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Challenges and Novel Approaches to Treating Myeloma … AZMN Roundtable March 2014

Scottsdale, Arizona. Rochester, Minnesota. Jacksonville, Florida. Challenges and Novel Approaches to Treating Myeloma … AZMN Roundtable March 2014. Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona. Managing myeloma: the components. Initial Therapy. Consolidation.

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Challenges and Novel Approaches to Treating Myeloma … AZMN Roundtable March 2014

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  1. Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Challenges and Novel Approaches to Treating Myeloma…AZMN RoundtableMarch 2014 Joseph Mikhael, MD, MEd, FRCPC, FACP Staff Hematologist, Mayo Clinic Arizona

  2. Managing myeloma: the components Initial Therapy Consolidation Maintenance Treatment of Relapsed disease Transplant Eligible Patients Consolidation/ Maintenance/ Continued therapy Transplant Ineligible patients Supportive Care

  3. Treatment sequence SCT VD/VRD Thal/Dex VD Rev/Dex CyBorD VTD VRD Nothing Thalidomide? Bortezomib? Lenalidomide? Bortezomib Lenalidomide Thalidomide Carfilzomib Pomalidomide Monoclonal Ab (CD38) Elotuzumab HDAC Bendamustine NEW Maintenance Front line treatment Relapsed Consolidation Induction Post consolidation Rescue SCT VAD DEX Nothing Prednisone Thalidomide Few options OLD

  4. IMPACT OF NOVEL THERAPY 2012/2013 Median 7.3 years 5 YEAR SURVIVAL BY AGE AGE ≤ 65 YRS AGE > 65 YRS 2006-2010 73% 56% 2001-2005 63% 31% 2012 ASH Abstract #3972 Kumar et al

  5. mSMART Mayo Stratification for Myeloma And Risk-adapted Therapy Newly Diagnosed Myeloma Website: www.msmart.org

  6. mSMART 2.0: Classification of Active MM FISH Del 17p t(14;16) t(14;20) GEP High risk signature All others including: Hyperdiploid t(11;14) t(6;14) Standard-Risk 60% High-Risk 20% Intermediate-Risk 20% • FISH • t(4;14)* • Cytogenetic Deletion 13 or hypodiploidy • PCLI >3% 3 years 4-5 years 8-10 years Mikhael et al Mayo Clinic Proceedings April 2013

  7. mSMART – Off-Study Transplant Eligible High Risk Intermediate Risk Standard Risk 4 cycles of VRd 4 cycles of CyBorD 4 cycles of Rda or CyBorD Collect Stem Cellsb Autologous stem cell transplant, especially if not in CR Autologous stem cell transplant Autologous stem cell transplant 2 cycles of Rd consolidation; Then Len maintenance if not in VGPR and Len responsive* Continue Rd;c or CyBorD for ~12 months V or VCd for minimum of 1 year Bortezomib based therapy for minimum of 1 year aBortezomib containing regimens preferred in renal failure or if rapid response needed b If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixafor cContinue Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year * Consider risks and benefits; consider limited duration 12-24 months Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v11 //last reviewed Dec 2013

  8. mSMART – Off-Study Transplant Ineligible High Risk Intermediate Risk Standard Risk* MP + weekly Bortezomib or weekly CyBorD for ~12 months VRd* for ~12 months, Rda, b Bortezomib based therapy for minimum of 1 year Continue VRd as maintenance for minimum of 1 year a Dex is usually discontinued after first year b Bortezomib containing regimens preferred in renal failure or if rapid response needed *Clinical trials strongly recommended as the first option Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v11 //last reviewed Dec 2013

  9. Screening LT Follow-Up Active Treatment + PFS Follow-up Phase PD or Unacceptable Toxicity PD, OS and Subsequent anti-MM Tx LEN + Lo-DEX until Progressive Disease LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 RANDOMIZATION 1:1:1 ARM A Arm A Rd FIRST Design: Lenalidomide and Low-dose Dexamethasone (Rd/Rd18) vs. MPT N = 535 n=535 LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm B Rd18 n=541 MEL + PRED + THAL 12 Cycles1 (72 wks) MELPHALAN 0.25mg/kg D1-4/42 PREDNISONE 2mg/kg D1-4/42 THALIDOMIDE 200mg D1-42/42 Arm C MPT n=547 Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 100 mg D1-42/42, Melphalan2 0.2 mg/kg D1–4 n= 1,623 - 18 countries from North America, Asia-Pacific, and Europe represented from 246 Centers • Stratification: age, country and ISS stage International Staging System; LT, long-term; PD, progressive disease; OS, overall survival 1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70. Facon T. et._ASH 2013: Abstract 2

  10. 100 80 60 40 20 0 FIRST Trial: Final PFSContinuous Rd  the risk of PFS events (PD or death) by 28% vs. MPT Hazard ratio Rd vs. MPT: 0.72; P = 0.00006 Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349 Patients (%) 72 wks 6 12 18 24 30 36 42 48 54 60 0 Time (months) mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone. Facon T. et._ASH 2013: Abstract 2

  11. 100 80 60 40 20 0 6 12 18 24 30 36 42 48 54 60 0 Rd Rd18 MPT 535 541 547 488 505 484 457 465 448 433 425 418 403 393 375 338 324 312 224 209 205 121 124 106 43 44 30 5 6 3 0 0 0 FIRST Trial: Overall Survival Interim Analysis574 deaths (35% of ITT) Patients (%) Hazard ratio Rd vs. MPT: 0.78; P = 0.0168 ( 22% risk of death with Rd) Rd vs. Rd18: 0.90; P = 0.307 Rd18 vs. MPT: 0.88; P = 0.184 The pre-specified boundary (p<0.0096) was not crossed for Rd_continuous vs MPT_18 months Overall survival (months) Facon T. et._ASH 2013: Abstract 2

  12. FIRST Trial: Conclusions Continuous Rd significantly extended PFS, with an OS benefit vs. MPT PFS: 3 yr PFS: 42% continuous Rd vs 23% Rd18 and MPT Planned interim OS: HR= 0.78 (P= 0.0168) but did NOT cross the pre-specified boundary (p<0.0096) Safety profile with continuous Rd was manageable Hematological and non-hematological AEs were as expected for Rd and MPT with more infections and cataract observed in the continuous Rd arm Incidence of hematological SPM was lower with continuous Rd vs. MPT Facon T. et._ASH 2013: Abstract 2

  13. Efficacy Comparisons Facon et al. ASH 2013 (Abstract 2), plenary presentation Palumbo et al. N Engl J Med 2012;366(19):1759-69 San Miguel et al. N Engl J Med 2008; 359: 906-917 San Miguel et al. J Clin Oncol 2013;31(4):448-55 Palumbo et al. ASH 2012 (Abstract 200), oral presentation Mateos et al. Blood 2012; 120: 2581-2588

  14. Relapsed Disease

  15. NEWER THERAPIES: ASH 2013 TOP 8 • Anti-CD 38monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284) • MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983) • ARRY 520 (abstracts #285 and #1982) • ACY-1215 (abstracts #759 and #3190) • Selinexor (also known as KPT-330, abstract #279) • Anti-CD 138 monoclonal antibody (BT062, indatuximab ravatansine, abstract #758) • Panabinostat (abstract #1970) • Bendamustine (abstract #1971)

  16. Monoclonal antibodies in MM Richardson et al. et al. IMW 2013 (Abstract P-214), poster presentation; Plesner et al. ASH 2013 (Abstract 1987), poster presentation; Martin et al. ASH 2013 (Abstract 284), oral presentation; http://www.clinicaltrials.gov/ct2/show/NCT00421525; http://www.clinicaltrials.gov/ct2/show/NCT00079716; http://www.clinicaltrials.gov/ct2/show/NCT00346255; http://www.clinicaltrials.gov/ct2/show/NCT01001442; Wong et al. ASH 2013 (Abstract 505), oral presentation; Hageman et al. Ann Pharmacother 2013;47:1069-74;

  17. Thomas G. Martin III1, Stephen A. Strickland2, Martha Glenn3, Wei Zheng4, Nikki Daskalakis5and Joseph R. Mikhael6 1University of California San Francisco, San Francisco, CA 2Vanderbilt-Ingram Cancer Center, Nashville, TN 3University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 4Sanofi Oncology, Cambridge, MA 5Sanofi US, Bridgewater, NJ 6Mayo Clinic in Arizona, Scottsdale, AZ *NCT01084252 Trial Sponsored by Sanofi, Cambridge, MA SAR650984, A CD38 Monoclonal Antibody in Patients with Selected CD38+ Hematological MalignanciesData From a Dose-Escalation Phase I Study (TED10893)*

  18. 1. Antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) Antibody Fc Receptor Complement SAR650984: A Humanized IgG1 Monoclonal Antibody 2. Complement-dependent cytotoxicity (CDC) NK cell, Macrophage 4. CD38 enzymatic activity inhibition 3. Direct apoptosis induction without crosslinking NAD cADPR ADPR

  19. SAR650984: Phase I Dose Escalation Study Primary Objective • Determine maximum tolerated dose (MTD)/maximum administered dose (MAD) Secondary Objective • Characterize safety profile • Evaluate pharmacokinetic (PK) profile • Assess pharmacodynamics, immunogenicity, and preliminary disease response

  20. SAR650984: Baseline Characteristics • 39 treated patients • Median age = 65.0 (40 - 85) • Prior therapies of myeloma patients (n=34) • Median = 6 (2 – 14) • At doses≥ 0.3 mg/kg - all patients received prior lenalidomide and bortezomib • At doses ≥ 10 mg/kg - 69% of patient received carfilzomib and/or pomalidomide

  21. SAR650984: Patients with Infusion ReactionsPatients treated at doses of 0.3 mg/kg Q2W or higher Mandatory Prophylaxis in All Patients* Symptoms of Infusion Reactions (N; max severity): Nausea (5; G 2); Pyrexia (4; G 1); Drug hypersensitivity, Chills (3; G 2); Headache (3; G 1); Vomiting , Hypoxia (2; G 2); Cytokine release syndrome, Dyspnea, Flushing, Nasal congestion, Bronchospasm, Tracheal stenosis, Laryngospasm (1; G 2); Influenza-like illness, Abdominal pain, Blurred vision, Lacrimation increased, Rhinorrhea, Cough, Restlessness (1; G 1) 7 No infusion reaction Number of Patients Grade 1 6 Grade 2 5 4 3 2 1 C1 C>11 C1 C>1 C1 C>1 C1 C>1 C = Cycle C1 C>1 C1 C>1 C1 C>1 *methylprednisolone 100 mg IV, diphenhydramine 50 mg IV, ranitidine 50 mg IV, and acetaminophen 650-1000 mg po (or equivalents)

  22. CR PR MR SD PD NA SAR650984: Time on Treatment by Best ResponseMyeloma Patients Treated at Doses of 1 mg/kg Q2W or higher CR * PR MR SD 1 mg/kg Q2W 3 mg/kg Q2W 5 mg/kg Q2W PD 10 mg/kg Q2W 10 mg/kg QW 20 mg/kg Q2W NA 0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75 Week * Off study since 23May2013 due to patient decision. Ongoing

  23. SAR650984: Phase 1 Response Summary CBR:38.5% ORR: 30.8%

  24. SAR650984: Phase 1 Response Summary • Overall Response Rate (CR+PR) • Dosing cohorts ≥1mg/kg = 25% (2 CR, 4 PR of 24) • Dosing cohorts ≥ 10 mg/kg = 31% (2 CR, 2 PR of 13) • Clinical Benefit Rate (CR+PR+MR) • Dosing cohorts ≥ 1mg/kg = 33% (2 CR, 4 PR, 2 MR of 24) • Dosing cohorts ≥ 10 mg/kg = 38% (2 CR, 2 PR, 1 MR of 13) • Median Time to Initial Response (CR, PR, MR) = 6.1 weeks (3.4 – 12.3) • In 8 responders the median duration of response 5.0 months (0 - 15.4) • 6 patients still on treatment • Median duration of follow up is 6.5 months (1.9-16.3)

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