Novel Therapeutics for Multiple Myeloma

Novel Therapeutics for Multiple Myeloma Marc S. Raab, MD Max-Eder-Group Experimental Therapies for Hematologic Malignancies Department of Medicine V, Heidelberg University Medical Center & German Cancer Research Center (DKFZ)

Novel Therapeutics success 1,056 patients grouped into 2001 2005 and 2006 2010 cohorts Survival improved over time, particularly in patients aged > 65 years (p = 0.001) Proportion surviving 1.0 Diagnosed 2006 2010 0.8 0.6 0.4 Diagnosed 2001 2005 0.2 0 0 1 2 3 4 5 Follow-up from diagnosis (years) Survival 2001 2005 2006 2010 Median OS, years 4.6 NR 0.001 1-year survival, % 83 90 5-year estimated OS, % Overall 48 66 > 65 years 31 56 0.001 < 65 years 63 73 NS p Kumar SK, et al. Blood. 2012;120:[abstract 3972]. Updated data presented at IMW2013.

Novel Therapeutics unmet medical need Patients refractory to bortezomib and relapsed or refractory to or ineligible to immunomodulatory drugs 100 Percentage (%) 80 60 40 20 Median PFS: 5 months (range 4 6) Median OS: 9 months 0 0 12 24 36 48 60 Months Kumar SK, et al. Leukemia. 2012;26:149-57.

Novel agents against myeloma Immunmodulators Thalidomide Lenalidomide Pomalidomide Proteasome-Inhibitors Bortezomib Carfilzomib Monoclonal ABs Elotuzumab Tabalumab Daratumumab Siltuximab BHQ880 MOR202

The second generation proteasome inhibitor: Carfilzomib Tetrapeptide epoxyketone Novel proteasome inhibitor Binds the β5 and β5 i subunits irreversibly H O H O N N N N N O O H O H O Carfilzomib Active against bortezomib-resistant MM cell lines and samples from pts with bortezomib resistance [1] O Well tolerated in phase II investigation [2] Active alone and in a number of combinations [3] in relapsed/refractory MM, as well as in initial therapy Recently FDA approved for rel/ref MM in US 1. Kuhn DJ, et al. Blood. 2007;110:3281-3290. 2. O Connor OA, et al. Clin Cancer Res. 2009;15:7085-7091. 3. Vij R, et al. Blood. 2012;[Epub ahead of print].

Carfilzomib: Phase II Studies efficacy Patients, % 100 80 60 40 20 Relapsed and refractory MM 003-A1 (73% BORT-refractory) Single agent + dex premed (N = 257) 5 18 Relapsed and/or refractory MM 004 (BORT-naive) Single agent (N = 67) 28 24 Relapsed MM 006 (75% prior BORT) CFZ + Rd (N = 51) 41 37 VGPR PR MR 0 13 Median 5 prior treatments Median 2 prior treatments 1 3 prior treatments Direct comparisons across studies are not possible, given differences in study design and patient populations. 12 Siegel D, et al. Blood. 2012;120:2817-25. Vij R, et al. Blood. 2012;119:5661-70. Wang M, et al. J Clin Oncol. 2011; 29:[abstract 8025]. Updated data presented at ASCO 2011. 2

Carfilzomib: Phase II Studies safety Incidence and severity of treatment-emergent adverse events ( 25%) and carfilzomib-related adverse events (n = 266) Adverse events Haematological All grades, n (%) Grades 3 or 4, n (%) All grades carfilzomibrelated, n (%) Anaemia 122 (46) 63 (24) 59 (22) Thrombocytopenia 103 (39) 77 (29) 77 (29) Lymphopenia 62 (23) 52 (20) 44 (17) Neutropenia 48 (18) 29 (11) 40 (15) Leukopenia 37 (14) 18 (6.8) 31 (12) Non-haematological Fatigue 130 (49) 20 (7.5) 98 (37) Other important toxicities included transient renal impairment and shortness of breath as well as hypertension and rare cases of significant cardiac dysfunction Siegel D, et al. Blood. 2012;120:2817-25.; updated at IMW2013

Other Novel Proteasome Inhibitors Marizomib and Ixazomib: 2 nd generation proteasome inhibitors with promising activity in RRMM: Marizomib (NPI 0052): induces apoptosis in cell lines resistant to conventional and bortezomib based therapies 1 in animal models, NPI 0052 was well tolerated and prolonged survival 1 active in RRMM patients (ORR ~ 25% at MTD +/ dex) 3 Ixazomib (MLN9708): shows selective anti MM activity in cell lines and an animal model 2 is currently being tested in clinical trials, with promising activity, esp. in combination, and has favourable tolerability 4 1. Chauhan D, et al. Cancer Cell. 2005;8:407-19. 2. Chauhan D, et al. Clin Cancer Res. 2011;17:5311-21; 3. Richardson et al, Blood 2011. 4.Kumar et al., Blood. 2012;120:[abstract 332].

Pomalidomide: Third Generation of IMiDs Pomalidomide: novel immunomodulatory agent structurally similar to thalidomide and lenalidomide [1] Distinct safety and efficacy profile Improved potency Clinical activity after use of bortezomib and lenalidomide shown in relapsed/refractory myeloma MTD: 2 mg once daily, 5 mg every other day, 4mg daily [1,2,4] Phase II data showed efficacy in combination with lowdose dexamethasone in relapsed myeloma patients [3] Recently approved for rel/ref MM in US NH 2 O O H N 1. Schey SA, et al. J Clin Oncol. 2004;22:3269-3276. 2. Streetly MJ, et al. Br J Haematol. 2008;141:41-51. 3. Lacy MQ, et al. J Clin Oncol. 2009;27:5008-5014. 4. Richardson PG, et al. ASH 2010 O N O

Pomalidomide: MM 003 Trial N = 455 Age 18 yrs 2 prior therapies Refractory to last treatment Refractory, intolerant or relapsed 6 mos (if PR) to BORT and LEN POM + LoDEX (n = 302): POM: 4 mg, d1 21 LoDEX: 40 mg ( 75 y) or 20 mg (> 75 y), d1, 8, 15, 22 28-day cycles HiDEX (n = 153): HiDEX: 40 mg ( 75 y) or 20 mg (> 75 y) d1 4, 9 12, 17 20 28-day cycles PD or intolerable AE PD Follow up for OS and SPM until 5 years postenrollment Companion trial MM 003C POM 21/28 days Primary endpoint: PFS Key secondary endpoints: OS, ORR ( PR), DoR, safety Dimopoulos MA, et al. Blood. 2012;120:[abstract LBA-6]. Updated data presented at IMW2013.

Pomalidomide: MM 003 Trial PFS ITT population LEN- and BORT-refractory Median PFS Median PFS POM + LoDEX (n = 302) 3.6 months POM + LoDEX (n = 221) 3.2 months Proportion of patients 1.0 0.8 0.6 0.4 0.2 0.0 HiDEX (n = 153) 1.8 months HR = 0.45 p< 0.001 0 4 8 12 16 PFS (months) Proportion of patients 1.0 0.8 0.6 0.4 0.2 0.0 HiDEX (n = 108) 1.7 months HR = 0.48 p< 0.001 0 4 8 12 16 PFS (months) ITT: intent-to-treat. Dimopoulos MA, et al. Blood. 2012;120:[abstract LBA-6]. Updated data presented at IMW2013.

Pomalidomide: MM 003 Trial overall survival ITT population* LEN- and BORT-refractory* Median OS (95% CI) Median OS (95% CI) POM + LoDEX (n = 302) NR (11.1 NE) POM + LoDEX (n = 221) NR (8.5 NE) 1.0 HiDEX (n = 153) 7.8 months (5.4 9.2) 1.0 HiDEX (n = 108) 7.4 months (4.3 9.2) Proportion of patients 0.8 0.6 0.4 0.2 0.0 HR = 0.53 p< 0.001 0 4 8 12 16 OS (months) Proportion of patients 0.8 0.6 0.4 0.2 0.0 HR = 0.56 p = 0.003 0 4 8 12 16 OS (months) * 29% of pts received POM after progressing on HiDEX. ITT: intent-to-treat Dimopoulos MA, et al. Blood. 2012;120:[abstract LBA-6]. Updated data presented at IMW2013.

Pomalidomide: MM 003 Trial safety Discontinuation due to AEs: 7% POM + LoDEX; 6% HiDEX VTE, all grades: 3% POM + LoDEX; 2% HiDEX Peripheral neuropathy, all grades: 12% POM + LoDEX; 11% HiDEX Grade 3 and 4 AEs, % POM + LoDEX (n = 300) HiDEX (n = 149) Neutropenia 42 15 Febrile neutropenia 7 0 Anaemia 27 29 Thrombocytopenia 21 24 Infections 24 23 Pneumonia 9 7 Haemorrhage 3 5 Glucose intolerance 3 7 Fatigue 5 5 Dimopoulos MA, et al. Blood. 2012;120:[abstract LBA-6]. Updated data presented at IMW2013.

Target Antibody Company Type CS1 Elotuzumab Abbot/BMS Humanized IL 6 Siltuximab Orthobiotec Chimeric CD138 BT062 Biotest Chimeric; conjugated to Maytansinoid Anti KIR IPH2101 Innate Pharma Fully Human CD40 SGN 40, HCD122 Dacetuzumab, Lucatumumab Seattle Genetics Novartis Humanized Fully Human CD56 IMGN901, Lorvotuzumab Meransine ImmunoGen Humanized; conjugated to Maytansinoid CD38 MOR202 MorphoSys Fully Human CD38 Daratumumab Genmab Fully Human RANKL Denosumab Amgen Fully Human DKK 1 BHQ880 Novartis Fully Human FGFR3 PRO 001 Prochon Biotech Genetech Humanized BAFF Ly2127399 Lilly Fully Human

Daratumumab Phase I/II Study in Relapsed/Refractory MM Daratumumab: anti-cd38 antibody; kills MM cells via ADCC, CDC, and induction of apoptosis Patients: relapsed/refractory MM ( 2 different therapies), not eligible for ASCT; 3 patients/dosing group Efficacy based on serum and/or urine M-component analyses Weekly x 8 w followed by /14d up to week 24w (MTD: 8 mg/kg) In 15 of 32 (47%).reduction in paraprotein (following 8 w of Dara in doses up to 24mg/kg) 4 PR (13%) + 6 MR (19%) + 5 SD At doses > 4mg/kg, 8 of the 12 (66%) had at least a MR Adverse events were manageable Plesner T, et al. ASCO 2012. Abstract 8019.

Daratumumab Phase I/II Study in Relapsed/Refractory MM Reletive change in paraproteine from baseline (%) 100 50 0-50 -100 9 2 1 mg/kg 2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg 5 1 20 19 10 12 31 16 29 8 13 C C A A A A A A B C A A C A A B A C A A A A A A B A B A A C A C 4 26 15 3 7 11 17 14 33 27 21 6 30 18 34 23 32 22 28 Patient number Plesner T, et al. ASH 2012. Abstract 8019, updated at IMW2013

A Phase 2 Study of Elotuzumab in Combination With Lenalidomide and Low-Dose Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma Sagar Lonial, 1,2 Andrzej J. Jakubowiak, 1,3 Sundar Jagannath, 1,4 Marc S. Raab, 5 Thierry Facon, 6 Ravi Vij, 1,7 Philippe Moreau, 8 Donna E. Reece, 9 Darrell White, 10 Lotfi Benboubker, 11 Jeffrey Zonder, 12 Jean-Francois Rossi, 13 Claire Tsao, 14 Teresa Parli, 14 Glenn Kroog, 15 Anil K. Singhal, 14 Paul G. Richardson, 1,16 on behalf of the 1703 Study Investigators 1 Multiple Myeloma Research Consortium, Norwalk, CT, USA; 2 Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA, USA; 3 University of Michigan, Ann Arbor, MI, USA; 4 Mount Sinai Medical Center, New York, NY, USA; 5 Universitaetsklinikum Heidelberg, Heidelberg, Germany; 6 Hopital Claude Huriez, Service des Maladies du Sang, Lille, France; 7 Washington University School of Medicine, St. Louis, MO, USA; 8 Hematology Department, University Hospital, Nantes, France; 9 Princess Margaret Hospital, Toronto, Ontario, Canada; 10 Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada; 11 CHU Tours-Hopital Bretonneau, Tours, France; 12 Karmanos Cancer Institute, Detroit, MI, USA; 13 CHU de Montpellier- Hopital Saint-Eloi, Montpellier, France; 14 Abbott Biotherapeutics Corporation, Redwood City, CA, USA; 15 Bristol-Myers Squibb, Princeton, NJ, USA; 16 Dana-Farber Cancer Institute, Boston, MA, USA

Elotuzumab efficacy Elotuzumab 10 mg/kg Elotuzumab 20 mg/kg Total Patients, n 36 37 73 ORR ( PR), n (%) 33 (92) 28 (76) 61 (84) CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12) VGPR, n (%) 17 (47) 14 (38) 31 (43) PR, n (%) 11 (31) 10 (27) 21 (29) <PR, n (%) 3 (8) 9 (24) 12 (16) Overall median time to response: 1 month (range, 0.7-19.2) Overall median time to best response: 2.5 months (range, 0.7-24.7) Median duration of objective response: 17.8 months (range, 1.0-30.4) Richardson PG, et al. ASH 2012. Abstract 202.

Elotuzumab efficacy Proportion of Progression Free Patients (%) 100 90 80 70 60 50 40 30 20 10 Median Time to Progression/Death: 10 mg/kg (n=36): not yet reached 20 mg/kg (n=37): 18.6 mos (95% CI 12.9-29.7) 10 mg/kg 0 0 3 6 9 12 15 18 21 24 27 30 33 Number at Risk: Months 36 32 30 29 23 20 18 18 13 9 3 0 37 29 26 23 21 17 15 13 13 10 3 0 At a median follow-up of 20.8 months, median PFS has not been reached in the 10 mg/kg arm 20 mg/kg Preliminary median PFS of 26.9 months was reported in the abstract; after 2.7 months of additional follow-up, no new PD or death reported. These pts had an increased PFS duration, and in the updated analysis, median PFS was not yet reached Richardson, et al. 2012 ASH Abstract 8020. Updated data presented at IMW2013.

Outlook Future of Myeloma Therapy Major advances: Bortezomib, Thalidomid, Lenalidomid 2nd Generation : Carfilzomib, Pomalidomid => major advances? more bullets in the pocket, but head-to-head comparisons are missing Antibodies: promising, but no phase III data yet Personalized therapy

Cereblon Predicts Sensitivity to Lenalidomid Lenalidomide resistant myeloma cells lack cereblon CRBN actin MM1.S MM1.S res Zhu YX, et al. Blood. 2011;118:4771-9.

Cereblon Predicts Sensitivity to Lenalidomid Gene Expression Levels of Cereblon Predict PFS of Pomalidomide Treated Patients P=0.0001 3 months versus 17 months Schuster SR, et al. Blood 2012;120:[abstract 194].

Cereblon Predicts Sensitivity to Thalidomid A Progression free survival C Progression free survival 1.0 0.8 0.6 0.4 0.2 > median < median 0.0 0 12 24 36 Months 1.0 0.8 0.6 0.4 0.2 > median < median p = 0.009 42 31 13 4 30 19 4 0 0.0 0 12 24 36 Months A-B: thal-treated, C-D: bort-treated p = 0.18 48 38 19 3 2 39 33 10 4 48 B Overall survival D Overall survival 1.0 0.8 0.6 0.4 0.2 1.0 0.8 0.6 0.4 0.2 > median 48 38 18 9 < median 40 31 16 6 0.0 0 12 24 36 Months > median 42 35 15 8 < median 47 43 25 10 0.0 0 12 24 36 Months p = 0.13 48 p = 0.81 48 Broyl A, et al. Blood. 2013;121:624-7. 1 1 60 2 60

Cereblon Predictor for Sensitivity to IMiDs? MM1.S OPM2 KMS11 JJN3 OCIMY5 OPM1 SKMM2 KMS12PE MM1.S res CRBN -actin Zhu YX, et al. Blood. 2011;118:4771-9.

Signaling in Myleoma Morgan et al., NatRevCan 2012

BRAF V600E, 2 4% in myeloma Cancer Discovery 2013.

Figure 2 BRAF V600E, 2 4% in myeloma #1 lines of therapy 1 st line #2 2 nd line 3 rd line #3 4 th line vemurafenib #4 remission BRAF V600E status #5 #6 mutated wildtype subclone extramedullary disease #7 0 1 2 3 4 Years after diagnosis of multiple myeloma Cancer Discovery 2013. 27

Clinical Inhibition of BRAF V600E Cancer Discovery 2013.

Clinical Inhibition of BRAF V600E Cancer Discovery 2013.