9/26/2016. Disclosures. Update on The Management of Relapsed and refractory Myeloma. Clinical Trial Support from: Celgene, BMS and Amgen

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1 Update on The Management of Relapsed and refractory Myeloma Ahmed Galal MD, MSc, FRCPC Avera Cancer Institute Disclosures Clinical Trial Support from: Celgene, BMS and Amgen Consultant for: Celgene, Millennium, BMS, Amgen Speaker for: Celgene, Millennium, BMS, Amgen, Gilead and Merck Overview of Hematologic Malignancies * Leukemias include acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, and other leukemia. 1. Surveillance, Epidemiology and End Results (SEER) Stat Fact Sheets. Available at: Accessed March 26, Siegel RL et al. Ca Cancer J Clin. 2015;65:

2 Epidemiology of MM in 2012* Prevalence More than 71,000 people in the US Incidence More than 21,000 people are diagnosed with MM each year in the US Annual age-adjusted incidence is 5.8 per 100,000 Mortality Nearly 11,000 US MM patients die each year The overall 5-year relative survival rate for was 41.1% Demographics Median age at diagnosis is 69 years Less than 3.8% of MM patients are younger than 45 years Incidence twice as high in African Americans as in whites More frequent in men than women *Based on SEER data and estimates published in National Cancer Institute. Surveillance Epidemiology and End Results (SEER) stat fact sheets. 4 /mulmy.html. Accessed October 2, Celgene Corporation FISH-Based Assays Prognosis may vary according to type of chromosomal abnormality 1-7* Chromosomal abnormality (FISH based) Incidence (%) Prognosis Isolated del 13 48% No significance t(14;20) 1.5% Poor t(11;14) 7.8%-21% No significance t(14;16) 1.9%-5% Poor t(4;14) 6.5%-15% Poor del 17p 11% Poor del 13 with del 17p t(4;14) 8.6% 11.9% Poor *Chromosomal abnormalities may be found in MGUS patients as well Avet-Loiseau H, et al. Blood. 2007;109(8): Dewald GW, et al. Blood. 2005;106(10): Fonseca R, et al. Cancer Res. 2004;64(4): Fonseca R, et al. Leukemia. 2009;23(12): Ross FM, et al. Haematologica 2010;95(7): Munshi NC. Hematology Am Soc Hematol Educ Program. 2008; Rajkumar SV, et al. Mayo Clin Proc. 2006;81(5): Celgene Corporation Trends in 10-Year Relative Survival of MM Period estimates of 10-year relative survival of patients with MM by major age groups in defined calendar periods from to year relative survival (%)* Age range Calendar period *Relative survival reflects survival of patients with cancer compared with survival of the general population. 6 Brenner H, et al. Blood. 2008;111(5): Celgene Corporation 2

3 Are we changing the clinical course of MM? Impact of novel agents Survival (years) Standard Risk 3 4 years 10 years Intermediate Risk t(4;14) 1 2 years 4-5 years High Risk 6 9 months 3 year Tumor Burden in MM 10 Asymptomatic Symptomatic M Protein g/dl 5 2 MGUS or Smoldering Myeloma Active Myeloma Relapse Plateau Remission Relapse Refractory Relapse Time 8 MGUS, monoclonal gammopathy of undetermined significance. 1. Adapted from Durie BG. International Myeloma Foundation. Concise Review of the Disease and Treatment Options: Multiple Myeloma Cancer of the Bone. 2011/2012 ed. Accessed November 5, Kumar SK, et al. Blood. 2008;111(5): McGuire TR. Multiple myeloma. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy: A Pathophysiologic Approach. 7th ed. New York, NY: McGraw-Hill; 2008: Celgene Corporation Role of Bone Marrow Microenvironment Osteoclast activating factors OAFs increase expression of receptor activator of nuclear factor-kb ligand MM cells ICAM-1 IL-6 TNF IL-1 Bone Marrow Stromal Cells VEGF bfgf Bone Marrow Vessels PBMC IL-2 IFN Hideshima et al. Blood 96: 2943, 2000 Davies et al. Blood 98: 210, 2001 Gupta et al. Leukemia 15: 1950, 2001 CD8+ T Cells NK Cells Mitsiades et al. Blood 99: 4525, 2002 Lentzsch et al Cancer Res 62: 2300,

4 Signaling Cascades Mediate Growth, Anti-Apoptosis, and Migration in Myeloma IL-6 IGF1 VEGF TNF IL-21 SDF-1 RAF MEK p42/44 MAPK Proliferation MM cells IL-6 IL-21 JAK STAT3 BCL-X L MCL1 Anti-apoptosis (drug resistance) IL-6 IGF1 VEGF TNF SDF-1 PI3K AKT (PKB) Caspase-9 BAD NF- B Cyclin D Cell cycle FKHR KIP1 PKC Migration BMSC Reprinted with permission from Hideshima T, Anderson KC. Nat Rev Cancer. 2002;2:927 Clinical Dilemma Myeloma clones are genetically heterogeneous at baseline Additional genetic changes during evolution: Serial acquisition as well as changes in earlier clones Subclones have different: Clonogenic potential Different levels of resistance Factors Influencing Treatment Decision Response to prior therapy; tolerability of prior therapy Patient-related factors such as age, cytogenetic profile, and clonal heterogeneity Aggressiveness and prognostic features of individual patients Number of relapses and refractory disease 4

5 Definitions According to the International Myeloma Working Group criteria: Progressive disease (PD) is defined by at least a 25% increase from nadir in the serum paraprotein (absolute increase must be >0.5 g/dl) Urine paraprotein (absolute increase must be >200mg/24 hours) Difference between involved and uninvolved serum-free light-chain (FLC) levels (with an abnormal FLC ratio and FLC difference >100 mg/l) In patients who lack measurable paraprotein levels (oligo- or nonsecretory myeloma), an increase in bone marrow plasma cells (>10% increase) New bone/soft tissue lesions increasing the size of existing lesions unexplained serum calcium >11.5 mg/dl Analyzing Measures of PFS and OS Endpoint measures that assess results across the entire duration of the trial and at particular time points of interest may facilitate improved understanding of immuno-oncology research 1-4 Measure of PFS/OS Across the Entirety of the Study Duration: Measures of PFS/OS Hazard ratio/relative risk reduction measures the magnitude of the difference between the two curves of a Kaplan-Meier plot 1,2 * Measures of PFS/OS at a Specific Point in Time: Time point analyses estimate the presence or absence of sustained benefit at time points of interest (eg, 24 months) 3 Median duration is the time at which 50% of patients have either progressed or died 4 *A log-rank test is conducted to determine statistical significance between arms (represented by a P value ) Spruance SL et al. Antimicrob Agents Chemother. 2004;48: Brody T. Clinical Trials: Study Design, End points and Biomarkers, Drug Safety, and FDA and ICH Guidelines. London: Academic Press, 2012: Rich JT et al. Otolaryngol Head Neck Surg. 2010;143: Friedman LM et al. Survival analysis. In: Friedman LM et al. Fundamentals of Clinical Trials, 4th ed. New York, NY: Springer;2010: Bland JM, Altman DG. BMJ. 2004;328: Evaluating Clinical Endpoints in Hematologic Malignancies Assessment of multiple measures can provide a broad picture of the difference between the investigational arm and the control arm with respect to progression-free survival and overall survival, as in the two hypothetical, randomized, controlled clinical trials described below Median duration Median duration P value* <0.05 P value* <0.05 Kaplan-Meier curve intended for illustrative purposes only. * Calculated by log-rank test. OS, overall survival; PFS, progression-free survival. 15 5

6 Evaluating Clinical Endpoints in Hematologic Malignancies (cont d) Assessment of multiple measures can provide a broad picture of the difference between the investigational arm and the control arm with respect to progression-free survival and overall survival, as in the two hypothetical, randomized, controlled clinical trials described below Median duration Time point analysis Median duration Time point analysis P value* <0.05 P value* <0.05 Kaplan-Meier curve intended for illustrative purposes only. * Calculated by log-rank test. OS, overall survival; PFS, progression-free survival. 16 Evaluating Clinical Endpoints in Hematologic Malignancies (cont d) Assessment of multiple measures can provide a broad picture of the difference between the investigational arm and the control arm with respect to progression-free survival and overall survival, as in the two hypothetical, randomized, controlled clinical trials described below Median duration Time point analysis Hazard ratio/ relative risk reduction Median duration Time point analysis Hazard ratio/ relative risk reduction P value* <0.05 P value* <0.05 Kaplan-Meier curve intended for illustrative purposes only. * Calculated by log-rank test. OS, overall survival; PFS, progression-free survival. 17 I-O Is an Evolving Cancer Treatment Modality in Hematology I-O is a fundamentally different approach to fighting cancer that harnesses the body s own immune system 1 Through I-O research, therapies are being investigated in an attempt to utilize the body's own immune system to fight cancer Murphy JF. Oncology. 2010;4: Borghaei H et al. Eur J Pharmacol. 2009;625: American Cancer Society: Detailed Guide for Non- Hodgkin Lymphoma. Available at Accessed September 25, Kirkwood JM et al. CA Cancer J Clin. 2012;62(5):

7 Immunotherapies Can Be Classified as Either Passive or Active Immunotherapies are agents that work with the immune system and can be divided into two categories 1 : Passive Immunotherapies Active Immunotherapies Act on the tumor and indirectly engage immune cells to elicit an antitumor immune response 1,2 Act directly on immune effector cells to elicit an antitumor immune response Finn OJ. Ann Oncol. 2012;23(suppl 8):viii6-viii9. 2. Mellman I et al. Nature. 2011;480: Rescigno M et al. Biochim Biophys Acta. 2007;1776: Activating and Inhibitory Pathways Under Investigation Natural Killer Cell Mediated Cytotoxicity Natural Killer Cell mediated cytotoxicity is a stepwise, targeted, and highly regulated process 1 Several activating receptors and inhibitory receptors are thought to be involved in regulating Natural Killer Cell activity, including CD137, SLAMF7, and KIR 2,3 1. Mace EM et al. Immunol Cell Biol. 2014;92: Long EO et al. Annu Rev Immunol. 2013;31: Benson DM Jr et al. J Clin Oncol. 2012;30: Activating and Inhibitory Pathways Under Investigation T-Cell Mediated Cytotoxicity Activation of T-cell mediated cytotoxicity is regulated by interactions involving receptors and ligands such as CD40L, CD137, CD28, and OX40 1,2 T-cell activity may be negatively regulated by pathways including LAG-3, CTLA-4, B7-H3, and PD-1 1 Tumors may enhance inhibitory pathways to block T-cell activation 1,2 *Defined receptors are not yet known and precise mechanism of T-cell inhibition by B7-H3 is currently unknown. CTLA-4, cytotoxic T-Lymphocyte-Associated Protein 4; LAG-3, lymphocyte activation gene Pardoll DM. Nat Rev Cancer. 2012;12: Kirkwood JM et al. CA Cancer J Clin. 2012;62:

8 Based on preclinical studies, Natural Killer Cells in the immune response to multiple myeloma Natural Killer Cells are among the body s first line of defense against cancer and may play an important role in the immune response to multiple myeloma 2,3 Natural Killer Cells are initially capable of recognizing and eliminating myeloma cells while sparing normal cells 4,5 As disease burden increases, however, Natural Killer Cells decrease in number and cytotoxic activity slows due to mechanisms of immune evasion and immunosuppression 2 22 FDA Approved Newer Agents New immunomodulatory drugs Proteasome pathway Histone deacetylase inhibitors Monoclonal antibodies 8

9 Carfilzomib in Relapsed/Refractory MM 003-A1 Single-Arm Pivotal Study (N = 266) Patients (%) Progressive disease required (>2 lines of therapy) Median 5.4 years from diagnosis (range, ) 99.6% prior bortezomib 80% refractory or intolerant to bortezomib and lenalidomide 0.4% CR* (n = 1) DCR = 69% CBR = 37% ORR = 24% 5.1% VGPR (n = 13) 18.3% PR (n = 47) 13.2% MR (n = 34) 31.5% SD (n = 81) 26.8% PD (n = 69) Well tolerated Very low rate of neuropathy G1/2 11.3% G3/4 1.1% Responses not affected by prior treatment or cytogenetics Abbreviations: CBR, clinical benefit rate; DCR, disease control rate; ORR, overall response rate; PD, progressive disease; SD, stable disease. Siegel DS, et al. Blood. 2012;120: Slide courtesy of Dr. Lonial. Carfilzomib, Pomalidomide, and Low-Dose Dexamethasone Heavily pretreated patients (median 5 prior lines of therapy); 49% had high/intermediate risk cytogenetics at baseline Response rates very good partial response: 27% Overall response rate: 70% Clinical benefit rate: 83% Duration of response: median 17.7 months Progression-free survival (PFS): median 9.7 months Overall survival (OS): median >18 months Response rates, PFS, and OS were independent of fluorescence in situ hybridization/cytogenetic risk status Carfilzomib/pomalidomide/low-dose dexamethasone was well tolerated No unexpected toxicities Shah J, et al. Blood. 2013;122:abstract 690. Study Design Carfilzomib, Cyclophosphamide, and Low-Dose Dexamethasone Phase II multicenter trial (10 centers) 28-day cycles Carfilzomib/Cyclophosphamide/Low-Dose Dexamethasone Induction (9 cycles) Carfilzomib Maintenance (Until Progression or Intolerance) Cycle 1 Cycles 2 9 Maintenance Carfilzomib 20 mg/m 2 IV (days 1,2) 36 mg/m 2 (days 8,9,15,16) Carfilzomib 36 mg/m 2 IV (days 1,2,8,9,15,16) Carfilzomib 36 mg/m 2 IV (days 1, 2, 15, 16) Cyclophosphamide 300 mg/m 2 (days 1,8,15) Dexamethasone 40 mg (days 1,8,15,22) Cyclophosphamide 300 mg/m 2 (days 1,8,15) Dexamethasone 40 mg (days 1,8,15,22) Bringhen S, et al Blood. 2013;122:abstract

10 CCd Study Results And Comparison with Other Regimens 100% 80% 60% 40% 20% 0% CCd 1 VMP 2 Rd 3 Abbreviations: CCd carfilzomib/cyclophosphamide/dexamethasone; CR, complete response; ncr, near-complete response; OS, overall survival; PFS, progression-free survival; Rd, lenalidomide/dexamethasone; scr, stringent complete response; VGPR, very good partial response; VMP, bortezomib/melphalan/prednisone. 1. Bringhen S, et al Blood. 2013;122:abstract San Miguel JF, et al. N Engl J Med. 2008;359: Rajkumar SV, et al. Lancet Oncol. 2010;11:

11 MM-003 Design POM + LoDEX vs HiDEX POM + LoDEX POM: 4 mg/day (days 1 21) DEX: 40 mg* (days 1, 8, 15, 22) Randomization 2:1 PD or unacceptable toxicity HiDEX DEX: 40 mg* (days 1 4, 9 12, 17 20) Patients were stratified by: Age ( 75 vs > 75 yrs) Number of prior treatments ( 2 vs 3) Disease population (refractory vs relapsed/refractory vs bortezomib intolerance) * 20 mg > 75 yrs Progression of disease was independently adjudicated in real time. Abbreviations: HiDEX, high-dose dexamethasone; LoDEX, low-dose dexamethasone; PD, progressive disease; POM, pomalidomide. San Miguel J, et al. Lancet Oncol. 2013;14: POM + LoDEX vs. HiDEX PFS POM + LoDEX: 4.0 months (95% CI ) HiDEX: 1.9 months (95% CI ) HR = 0.48 (95% CI ), P <.0001 OS POM + LoDEX: 12.7 months (95% CI ) HiDEX: 8.1 months (95% CI ) HR = 0.74 (95% CI ), P =.0285 Abbreviations: HiDEX, high-dose dexamethasone; HR, hazard ratio; LoDEX, low-dose dexamethasone; OS, overall survival; PFS, progression-free survival; POM, pomalidomide. San Miguel J, et al. Lancet Oncol. 2013;14: Pomalidomide-dex vs dex (phase III) Improved Overall Survival n= 455 HR=

12 PFS Based on Cytogenetic Profile POM + LoDEX significantly improved PFS vs. HiDEX regardless of the presence of del17p or t(4;14) Subgroup ITT Population POM + LoDEX a HiDEX a HR (95% CI) 253/ / ( ) del(17p)/t(4;14) 71/77 32/ ( ) Standard-Risk Cytogenetics 126/148 63/ ( ) Favors POM + LoDEX Favors HiDEX Note: Data shown only for pts with available cytogenetics; totals will not sum. a Number of events/number of patients. Dimopoulos MA, et al. ASH 2013 [abstract 408]. MM-005 Study Design: POM + BORT + LoDEX Phase 1, multicenter, open-label, dose-escalation study; design; 21-day cycles POM: days 1-14 BORT: days 1, 4, 8, 11 LoDEX: days 1-2, 4-5, 8-9, April 2013: study amended to allow SC BORT in 6 patients Cohort 1 (n=3) Cohort 2 (n=3) Cohort 3 (n=3) Cohort 4 (n=3) Cohort 5 (n=3) Expansion cohort (n=6) SC BORT (n=6) POM: 1 mg/day POM: 2 mg/day POM: 3 mg/day POM: 4 mg/day POM: 4 mg/day POM: 4 mg/day BORT: 1 mg/m 2 IV BORT: 1 mg/m 2 IV BORT: 1 mg/m 2 IV BORT: 1 mg/m 2 IV BORT: 1.3 mg/m 2 IV MTD/MPD BORT: 1.3 mg/m 2 SC LoDEX: 20 mg* LoDEX: 20 mg* LoDEX: 20 mg* LoDEX: 20 mg* LoDEX: 20 mg* LoDEX: 20 mg* *10 mg for patients age >75 Abbreviations: 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 Pom + LoDEX + Bortezomib in Relapsed MM Cohort ORR Cohort 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%)* * 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

13 Based on preclinical studies, EMPLICITI (elotuzumab) directly activates the immune system 6 EMPLICITI is an immunostimulatory antibody that specifically targets the SLAMF7 protein 6 SLAMF7 is expressed on Natural Killer Cells (NKC) and myeloma cells 6 SLAMF7 is also expressed on plasma cells and at lower levels on specific immune cell subsets of differentiated cells within the hematopoietic lineage 6 ADCC=antibody-dependent cellular cytotoxicity; SLAMF7=signaling lymphocytic activation molecule family member 7. Please see Important Safety Information throughout the presentation and the full Prescribing Information available at this presentation. 37 A Phase 3, randomized, open-label study, evaluated the efficacy and safety of EMPLICITI (elotuzumab) in combination with Rd 6 Co-primary endpoints: Progression-free survival; Overall response rate 6 Minimum follow-up of 24 months 6 * Prior to EMPLICITI infusion, dexamethasone was administered as a divided dose: an oral dose of 28 mg and an intravenous dose of 8 mg. In the control group and on weeks without EMPLICITI, dexamethasone 40 mg was administered as a single oral dose. Each cycle was 28 days. 6 Please see Important Safety Information throughout the presentation and the full Prescribing Information available at this presentation. 38 In combination with Rd relative to Rd alone in patients who had received 1 to 3 prior therapies, EMPLICITI (elotuzumab) delivered a benefit in PFS that was maintained over time 6,8 EMPLICITI + Rd delivered 19.4 months [95% CI, 16.6, 22.2] of median PFS vs 14.9 months [95% CI, 12.1, 17.2] with Rd alone 6 At the time of this PFS analysis, there were fewer deaths in the ERd arm vs the Rd arm (94 [29%] vs 116 [36%]) 6 * p-value based on the log-rank test stratified by β2 microglobulins (<3.5 mg/l vs 3.5 mg/l), number of prior lines of therapy (1 vs 2 or 3), and prior immunomodulatory therapy (no vs prior thalidomide only vs other). 6 CI=confidence interval; ERd=EMPLICITI + lenalidomide + dexamethasone; HR=hazard ratio; PFS=progression-free survival; Rd=lenalidomide + dexamethasone. Please see Important Safety Information throughout the presentation and the full Prescribing Information available at this presentation

14 ELOQUENT-2: Conclusions Elotuzumab in combination with len/dex improved PFS and ORR At 3-yr follow-up, pts receiving Elotuzumab had 27% reduction in risk of progression or death vs len/dex alone Pts in elotuzumab arm had median delay of 1 yr in time to next treatment vs len/dex arm Interim OS analysis shows trend in favor of Elotuzumab arm Elotuzumab plus len/dex toxicity profile consistent with prior studies with minimal increase in toxicities vs len/dex alone Dimopoulos MA, et al. ASH Abstract 28. Slide credit: clinicaloptions.com TOURMALINE-MM1: Study Design Randomized, double-blind, placebo-controlled phase III trial [1] Stratified by prior therapy (1 vs 2-3), ISS stage (I-II vs III), and prior PI exposure (yes vs no) R/R MM pts with measurable disease; 1-3 prior treatments; CrCl 30 ml/min; not refractory to PIs or lenalidomide (N = 722) 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) Placebo D1,8,15 + Lenalidomide 25 mg* D Dexamethasone 40 mg D1,8,15,22 (n = 362) *10 mg for pts with CrCl 60 or 50 ml/min. 28-day cycles until PD or unacceptable toxicity TOURMALINE-MM1: PFS Addition of ixazomib to Rd resulted in 35% improvement in PFS vs Rd alone 100 Median PFS: IRd: 20.6 mos Placebo-Rd: 14.7 mos 80 Probability of PFS (%) Log-rank P =.012 HR (95% CI): ( ) Number of events: IRD 129; placebo-rd Time from randomization (mos) PFS benefit with ixazomib seen in all prespecified subgroups, including cytogenetic high risk, PI and IMiD exposed Moreau P, et al. ASH Abstract

15 TOURMALINE-MM1: Response Characteristic ORR, % CR VGPR PR Ixazomib + Rd (n = 360) Placebo + Rd (n = 362) P Value Median time to response, mos Median DoR, mos Median TTP, mos HR: Moreau P, et al. ASH Abstract 727. TOURMALINE-MM1: Conclusions 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] 1. Moreau P, et al. ASH Abstract FDA.gov. Accessed December 8, PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN RELAPSED/REFRACTORY MM Favorable safety profile as monotherapy In 15 of 32 (47%) showed benefit 4 patients achieving PR (13%) 6 patients achieving MR (19%) 5 patients achieving SD (16%) At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%) To be combined with lenalidomide dexamethasone Plesner et al ASH

16 Daratumumab and lenalidomide dexamethasone in relapsed MM The best change in response paraprotein evaluated according to IMWG A: serum M-protein, B: urine-m-protein Plesner et al ASH Development of Rationally Based Combination Therapies (HDAC and Proteasome Inhibitors) 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 inhibitors Hideshima T, et al. Clin Cancer Res. 2005;11: Catley L, et al. Blood. 2006;108: Anderson KC. J Clin Oncol. 2012;30: Clinical Data with Histone Deacetylases Panobinostat Panobinostat + bortezomib (BTZ) + dexamethasone (PANORAMA2) 1 Phase II (N = 55) 2 previous therapies, including an immunomodulatory drug, BTZ-refractory Results Objective response rate (ORR): 34.5% (near complete response [ncr]): 1.8%) Progression-free survival (PFS): 5.4 months Panobinostat + BTZ + dexamethasone (PANORAMA1) 2 Phase III (N = 768) 1-3 previous therapies Results (vs placebo + BTZ + dexamethasone) PFS: 12 vs 8.1 months (HR 0.63, P <.0001) ORR: 61% vs 55% (ncr/cr: 28% vs 16%) Duration of response: 13.1 vs 10.9 months 1. Richardson PG, et al. Blood. 2013;122: Richardson PG, et al. J Clin Oncol. 2014;32(5s):abstract

17 Promising Therapeutic Modalities Under Development Kelley et al ASH 2013 Background: Targeting KSP with ARRY 520 (Filanesib) Filanesib is a targeted Kinesin Spindle Protein (KSP) inhibitor KSP is a microtubule motor protein critical to the function of proliferating cells KSP inhibition induces aberrant mitotic arrest and rapid cell death Novel mechanism of action for MM Preferentially acts on MCL 1 dependent cells including MM Not expected to be cross resistant with other drugs Lonial et al ASH

18 CAR-BCMA T Cells in Myeloma: Background B-cell maturation antigen (BCMA): protein in TNF superfamily expressed by normal and malignant plasma cells and B cells [1] Autologous T cells can be genetically modified to express chimeric antigen receptors (CARs) specific for malignancyassociated antigens BCMA a potential target for CAR T-cell therapy for MM BCMA expressed uniformly on malignant plasma cells from 60%- 70% of patients with MM Current study evaluated CAR-BCMA T cell infusion for treatment of advanced MM [2] Autologous T-cells were stimulated, transduced with CAR-BCMA retroviruses, and cultured for 9 days before infusion 1. Carpenter RO, et al. Clin Cancer Res. 2013;19: Ali SA, et al. ASH Abstract LBA-1. CAR-BCMA T Cells in Myeloma: Study Design First-in-human phase I trial Pts with advanced R/R MM; 3 prior lines of therapy; normal organ function; clear, uniform BCMA expression on myeloma cells (N = 12) Cyclophosphamide 300 mg/m 2 Fludarabine 30 mg/m 2 QD for 3 days CAR-BCMA T cells* Single infusion *Dose escalation of CAR+ T cells/kg 0.3 x x x x 10 6 CAR-BCMA expression determined by flow cytometry Ali SA, et al. ASH Abstract LBA-1. CAR-BCMA T Cells in Myeloma: Conclusions First demonstration that CAR-T cells have activity in measurable MM CAR-BCMA T cells eliminated plasma cells without causing direct organ damage Responses included ongoing scr in patient with significant burden of chemotherapy-resistant disease Substantial but reversible toxicity comparable to that observed in previous CAR T cell studies Highest dose level of CAR-BCMA T cells to be reserved for patients with 50% bone marrow plasma cells Authors conclude that CAR-BCMA T cells represent a promising novel therapy for MM Ali SA, et al. ASH Abstract LBA-1. 18

19 TF5 Treatment of Multiple Myeloma: Conclusions In newly diagnosed transplant candidates, three drug regimens incorporating immunomodulatory drugs and proteasome inhibitors before and after transplant can prolong PFS and OS. Lenalidomide dex until progression is standard of care for non transplant patients with newly diagnosed myeloma. Lenalidomide maintenance until progression prolongs PFS and OS, with an increased risk of secondary cancers in patients who have received MP or high dose therapy and ASCT. TF6 Treatment of Multiple Myeloma: Conclusions Pomalidomide low dose dex is active in relapsed refractory MM, (including 17p deletion) Bortezomib or Carfilzomib and pomalidomide low dose dex increases response and is tolerated in relapsed refractory MM Novel agents including oral proteasome inhibitor ixazomib, monoclonal antibodies SAR and daratumumab, KSP inhibitor filanesib, and HDAC6 inhibitor ricolinostat demonstrate promising activity in relapsed refractory MM Incorporation of novel therapies at all stages of disease is further improving patient outcome in MM 19

20 Slide 55 TF5 Dr Anderson and Dr Lonial: please provide overall conclusions for the slide set. Terrence Fagan, 1/3/2014 Slide 56 TF6 Dr Anderson and Dr Lonial: please provide overall conclusions for the slide set. Terrence Fagan, 1/3/2014