Target Audience. This activity has been designed to meet the educational needs of hematologistoncologists

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1 Target Audience This activity has been designed to meet the educational needs of hematologistoncologists and medical oncologists involved in the care of patients with multiple myeloma 1

2 Learning Objectives At the conclusion of this activity, participants should be able to: Utilize the International Staging System (ISS), cytogenetics, fluorescence in situ hybridization (FISH), and gene expression profiling to define patient prognosis and risk stratification Select treatment combinations in the frontline setting based on risk and patient-specific characteristics Assess treatment response to induction therapy and determine which patients will benefit from consolidation and/or maintenance therapy Select an appropriate course of therapy for patients who have relapsed from or become refractory to initial treatment Anticipate and proactively manage disease- and treatment-related side effects and toxicities to maintain compliance with treatment at the dose and schedule that is optimal to achieve best response Distinguish between the various novel agents in clinical development based on their mechanisms of action, safety, and preliminary efficacy Community Case: SMM to Symptomatic MM Jesus G. Berdeja, MD Director, Multiple Myeloma Research Sarah Cannon Research Institute Attending Physician Tennessee Oncology Nashville, Tennessee 2

3 Disclosures No relevant financial relationships Case Details 58-year-old woman referred for evaluation of an elevated protein on routine laboratories She is asymptomatic Past medical history Hypertension Medications Amlodipine Multivitamin NKDA Social history 5th grade teacher, married, has two children Does not drink or smoke Family history Not contributory, three full siblings in good health Physical exam Unremarkable Initial laboratory evaluation SPEP/IFE: 2 g/dl abnormal protein corresponding to IgGλ monoclonal protein 3

4 Further Workup CBC CMP WBC Hb Platelets Creatinine Ca Albumin LDH SPEP/IFE 24h UPEP/IFE 5.2 K/μL 13.0 g/dl 200 K/μL 0.8 mg/dl 9.0 mg/dl 4.0 g/dl 200 U/L 2.1 g/dl abnormal protein corresponding to IgGλ monoclonal protein 50 mg/24 h abnormal protein, λ light chains by IFE SFLC SFκLC 8 mg/l SFλLC 115 mg/l Ratio 0.07 ( ) Skeletal survey Bone marrow biopsy Normal bone mineralization, no lytic lesions or fractures Normocellular bone marrow (40%); 15% replaced by plasma cells expressing CD38, CD56 and λ-restricted; cytogenetics 46,XX[20] FGFR3/IGH fusion signal pattern consistent with t(4;14) Question What is the diagnosis? A. Monoclonal gammopathy of undetermined significance (MGUS) B. Smoldering multiple myeloma (SMM) C. Active MM D. Other 4

5 Question Which of the following would you start the patient on? A. Bisphosphonate B. Calcium C. I would not provide anything Question What additional imaging tests would you perform on this patient? A. Positron emission tomography (PET) B. Magnetic resonance imaging (MRI) C. No further imaging 5

6 Question How would you manage this patient? A. Induction treatment for active MM B. Close observation C. Lenalidomide-dexamethasone D. Clinical trial E. Other Initial Management The patient is diagnosed with smoldering MM Treatment was delayed and patient was monitored closely every 3 6 months Case continues Over the next 2 years the patient has done well but now presents with progressive fatigue 6

7 Workup Now Shows CBC CMP SFLC WBC 5.0 K/μL Hb 9.8 g/dl Platelets 140 K/μL Creatinine 1.3 mg/dl Ca 12.0 mg/dl Albumin 3.0 g/dl β2-microglobulin 5.4 mg/l SPEP/IFE 3.4 g/dl abnormal protein corresponding to IgGλ monoclonal protein IgA 43 mg/dl IgG 4,100 mg/dl IgE 30 mg/dl 24h UPEP/IFE 350 mg/24h abnormal protein, λ light chains by IFE SFκLC 4 mg/l SFλLC 150 mg/l Ratio 0.03 ( ) Skeletal survey Diffuse osteopenia, scattered small lytic lesions throughout skull Bone marrow biopsy Hypercellular bone marrow (70%); 50% replaced by plasma cells expressing CD38, CD56 and λ-restricted; cytogenetics 46,XX[20] FGFR3/IGH fusion signal pattern consistent with t(4;14) Question What would be your recommendation for initial treatment? A. Melphalan, prednisone, bortezomib (VMP) B. Bortezomib, thalidomide, dexamethasone (VTD) C. Lenalidomide + low-dose dexamethasone (Ld) D. Lenalidomide, bortezomib, dexamethasone (RVD) E. Cyclophosphamide, bortezomib, dexamethasone (CyBorD) F. Carfilzomib, lenalidomide, dexamethasone (KRD) G. Other 7

8 2015 v2 NCCN Treatment Options for Untreated Active Multiple Myeloma Transplant Eligible Preferred regimens (Category 1) BTZ/DEX BTZ/Cyclophos/DEX BTZ/Dox/DEX BTZ/LEN/DEX BTZ/Thal/DEX LEN/DEX Transplant Ineligible Preferred regimens (Category 1) BTZ/DEX LEN/low-dose DEX MEL/Pred/BTZ MEL/Pred/LEN MEL/Pred/Thal The NCCN Clinical Practice Guidelines in Oncology Multiple Myeloma (Version ) National Comprehensive Cancer Network, Inc. Available at: Accessed November 21, Initial Treatment Course The patient is treated with RVD (lenalidomide, bortezomib, dexamethasone) 4 cycles Achieving a VGPR (undetectable M protein by SPEP and UPEP but + serum IFE) Treatment tolerated well except for grade 1 peripheral neuropathy mostly in feet 8

9 Question Based on the patient s response to induction therapy, you collect stem cells. What would you consider next? A. No further treatment B. Proceed to transplant C. Continue RVD Initial Treatment Course Given the patient s age and otherwise good health, she undergoes ASCT in first remission Cyclophosphamide/GCSF mobilization CD34+ cells/kg collected Melphalan 200 mg/m 2 followed by reinfusion of CD34+ cells/kg Treatment tolerated well except for a short admission to the hospital for neutropenic fever that resolved without sequelae 9

10 How Is Risk Assessment Useful? From Smoldering to Symptomatic Myeloma A. Keith Stewart, MBChB, MRCP, FRCPC, MBA Dean for Research Vasek and Anna Maria Polak Professor of Cancer Research Consultant, Division of Hematology/Oncology Mayo Clinic Scottsdale, Arizona Disclosures Consultant/Advisor: Array Biopharma, Bristol-Myers Squibb, Celgene, Genentech, Janssen, Novartis, Sanofi 10

11 Key Points From Patient Case A patient with SMM 15% plasma cells Abnormal to normal FLC ratio 14 M spike 2.1 g/dl Normal skeletal survey t(4;14) SMM, smoldering multiple myeloma; FLC, free light chain Criteria for Diagnosis of Myeloma MGUS <3 g M spike <10% plasma cells AND SMM 3 g M spike 10% plasma cells Active MM 10% plasma cells M spike + AND No anemia, bone lesions, normal calcium, and kidney function Anemia, bone lesions, high calcium, or abnormal kidney function MGUS, monoclonal gammopathy of unknown significance Kyle RA et al. Leukemia. 2009;23:3. Kyle RA et al. N Engl J Med. 2002;346:

12 Risk Assessment in Smoldering MM Figure 3, page 788 from Dispenzieri A, et al. Blood. 2008;111:785. Table 3, page 788 from Dispenzieri A, et al. Blood. 2008;111:785. Lenalidomide and Dexamethasone for High-Risk Smoldering MM: Schedule of Therapy Treatment arm (n = 57) Control arm (n = 62) Induction Nine 4-week cycles Lenalidomide 25 mg/daily during 21 d every 28 d Dexamethasone 20 mg D1 D4 and D12 D15 every 28 d Therapeutic abstention Maintenance Lenalidomide 10 mg/daily during 21 d every month* Therapeutic abstention Amendment on August 2011: Stop treatment at 2 years of treatment *Low-dose DEX will be added at the moment of biological progression Mateos MV et al. N Engl J Med. 2013;369:

13 Lenalidomide and Dexamethasone for High-Risk Smoldering MM Figure 2A, page 433 from Mateos MV, et al. N Engl J Med. 2013;369:438. Figure 2B, page 433 from Mateos MV, et al. N Engl J Med. 2013;369:438. Challenges to Interpretation Method for classifying high risk patients High early death rate after diagnosis of active disease Conclude: still recommend observation, but New definition of smoldering vs active myeloma required 13

14 Plasma Cells Can Predict for Progression Figure 2B, page 949 from Kastritis E, et al. Leukemia. 2013;27:947. Freelight Ratio >100 Predicts Risk Figure 2 from Larsen JT et al. Leukemia. 2013;27:

15 Re-Definition of Active Myeloma Figure 4, [age 4178 from Dispenzieri A, et al. Blood. 2013; 122:4172. Improving Survival in MM Proportion Surviving Follow Up From Diagnosis (Years) Adapted from Kumar SK et al. Leukemia. 2014;28:

16 Improving Survival in MM Proportion Surviving % of patients live less than 3 years Follow Up From Diagnosis (Years) Adapted from Kumar SK et al. Leukemia. 2014;28:1122. ISS (International Staging System) for Multiple Myeloma Modified from Table 2, page 3415 from Greipp PR, et al. J Clin Oncol. 2005; 23:3412. Figures 3A and 3B, page 3418 from Greipp PR, et al. J Clin Oncol. 2005;23:

17 IFM Predictors of Early Death Risk of early death from progression (multivariate logistic regression analysis) related to three independent variables: High LDH > normal, P=0.012 ISS3, P=0.020 t(4;14) and/or 17p, P= IFM, Intergroupe Francophone du Myélome; LDH, lactate dehydrogenase Moreau P et al. J Clin Oncol. 2014;32:2173. Gene Expression and Prognosis ifish - del(17p), t(4;14) vs SKY92 high-risk signature Risk stratified based on ifish Cumulative Overall Survival HR = P = 4.5E-05 Cohort A it(4;14);idel17p pos (n = 64) it(4;14);idel17p neg (n = 181) Time (Months) ifish SKY92 14% 12% 12% Neg = 62% Risk stratified based on SKY92 Cumulative Overall Survival HR = P = 1.9E-12 Cohort A SKY92 pos (n = 60) SKY92 neg (n = 185) Time (Months) Van Vliet M et al. Haematologica. 2013;98. Abstract S

18 High 20% FISH del 17p t(14;16) t(14;20) GEP High-risk signature msmart 2.0 Variable Outcomes in MM Intermediate 20% FISH t(4;14) Cytogenetic deletion 13 or hypodiploidy High LDH and/or β2m Standard 60% Others Hyperdiploid t(11;14) t(6;14) Normal LDH and β2m 3 years 4 5 years 10 years msmart, Mayo Stratification of Myeloma and Risk-Adapted Therapy; FISH, fluorescence in situ hybridization; GEP, gene expression profile Mikhael JR et al. Mayo Clin Proc. 2013;88:

19 Clonal Tides Figure 4, page 1073 from Keats JJ, et al. Blood. 2012;120:1067. MMRF CoMMpass SM Study The CoMMpass SM longitudinal study is a core element of the MMRF Personalized Medicine program to identify patient segments based on molecular profiling. Centralized molecular tests: Target enrollment: >1,000 newly diagnosed patients Longitudinal clinical data and molecular profiling Duration: ~10 years Sites: 92 community and academic cancer centers Industry partners: Millennium, Onyx, Janssen, BMS Flow cytometry & BRAF mutations* RNA sequencing expression analysis Whole-exome DNA sequencing Whole-genome chromosome analysis Cytospin slides for FISH biorepository of PBMNC, plasma, tumor Veridex CMMC assay (PBL) *CLIA lab results Implemented in Q PBMNC, peripheral blood mononuclear cell; CMMC, circulating MM cells; PBL, peripheral blood lymphocytes CoMMpass, Relating Clinical Outcomes in MM to Personal Assessment of Genetic Profile. 19

20 CoMMpass SM : Enrollment to Date Patients (n) 775 patients enrolled as of 01DEC14 Active patients/mo Projected active patients Actual active patients Gene Myeloma-Specific Mutation Panel Mutated in 3% of patients Actionable (eg, FGFR3, IDH, RAF, EGFR) Drug resistance (CRBN, IZKF, XBP) Pathway (eg, NFkappaB) 10 ng DNA (as few as 10 cells) Four samples per chip Fast turnaround 1000 coverage FGFR, fibroblast growth factor receptor; IDH, isocitrate dehydrogenase; EGFR, epidermal growth factor receptor; DNA, deoxyribonucleic acid 20

21 Myeloma-Specific Gene Mutation Panel Tracks Clonal Changes Over Time Patient One Patient Two Patient Three FAM46C 24% 92% 88% FAT1 73% KRAS 28% 60% 53% SP140 48% 37% 85% 23% SPEN 18% TP53 24% 92% 82% 94% 78% 88% Kortuem KM et al. Blood. 2014;124. Abstract 169. Summary High-risk smoldering MM needs treatment Genetically defined high-risk disease requires a different approach Clonal heterogeneity is prevalent Multiagent chemotherapy is logical Clonal tides evident Continuous therapy is logical The minor clone is lethal CR is a goal Mutation profiling can identify drug-resistant clones and remission status in real time 21

22 Should We Strive for Deepest Remission Possible in All Patients? Michele Cavo, MD, PhD Professor of Hematology Faculty of Medicine and Surgery Bologna University School of Medicine Head, Institute of Hematology and Medical Oncology Seràgnoli S. Orsola University Hospital Bologna, Italy Disclosure Consultant/Advisor: Bristol-Myers Squibb, Celgene, Janssen, Millennium, Onyx Speakers Bureau: Celgene, Janssen 22

23 Key Points From Patient Case Diagnosis of symptomatic IgG/λ MM, evolved from prior smoldering MM Main characteristics at the time symptomatic MM was diagnosed Age 60 years International Staging System (ISS) 2 Hypercalcemia (12 mg/dl) Lytic lesions (skull) Anemia (Hb 9.8 g/dl) Induction treatment consisted of: RVD 4 cycles VGPR (G1 PN) Consolidation after induction treatment consisted of: Single ASCT CR Treatment Options for NDMM Outside Clinical Trials Figure 1, page 594 from Ludwig H, et al. Oncologist. 2012;17:

24 Overview Treatment goals in transplant-eligible newly diagnosed MM patients Importance of quality of response to induction therapy Choice of optimal induction treatment Role and clinical relevance of posttransplant consolidation therapy Achievement of MRD negativity as an endpoint of current treatment strategies New Treatment Paradigm for Patients Who Are Eligible for ASCT NOVEL AGENTS Induction therapy Autograft 1 or 2 Consolidation Maintenance Cavo M et al. Blood. 2011;117:

25 Goals of Novel Agent-Based Induction Therapy Goals of Novel Agent Based Induction Therapies Achieve a rapid and high-quality response (CR) Promptly reverse severe disease-related complications, such as renal failure and hypercalcemia Ameliorate symptoms Reduce tumor burden and bone marrow plasma cell infiltration, enabling successful collection of PBSCs Minimize possible toxicities precluding subsequent ASCT Improve post-asct outcomes CR, complete response; PBSC, peripheral blood stem cells; ASCT, autologous stem cell transplantation Cavo M et al. Blood. 2011;117:6063. Ludwig H et al. Oncologist. 2014;19:

26 Importance of Quality of Response to Induction Therapy Achievement of High-Quality Response After Induction Therapy Prognosticates for Extended PFS After ASCT Figure 1A, page 3043 from Moreau P, et al. Blood. 2011;117:3041. and Table 4, page 2081 from Cavo M, et al. Lancet. 2010;376:

27 Novel Agent Based Induction: 2 vs 3 vs 4 Drug Regimens Novel Agent Based Induction Therapies for Patients Eligible for a Transplant From Table 2, page 36 from Cavo M, et al. Blood. 2005;106:35. 27

28 Novel Agent Based Induction Therapies for Patients Eligible for a Transplant 2-drug combinations 3-drug combinations 4-drug combinations Bortezomibbased Thalidomidebased Lenalidomidebased VD TD Rd RD* PAD VCD TAD CTD Regimens in yellow: evidence from phase III trials *Trial was performed in SCT-eligible and ineligible patients RAD CRD Bortezomib + IMiD-based VTD VRD Carf-RD/-TD Ixa-RD VTDC RVCD RVDD IMiD, immunomodulatory drug Adapted from Cavo M et al. Blood. 2011;117:6063. Rosinol L et al. Expert Rev Hematol. 2014;7:43. Ludwig H et al. Leukemia. 2014;28:981. Induction Regimens Determined by Referring Physicians for Patients Referred for ASCT at Mayo Clinic Figure 1, page 884 from Gertz MA, Dingli D. Blood. 2014;124:

29 Choice of Optimal Induction Treatment Novel Agent Based Induction vs Conventional Therapy (Phase 3 Studies) Postinduction Response Post-ASCT Response Survival Induction Number VGPR VGPR PFS Regimen of Cycles CR (%) (%) CR (%) (%) (months) OS (months) TAD VAD CTD Not reached C-VAD Not reached VD yr 81% VAD yr 77% PAD 4,5 3 11* 42 31* Not reached VAD 3 5* 14 15* *Includes ncr Per-protocol analysis OS, overall survival 1. Lokhorst HM et al. Blood. 2010;15: Morgan GJ et al. Haematologica. 2012;97: Harousseau JL et al. J Clin Oncol. 2010;28: Sonneveld P et al. J Clin Oncol. 2012;30: Sonneveld P et al. Blood. 2013;122. Abstract 404. Updated data presented at ASH

30 Novel Agent Based Induction vs Conventional Therapy (Phase 3 Studies) Postinduction Response Post-ASCT Response Survival Induction Number VGPR VGPR PFS Regimen of Cycles CR (%) (%) CR (%) (%) (months) OS (months) TAD VAD CTD Not reached C-VAD Not reached Novel agent based induction showed clear benefit compared with VAD conventional chemotherapy. VD yr 81% VAD yr 77% PAD 4,5 3 11* 42 31* Not reached VAD 3 5* 14 15* *Includes ncr Per-protocol analysis OS, overall survival 1. Lokhorst HM et al. Blood. 2010;15: Morgan GJ et al. Haematologica. 2012;97: Harousseau JL et al. J Clin Oncol. 2010;28: Sonneveld P et al. J Clin Oncol. 2012;30: Sonneveld P et al. Blood. 2013;122. Abstract 404. Updated data presented at ASH Doublet vs Triplet Combinations: Evidence From Phase 3 Studies Number of Cycles Postinduction Response Post-ASCT Response Survival Induction VGPR VGPR PFS Regimen CR (%) (%) CR (%) (%) (months) OS (months) VTD 1, yr 75% TD yr 69% VTD NR 56 4-yr 74% TD NR 28 4-yr 65% vtd VD No difference 1. Cavo M et al. Lancet. 2010;379: Cavo M et al. Blood. 2013;122. Abstract Updated data presented at ASH Rosiñol L et al. Blood. 2012;120: Moreau P et al. Blood. 2011;118:

31 Doublet vs Triplet Combinations: Evidence From Phase 3 Studies Number of Cycles Postinduction Response Post-ASCT Response Survival Induction VGPR VGPR PFS Regimen CR (%) (%) CR (%) (%) (months) OS (months) VTD 1, yr 75% TD yr 69% VTD yr 74% Triplet VTD combination showed superior outcomes over doublet regimen (TD or VD). TD yr 65% vtd Not reported VD Not reported 1. Cavo M et al. Lancet. 2010;379: Cavo M et al. Blood. 2013;122. Abstract Updated data presented at ASH Rosiñol L et al. Blood. 2012;120: Moreau P et al. Blood. 2011;118:5752. Meta-Analysis of Phase 3 Trials: Bortezomib-Based vs Nonbortezomib-Based Induction BTZ based n = 787 (VD, PAD, VTD) N = 1,572 Non-BTZ based n = 785 (VAD, TD) Outcome BTZ Based Non-BTZ Based P Value CR + ncr, % 23 8 <0.001 PFS, months < yr OS, % Bortezomib-based induction (VD, PAD, VTD) was superior to VAD or TD induction In general, safety profile was comparable between the groups Discontinuation due to AE was low in both groups (6% vs 5%) PN rates during induction were 19% vs 7% (grade 3: 3% vs 2%) for BTZ based vs non-btz based AE, adverse events; PN, peripheral neuropathy Sonneveld P et al. J Clin Oncol. 2013;31:

32 Induction Regimen Overview of Bortezomib- Lenalidomide Based Induction Number of Cycles Postinduction Response Post-ASCT Response CR (%) VGPR (%) CR (%) VGPR (%) VRD * Not reported VRD Not reported VRD *Best response 1. Richardson P et al. Blood. 2010;116: Kumar S et al. Blood. 2012;119: Roussel M et al. J Clin Oncol. 2014;32:2712. Overview of Bortezomib- Cyclophosphamide Based Induction Induction Regimen Number of Cycles CyBorD 1,2 4 Postinduction Response CR (%) 39 (+ ncr) *Response evaluated after four cycles VGPR (%) CR (%) 61 Post-ASCT Response 70 (+ ncr) VGPR (%) PFS (months) Survival OS (months) VCD (+ ncr) 36.6 Not reported Not reported VCD 4 6 3* 13* Not reported 1-yr 93% 1-yr 100% VCD-mod * 41* Not reported 1-yr 100% 1-yr 100% 1. Reeder C et al. Leukemia. 2009;23: Reeder CB et al. Br J Haematol. 2014;167: Einsele H et al. Blood. 2009;114. Abstract Kumar S et al. Blood. 2012;119:

33 Overview of Lenalidomide-Based Combinations for Induction Induction Regimen Number of Cycles CR (%) Response VGPR (%) PFS (months) Survival OS (months) Rd/RD /2.3 24/42 19/25 3-yr 92% BiRd yr 75% Carf-RD (+ ncr) mo 91% NA CRD NA NA 1. Rajkumar SV et al. Lancet Oncol. 2010;11: Rossi A et al. Blood. 2013;121: Korde N et al. Blood. 2013;122. Abstract Pawlyn C et al. Blood. 2013;122. Abstract 540. Updated data presented at ASH Four-Drug vs Triplet Combinations: Evidence From Phase 2 Trials Induction Regimen *Including ncr Number of Cycles Postinduction Response CR (%) VGPR (%) Post-ASCT Response CR (%) VGPR (%) PFS (months) Survival OS (months) VDCR NR NR 1-yr 86% 1-yr 92% VDR NR NR 1-yr 83% 1-yr 100% VDC NR NR 1-yr 93% 1-yr 100% VTD * 69 85* yr 80% VTDC 4 44* 69 77* yr 80% 1. Kumar S et al. Blood. 2012;119: Ludwig H et al. J Clin Oncol. 2013;31:

34 Four-Drug vs Triplet Combinations: Evidence From Phase 2 Trials Induction Regimen Number of Cycles Postinduction Response CR (%) VGPR (%) Post-ASCT Response CR (%) VGPR (%) PFS (months) Survival OS (months) VDCR NR NR 1-yr 86% 1-yr 92% VDR NR NR 1-yr 83% 1-yr 100% So far, current evidence does not show an additional VDC NR NR 1-yr 93% 1-yr 100% benefit of four-drug combinations over triplets. VTD * 66 85* yr 80% VTDC 4 44* 69 77* yr 80% *Including ncr 1. Kumar S et al. Blood. 2012;119: Ludwig H et al. J Clin Oncol. 2013;31:247. New Combination Regimens: Ixazomib 34

35 Phase 1/2 Ixazomib (MLN9708) + Lenalidomide + Dexamethasone (IRd) N = 64, IRd induction followed by ASCT (in eligible pts) and ixazomib maintenance Efficacy Median drug exposure: 6 cycles Estimated PFS probability at 1 year: 93% Safety Most common grade 3 AEs: rash, neutropenia, vomiting 43% of patients reported treatment-emergent PN Grade 1-2, 32%; grade 3-4, 6% 5 (8%) patients discontinued treatment due to AEs Patients (%) Response Rates ORR: 92% 27% 31% 34% Ird (n = 64) CR VGPR PR Kumar SK et al. Blood. 2012;120. Abstract 332. Kumar SK et al. Lancet Oncol. 2014;15:1503. Role of Post-ASCT Consolidation Therapy 35

36 CR: Do We Care? Newly diagnosed CR Stringent CR Disease burden Molecular/flow CR ?Cure? 0.0 Superior Outcomes for Patients Achieving scr After ASCT Compared to Those Achieving Less Than scr from Kapoor P, et al. J Clin Oncol. 2013;31:

37 Phase 3 VTD vs TD: Response Rates to ASCT and Consolidation Therapy After second ASCT (%) CR CR/nCR VTD (N = 160) TD (N = 161) P After consolidation therapy (%) CR CR/nCR Cavo M et al. Blood. 2012;120:9. Phase 3 VTD vs TD: PFS and OS After Consolidation Figure 2B and 2C, page 15 from Cavo M, et al. Blood. 2012;120:9. 37

38 Cox Regression Analysis of PFS From Start of Consolidation Therapy in Subgroups of Patients With Poor Prognosis Table 5, page 15 from Cavo M, et al. Blood. 2012;120:9. Phase 2 Study of RVD-ASCT-RVD Response Rates 100 ORR: 93% ORR: 93% ORR: 97% ORR: 100% 10% 80 23% 13% 27% 40% 48% 47% 50% 58% 60 35% 20% 10% 10% 40 23% 37% 26% 20 35% 0 23% 10% 16% Induction ASCT Consolidation Best Response MRD negative 16% 54% 58% 68% Patients (%) scr CR VGPR PR Depth of response continued to improve throughout treatment Lenalidomide maintenance improved response in 8 (27%) patients Overall, 68% of patients achieved MRD negativity 15 of the 26 patients who achieved at least VGPR were MRD negative MRD, minimal residual disease assessed by flow cytometry Roussel M et al. J Clin Oncol. 2014;32:

39 Phase 2 Study of RVD-ASCT-RVD: Progression-Free Survival PFS in the ITT population according to MRD status Figure 1, page 2715 from Roussel M, et al. J Clin Oncol. 2014;32:2712. PFS in high-risk cytogenetic patients similar to ITT 3-yr PFS: 86% The 3-yr OS for ITT population was 100% ITT, intent to treat New Combination Regimens Extend Therapeutic Options: Carfilzomib 39

40 Phase 2 Trial of Carfilzomib- Thalidomide-Dexamethasone (KTd) N = 91, KTd induction followed by ASCT and KTd consolidation Efficacy ORR ( PR) after consolidation was 96% High-risk patients: ORR = 94% PFS and OS: not yet reached Safety Most common grade 3/4 AEs were gastrointestinal and haematological Peripheral neuropathy grade 3, 1%; grade 4, 0% Patients (%) ORR: 90% After Induction Response Rates ORR: 96% ORR: 96% After HDM After Consolidation CR VGPR PR Sonneveld P et al. Blood. 2014; November 14 [Epub ahead of print]. Phase 2 Trial of Carfilzomib- Lenalidomide-Dexamethasone (KRd) N = 31, KRd induction followed by ASCT and KRd consolidation + maintenance Efficacy ORR ( PR) after 4 cycles was 96% MRD-negative status was achieved in 86% of patients with ncr after consolidation After 6-month follow-up, 97% of patients were progression-free Safety Most common grade 3/4 AEs were haematological and hypophosphatemia Cardiac events (grade 1 3) were experienced by 13% of patients PN limited to grade 1/2 (37% during induction, 17% during consolidation) Patients (%) Response Rates ( VGPR) 64% 92% 100% After Induction (n = 23) After HDM (n = 12) After Consolidation (n = 9) scr/cr ncr VGPR Zimmerman TM et al. Haematologica. 2014;99. Abstract P

41 Consolidation: Overview of Evidence From Phase 2/3 Studies Figure 2, page 498 from McCarthy PL, Hahn T. Hematology Am Soc Hematol Educ Program. 2013;2013:496. McCarthy PL, Hahn T. Hematology Am Soc Hematol Educ Program. 2013;2013:496. Importance of Achieving MRD Negativity After Autologous Transplantation 41

42 Impact of MRD Detection by Flow Cytometry on Clinical Outcomes After High-Dose TX and ASCT Figures 1C and 1D, page 4020 from Paiva B, et al. Blood. 2008;112:4017. Outcomes After ASCT According to MRD Levels by Deep Sequencing Figure 1A, page 3076 from Martinez-Lopez J, et al. Blood. 2014;123:3073. Figure 1B, page 3076 from Martinez-Lopez J, et al. Blood. 2014;123:3073. Figure 2A, page 3076 from Martinez-Lopez J, et al. Blood. 2014;123:3073. Figure 2B, page 3076 from Martinez-Lopez J, et al. Blood. 2014;123:

43 Combining Immunophenotypic CR With Cytogenetics for Predicting the Risk of Relapse for Patients in CR After ASCT Figure 1C, page 688 from Paiva B, et al. Blood. 2012;119:687. Figure 1D, page 688 from Paiva B, et al. Blood. 2012;119:687. Conclusions Achieving maximal response pretransplantation is an early predictor of improved outcomes after ASCT Induction therapy with triplet novel agent based induction regimens can contribute to improved outcomes ASCT is complementary with novel agents and can increase the overall rate of CR 10% to 20% New combinations (eg, with carfilzomib and ixazomib) show promising results Although not yet a standard, posttransplant consolidation seems beneficial to clinical outcomes, particularly for high-risk patients MRD negativity should be the new endpoint of current treatment strategies 43

44 Panel Discussion Community Case: Patient Receiving Maintenance Therapy Jesus Berdeja, MD 44

45 Post ASCT: D100 Visit Patient is doing well, feeling stronger CBC CMP SFLC WBC Hb Platelets Creatinine Ca Albumin LDH SPEP/IFE 24h UPEP/IFE SFκLC SFλLC 3.2 K/μL 11.0 g/dl 130 K/μL 0.8 mg/dl 9.0 mg/dl 3.5 g/dl 200 U/L 0 g/dl abnormal protein, negative for monoclonal protein 0 mg/24 h abnormal protein, negative for monoclonal protein 4 mg/l 30 mg/l Ratio 0.13 ( ) Skeletal survey No new abnormalities detected Bone marrow biopsy Normocellular bone marrow (40%); no morphologic evidence of abnormal plasma cells; cytogenetics 46,XX[20] Patient is in a complete remission (CR). Question Do you recommend maintenance? A. Yes B. No C. Not sure 45

46 Question Which maintenance treatment do you recommend? A. Lenalidomide B. Bortezomib C. Lenalidomide, bortezomib D. Thalidomide E. Prednisone F. Clinical trial G. I don t use maintenance Question Would your maintenance choice change if the patient had low-risk cytogenetics? A. Yes B. No C. Not sure 46

47 Maintenance Treatment The patient is initiated on lenalidomide 10 mg PO daily Over the next 6 months the patient s CBC repeatedly shows ANCs in the range, platelet counts range Lenalidomide is reduced to 5 mg PO daily Maintenance Treatment Continued 1 year post ASCT the patient restaging studies show: CBC SFLC WBC ANC Hb Platelets SPEP/IFE 24h UPEP/IFE 1.8 K/μL 700 K/μL 9.6 g/dl 90 K/ L 0 g/dl abnormal protein, negative for monoclonal proteins 0 mg/24 h abnormal protein, negative for monoclonal proteins SFκLC 4 mg/l SFλLC 5 mg/l Ratio 0.8 ( ) Skeletal survey No new abnormalities detected Bone marrow biopsy Hypocellular bone marrow (20%); normal trilineage hematopoiesis; no morphologic evidence of abnormal plasma cells; cytogenetics 46,XX[20] The patient is now in a stringent complete remission (scr). 47

48 Question What do you do regarding maintenance? A. Continue lenalidomide B. Switch to a different agent such as bortezomib C. Stop maintenance and observe D. Clinical trial E. I don t use maintenance therapy Maintenance Case, continued Based on the continued cytopenias lenalidomide is stopped Patient is started on bortezomib 1.3 mg IV every other week 4 months later the patient reports worsening neuropathies in her hands and feet Bortezomib is switched from IV to SQ with improvement of symptoms Unfortunately, over the next 6 months, the patient misses several appointments for bortezomib treatment; she is having difficulty finding transportation for her visits and is asking about taking a break from therapy 48

49 Balancing Maximum Benefit with Quality in Life Donna E. Reece, MD Director, Program for Multiple Myeloma and Related Disorders Professor of Medicine Department of Medical Oncology Princess Margaret Cancer Centre University Health Network Toronto, Ontario, Canada Disclosures Consultant/Advisor: Amgen, Celgene, Janssen, Johnson & Johnson, Onyx Research Grant: Bristol-Myers Squibb, Celgene, Janssen, Johnson & Johnson, Merck, Millennium, Novartis, Otsuka 49

50 Case Study Considerations 60-year-old woman with ISS stage 2 myeloma and t(4;14) in CR after bortezomib-based induction and ASCT What can we expect from her therapy so far? What can we expect from lenalidomide maintenance? ISS, International Staging System; CR, complete remission; ASCT, autologous stem cell transplant Case Study Prognosis of t(4;14) myeloma patients treated with bortezomib-based induction therapy and ASCT Results of phase 3 trials with patients randomized at diagnosis # ASCT Consolidation Maintenance PFS OS Study N Induction Avet-Loiseau/ BD 1 or 2 Sonneveld/ PAD 1 or 2 Bortezomib X 2 yrs Cavo/ VTD 2 VTD Dexamethasone 28 mos 25.3 mos 69% (3yr) 63% (4 yrs) 66% (3 yrs) Avet-Loiseau H et al. J Clin Oncol. 2010;28: Sonneveld P,et al. J Clin Oncol. 2012;30:2946. Cavo M et al. Lancet. 2010;376:

51 Case Study Lenalidomide maintenance after ASCT Patients with t(4;14) randomized post-asct in IFM trial Study N Induction Avet-Loiseau/ VAD or BD # ASCT Consolidation Maintenance PFS OS 1 or 2 Len Len 27 NA Len Placebo 15 NA This patient is similar to those randomized to LEN post- ASCT (although consolidation with LEN not given) She has not experienced severe ASCT toxicity or early relapse Available data suggest lenalidomide maintenance is reasonable Long-term suppressive therapy with bortezomib is also reasonable, although optimal duration uncertain Avet-Loiseau H et al. Presented at: ASH 52nd Annual Meeting; December 2010; Orlando, Florida. Abstract Background There has been increasing acceptance that continuous or long-term therapy is efficacious in myeloma However, the anti-myeloma benefits of continuous therapy must be balanced with the toxicities of prolonged treatment 51

52 Aims Discuss biological considerations of continuous therapy Highlight evidence from phase 3 trials evaluating continuous treatment as part of first-line therapy Transplant-eligible patients Transplant-ineligible patients Review incidence and management of toxicity of continuous therapy Continuous Therapy in Myeloma Concerns-1 Myeloma is not one disease 1 At least 7 subtypes based on cytogenetic and molecular features Highest risk cytogenetic subtypes by FISH t(4;14) del 17p t(14;16) Abnormalities of chromosome 1 Likely that not all patients require continuous therapy Clonal tiding 2 Progression is not a linear process 2 Concern about driving resistant clone(s) with low-dose singleagent maintenance Figure 4, page 1073 from Keats JJ, et al. Blood. 2012; 120: Bergsagel PL, Chesi M. Hematol Oncol. 2013;31(Suppl 1): Keats JJ et al. Blood. 2012;120:

53 Continuous Therapy in Myeloma Concerns-2 Effects on immune system Effects on hematopoiesis/marrow microenvironment Potential effects on mechanisms of drug resistance Toxicity 1 Early (fatigue, GI toxicity, myelosuppression, peripheral neuropathy, VTE, diarrhea, others) Late (secondary primary malignancy, decreased marrow reserve) GI, gastrointestinal; VTE, venous thromboembolism 1. Ludwig H et al. Blood. 2012;119:3003. Post-ASCT Maintenance 53

54 Post-ASCT Maintenance Therapy Phase 3 Trials Thalidomide: 7 trials 1-7 Bortezomib: 3 trials 8-10 HOVON MM 65/GMMG-HD4 ( 24 months) Nordic Myeloma Study Group trial ( 7 months) PETHEMA/GEM (with thalidomide) ( 36 months) Lenalidomide: 3 trials IFM : lenalidomide consolidation in all followed by lenalidomide vs placebo CALBG trial: lenalidomide vs placebo RV-MM-PI: lenalidomide vs observation* *Includes a non-asct arm 1. Attal M et al. Blood. 2006;108; Spencer A et al. J Clin Oncol. 2009;27: Barlogie B et al. N Engl J Med. 2006;354: Lokhorst HM et al. Blood. 2010;115: Morgan GJ et al. Blood. 2012;119:7. 6. Maiolino A et al. Am J Hematol. 2012;87: Stewart AK et al. Blood. 2013;121: Sonneveld P et al. J Clin Oncol. 2012;30: Mellqvist U-H et al. Blood. 2013;121: Rosinol L et al. Blood. 2012;120. Abstract Attal M et al. N Engl J Med. 2012;366: McCarthy PL et al. N Engl J Med. 2012;366: Palumbo A et al. N Engl J Med. 2014;371:895. Thalidomide Maintenance After SCT Author/Year N Attal Spencer Thalidomide dose (mg)/duration Thal 200 (median dose) vs obs/progression Thal pred vs pred/12 months PFS/ EFS Maiolino Thal dex vs dex/12 months Barlogie 4 * 668 Thal 100/progression + Overall Survival NS NS (+ in high-risk) Lokhorst 5 * 556 Thal 50/ progression + NS Stewart Thal pred vs obs/48 months Morgan 7 * 820 Thal 100/progression + *Thalidomide also given as part of induction therapy + NS + (if optimal relapse Rx) 1. Attal M et al. Blood. 2006;108; Spencer A et al. J Clin Oncol. 2009;27: Maiolino A et al. Am J Hematol. 2012;87: Barlogie B et al. N Engl J Med. 2006;354: Lokhorst HM et al. Blood. 2010;115: Stewart AK et al. Blood. 2013;121: Morgan GJ et al. Blood. 2012;119:7. 54

55 PFS Study Attal Barlogie Spencer Ludwig MRC-My-IX NCIC MY.10 Total (95% CI) Thalidomide Maintenance Post-ASCT Meta-Analysis Maintenance N ,186 Control N ,509 Hazard Ratio (fixed) 95% CI Hazard Ratio (fixed) 95% CI 0.69 [0.54, 0.88] 0.70 [0.57, 0.86] 0.50 [0.35, 0.71] 0.55 [0.36, 0.85] 0.73 [0.62, 0.87] 0.56 [0.43, 0.73] 0.66 [0.60, 0.73] OS Study Maintenance N Control N Hazard Ratio (fixed) 95% CI Hazard Ratio (fixed) 95% CI Attal Barlogie Spencer Ludwig NCIC MY.10 Total (95% CI) , [0.37, 0.93] 0.81 [0.64, 1.03] 0.41 [0.22, 0.76] 0.93 [0.53, 1.65] 0.77 [0.53, 1.12] 0.74 [0.63, 0.88] Favors treatment Favors control Nooka AK et al. Blood. 2011;118. Abstract Results of Canadian MY-10 Trial Figure 2A, page 1520 from Stewart AK, et al. Blood. 2103; 121:1517. Figure 2B, page 1520 from Stewart AK, et al. Blood. 2103; 121:

56 Post-ASCT Bortezomib Therapy Study/ Year Time Randomized N Bortezomib Regimen Control Arm Median PFS (mos) Median OS (mos) Sonneveld At diagnosis mg/m 2 Q 2 wks 2 yrs BTZ Thal 35* 28 61%* vs 55% at 5 yrs Mellqvist Post- ASCT mg/m 2 20 doses (7 mos) BTZ None 27* 20 NS (75 80% at 3 yrs) Rosinol Post- ASCT mg/m 2 D 1,4,8,11 q 3 mo + thal 100 mg/d 3 yrs VT Thal IFN ~43* ~36 ~24 NS *Statistically significant 1. Sonneveld P et al. J Clin Oncol. 2012;30: Mellqvist U-H et al. Blood. 2013;121: Rosinol L et al. Blood. 2012;120. Abstract 334. Summary of Phase 3 Trials Lenalidomide Maintenance vs Placebo After ASCT Author/ Study Attal 1 (IFM ) McCarthy 2 (CALBG ) N Pre-ASCT Induction VAD or BD LEN 35% BTZ 41% THAL 45% # ASCT 1 or 2 Consolidation LEN 25 mg 2 mos in all 1 PFS/TTP Median (months) LEN 41* Observation 23 LEN 46* Observation 27 OS (%) 73% 75% (4-year) 88%* 80% (3 year) *Statistically significant 1. Attal M et al. N Engl J Med. 2012;366: McCarthy PL et al. N Engl J Med. 2012;366:

57 Patients (%) N at risk Lenalidomide Placebo Lenalidomide Maintenance Effect on PFS/TTP: Updated P<0.001 IMF Median PFS Placebo 24 months Lenalidomide 46 months Lenalidomide Placebo Months of follow-up Median follow-up 67 mos CALGB Estimated HR = 0.51 (95% CI = ) Median TTP 50 vs 27 months (P<0.01) Lenalidomide Placebo 146 events on placebo 104 events on lenalidomide Time Since AHCT (Months) Median follow-up ~48 mos. 1. Attal M et al. Blood. 2013;122. Abstract McCarthy PL et al. Presented at: 14th IMW; April 2013; Kyoto, Japan. Abstract S28. Patients Alive (%) N at risk Lenalidomide Placebo Lenalidomide Maintenance Effect on Overall Survival P=0.80 IMF Median OS Placebo 18 months Lenalidomide 82 months Lenalidomide Placebo Months of follow-up Median follow-up 67 mos. P= CALGB Estimated HR = 0.61 (95% CI = ) Lenalidomide Placebo Median OS NYR vs 73 months (P=0.008) 69/229 (30%) deaths on placebo 47/231 (20%) deaths on lenalidomide Time Since AHCT (Months) Median follow-up ~48 mos. P= Attal M et al. Blood. 2013;122. Abstract McCarthy PL et al. Presented at: 14th IMW; April 2013; Kyoto, Japan. Abstract S28. 57

58 Significant Toxicities With LEN Maintenance in Phase 3 Trials Toxicity (Grade 3/4) IMF ,2 CALGB 3,4 LEN Placebo LEN Placebo Neutropenia 43% 14% 43% 9% Thrombocytopenia 12% 6% 13% 4% Febrile neutropenia 2% 0.1% 6% 2% Documented infection 10% 4% 16% 5% DC lenalidomide 6% 4% 13% 2% 2 malignancy N=37 (13%) N = 21 (7%) N = 26 (11.3%) N = 9 (3.9%) 1. Attal M et al. N Engl J Med. 2012;366: Attal M et al. Blood. 2013;122. Abstract McCarthy PL et al. N Engl J Med. 2012;366: McCarthy PL et al. Presented at: 14th IMW; April 2013; Kyoto, Japan. Abstract S28. RV-MM-PI209 ASCT vs MPR +/- LEN Maintenance Rd 4 months (lenalidomide + low-dose DEX) Randomize Melphalan 200 mg/m 2 + ASCT 2 MPR 6 months (melphalan + lenalidomide + prednisone) Randomize Lenalidomide maintenance No maintenance Palumbo A et al. N Engl J Med. 2014;371:

59 RV-MM-PI209 ASCT vs MPR ± LEN Maintenance Figure 2A, page 900 from Palumbo A, et al. N Engl J Med. 2014; 371:895. Significant Toxicities With LEN Maintenance in Phase 3 Trials Toxicity (Grade 3/4) LEN 5 15 mg/day 1-4 LEN 10 mg days 1 21 [5] IFM CALGB LEN OBS Neutropenia 43% 43% 23.3% 0% Thrombocytopenia 12% 13% 4.3% 0% Febrile neutropenia 2% 6% Documented infection 10% 16% 6% 1.7% DC lenalidomide 6% 13% 5.2% 2 malignancy N = 37 (13%) N = 26 (11.3%) N = 5 (4.3%) N = 5 (4.3%) 1. Attal M et al. N Engl J Med. 2012;366: Attal M et al. Blood. 2013;122. Abstract McCarthy PL et al. N Engl J Med. 2012;366: McCarthy PL et al. Presented at: 14th IMW; April 2013; Kyoto, Japan. Abstract S Palumbo A et al. N Engl J Med. 2014;371:

60 Postinduction Maintenance Transplant-Ineligible Patients Postinduction Maintenance Therapy Phase 3 Trials in Elderly Patients Thalidomide: 5 trials 1-6 MP vs MPT + T (3 trials) MP or THAL/DEX IFN vs IFN + T MP or CTD observation or T Bortezomib: 2 trials 7,8 GEM2005 (VMP or VTP induction VT vs VP 3 years) GIMEMA (VMP vs VMPT VT 2 years) Lenalidomide: 3 trials 9-11 MM015 (MP vs MPR vs MPR R) MM020 (MPT vs LEN/DEX for 18 months vs LEN/DEX until prog) RV-MM-PI209 nontransplant arm (Rd MPR R vs observation) MP thalidomide vs lenalidomide 12 MPT T vs MPR R (ECOG E1A06) 1. Palumbo A et al. Lancet. 2006;367: Palumbo A et al. Blood. 2008;112: Wijermans P et al. J Clin Oncol. 2010;28: Waage A et al. Blood. 2010;116: Ludwig H et al. Haematologica. 2010;95: Morgan GJ et al. Blood. 2012;119:7. 7. Mateos MV et al. Blood. 2014;124: Palumbo A et al. J Clin Oncol. 2010;28: Palumbo A et al. N Engl J Med. 2012;366: Benboubker L et al. N Engl J Med. 2014;371:906. Palumbo A et al. N Engl J Med. 2014;371: Stewart AK et al. J Clin Oncol. 2014;32. Abstract

61 Thalidomide Maintenance in Elderly Myeloma Patients Author/Year Induction Therapy Thalidomide daily dose (mg) PFS/ EFS Palumbo/2006, ,2 MPT Thal NS Wijermans/ MPT Thal OS Waage/ MPT Thal NS Ludwig/ MP or Thal/Dex Thal α-ifn + NS Morgan/ MP or CTD Thal Palumbo A et al. Lancet. 2006;367: Palumbo A et al. Blood. 2008;112: Wijermans P et al. J Clin Oncol. 2010;28: Waage A et al. Blood. 2010;116: Ludwig H et al. Haematologica. 2010;95: Morgan GJ et al. Blood. 2012;119:7. Continuous Therapy With Bortezomib in Elderly Myeloma Patients Study Regimen Overall Response rate (CR) (%) Median PFS/EFS (months) Median OS (months) Palumbo 1,2 (GIMEMA) VMP VMPT+ VT 81 (24) 90* (38) 24.8* year 51% 5-year 61%* Mateos 3,4 (GEM2005) VMP + VT VMP + VP VTP + VT VTP + VP 80 (20) 81 (28) 32* 23 63* 43 *Statistically significant 1. Palumbo A et al. J Clin Oncol. 2010;28: Palumbo A et al. J Clin Oncol. 2014;32: Mateos MV et al. J Clin Oncol. 2010;28: Mateos MV et al. Blood. 2014;124:

62 Continuous Therapy With Lenalidomide in Elderly Myeloma Patients: PFS Figure 2A, page 1765 from Palumbo A, et al. N Engl J Med. 2012; 366:1759. Figure 1A, page 912 from Benboubker L, et al. N Engl J Med. 2014;371:906. RV-MM-PI209 ASCT vs MPR +/- LEN Maintenance Rd 4 months (lenalidomide + low-dose DEX) Randomize Melphalan 200 mg/m 2 + ASCT 2 MPR 6 months (melphalan + lenalidomide + prednisone) Randomize Lenalidomide maintenance No maintenance Palumbo A et al. N Engl J Med. 2014;371:

63 RV-MM-PI209 ASCT vs MPR ± LEN Maintenance Figure 2A, page 900 from Palumbo A, et al. N Engl J Med. 2014; 371:895. Meta-Analyses of Continuous Therapy Meta-analysis of four LEN maintenance trials 1 Post-ASCT: IFM and CALGB studies 2,3 Non-ASCT: MM-015 trial of MP vs MPR vs MPR-R 4 RV-MM-PI205 5 Meta-analysis of continuous therapy (n = 1,218) 4-7 Includes LEN and BTZ maintenance studies Mostly non-asct patients 1. Singh P et al. Blood. 2013;122. Abstract Attal M et al. N Engl J Med. 2012;366: McCarthy PL et al. N Engl J Med. 2012;366: Palumbo A et al. N Engl J Med. 2012;366: Gay F et al. Blood. 2013;122. Abstract Palumbo A et al. J Clin Oncol. 2014;32: Palumbo A et al. N Engl J Med. 2014;371:

64 Meta-Analysis of Lenalidomide Maintenance From abstract Singh P, et al. Blood. 2013;122. Abstract 407. Continuous vs Fixed Duration Therapy 1-Year Landmark Analysis Inductionconsolidation Maintenance PFS1 N = 687 2nd PFS N = 1,218 PFS2 Overall survival Palumbo A et al. J Clin Oncol. 2014;32. Abstract

65 Conclusion From Meta-Analysis Continuous N = 1,218 Therapy 1-year landmark analysis Fixed Duration of Therapy P value Median PFS1 32 months 16 months <0.001 Median PFS2 55 months 40 months < year OS 69% 60% N = 687 Median second PFS Continuous Therapy Fixed Duration of Therapy P value 15 months 15 months Palumbo A et al. J Clin Oncol. 2014;32. Abstract Common Toxicities With Lenalidomide Maintenance Overall Incidence Toxicity (Grades 3 4) (%) Fatigue 47 (5 6) Diarrhea 40 (2 5) Dizziness 22 (0) Rash 20 (3 4) Thrombosis (VTE/PE) 1 7 (1 2) Muscle spasms 39 (1) Attal M et al. N Engl J Med. 2012;366:1782. McCarthy PL et al. N Engl J Med. 2012;366:

66 Management of Common Toxicities With Lenalidomide Maintenance Fatigue QHS dosing (?) Dose reduction Diarrhea Antidiarrheal agents Bile salt binders/low-fat diet (eg, colesevelam, cholestyramine)* Rash Topical steroids/oral antihistamines Hold/reduce dose Thrombosis (VTE/PE) Prophylaxis not essential for single agent in absence of prior thrombotic event Some recommend ASA anyway Muscle spasms Quinine sulfate 300 mg qhs Clonazepam in severe cases Reece D et al. Adv Hematol. 2012;2012: *Pawlyn C et al. Blood. 2014;124:2467. Minimizing Toxicity of Bortezomib Peripheral neuropathy Weekly dosing 1 Subcutaneous administration 2 Diarrhea 3 Ondansetron premedication Antidiarrheal agents Subcutaneous administration Infection Antizoster prophylaxis with acyclovir or related antiviral agent Figure 2, page 4749 from Bringhen S, et al. Blood. 2010; 116: Bringhen S et al. Blood. 2010;116: Moreau P et al. Lancet Oncol. 2011;12: Velcade [borezomib]. Package Insert. 66

67 Summary/Conclusions Continuous therapy emerging as important strategy for improving PFS and likely survival Further studies are needed Determine prospectively which patients do not need such therapy Monitor minimal residual disease to optimize the therapeutic regimen/duration Management of side effects key to ensuring good QoL Choice of agents/regimens Example: LEN better tolerated than thalidomide 1 Dose adjustments Symptom management Monitoring incidence/risk factors for late toxicity important Secondary primary malignancy Example: concomitant MEL and LEN increases risk 2 1. Stewart AK et al. J Clin Oncol. 2014;32. Abstract Palumbo A et al. Lancet Oncol. 2014;15:333. Community Case: Treatment Options When Patients Relapse Jesus Berdeja, MD 67

68 Case, continued 2 years later the patient reports new-onset back pain worsening over the last 2 weeks Neurological examination is intact Plain films of LS spine reveal a new compression fracture at L4 MM evaluation now CBC CMP SFLC WBC 3.2 K/μL Hb 9.8 g/dl Platelets 120 K/μL Creatinine 1.5 mg/dl Ca 10.8 mg/dl Albumin 3.0 g/dl SPEP/IFE 1.4 g/dl abnormal protein corresponding to IgGλ monoclonal protein IgA 40 mg/dl IgG 2,100 mg/dl IgM 30 mg/dl 24h UPEP/IFE 320 mg/24h abnormal protein, λ light chains SFκLC 5 mg/l SFλLC 110 mg/l Ratio 0.04 ( ) Skeletal survey Diffuse osteopenia, scattered small lytic lesions throughout skull, bilateral humeri, compression fracture L4 Bone marrow biopsy Normocellular bone marrow (40%); 30% replaced by plasma cells expressing CD38, CD56 and λ-restricted; cytogenetics 46,XX[20] FGFR3/IGH fusion signal pattern consistent with t(4;14) 68

69 Question What would you use for treatment of MM in first relapse? A. Bortezomib + dexamethasone ± cyclophosphamide B. Lenalidomide + dexamethasone C. Bortezomib, lenalidomide, and dexamethasone D. Carfilzomib + dexamethasone E. Pomalidomide + dexamethasone F. Clinical trial G. Other 2015 v2 NCCN Treatment Options for Relapsed Multiple Myeloma Repeat primary induction (if relapse >6 months) Category 1 BTZ BTZ/liposomal dox LEN/DEX Category 2A BTZ/DEX BTZ/LEN/DEX BTZ/Thal/DEX Thal/DEX Cy/BTZ/DEX Cy/LEN/DEX Bendamustine DCEP DT-PACE ± BTX Carfilzomib Pomalidomide/DEX High-dose Cy The NCCN Clinical Practice Guidelines in Oncology Multiple Myeloma (Version ) National Comprehensive Cancer Network, Inc. Available at: Accessed November 21,

70 Treatment at First Relapse The patient undergoes treatment with RVD (lenalidomide, bortezomib, dexamethasone) 4 cycles achieving a VGPR Treatment tolerated reasonably well but peripheral neuropathy worsens to grade 2 and bortezomib is stopped Lenalidomide, dexamethasone is continued Case, continued Prior to cycle 6 LEN/DEX restaging studies now show: SPEP 0.8 g/dl Repeat studies and bone marrow biopsy 1 week later: CBC CMP SFLC WBC 3.0 K/μL Hb 9.2 g/dl Platelets 80 K/μL Creatinine 1.8 mg/dl Ca 10.2 mg/dl Albumin 2.8 g/dl SPEP/IFE 1.1 g/dl abnormal protein corresponding to IgGλ monoclonal protein IgA 30 mg/dl IgG 1,900 mg/dl IgM 30 mg/dl 24h UPEP/IFE 600 mg/24 h abnormal protein, λ light chains SFκLC 5 mg/l SFλLC 180 mg/l Ratio 0.03 ( ) Skeletal survey Diffuse osteopenia, scattered small lytic lesions throughout skull, bilateral humeri, compression fracture L4, unchanged Bone marrow Hypocellular bone marrow (30%); 60% replaced by biopsy plasma cells expressing CD38, CD56 and -restricted 70

71 Question What would you recommend next? A. Bortezomib, liposomal doxorubicin B. Carfilzomib +/- dexamethasone C. Pomalidomide, dexamethasone D. Clinical trial E. other Question If a clinical trial is available for this patient, which investigational agent would you choose? A. Oral proteasome inhibitor B. Histone deacetylase inhibitor C. Monoclonal antibody to cell surface protein D. Kinesin spindle protein inhibitor 71

72 Treatment of Relapsed/Refractory MM You proceed with carfilzomib 20 mg/m 2 IV D1 and D2 and increase to 27 mg/m 2 for subsequent doses After four cycles your patient is in a partial remission (PR) She is tolerating treatment well but has missed a few appointments over the last 2 cycles, unable to find transportation for the twice-weekly clinic visits Clinical Considerations for Treatment Selection in Relapsed/Refractory Disease Ravi Vij, MD Associate Professor of Medicine Division of Medical Oncology, Section of Bone Marrow Transplantation and Leukemia Washington University School of Medicine St. Louis, Missouri 72

73 Disclosures Consultant/Advisor: Bristol-Myers Squibb, Celgene, Lilly, Onyx Research Grant: Celgene, Onyx Speakers Bureau: Celgene, Millennium, Onyx Key Points From Patient Case Relapsed MM t(4;14) patient in PR Previous treatment consisted of RVD 4 VGPR (G1 PN) ASCT in first remission CR LEN maintenance (dose-reduced due to neutropenia) scr 1 yr post ASCT but problems with cytopenias IV bortezomib Worsening neuropathy (within 4 mos) switched to SC; patient noncompliant with therapy due to transportation issues Relapsed 2 yrs post-asct RVD 4 VGPR (G2 PN), BTZ stopped LEN/DEX 5 Disease progression Carfilzomib PR but again noncompliant due to transportation issues 73

74 When to Consider Retreatment? Biochemical relapse Patients with asymptomatic rise in M protein can be observed 1 Caveat: patients with known aggressive or high-risk disease should be considered for salvage, even in the setting of biochemical relapse 2? a significant paraprotein relapse (defined as doubling of the M component in two consecutive measurements separated by 2 months or an increase in the absolute levels of serum M protein by 1 g/dl) 2 Clinical relapse Based on direct indicators of increasing disease and/or endorgan dysfunction 3 1. Lonial S. Hematology Am Soc Hematol Educ Program. 2010; Rajkumar SV et al. Blood. 2011;117: Durie BM et al. Leukemia. 2006;20:1467. Factors in Selecting Salvage Therapy DISEASE-RELATED DOR to initial therapy FISH/cytogenetics REGIMEN-RELATED Prior drug exposure Toxicity of regimen Mode of administration Previous SCT PATIENT-RELATED Pre-existing toxicity Comorbidities Age Performance status DOR, duration of response; FISH, fluorescent in situ hybridization; SCT, stem cell transplant Lonial S. Hematology Am Soc Hematol Educ Program. 2010;

75 Carfilzomib Monotherapy in Heavily Pretreated MM Patients, Phase 2b MM: Progressive disease 2 prior therapies for relapsed disease including bortezomib, thalidomide or lenalidomide, an alkylating agent, or an anthracycline alone or in combination 003-A A1 2 Carfilzomib 20 mg/m 2 days 1, 2, 8, 9, 15, 16 every 28 days (N = 46) Carfilzomib Dose escalation to 27 mg/m 2 after cycle 1 up to 12 cycles (N = 266) Primary end points: ORR ( partial response) Secondary end points: clinical benefit response rate ( minimal response), DOR, PFS, OS, safety ORR, overall response rate; PFS, progression-free survival; OS, overall survival 1. Jagannath S et al. Clin Lymphoma Myeloma Leuk. 2012;12: Siegel DS et al. Blood. 2012;120:2817. Carfilzomib in Relapsed/Refractory MM 003-A1 Single-Arm Pivotal Study (N = 266) Progressive disease required (>2 lines of therapy) Median 5.4 years from diagnosis (range, ) 99.6% prior bortezomib 88% refractory or intolerant to bortezomib Patients (%) % 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 12% G3/4 0.8% Responses not affected by prior treatment or cytogenetics. DCR, disease control rate; CBR, clinical benefit rate; CR, complete response; VGPR, very good partial response; PR, partial response; MR, minor response; SD, stable disease; PD, progressive disease Siegel DS et al. Blood. 2012;120:

76 Carfilzomib in MM Patients Following 1 3 Prior Therapies 004, Phase 2 Relapsed/refractory MM 1 3 prior therapies (N = 164) Carfilzomib 1:1 Cohort 1 20 mg/m 2 (all treatment cycles) Carfilzomib Cohort 2 20 mg/m 2 (cycle 1) 27 mg/m 2 Bortezomib-treated (n = 35) Bortezomib-naïve (n = 59) Bortezomib-naïve (n = 70) Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles Bortezomib-naïve 1 Bortezomib-treated 2 N Median age 65 years 63 years Median # prior therapies Vij R et al. Blood. 2012; 119: Vij R et al. Br J Haematol. 2012;158:739. Carfilzomib Monotherapy MM Patients With 1 3 Prior Therapies Carfilzomib Cohort 1 (20 mg/m 2 ) Bortezomib-naive 1 Cohort 2 (20 27 mg/m 2 ) *Calculated for ORR patients Precise estimate not determined since 4/6 patients with responses had DOR censored at study close Bortezomibtreated 2 Cohort 1 (20 mg/m 2 ) N ORR (%) CBR (%) CR VGPR Median TTP (mos) 8.3 NR 4.6 Median DOR (mos) 13.1* NR >10.6 Median PFS (mos) 8.2 NR 4.6 TTP, time to progression; NR, not reached 1. Vij R et al. Blood. 2012; 119: Vij R et al. Br J Haematol. 2012;158:

77 Carfilzomib/Lenalidomide/ Dexamethasone In patients with relapsed or progressive MM and 1 3 previous therapies (25.0% refractory to bortezomib and 44.2% refractory to lenalidomide) ORR: 76.9% Median time to response: 0.95 mos Median DOR: 22.1 mos Response rates in bortezomib- and lenalidomide-refractory patients: ~70% AEs Carfilzomib/lenalidomide/dexamethasone well tolerated overall >94% experienced grade 3/4 AEs, mostly hematologic Consistent with results of other triplet combinations in this setting AE, adverse event Wang M et al. Blood. 2013;122:3122. Dose Escalation of Carfilzomib CFZ 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 + DEX 8 mg premedication (28-day cycle) Cycle 1 (days 1 and 2): 20 mg/m 2 followed by escalation to 56 mg/m 2 77% BTZ-refractory; 22% prior auto- and allo-hsct Results ORR (per protocol*, n = 35): 51% (1 CR, 8 VGPR, 9 PR) ORR (all evaluable, n = 42): 55% (1 CR, 9 VGPR, 13 PR) Median PFS: 4.1 months Median OS: 20.3 months (median follow-up 9.6 months) 39% patients required a dose reduction *After four cycles or whose disease progressed prior to completion of four cycles (primary end point in per-protocol population) HSCT, hematopoietic stem cell transplantation; ITT, intent-to-treat Lendvai N et al. Blood. 2014;124:

78 Dose Escalation of Carfilzomib CFZ 30-minute IV infusion on days 1, 2, 8, 9, 15, and 16 Cycle 1 (days 1 and 2): 20 mg/m 2 escalation to 45 or 56 mg/m 2 DEX 20 mg prior to CFZ on days 1, 2, 8, 9, 15, and 16 DEX 40 mg administered on day 22 Median four lines prior treatment; 96% patients prior to BTZ Results (in patients completing at least two cycles); n = 20 ORR: 55% (VGPR: n = 2; PR: n = 9); SD: n = 6; PD: n = 3 Discontinued due to PD: N = 6 (45 mg/m 2 ) Discontinued due to SAE: N = 1 (56 mg/m 2 ) SAE, severe adverse event Badros AZ et al. Blood. 2012;120. Abstract A Phase 1, Dose-Escalation Study (Champion-1) Investigating Weekly CFZ in Combination With DEX for Patients With Relapsed or Refractory MM Cycles 1 8* D1 D8 D15 Week 1 Week 2 Week 3 Week 4 D1 D8 D15 D22 Carfilzomib, mg/m 2 IV, weekly Dexamethasone, 40 mg IV or PO, weekly Cohort Carfilzomib mg/m 2 Dexamethasone mg *During cycles 9 and beyond, dexamethasone was administered (IV/PO) on D1, D8, and D15. All patients received 20 mg/m 2 carfilzomib on D1 of cycle 1; subsequent doses were escalated to the indicated levels. Berenson JR et al. Blood. 2013;122. Abstract

79 Champion-1: Results 45 mg/ 2 56 mg/m 2 70 mg/m 2 88 mg/m 2 DLTs Expansion cohort DLT 1 G3 dyspnea (d 16 18) 2 G3 dyspnea (d 9-11) G3 vomiting (d 15) All MTD N ORR (%) CBR (%) Median tx duration (mo) Median time to response in pts with PR (mo) 1.0 (range, 0.7 to 1.9) MTD of weekly CFZ in combination with weekly DEX (40 mg) was 70 mg/m 2. DLT, dose-limiting toxicity; MTD, maximum tolerated dose Berenson JR et al. Blood. 2013;122. Abstract Phase 3 Studies ASPIRE 1 FOCUS 2 Multiple myeloma 1 3 prior therapies R 1:1 Relapsed/refractory multiple myeloma* R 1:1 Carfilzomib Lenalidomide Dexamethasone Lenalidomide Dexamethasone Carfilzomib Best supportive care Met primary end point KRd median 26.3 months vs Rd median 17.6 months (HR = 0.690, P<0.0001) R, randomization; KRd, carfilzomib-lenalidomide-low dose dexamethasone; Rd; lenalidomide-low dose dexamethasone; HR, hazard ratio Failed to meet primary end point* (Prior treatment must have included bortezomib, lenalidomide or thalidomide, alkylating agent, corticosteroids, and anthracycline) 1. Stewart AK et al. Blood. 2014;124. Abstract Ludwig H et al. Presented at: The European Society of Medical Oncology Madrid, Spain. Abstract LBA28. 79

80 Pomalidomide in Relapsed/Refractory Multiple Myeloma Phase Population N Treatment Median Prior Tx (Range) PR (%) 1 1 prior Tx 1 24 POM: 1, 2, 5, 10 mg 3 (1 6) prior Tx including LEN and BTZ* prior Tx including LEN and BTZ POM: 2, 3, 4, 5 mg DEX: 40 mg/week 6 (2 17) 21 POM: 4 mg ± DEX: 40 mg/week 5 (1 13) *Patients were refractory to last line of therapy. DEX added if patient experiences NR or PD after four cycles of POM. 33 (POM + LoDEX) 18 (POM) 2 LEN- and BTZ-resistant/refractory 4 84 POM: 4 mg DEX: 40 mg/week 5 (1 13) prior therapies 5 60 POM: 2 mg 2 (1 3) 63 2 LEN refractory 6 34 POM: 2 mg 4 (1 14) 32 BTZ/LEN refractory 7 35 POM: 2 mg 6 (3 9) POM: 4 mg 6 (2 11) 29 2 LEN refractory 1 3 prior therapies 8 60 POM: 4 mg 2 (1 5) 38 POM, pomalidomide; mo, month; NR, not reached 1. Schey SA et al. J Clin Oncol. 2004;22: Richardson PG et al. Blood. 2013;121: Richardson PG et al. Blood. 2014;123: Leleu X et al. Blood. 2013;121: Lacy MQ et al. J Clin Oncol. 2009;27: Lacy MQ et al. Leukemia. 2010;24: Lacy MQ et al. Blood. 2011;118: Lacy MQ et al. Blood. 2012;120. Abstract 653. MM-003 POM + LoDEX in RRMM Phase 3: Trial Design Primary end point: PFS Key secondary end points: OS, ORR ( PR), TTP, DOR, safety, QoL 28-day cycles RANDOMIZATION 2:1 (n = 302) POM: 4 mg D1 21 LoDEX: 40 mg ( 75 years) 20 mg (>75 years) D1, 8, 15, 22 HiDEX: (n = 153) 40 mg ( 75 years) 20 mg (>75 years) D1 4, 9 12, PD* or intolerable AE PD* Follow-up for OS and SPM until 5 years postenrollment Companion trial MM-003C POM 21/28 days Thromboprophylaxis was indicated for those receiving POM or with DVT history. *PD was independently adjudicated in real time. LoDEX, low-dose dexamethasone; RRMM, relapsed/refractory multiple myeloma; HiDEX, high-dose dexamethasone; SPM, secondary primary malignancy; DVT, deep vein thrombosis; QoL, quality of life San Miguel J et al. Lancet Oncol. 2013;14:

81 MM-003 POM + LoDEX in RRMM Phase 3: PFS, ITT Population* Figure 2A, page 1059 from San Miguel J, et al. Lancet Oncol. 2013;14:1055. MM-003 POM + LoDEX in RRMM Phase 3: OS, ITT Population Figure 3A, page 1060 from San Miguel J, et al. Lancet Oncol. 2013;14:

82 Other Pomalidomide Combinations Pts, n Median No. Prior Regimens Refractory to Recent Therapy (%) ORR (%) POM + BTZ + low-dose DEX (PVD) (1 4) POM + CFZ + DEX (2 15) NR 64 POM + cyclophosphamide + prednisone 3 69 POM + DEX + clarithromycin (1 3) NR ( 3) NR 41 NR Richardson PG et al. Blood. 2013;122. Abstract Shah JJ et al. Blood. 2013;122. Abstract Larocca A et al. Blood. 2013;122: Mark TM et al. Blood. 2011;118. Abstract 635. PANORAMA 1 Study Design Randomized, Double-Blind, Phase 3 Study in Relapsed or Relapsed and Refractory MM Patients (N = 768) Relapsed or relapsed/refractory MM (BTZ-ref excluded) 1 3 prior lines of therapy Stratification factors Prior lines of therapy Prior BTZ Treatment Phase 1 Eight 21-d cycles (24 wks) 1:1 PAN + BTZ + DEX Placebo + BTZ + DEX Treatment Phase 2 Four 42-d cycles (24 wks) 1:1 PAN + BTZ + DEX Placebo + BTZ + DEX Patients with clinical benefit* in Treatment Phase I can proceed to Treatment Phase 2 Follow-up *Achieving no change according to modified EBMT criteria (SD or better) Primary end point: PFS (per modified EBMT criteria; confirmed by IRC) 1,2 Key secondary end point: OS Other secondary end points: ORR, ncr/cr rate, DOR, TTR, TTP, QoL, and safety Study conducted at 215 centers across 34 countries. EBMT, Group for Blood and Marrow Transplantation; IRC, independent review committee 1. Blade J et al. Br J Haematol. 1998;102: Richardson PG et al. N Engl J Med. 2003;348:2609. Richardson PG et al. J Clin Oncol. 2014;32. Abstract

83 PANORAMA 1 Efficacy: Response ORR, (PR or better) [95% CI] CR/nCR rate [95% CI] Median DOR [95% CI] Median TTR [95% CI] Median TTP [95% CI] *Post-hoc analysis PAN-BTZ-Dex (n = 387) 60.7% [55.7, 65.6] 27.6% [23.2, 32.4] 13.1 mos [11.8, 14.9] 1.5 mos [1.4, 1.6] 12.7 mos [ ] Pbo-BTZ-Dex (n = 381) P value 54.6% [49.4, 59.7] 15.7% [12.2, 19.8] 10.9 mos [9.2, 11.8] 2.0 mos [1.6, 2.8] 8.5 mos [ ] * CR/nCR rate was nearly doubled vs control arm (scr in PAN arm 2% vs 0% placebo arm) Clinically meaningful improvements in median DOR and TTP N/A N/A N/A Richardson PG et al. J Clin Oncol. 2014;32. Abstract Progression-Free Survival Probability (%) PANORAMA 1 PFS: Primary End Point Met PAN-BTZ-Dex Pbo-BTZ-Dex Events PAN-BTZ-DEX 207/387 Median PFS (95% CI) months HR (95% CI) P value Number of patients at risk Months PAN-BTZ-DEX Pbo-BTZ-DEX Pbo-BTZ-DEX 260/ (10.3, 12.9) ( ) (7.6, 9.2) Primary end point was met (P<0.0001), with clinically relevant increase in median PFS of 3.9 months for PAN-BTZ-DEX arm < Pbo, placebo Richardson PG et al. J Clin Oncol. 2014;32. Abstract

84 PANORAMA 1 Nonhematologic AEs Grade 3/4 Diarrhea and Asthenia/Fatigue Observed PAN-BTZ-DEX (n = 381) Pbo-BTZ-DEX (n = 377) Preferred term % All grades Grade 3/4 All grades Grade 3/4 Diarrhea Peripheral neuropathy* Asthenia/fatigue Nausea Peripheral edema Decreased appetite Constipation Pyrexia Vomiting Cough *Combined incidence of hypoesthesia, muscular weakness, neuralgia, neuropathy peripheral, paraesthesia, peripheral sensory neuropathy, polyneuropathy. Discontinuation due to diarrhea (4.5%) and fatigue (2.9%) on PAN arm. Richardson PG et al. J Clin Oncol. 2014;32. Abstract PANORAMA 1 Hematologic Lab Abnormalities PAN-BTZ-DEX (n = 381) Pbo-BTZ-DEX (n = 377) Lab abnormality % All grades Grade 3/4 All grades Grade 3/4 Thrombocytopenia Lymphopenia Neutropenia Anemia Discontinuation due to thrombocytopenia on PAN 1.6% (vs 0.5%) Grade 3/4 hemorrhages on PAN 4.2% (vs 2.4%) Grade 4 neutropenia on PAN 6.6% (vs 2.4%) Febrile neutropenia on PAN 1% (vs 0.5%) Richardson PG et al. J Clin Oncol. 2014;32. Abstract

85 PANORAMA 1: Relative Potency of Pan-DACi Evaluated as Treatment for MM Potency Profiles of DACi IC 50 of Enzyme Inhibition [nm] Class I Histone, Transcription Factors HDAC 1 HDAC 2 HDAC 3 HDAC 8 HDAC 4 HDAC 5 Class II Chaperones, Tubulin HDAC 6 HDAC 7 HDAC 9 HDAC 10 Class IV Panobinostat Vorinostat ,069 15, , Romidepsin , ACY ,000 7,000 5, ,400 >1,000 NR >1,000 HDAC 11 Implicated as potential tumor targets in MM DACis demonstrate differential inhibitory activity towards HDAC enzymes Panobinostat demonstrates low nanomolar activity against class I, II, and IV HDAC enzymes HDAC6 has been implicated as an important target in MM 4 1. Atadja P. Cancer Lett. 2009;280: Heise C et al. Presented at: 4 th Annual HDAC Inhibitors. Meeting; November 2, 2010; Boston, Massachusetts [abstract]. 3. Santo L et al. Blood. 2012;119: Hideshima T et al. Mol Cancer Ther. 2011;10:2034. HDAC, histone deacetylase Richardson PG et al. J Clin Oncol. 2014;32. Abstract Summary Both carfilzomib and pomalidomide as monotherapy and in combination regimens have shown activity in patients not responding to bortezomib- and lenalidomidecontaining regimens The role of HDAC inhibitors for patients with relapsed/refractory disease remains to be defined The ultimate choice of treatment for patients with relapsed/refractory MM depends on disease, regimen, and patient-related factors 85

86 Panel Discussion A Look Forward: What to Expect in 2015 Thomas G. Martin, III, MD Professor of Clinical Medicine Associate Director Myeloma Program University of California, San Francisco Medical Center Clinical Research Director Hematologic Malignancies UCSF Helen Diller Family Comprehensive Cancer Center San Francisco, California 86

87 Disclosures Speakers Bureau: Millennium The Unmet Medical Need Success is measured by improved PFS and OS Few patients cured with current therapy Median PFS for frontline nontransplant therapy only m Continuous therapy potential for toxicity quality of life Clonal tides 1 7 subclones at diagnosis Target subclones Resistant clones Only two blockbuster classes NEED additional active classes: blockbusters > backpacks 2021: myeloma market estimated at $7 billion PFS, progression-free survival; OS, overall survival Figure 3A, page 95 from Lohr JG, et al. Cancer Cell. 2014;25:91. Figure 3B, page 95 from Lohr JG, et al. Cancer Cell. 2014;25:91. 87

88 Promising Drug Classes in MM Novel Agents/ Classes/Mechanism HDAC Antibodies & Immunotherapies Elotuzumab Molecularly Targeted Therapies B-RAF SINE/KPT330 Anti-CD38 Abs IGF-1R/ALK KSP Adoptive, CAR T cell FGFR3 p97 PD-1, PDL-1 Abs CDK BTK Vaccines IDH1/2 Proteasome inhibitors: 2nd generation/oral Immunomodulatory drugs: 4th generation Monoclonal Antibody Based Therapy Current Agents in Clinical Trials Antibody Elotuzumab Dara, SAR650984, Mor202 B-B4, nbt062 DL101 Lucatumumab AVE1642 IPH 2101 MK-3475, BMS Target SlamF7 CD38 CD138 CD138 CD40 IGF-1 KIR PD1, PDL1 88

89 Monoclonal Antibodies: Elotuzumab (anti-slamf7) ELO + LEN + LoDex in relapsed/refractory MM (LEN naïve) ELO 10 mg/kg ELO 20 mg/kg Total Patients, n OR ( 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) Little difference in response, regardless of poor cytogenetics ORR 80% and 84%, high-risk and standard-risk, respectively PFS in 10 mg/kg cohort ~33 months Two large phase 3 trials comparing LEN/LoDex vs ELO/LEN/LoDex* ELO, elotuzumab; LEN, lenalidomide; LoDex, low-dose dexamethasone; OR, odds ratio; PR, partial response; CR, complete response; VGPR, very good partial response; ORR, overall response rate Richardson PG et al. Blood. 2012;120. Abstract 202. * Maximum % Change In Serum M-Component Monoclonal Peak 1 (g/l) Daratumumab: A Novel Anti-CD38 Monoclonal Antibody Maximal Reduction of Serum M-Component Dose 4 24 mg/kg Qwk ORR ~42% mg/kg 2 mg/kg 0.05 mg/kg 4 mg/kg BM, bone marrow; SD, stable disease; MR, minimal response; FLC, free light chain 0.1 mg/kg 8 mg/kg 0.5 mg/kg 16 mg/kg 1mg/kg Plesner T et al. Blood. 2012;120. Abstract

90 Daratumumab: Single Agent in Relapsed MM Part 2: Optimizing Dose and Infusion Times Weekly dosing A: DAR 8 mg/kg B: DAR 8 mg/kg C: DAR 8mg/kg D: DAR 16 mg/kg Infusion time n # priors ORR 8% 35% Best responses PRs 2 CR 1 PR DAR, daratumumab Lokhorst HM et al. J Clin Oncol. 2014;32. Abstract SAR650984: Anti-CD38 mab Phase 1 Single Agent Single-agent study: TED10893 Change in Paraprotein (%) Accelerated escalation 1 patient/cohort mg/kg q2w mg/kg q2w 0.01 mg/kg q2w 0.03 mg/kg q2w 0.1 mg/kg q2w % 50% 90% CBR, clinical benefit response SAR Responses Maximum change in paraprotein Basic escalation 3 6 patients/cohort 0.3 mg/kg q2w 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q2w 10 mg/kg q2w 10 mg/kg q1w 20 mg/kg q2w 20 mg/kg q1w 1 mg/kg q2w 3 mg/kg q2w 5 mg/kg q2w 10 mg/kg q2w 10 mg/kg q1w 20 mg/kg q2w Patients (%) Expansion cohorts (n = 36) At recommended Phase 2 dose in patients with MM Standard risk High risk Minimal response Partial response Complete response 20 ORR = 32% CBR 37% N = 19 0 SAR 10 mg/kg q2w Martin TG et al. J Clin Oncol. 2014;32. Abstract

91 SAR650984: Anti-CD38 mab Phase 1: With LEN/LoDex SAR650984/LEN/LoDex Adults with RRMM 2 prior therapies Prior IMiD therapy permitted Refractory to IMiD OK STUDY Population Median 4 prior Lines 81% IMiD refractory 52% bortezomib refractory 48% carfilzomib refractory Standard dose escalation (3 + 3 design) 3 6 patients per cohort Expansion cohort 18 patients SAR IV, Days 1 and 15 per 28 day cycle* Cohort 1 3 mg/kg Cohort 2 5 mg/kg Cohort 3 10 mg/kg 10 mg/kg Lenalidomide 25 mg on days 1 21 per 28-day cycle Dexamethasone 40 mg Qw (Days 1, 8, 15, and 22) *Methylprednisolone 100 mg IV, diphenhydramine 50 mg iv, ranitidine 50 mg IV, and acetaminophen 650 1,000 mg po (or equivalents) MTD not reached RRMM, relapsed/refractory multiple myeloma; IMiD, immunomodulators Martin TG et al. J Clin Oncol. 2014;32. Abstract SAR650984: Anti-CD38 mab Phase 1: RESULTS Phase 1: SAR/LEN/LoDex All Number of patients (%) (n = 31) Overall response rate 18 (58) Very good partial response 7 (23) Partial response 11 (35) Minimal response 2 (6) Clinical benefit (MR or better) 20 (65) Stable disease 3 (10) Progressive disease 7 (23) Not evaluable 1 (3) Patients (%) ORR 25% CBR 50% 25% 25% 3 (n = 4) ORR 67% 67% 5 (n = 3) Minimal response Partial response Very good partial response ORR 63% CBR 67% 4% 38% 25% 10 (n = 24) ORR 58% CBR 65% 6% 35% 23% Overall (n = 31) SAR dose level, mg/kg q2w Martin TG et al. J Clin Oncol. 2014;32. Abstract

92 ARRY-520: Targeting KSP ARRY-520 is a targeted kinesin spindle protein (KSP) inhibitor Novel mechanism of action critical to the function of proliferating cells Little cross-resistance to other drugs Phase 2 [1] RRMM: >2 priors With or without DEX Phase 1 [2] With carfilzomib RRMM 1. Lonial S et al. Blood. 2013;122. Abstract 285. DEX, dexamethasone 2. Shah J et al. Haematologica. 2013;98. Abstract S579. ARRAY : Phase 2 Study Design Cohort 1: ARRY-520 Single Agent ARRY mg/m 2 q2 weeks G-CSF G-CSF 2-stage, single-arm study Cohort 2: ARRY Dexamethasone Combination ARRY mg/m 2 q2 weeks G-CSF Dexamethasone 40 mg PO weekly G-CSF, granulocyte colony stimulating factor G-CSF 2-stage, single-arm study Lonial S et al. Blood. 2013;122. Abstract

93 ARRY Predose AAG Levels Correlate With Clinical Outcome 2.8 AAG (g/l) High (AAG) Partial response Minimal response Time on Treatment (months) AAG Cutoff 1.1 g/l in Array ELISA was qualitatively assigned Absolute value of cutoff is likely to change in final assay AAG, α-1 acid glycoprotein Lonial S et al. Blood. 2013;122. Abstract 285. ARRAY : Low AAG Is Associated With Higher ORR ARRY-520 Single Agent ARRY DEX All Pts* AAG-High AAG-Low All Pts AAG-High AAG-Low n ORR ( PR) 5 (16%) 0 (0%) 5 (24%) 8 (15%) 0 (0%) 7 (19%) CBR ( MR) 6 (19%) 0 (0%) 6 (29%) 11 (20%) 0 (0%) 10 (28%) Duration of response (months) Time to next treatment (Months) OS (months) *5 patients did not have a baseline AAG measurement 4 patients did not have a baseline AAG measurement, including 1 responder Lonial S et al. Blood. 2013;122. Abstract

94 Novel Drugs: Nuclear Export Inhibitors Cancer cells overexpress XPO1 TSPs assess DNA damage/cell fate SINE compounds inhibit XPO1- Nuclear localization and activation of multiple TSPs Reduces oncoproteins MYC, BCL2/BCL6, CycD1; inhibits NF-kB XPO1, exportin-1; TSP, tumor suppressor protein; SINE, selective inhibitor of XPO1 Chen C et al. Presented at: EHA Annual Meeting; June 2014; Milan, Italy. Abstract P953. SINE in Multiple Myeloma: Ex Vivo KPT-330 potent inhibitor of XPO 800 Tumor Volume ±SEM Vehicle KPT mg/kg MWF Dexamethasone 1 mg/kg Combination Mean Percent Weight Change (±SEM) Days Days Vehicle KPT-330 Dexamethasone Combination % TGI Treatment (day 22) Selinexor (KPT-330) 25 Dexamethasone 4 Selinexor + dexamethasone 57 94

95 SINE Inhibitor: Phase 1 Trial in Advanced Hematologic Malignancies Focus on MM EHA Update Data Through June 2014 Best Responses in Patients With MM as of 5-June-2014 Treatment N CBR* ORR scr PR MR SD PD NE Selinexor 17 4 (24%) 4 (24%) 8 (47%) 3 (18%) 2 (12%) low dose Selinexor high dose Selinexor + low DEX 17 2 (12%) 1 (6%) 1 (6%) 1 (6%) 8 (47%) 3 (18%) 4 (24%) 8 6 (75%) 4 (50%) 1 (12%) 3 (38%) 2 (25%) 1 (12%) 1 (12%) *Clinical benefit response = MR + PR + scr Overall response rate = scr + PR scr, stringent complete response; PD, progressive disease; NE, nonevaluable Chen C et al. Presented at: EHA Annual Meeting; June 2014; Milan, Italy. Abstract P953. Protein Homeostasis: p97 inhibition Adapted from Figure 2, page 139 from Eisele F, et al. Chapter 11 Ubiquitylation in the ERAD pathway. In: Groettrup M, ed. Conjugation and Deconjugation of Ubiquitin Family Modifiers. Springer; CB-5083 Oral p97 inhibition Phase 1: design RRMM Expansion cohort at RP2D Progression or SD add DEX RP2D, recommended phase 2 dose US National Institutes of Health. ClinicalTrials.gov. Available at: Adapted from Eisele F et al. Chapter 11 Ubiquitylation in the ERAD pathway. In: Groettrup M, ed. Conjugation and Deconjugation of Ubiquitin Family Modifiers. Springer;

96 Precision Medicine: Molecular Targets Actionable genomic alterations: occur in ~50% of patients FGFR3 (5%) IDH1/2 (5%) IGF1R and ALK (5%) MyD88 (3%) Others (11%) KRAS and NRAS (40%) PI3K-AKT (5%) CDKN2C and CCND1 (18%) BRAF (8%) Lohr JG et al. Cancer Cell. 2014;25:91. Precision Medicine: Molecular Therapies MMRC Master Protocol Potential for evaluating treatments based on genomics Relapsed patients Genomic profiling for alterations No detectable actionable alterations RAF or RAS mutations 1p/1q alterations or CCND1 activation Del17p FGFR3 activating mutations and t(4;14) P13K/AKT activating alterations IGF1R/ALK activating alterations IDH1/2 activating mutations SOC Immune SOC BRAFi and/or MEKi SOC CDKi SOC Mdm2i SOC FGFRi SOC P13Ki or AKTi SOC IGF1R and ALKi SOC IDHi 96

97 Conclusions: Novel Targets/Drugs Many new promising agents Blockbusters: anti-cd38 monoclonal antibodies Potential blockbusters: ARRY520, PD-1, PDL-1 SINE inhibitors, ACY1215, PIM inhibitors, bromodomain inhibitors Future goals/directions Expand the use of immunotherapeutics Novel antibodies and ADC s Vaccines and CAR-T s Identify biomarkers predictive of response Investigate using genomic data to select therapy Myeloma Therapy Estimated Launch Timeline Lenalidomide (NDMM) Celgene Ixazomib (RRMM) MLNM Pomalidomide (RRMM, 2L) Celgene Proteasome Inhibitors and IMiDs Carfilzomib (RRMM, 2L) Amgen Carfilzomib (NDMM) Amgen Ixazomib (NDMM) MLNM Panobinostat (RRMM) Novartis negative ODAC approval TBD Novel Mechanisms Elotuzumab (RRMM) BMS/AbbVie Daratumumab (RRMM, AA) Genmab/J&J Aplidin (RRMM) PharmaMar SAR650984* (RRMM) Sanofi Daratumumab (NDMM, 2L) Genmab/J&J Filanesib (ARRY-520)* (RRMM) Array MOR03087* (RRMM) MorphoSys/Celgene Daratumumab (NDMM) Genmab/J&J Estimates generally based on study timing information available in clinicaltrials.gov. *Ph III studies not yet initiated. Estimated approval timing based on analyst projections. 97

98 Precision Medicine: The Future of Drug Development Transduction GFP/luc fusion Monoculture format 384 well HT evaluation Workflows support: Single agent Combinations Drug libraries Coculture format BM stroma and/or immune effectors Validation in primary myeloma samples Differential Agent Potency Pearson & Spearman correlations Integration of: 1. Gene expression 2. Whole exome seq 3. Copy number Patient BMSCs In vivo Cross-referencing to clinical datasets Rational access to annotated biosamples Expression Mutation Copy number Correlates for response associates putative correlates to clinical populations 98