Advances in the Management of Relapsed/Refractory Multiple Myeloma Robert Z. Orlowski, Ph.D., M.D. Director, Myeloma Section Florence Maude Thomas Cancer Research Professor Departments of Lymphoma/Myeloma & Experimental Therapeutics Principal Investigator, MD Anderson SPORE in Multiple Myeloma Chair, Southwest Oncology Group Myeloma Committee

2013 ASH Abstract 406 Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma: Follow-up Analysis of the IFM 2005-02 Trial Michel Attal, Valérie Lauwers-Cances, Gérald Marit, Denis Caillot, Thierry Facon, Cyrille Hulin, Philippe Moreau, Claire Mathiot, Murielle Roussel, Catherine Payen, Pascale Olivier, and Hervé Avet-Loiseau

Study Design

Analysis After Relapse Primary analysis: len had better PFS, same OS Current data suggest len may cause myeloma chemoresistance BUT … PFS from Relapse Median 2nd PFS Placebo 24 Months Lenalidomide 13 Months OS from Relapse Median survival Placebo 48 Months Lenalidomide 29 Months

Choice of Second Line Therapy Matters 2nd line IMiD-based 2nd line bortezomib-based P<0.003 P=0.28 Placebo Placebo LEN LEN

Outline Current standards of care and novel regimens that take advantage of them Emerging agents showing activity in the relapsed and relapsed/refractory setting

Alegre, A et al. Haematologica. 87:609, 2002. Types of Relapse Alegre, A et al. Haematologica. 87:609, 2002.

Outcomes After Relapse From SCT Zamarin, D et al. Bone Marrow Transplant. 48:419, 2013.

APEX : Bortezomib vs. Dex 78% improvement in median time-to-progression 1.0 Median TTP All Pts Post-1st relapse 0.9 Bortezomib 6.2 mos 7.0 mos 0.8 3.5 mos 5.6 mos Dexamethasone 0.7 0.6 Proportion of patients 0.5 0.4 P = .0001 0.3 Bortezomib 0.2 Dexamethasone 0.1 0.0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 Time (days) Richardson, PG et al. N. Engl. J. Med. 352:2487, 2005.

SC vs. IV Bortezomib ± Dex Response rate, % Bortezomib IV ± dex (N=73) Bortezomib SC ± dex (N=145) ORR (CR + PR) 52 CR* 12 10 PR 40 42 nCR VGPR 3 5 ≥VGPR (CR + nCR + VGPR) 25 Response improvement (cycle 4  8) in patients who received dex, n/N (%) n=39 n=82 PR  CR 2/15 (13%) 4/31 (13%) <PR  PR 7/23 (30%) 14/47 (30%) Moreau, P et al. Lancet Oncol. 12:431, 2011.

Moreau, P et al. Lancet Oncol. 12:431, 2011. TTP of SC vs. IV Vd 100 90 80 70 60 50 40 30 20 10 ORR identical after 4 cycles Patients without PD (%) IV : 9.4 months SC: 10.4 months (0.839 HR; P-value 0.38657) 0 50 100 150 200 250 300 350 400 450 500 550 600 Days from randomization No. patients at risk IV SC 74 60 56 50 36 24 16 10 7 5 4 3 1 148 126 109 93 72 51 32 18 13 8 5 2 1 Moreau, P et al. Lancet Oncol. 12:431, 2011.

Bortezomib/PLD vs. Bortezomib PLD + Bortezomib 9.3 months Bortezomib 6.5 months Statistical analysis: HR (95% CI) 1.82 (1.41-2.35) p = 0.000004 Percent of Patients Progression-Free 100 200 300 400 500 20 40 60 80 Orlowski, RZ et al. J. Clin. Oncol. 25:3892, 2007.

Weber, DM et al. N. Engl. J. Med. 357:2133, 2007. Len/Dex vs. Dex Weber, DM et al. N. Engl. J. Med. 357:2133, 2007.

Carfilzomib : Approved in July, 2012 Results from PX-171-003-A1 study of carfilzomib in patients with relapsed and refractory myeloma But, approved for patients who have had at least 2 prior lines of therapy Siegel, DS et al. Blood 120:2817, 2012.

Long-term Outcomes Siegel, DS et al. Blood 120:2817, 2012.

Toxicities Most notable for the lower risk of peripheral neuropathy overall, and especially for the low rates of grade 3 or 4 events in this category Siegel, DS et al. Blood 120:2817, 2012.

Len/Carfilzomib/Dex Wang, M et al. Blood 122:3122, 2013.

Pomalidomide : Approved in February, 2013 Approval based on the results of the MM-002 study For patients with at least two prior lines of therapy

Pomalidomide Efficacy Data Richardson, P et al. Blood preprint online, 2014.

Richardson, P et al. Blood preprint online, 2014. Durability Data Richardson, P et al. Blood preprint online, 2014.

2013 ASH Abstract 690 Phase I/II Dose Expansion of a Multi-Center Trial of Carfilzomib and Pomalidomide with Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma Jatin J. Shah, Edward A. Stadtmauer, Rafat Abonour, Adam D. Cohen, William Bensinger, Cristina Gasparetto, Jonathan L. Kaufman, Suzanne Lentzsch, Dan T. Vogl, Robert Z. Orlowski, Erica L. Kim, Natalia Bialas, David D. Smith, and Brian GM Durie

Car/Pom/Dex Cycle 1-6: 28 day cycle Carfilzomib Pomalidomide 9 15 16 Pomalidomide 1 21 Dexamethasone 1 8 15 22

Response Data Best overall response N=79 VGPR 21 (27%) PR 34 (43%) MR 10 (13%) SD 13 (16%) PD 1 (1%) ORR = 70% CBR = 83%

Long Term Outcomes

2013 ASH Abstract 689 Pomalidomide + Low-dose Dexamethasone in Relapsed or Refractory Multiple Myeloma with Deletion 17p and/or Translocation t(4;14) Xavier Leleu, Lionel Karlin, Margaret Macro, Cyrille Hulin, Laurent Garderet, Murielle Roussel, Bertrand Arnulf, Brigitte Pegourie, Brigitte Kolb, Anne-Marie Stoppa, Sabine Brechiniac, Mauricette Michallet, Gerald Marit, Claire Mathiot, Anne Banos, Laurence Lacotte, Mourad Tiab, Mamoun Dib, Jean-Gabriel Fuzibet, Marie-Odile Petillon, Philippe Rodon, Marc Wetterwald, Bruno Royer, Laurence Legros, Lotfi Benboubker, Olivier Decaux, Denis Caillot, Martine Escoffre-Barbe, Jean Paul Fermand, Philippe Moreau, Michel Attal, Hervé Avet-Loiseau, and Thierry Facon

Pomalidomide and Deletion 17p Time to Progression Response rate with pom/dex comparable in patients ± del 17p Pom may overcome this poor risk lesion del17p t(4;14) All del17p All t(4;14)

Pomalidomide/Bortezomib/Dex 3 + 3 Design (21-day cycles) Cohort POM (D1-14) BORT (D1, 4, 8, 11*) LoDEX (D1-2, 4-5, 8-9, 11-12†) 1 (n = 3) 1 mg/day 1 mg/m2 20 mg‡ 2 (n = 3) 2 mg/day 3 (n = 3) 3 mg/day 4 (n = 3) 4 mg/day 5 (n = 3) 1.3 mg/m2 Expansion cohort (n = 6) at MTD/MPD Evaluation Every 21 Days (± 3 Days) Follow-Up for OS and SPM Until 5 Years Post-enrollment *For cycles 1-8, then D1, 8 for cycles 9+; †For cycles 1-8, then D1-2, 8-9 for cycles 9+; ‡10 mg for pts aged > 75 yrs Richardson, PG et al. ASH Abstract 727, 2012.

Richardson, PG et al. ASH Abstract 727, 2012. Response Summary Cohort Best Response Cohort 1 (n = 3) 1 VGPR, 1 PR, 1 SD Cohort 2 (n = 3) 1 PR, 2 SD Cohort 3 (n = 3) 2 VGPR, 1 PR Cohort 4 (n = 3) 1 VGPR, 2 PR Cohort 5 (n = 3) 2 PR, 1 SD ORR (≥ PR): 73%; VGPR: 27%; SD: 27% Median time to response: 1 cycle (range 1-2) Most responses are ongoing Richardson, PG et al. ASH Abstract 727, 2012.

Shah, JJ et al. ASH Abstract 75, 2012. Len/Thal/Dex N = 61 Overall Response Rate ( ≥ PR) 31 (51%) Stable Disease 15 (25%) Minimal Response 8 (13%) Partial Response 19 (31%) VGPR 4 (7%) nCR/CR Progressive Disease 7 (11%) Clinical Benefit Ratio (≥ MR) of 64% Shah, JJ et al. ASH Abstract 75, 2012.

Outcomes in Len Refractory Disease Overall Response 13 (34%) Stable Disease 12 (29%) Minimal Response 8 (20%) Partial Response 11 (27%) VGPR 1 (2%) CR / nCR 2 (5%) Progressive Disease 7 (17%) Lenalidomide Refractory: Clinical Benefit Ratio (≥ MR) of 51% Lenalidomide Naïve: Overall Response (≥ PR) of 14/16 (88%) Shah, JJ et al. ASH Abstract 75, 2012.

Outline Current standards of care and novel regimens that take advantage of them Emerging agents showing activity in the relapsed and relapsed/refractory setting

Novel Agents : Elotuzumab + Len/Dex Elotuzumab 10 mg/kg Elotuzumab 20 mg/kg Total Pts, n 31 32 63 ≥ PR, n (%) 28 (90) 23 (72) 51 (81) Stringent CR, n (%) 1 (3) 2 (3) CR, n (%) 2 (7) 3 (5) VGPR, n (%) 10 (32) 8 (25) 18 (29) PR, n (%) 15 (48) 13 (41) 28 (44) SD, n (%) 3 (10) 7 (22) 10 (16) PD, n (%) 0 (0) Not evaluable, n (%) 2 (6) Richardson, PG et al. 2010 ASH Abstract 986.

Other Antibodies : Daratumumab Part 1 Open label, weekly i.v. infusion, 8 weeks Dose-escalation: 3+3 scheme* 0.005→0.05→0.1→0.5→1.0 →2.0→4.0→8.0→16.0 →24.0 mg/kg Dose-escalation cohorts Part 2 Open label, single arm, i.v. infusion weekly: 8 weeks every other week: 16 weeks every fourth week: up to 96 weeks 8 mg/kg, 16 patients Expansion cohort Plesner, T et al. ASH Abstract 73, 2012.

Paraprotein Responses < 1 mg/kg 2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg A A B A C A A A A A A B A B A A C A C C C A A A A A A B C A A C Plesner, T et al. ASH Abstract 73, 2012.

2013 ASH Abstract 1986 Preliminary Safety and Efficacy Data of Daratumumab in Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple Myeloma Torben Plesner, Tobias Arkenau, Henk Lokhorst, Peter Gimsing, Jakub Krejcik, Charlotte Lemech, Monique C. Minnema, Ulrik Lassen, Andrew Cakana, Nikolai Constantin Brun, Linda Basse, Antonio Palumbo, and Paul G. Richardson

Response Data

Adverse Events

2013 ASH Abstract 284 SAR650984, a CD38 Monoclonal Antibody in Patients with Selected CD38+ Hematological Malignancies- Data from a Dose-Escalation Phase I Study Thomas G Martin III, Stephen A. Strickland, Martha Glenn, Wei Zheng, Nikki Daskalakis, and Joseph R. Mikhael

Response Data Binds different epitope than daratumumab CR PR MR Median prior therapies = 6 Patients treated > 10 mg/kg Q2W >PR 30.8% SD 1 mg/kg Q2W 3 mg/kg Q2W PD 5 mg/kg Q2W 10 mg/kg Q2W 10 mg/kg QW 20 mg/kg Q2W NA 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 Week Binds different epitope than daratumumab

2013 ASH Abstract 283 Novel AKT Inhibitor Afuresertib in Combination with Bortezomib and Dexamethasone Demonstrates Favorable Safety Profile and Significant Clinical Activity in Patients with Relapsed/Refractory Multiple Myeloma Peter M Voorhees, Andrew Spencer, Heather J. Sutherland, Michael E O'Dwyer, Shang-Yi Huang, Keith Stewart, Ajai Chari, Michael Rosenzwieg, Ajay K. Nooka, Cara A Rosenbaum, Craig C Hofmeister, Deborah A Smith, Joyce M Antal, Ademi Santiago-Walker, Jennifer Gauvin, Joanna B Opalinska and Suzanne Trudel

Analysis After Relapse Dose Cohort N Best Unconfirmed Response NE PD SD MR PR VGPR CR sCR ORR (>PR ) CBR (>MR) Part 1 34 2 3 10 13 1 50% 56% Part 2 37 7 14 8 65% 73% PK/PD 5 40%

Activity by Prior Bortezomib Exposure Naïve (n=13) Relapsed (n=44) Refractory (n=23) Unk Part 1 2/3 (67%) 10/18 (56%) 5/13 (38%) - Part 2 6/10 (60%) 17/26 (65%) 1/1 (100%) PK/PD NA 4/9 (44%) 1/10 (10%) Total 62% 61% 43% Akt inhibition may be attractive in myeloma!

2013 ASH Abstract 285 Prolonged Survival and Improved Response Rates with ARRY-520 in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with Low α-1 Acid Glycoprotein (AAG) Levels: Results From a Phase 2 Study Sagar Lonial, Jatin J. Shah, Jeffrey Zonder, William I. Bensinger, Adam D. Cohen, Jonathan L. Kaufman, Ajay K. Nooka, Donna M. Weber, Brandi Hilder, Selena A Rush, Ann Ptaszynski, Duncan Walker, and Robert Z. Orlowski

Mechanism of Action

Study Design

Response Data

AAG and Outcomes

2013 ASH Abstract 123 Identification of Tight Junction Protein (TJP)-1 as a Modulator and Biomarker of Proteasome Inhibitor Sensitivity in Multiple Myeloma Xing-Ding Zhang, Verrabhadran Baladandayuthapani, Heather Lin, George Mulligan, Bin Li, Dixie-Lee Esseltine, Lin Qi, Jian-Liang Xu, Walter Hunziker, Bart Barlogie, Saad Usmani, Qing Zhang, John Crowley, Bing-Zong Li, Hui-Han Wang, Jie-Xin Zhang, Isere Kuiatse, Jin-Le, Tang, Hua Wang, Richard Eric Davis, Wen-Cai Ma, Zhi-Qiang Wang, Lin Yang, and Robert Z. Orlowski

TJP1 Sensitizes to Bortezomib High TJP1 = Good response to bortezomib

Proteasomal Degradation CRBN and IMiDs Thalidomide LEN DDB1 Cul4A CRBN ? Proteasomal Degradation Teratogenicity ? Roc1 Multiple Myeloma Lenalidomide E3 Ubiquitin Ligase Zhu et al, Blood 2011 Lopez-Girona et al, Leukemia 2012 Ito et al, Science 2010 Pomalidomide Courtesy of Monica Schenone

Multiple Myeloma/ B-NHL Ikaros & IMiDs First drug described to increase ubiquitin ligase activity – by inducing ubiquitination of IKZF1 and IKZF3 Might help to develop new drugs that similarly target other “undruggable” proteins Thalidomide LEN Lenalidomide DDB1 Multiple Myeloma/ B-NHL IL2 release CRBN Cul4A IKZF1/3 IKZF1/3 Roc1 Pomalidomide Jan Krönke and Investigators from Brigham and Women’s, Broad Institute and Dana-Farber Institute, ASH 2013 LBA-5

Strategy : Combos or Single Agents? Garderet, L et al. J Clin Oncol. 30:2475, 2012.

Advances in the Management of Relapsed/Refractory Myeloma : Summary Robert Z. Orlowski, Ph.D., M.D. Director, Myeloma Section Florence Maude Thomas Cancer Research Professor Departments of Lymphoma/Myeloma & Experimental Therapeutics Principal Investigator, MD Anderson SPORE in Multiple Myeloma Chair, Southwest Oncology Group Myeloma Committee

Relapsed and/or Refractory Myeloma Current portfolio of drugs includes 1st and 2nd generation PIs & IMiDs Novel combination regimens can be used that provide additional options Combining an IMiD with a PI probably results in greater benefit than relying on only one Select treatment based on past and most recent lines, since sequence of therapy really matters

Relapsed and/or Refractory Myeloma Monoclonal antibodies with single-agent activity (daratumumab, SAR650984) or in combinations (these and elotuzumab) are attractive approaches Novel agents with new mechanisms of action (filanesib, afuresertib) will be entering registration studies Better molecular understanding of myeloma will allow us to personalize therapy

MDACC Myeloma Center Referral Line : 1-855-MYELOMA (toll-free) Drs. Elisabet Manasanch, Robert Orlowski (rorlowsk@mdanderson.org), Jatin Shah, Sheeba Thomas, Michael Wang, Donna Weber E-mail: myelomatrial@mdanderson.org Twitter: @Myeloma_Doc 56