treatment armsBTZ 1.3 mg/m2BTZ 1.3 mg/m2

BTZ 1.0 mg/m2BTZ 1.3 mg/m2

High-dose DEX 40 mgPLD 30 mg/m2 + BTZ 1.3 mg/m2

BTZ 1.3 mg/m2 Primary endpointORR: 35%ORR: 50% (1.3 mg/m2)

ORR: 33% (1.0 mg/m2)TTP: 6.22 mo (BTZ)

TTP: 3.49 mo (High-dose DEX)TTP: 9.3 mo (PLD + BTZ)

TTP: 6.5 mo (BTZ)BortezomibKey Clinical Trials in Relapsed/Refractory MM PatientsAbbreviations: BTZ, bortezomib; DEX, dexamethasone; ORR, overall response rate; PLD, pegylated liposomal doxorubicin; TTP, time to progression.

1. Richardson PG, et al. N Engl J Med. 2003;348:2609-2617. 2. Jagannath S, et al. Br J Haematol. 2004;127: 165-172. 3. Richardson PG, et al. N Engl J Med. 2005;352:2487-2498. 4. Orlowski RZ, et al. J Clin Oncol. 2007; 25:3892-3901.15

VISTA1(Phase III)

IFM 2005-012(Phase III)

GIMEMA Italian Myeloma Network3(Phase III)

HOVON-65/ GMMG-HD44(Phase III)Patient populationPreviously untreatedPreviously untreatedPreviously untreatedPreviously untreatedN682482480827Treatment armsBTZ 1.3 mg/m2 + MP

MP alone

VD (BTZ 1.3 mg/m2 + DEX 40 mg)

VAD VTD (BTZ 1.3 mg/m2 + THAL + DEX 40 mg)

TDPAD(BTZ 1.3 mg/m2 + DOX + DEX 40 mg)

VADPrimary endpointTTP: 24.0 mo (BTZ + MP)

TTP: 16.6 mo (MP alone)Postinduction CR/nCR: 14.8% (VD)

Postinduction CR/nCR: 6.4% (VAD)Postinduction CR/nCR: 31% (VTD)

Postinduction CR/nCR: 11% (TD)PFS: 35 mo (PAD)

PFS: 28 mo (VAD)BortezomibKey Clinical Trials in Previously Untreated MM PatientsAbbreviations: BTZ, bortezomib; CR, complete response; DEX, dexamethasone; DOX, doxorubicin; MP, melphalan/prednisone; nCR, near complete response; PFS, progression-free survival; TD, thalidomide/dexamethasone; THAL, thalidomide; TTP, time to progression; VAD, vincristine/doxorubicin/dexamethasone.

1. San Miguel JF, et al. N Engl J Med. 2008;359:906-917. 2. Harousseau JL, et al. J Clin Oncol. 2010;28:4621-4629. 3. Cavo M, et al. Lancet. 2010;376:2075-2085. 4. Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. 16

PX-171-003-A01 (Phase II)

PX-171-003-A12(Phase II)PX-171-0043Cohort 1(Phase II)

Patient populationRelapsed/refractory (2 prior therapies including BTZ + IMiD)Relapsed/refractory (99.6% prior BTZ)Relapsed/refractory(1-3 prior therapies, including BTZ)

N46 (42 evaluable for efficacy)266 (257 evaluable for efficacy)

35Treatment armsCFZ 20 mg/m2CFZ 20/27 mg/m2CFZ 20 mg/m2Primary endpointORR: 16.7%ORR: 23.7%ORR: 17.1%CarfilzomibKey Clinical Trials in Relapsed/Refractory MM Patients with Prior BortezomibAbbreviations: BTZ, bortezomib; CFZ, carfilzomib; IMiD, immunomodulatory drug; ORR, overall response rate.

1. Jagannath S, et al. Clin Lymphoma Myeloma Leuk. 2012;12:310-318. 2. Siegel DS, et al. Blood. 2012;120: 2817-2825. 3. Vij R, et al. Br J Haematol. 2012;158:739-748. 17PX-171-0041Cohort 1(Phase II)PX-171-0041Cohort 2(Phase II)Patient populationRelapsed/refractory (BTZ naive)

Relapsed/refractory (BTZ naive)N5970 (67 evaluable for efficacy)Treatment armsCFZ 20 mg/m2CFZ 20/27 mg/m2

Primary endpointORR: 42.4%ORR: 52.2%CarfilzomibKey Clinical Trials in Bortezomib-Naive Relapsed/Refractory MM PatientsAbbreviations: BTZ, bortezomib; CFZ, carfilzomib; ORR, overall response rate.

1. Vij R, et al. Blood. 2012;119:5661-5670. 18

Single-Agent Ixazomib1(Phase I)Ixazomib Lenalidomide Dexamethasone2(Phase I/II)Patient populationRelapsed/refractoryNewly diagnosedN60(50 evaluable for efficacy)64(56 treated at RP2D)CohortsDose escalation cohort: Ixazomib 0.24-3.95 mg/m2

Dose expansion cohort:Ixazomib 2.97 mg/m2

Phase I: Ixazomib 3.0 or 3.7 mg + Len 25 mg + Dex 20/10 mg

Phase II: Ixazomib RP2D (3.0 mg)+ Len 25 mg + Dex 20/10 mg

Followed by ixazomib maintenanceResultsORR: 18%ORR: 95%*

61%* had 100% decreases in M-protein or serum FLC from baselineIxazomibKey Clinical Trials Abbreviations: Dex, dexamethasone; FLC, free light chain; Len, lenalidomide; ORR, overall response rate; RP2D, recommended phase II dose.

Kumar SK, et al. Blood. 2014 [Epub ahead of print] 2. Richardson PG, et al. Blood. 2013;122:abstract 535. Richardson PG, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation. *Patients treated at RP2D.19Ixazomib/Lenaldiomide/Dexamethasone in Newly Diagnosed Multiple Melanoma1,2 1. Richardson PG, et al. Blood. 2013;122:abstract 535. 2. Richardson PG, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.In a phase I/II study of ixazomib, lenalidomide, and dexamethasone in newly diagnosed MM patients

Response was evaluated in 56 patients receiving ixazomib at the recommended phase II dose (3.0 mg)Phase I cohort: n = 7Phase II cohort: n = 49There was a complete resolution of M-protein in many patients (61% had 100% decreases in M-protein)202 phase I trials (N = 34) of marizomib twice weekly (days 1, 4, 8, and 11 of 21-day cycles) low-dose dexamethasoneRelapsed/refractory MM (88% prior bortezomib)Maximum tolerated dose 0.4 mg/m2 over a 60-minute infusion0.5 mg/m2 over a 120-minute infusionMost common adverse effects: fatigue, nausea, vomiting, dizziness, headache, diarrhea, constipation, insomnia, anorexia, dyspneaNo peripheral neuropathy, myelosuppression, or thrombocytopeniaOverall response rate: 20%Marizomib Clinical DataRichardson PG, et al. Blood. 2011;118:abstract 302.Approaches to TherapyTiming/Sequencing of TreatmentInduction therapyMaintenance therapyTreating relapsed/refractory MMPIs in combination therapy to improve outcomesManaging adverse effects

Approaches to TherapyTiming/Sequencing of Treatment23

Outcomes for patients are clearly improvedThe use of high-dose therapy or melphalan-based novel agent inductions have doubled median survival for nearly all patients

The Good NewsWith permission from Kumar SK, et al. Blood. 2008;111:2516-2520.24Bortezomib, lenalidomide, thalidomide, liposomal doxorubicin, carfilzomib, pomalidomideTarget MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivoEffective in relapsed/refractory, relapsed MM and now part of induction, consolidation, and maintenance therapy9 FDA approvals in the last decade and median survival prolonged from 2-3 years to at least 5-7 years, with additional prolongation seen from maintenanceNew approaches needed to treat and ultimately prevent relapseIntegration of Novel Therapy Into Myeloma ManagementFor conventional low- and high-dose therapyNonhyperdiploid worse prognosis than hyperdiploid1,2 t(11;14), hyperdiplody - standard risk2 t(4;14), t(14;16), t(14;20), del(17p), del(13q14) -high risk1-4

For novel treatmentsBortezomib, but not lenalidomide, can at least partially overcome t(4;14), del(13q14)5,6

del(17p), p53 remains high risk5

Chromosomes and Prognosis in Multiple Myeloma1. Avet-Loiseau H, et al. Leukemia. 2013;27:711-717. 2. Mikhael JR, et al. Mayo Clin Proc. 2013;88:360-376. 3. Palumbo A, et al. J Clin Oncol. 2014;32:587-600. 4. Munshi NC, et al. Blood. 2011;117:4696-4700. 5. Avet-Loiseau H, et al. J Clin Oncol. 2010; 28:4630-4634. 6. Jagannath S, et al. Leukemia. 2007;21:151-157. 26Induction Therapy27Impact of Novel Agents in the Treatment of Elderly Pts with Newly Diagnosed MMSubstantial improvements in PFS and OS*Median OS not reached. 7. San Miguel JF, et al. N Engl J Med. 2008;359:906-917. 8. Mateos MV, et al. J Clin Oncol. 2010;28:2259-2266. 9. Palumbo A, et al. N Engl J Med. 2012;366:1759-1769.10. Mateos MV, et al. Haematologica. 2008;93:560-565.11. Palumbo A, et al. Blood. 2010;116:abstract 620.12. Mateos MV, et al. Lancet Oncol. 2010;11:934-941.1. Palumbo A, et al. Blood. 2008; 112:310-3114.2. Facon T, et al. Lancet. 2007; 370:1209-1218.3. Hulin C, et al. J Clin Oncol. 2009; 27:3664-3670.4. Waage A, et al. Blood. 2010;116:1405-1412.5. Wijermans P, et al. J Clin Oncol. 2010; 28:3160-3166.6. Beksac M, et al. Eur J Haematol. 2011;86:16-22.Median PFS (mo)Median OS (mo)MP1-10112029.149.4MPT1-61527.52751.6VMP7,8,1121.727.468.5% (3-y OS)*MPR-R931N/AVMP-VT/VP123474% (3-y OS)*VMPT-VT1137.285% (3-y OS)*Abbreviations: MP, melphalan/prednisone; MPR-R, melphalan/prednisone/lenalidomide followed by lenalidomide maintenance; MPT, melphalan/prednisone/thalidomide; N/A, not available; VMP, bortezomib/melphalan/prednisone; VMP-VT/VP, bortezomib/melphalan/prednisone followed by bortezomib/thalidomide or bortezomib/prednisone maintenance; VMPT-VT, bortezomib/melphalan/prednisone/thalidomide followed by bortezomib/thalidomide maintenance.28Phase II study of carfilzomib/cyclophosphamide/dexamethasone in newly diagnosed MM patients 65 years old (N = 58)Up to nine 28-day cycles followed by carfilzomib maintenanceResponse rates PR: 95% VGPR: 71%nCR: 49% sCR: 20%2-year PFS: 76%2-year OS: 87%Carfilzomib in Elderly Patients with Newly Diagnosed MMAbbreviations: nCR, near complete response; OS, overall survival; PFS, progression-free survival; PR, partial response; sCR, stringent complete response; VGPR, very good partial response.Bringhen S, et al. Blood. 2014;124:63-69 .Patients were stratified by: AgeCountryISS stage1. Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.Abbreviations: ISS, International Staging System; LEN, lenalidomide; Lo-DEX, low-dose dexamethasone; LT, long-term; MEL, melphalan; PD, progressive disease; PFS, progression-free survival; PRED, prednisone; OS, overall survival. FIRST TrialStudy Design1,2Randomization 1:1:1ScreeningPD, OS, and subsequent MM TxActive treatment + PFS follow-up phaseLT follow-upArm A: Continuous RdLEN + Lo-DEX continuouslyLEN25 mg D1-21/28Lo-DEX40 mg D1,8,15, & 22/28Arm B: Rd18LEN + Lo-DEX: 18 Cycles (72 weeks) LEN25 mg D1-21/28Lo-DEX40 mg D1,8,15, & 22/28Arm C: MPTMEL + PRED + THAL: 12 Cycles (72 weeks) MEL0.25 mg/kg D1-4/42PRED2 mg/kg D1-4/42THAL200 mg D1-42/42PD or unacceptable toxicityThe FIRST trial was a randomized multicentre, open-label, pivotal phase III trial with 3 comparison arms. FIRST was designed to compare the efficacy and safety of Rd, given continuously or for a fixed number of cycles, with MPT. Patients were stratified according to age (75 years vs. >75 years), ISS disease stage (I and II vs. III), and country.Starting doses of LEN were adjusted based on renal function (20 mg/D 10 mg/D 15 mg/every other day).Starting doses of DEX were adjusted based on age (40 mg 20 mg). Starting dose of MEL was adjusted based on age and ANC, platelet count, and renal function (0.25/0.125 mg/kg 0.20/0.10 mg/kg) Starting dose of THAL was adjusted based on patient age (200 mg 100 mg)All patients received low-dose aspirin (70-100 mg/day) or other prophylactic anticoagulation throughout the study. The active treatment and PFS follow-up phase was followed by a long-term follow-up phase to assess OS and the impact of subsequent therapy

30Abbreviations: MPT, melphalan/prednisolone/thalidomide; PFS, progression-free survival; Rd, lenalidomide/low-dosedexamethasone. 1. Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.Median PFSRd (n = 535): 25.5 monthsRd18 (n = 541): 20.7 monthsMPT (n = 547): 21.2 months3-year PFSRd (n = 535): 42%Rd18 (n = 541): 23%MPT (n = 547): 23%Hazard ratioRd vs MPT: 0.72, P = .00006Rd vs Rd18: 0.70, P = .00001 Rd18 vs MPT: 1.03, P = .70349FIRST TrialFinal Progression-Free Survival1,2With regard to the primary endpoint, continuous Rd significantly reduced the risk of disease progression by 28% compared with MPT (hazard ratio 0.72; P = 0.0006)Continuous Rd also significantly reduced the risk of disease progression by 30% compared with giving Rd for 72 weeks (hazard ratio 0.70; P = 0.0001)There was no significant difference in PFS between Rd given for 72 weeks and MPT (hazard ratio 1.03; P = 0.70349).Median PFS was 25.5 months with continuous Rd, compared with 20.7 months with Rd for 72 weeks and 21.2 months with MPTThe benefit was independent of age, gender, race, geographic region, ISS stage, renal function, beta-2-microglobulin level, albumin level, ECOG performance status, lactate dehydrogenase level, and cytogenetic risk.31Cytogenetics high-risk included t(4;14), t(14;16), del(17p)Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.AgeGenderISSRenal dysfunctionECOG PSLDHCytogenetics high risk

FIRST TrialConsistent PFS Benefit Across Subgroups1,2The PFS benefit of continuous Rd over MPT was independent of most baseline characteristics, including age, gender, race, geographic region, ISS stage, renal function, beta-2-microglobulin level, albumin level, ECOG performance status, and cytogenetic risk (please confirm High-risk cytogenetics)32Median time to progression (TTP)Rd (n = 535): 32.5 monthsRd18 (n = 541): 21.9 monthsMPT (n = 547): 23.9 monthsHazard ratioRd vs MPT: 0.68, P = .00001Rd vs Rd18: 0.62, P .00001 Rd18 vs MPT: 1.11, P = .21718Median time to 2nd antimyeloma therapy (measure of whether a more malignant relapse may have been selected)Rd (n = 535): 39.1 monthsRd18 (n = 541): 28.5 monthsMPT (n = 547): 26.7 monthsHazard ratioRd vs MPT: 0.66, P = .00001Rd vs Rd18: 0.74, P = .00067 Rd18 vs MPT: 0.88, P = .12333

Abbreviations: MPT, melphalan/prednisone/thalidomide; Rd, lenalidomide/low-dose dexamethasone.1. Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.FIRST TrialTTP and Time to 2nd Antimyeloma Therapy1,2Similar results were seen in terms of time to progression (TTP) and time to 2nd line antimyeloma therapy (TAMT)Continuous Rd significantly prolonged TTP and TAMT compared with MPT TTP: 32.5 vs 23.9 months; hazard ratio 0.68; P = 0.00001TAMT: 39.1 vs 26.7 months; hazard ratio 0.66; P < 0.00001Continuous Rd also significantly prolonged TTP and TAMT compared with Rd given for 72 weeksThere was no significant difference in TTP and TAMT between Rd given for 72 weeks and MPTCurves are separating early for Time to 2nd AMT continuous Rd vs. MPTTime to 2nd AMT clearly illustrates that the choice of prior Tx matters

33Overall response rate ( partial response)Continuous Rd (n = 535): 75.1%Rd18 (n = 541): 73.4%MPT (n = 547): 62.3%Duration of response (median)1,2Continuous Rd (n = 535): 35.0 monthsRd18 (n = 541): 22.1 monthsMPT (n = 547): 22.3 months FIRST TrialResponse EndpointsResponse assessment for Rd obtained q4wk and for MPT q6wk; response and progression rate based on IRAC assessment.Abbreviations: MPT, melphalan/prednisone/thalidomide; Rd, lenalidomide/low-dose dexamethasone. 1. Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.Response rates were significantly (?) higher with Rd, given either continuously or for 72 weeks, compared with MPT (75.1%, 73.4%, and 62.3%, respectively)Responses may have been more rapid with Rd therapy compared with MPT (1.8 months vs 2.8 months), although this may be attributed to differences in response evaluation timing: response was assessed every 4 weeks in the Rd groups and every 6 weeks in the MPT groupResponses also appeared to be more durable in the continuous Rd group compared with the MPT group (35.5 months vs 22.3 months)

34Continuous lenalidomide/low-dose dexamethasone (Rd) is a new standard of care for newly diagnosed, transplant-ineligible MM patientsProgression-free survival (PFS)Continuous Rd vs melphalan/prednisone/thalidomide (MPT): HR = 0.72 (P = .00006): consistent across most subgroupsContinuous Rd vs Rd18: HR = 0.70 (P = .00001)3-year PFS: 42% continuous Rd vs 23% Rd18 and MPTOverall survival (planned interim analysis)Continuous Rd vs MPT: HR = 0.78 (P = .0168)Rd was superior to MPT for secondary efficacy endpointsAdverse effects (hematologic and nonhematologic) for Rd and MPT were as expected Hematologic secondary primary malignancies: lower with continuous Rd vs MPT

FIRST TrialConclusions1,21. Facon T, et al. Blood. 2013;122:abstract 2. 2. Facon T, et al. Presented at: 55th ASH; December 7-10, 2013; New Orleans, LA. Oral presentation.This is the largest registrational phase III trial conducted in transplant ineligible patients with newly diagnosed myeloma comparing Rd (an alkylator-free doublet) vs. the triplet MPT. EfficacyThe study met its primary endpoint - PFSContinuous administration of Rd, significantly reduced the risk of progression or death by 28% vs. MPT. The PFS clinical benefit is associated with an OS advantage associated with continuous Rd vs. MPT.All other secondary endpoints were positiveSafety Rd is as good as MPT in regards to safetySimilar safety seen across the armsContinuous Rd is not associated with increased safety concernsSPM was higher with MPT vs Rd consistent with previous reports, in which it has been hypothesized that the increased SPM risk in patients treated with lenalidomide may be related to prior or concurrent melphalan use (Palumbo 2012; Attal 2012; McCarthy 2012; Dimopoulos 2012)Implications & PerspectiveRd should be a new standard of careResults with a 2-drug regimen at least comparable to that achieved with a 3-drug regimenReserve alkylating agents for later in treatmentFuture development: novel agents in combination with Rd rather than alkylating agents

35

Abbreviations: CR, complete response; CVD, cyclophosphamide/bortezomib/dexamethasone; CVRD, cyclophosphamide/bortezomib/lenalidomide/dexamethasone; nCR, near complete response; ORR, overall response rate; PAD, bortezomib/doxorubicin/dexamethasone; RD, lenalidomide/dexamethasone; RVD, lenalidomide/bortezomib/dexamethasone; TD, thalidomide/dexamethasone; VAD, vincristine/doxorubicin/dexamethasone; VGPR, very good partial response; VTD, bortezomib/thalidomide/dexamethasone. With permission from Stewart AK, et al. Blood. 2009:114:5436-5443. Combinations in the Upfront Treatment of MM 36Bortezomib Induction and Maintenance in ASCTAbbreviations: ASCT, autologous stem cell transplantation; CAD, cyclophosphamide/doxorubicin/dexamethasone; GCSF, granulocyte colony-stimulating factor; MEL, melphalan; NDMM, newly diagnosed multiple myeloma; PAD, bortezomib/doxorubicin/dexamethasone; VAD, vincristine/doxorubicin/dexamethasone.

Sonneveld P, et al. J Clin Oncol. 2012;30\:2946-2955.RandomizationCAD + GCSFCAD + GCSFMEL 200 + ASCTMEL 200 + 2nd ASCTMaintenanceMEL 200 + 2nd ASCT MEL 200 + ASCTAllogeneic SCTBortezomib 1.3 mg/m2 IVDoxorubicin 9 mg/m2Dexamethasone 40 mgThalidomide50 mg/d 2 yBortezomib 1.3 mg/m2/2 wk 2 yPatients with NDMMTransplantation-eligibleAge 1865

PAD3 cyclesVAD3 cyclesBortezomib-based treatment in newly diagnosed, transplant-eligible MM patients Progression-free survival (PFS): HR = 0.78 (P = .002)*Overall survival (OS): HR = 0.80 (P = .047)*

Bortezomib significantly improved PFS (P = .003) and OS (P 75Abbreviations: BORT, bortezomib; IV, intravenous; LoDEX, low-dose dexamethasone; MPD, maximum planned dose; MTD, maximum tolerated dose; OS, overall survival; POM, pomalidomide; RBC, red blood cell; SC, subcutaneous; SPM, second primary malignancy.Richardson PG, et al. Blood. 2013;122:abstract 1969.Cohort 1 (n=3)Cohort 2(n=3)Cohort 3(n=3)Cohort 4(n=3)Cohort 5(n=3)Expansion cohort(n=6)POM: 1 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*POM: 2 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*

POM: 3 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*POM: 4 mg/day

BORT: 1 mg/m2 IV

LoDEX: 20 mg*POM: 4 mg/day

BORT: 1.3 mg/m2 IV

LoDEX: 20 mg*MTD/MPD

SC BORT(n=6)POM: 4 mg/day

BORT: 1.3 mg/m2 SC

LoDEX: 20 mg*71Pom + LoDEX + Bortezomib in Relapsed MM * 8 of 9 patients were evaluable for response; one patient discontinued study treatment in cycle 2 due to treatment-unrelated metastatic pancreatic cancer. Abbreviations: Exp, expansion; ORR, overall response rate.Richardson PG, et al. Blood. 2013;122:abstract 1969.CohortORRCohort 1 (n=3)2 (67%)Cohort 2 (n=3)1 (33%)Cohort 3 (n=3)3 (100%)Cohort 4 (n=3)3 (100%)Cohort 5 + Exp Cohort (n=9)6 (67%)*72Development of Rationally Based Combination Therapies (HDAC and Proteasome Inhibitors)Hideshima T, et al. Clin Cancer Res. 2005;11:8530-8533. Catley L, et al. Blood. 2006;108:3441-3449. Anderson KC. J Clin Oncol. 2012;30:445-452. HDAC inhibitors

Examples include vorinostat, panobinostat, and ricolinostat (ACY-1215)

Block accessory pathway for protein degradation, which becomes activated when you block the proteasome using proteasome inhibitorsVANTAGE 088International, Multicenter, Randomized, Double-Blind Study of Vorinostat or Placebo with Bortezomib in Relapsed MMVorinostat + bortezomib in patients with relapsed and refractory MMResults (vs placebo + bortezomib)Overall response rate: 56.2% vs 40.6% (P