Topics. When to treat? Smoldering vs Symptomatic Choice of Induction regimen Role of HDT Role of consolidation/maintenance

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1 Initial Therapy Sagar Lonial, MD Chair and Professor Department of Hematology and Medical Oncology Chief Medical Officer, Winship Cancer Institute Emory University School of Medicine

2 Topics When to treat? Smoldering vs Symptomatic Choice of Induction regimen Role of HDT Role of consolidation/maintenance

3 Criteria for Diagnosis of Myeloma MGUS < 3 g M spike < 10% plasma cells SMM 3 g M spike 10% plasma cells Active MM 10% plasma cells M spike + AND 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; SMM = smoldering multiple myeloma. Kyle et al, 2009.

4 Not all Smoldering patients are the same 27% will convert in 15 years Roughly 2% per year Kyle R et al. N Engl J Med 2007;356:

5 Free Light is Useful for Risk Assessment in AMM Dispenzeri et al Blood 2008

6 Updated IMWG Criteria for Diagnosis of Multiple Myeloma MGUS M-protein < 3 g/dl Clonal plasma cells in BM < 10% No myeloma defining events Smoldering Myeloma M-protein 3 g/dl (serum) or 500 mg/24 hrs (urine) Clonal plasma cells in BM 10% - 60% No myeloma defining events Multiple Myeloma Underlying plasma cell proliferative disorder AND 1 or more myeloma defining events including either: 1 CRAB feature(s) OR 1 Biomarker Driven C: Calcium elevation (> 11 mg/dl or > 1 mg/dl higher than ULN) R: Renal insufficiency (creatinine clearance < 40 ml/min or serum creatinine > 2 mg/dl) A: Anemia (Hb < 10 g/dl or 2 g/dl < normal) B: Bone disease ( 1 lytic lesions on skeletal radiography, CT, or PET-CT) Biomarker driven (1) Sixty-percent ( 60%) clonal PCs by BM; (2) serum free Light chain ratio involved:uninvolved 100; (3) >1 focal lesion detected by MRI Rajkumar SV, et al. Lancet Oncol. 2014;15:e538-e548.

7 ECOG/SWOG: Phase III Asymptomatic Myeloma*(PI: SL) Lenalidomide vs. observation No Dex to isolate the effect of len R A N D O M IZ A TI O N Lenalidomide Observation CR/PR/ Stable Prog. anytime Continue therapy till prog. or toxicity Off Rx Control/standard arm

8 Ongoing Investigations RD + Dara RD+ Pembro/nivo Vaccine + len + Durva KRD auto transplant KRD KRD + Dara auto KRD Len

9 PETHEMA Cure with old Drugs Functional cure? Martinez-Lopez et al, Blood 2011

10 Survival outcomes in newly diagnosed myeloma patients with RVD induction among all patients (at a median follow up of 66 months) Nooka et al, unpublished

11 Three Drugs Are Better Than Two ORR VGPR TD RD VD VTD VCD RVD

12 Induction regimens in MM Progression Free Survival Overall Survival Nooka et al. Cancer DOI: /cncr.28325

13 Impact of IMIDs on OS and PFS with translocations Barwick et al

14 CR and VGPR rates in high risk subgroups of patients Does it matter which 3 drugs are used? P<0.001 P<0.001 P=0.155 P<0.001 Cavo et al, Leukemia 2016 Responses to both VTD and VCD were reassessed centrally

15 Randomized Trial VTD vs VCD Shows superiority of IMID/PI VCD is no longer a reasonable induction choice Moreau et al, Blood 2016

16 RVD is better than VCD Compass trial, IA9

17 SWOG S0777 Study Design (continued) VRd Rd After induction Rd Maintenance Until PD, Toxicity or Withdrawal Lenalidomide 25 mg PO days 1-21 Dexamethasone 40 mg PO days 1, 8,15, 22 All patients received Aspirin 325 mg/day VRd patients received HSV prophylaxis Durie et al, Lancet

18 Confirmed Response*: VRd versus Rd VRd Rd CR 15.7% 8.4% VGPR 27.8% 23.4% PR 38% 39.7% ORR (PR or better) 81.5% 71.5% SD 15.7% 24.3% SD or better 97.2% 95.8% PD or Death 2.8% 4.2% *Assessable patients Durie et al, Lancet

19 Progression-Free Survival By Assigned Treatment Arm Log-rank P value = (one sided)* HR = (0.560, 0.906)* *Stratified *Assessable patients Durie et al, ASH Durie et al, Lancet

20 Overall Survival By Assigned Treatment Arm HR = (0.516, 0.973)* Log-rank P value = (two sided)* *Stratified *Assessable patients 20 Durie et al, Lancet

21 Where are we? Risk stratify Smoldering IMID/PI combination is the standard of care Which PI?

22 KRD for newly diagnosed Myeloma

23 Frontline Therapy with Carfilzomib, Lenalidomide, and Dexamethasone (KRd) Induction Followed By Autologous Stem Cell Transplantation, KRd Consolidation and Lenalidomide Maintenance in Newly Diagnosed Multiple Myeloma (NDMM) Patients: Primary Results of the Intergroupe Francophone du Myélome (IFM) KRd Phase II Study NCT M. Roussel, V. Lauwers-Cances, N. Robillard, K. Belhadj, T. Facon, L. Garderet, M. Escoffre, B. Pegourie, L. Benboubker, D. Caillot, C. Fohrer, P. Moreau, X. Leleu, H. Avet-Loiseau, and M. Attal for the IFM

24 STUDY DESIGN Induction KRd day cycles Carfilzomib/Len/Dex PBSC harvest: Cyclophosphamide high dose Intensification HD Melphalan 200 mg/m2 Open-label, multicenter, phase II study in frontline MM pts < 65 yrs KRd Induction Carfilzomib 20-36mg/m2 D1, 2, 8, 9, 15, 16 Lenalidomide 25 mg D1-21 Dexamethasone 20 mg1-2, 8-9, 15-16, Mandatory LMWH KRd Consolidation Consolidation KRd day cycles Carfilzomib/Len/Dex Carfilzomib 36mg/m2 D1,2, 8, 9, 15, 16 Lenalidomide 25 mg D1-21 Dexamethasone 20 mg D1, D8, D15, D22 Maintenance Lenalidomide 10mg D cycles (1 year) MRD evaluation for VGPR pts (CMF/NGS)

25 RESPONSE RATES at the completion of Consolidation N=46 n % scr MRD - CMF MRD - NGS 23/34 68 At least CR At least VGPR ORR PD patients were not evaluable due to toxicities MRD CMF 10-4 /10-5 MRD NGS clonoseq Adaptive 10-6

26 RESPONSE RATES Post Induction Post ASCT Post Consolidation Best Response n n n n % scr CR+sCR VGPR VGPR or better PR ORR PD 1 1 1

27 CARDIO-VASCULAR + PULMONARY TOXICITIES all grades 25 CARDIAC AND VASCULAR EVENTS Total No of events No of patients (%) Cardiac Failure 2 2 (4) Pulmonary Embolism 2 2 (4) Venous Thrombosis 2 2 (4) Intra Cardiac Thrombus 1 1 (2) Superfical Thrombosis 8 8 (17) Bradycardia 2 2 (4) Arrhythmia 1 1 (2) Atrial Fibrillation 1 1 (2) Tachycardia 1 1 (2) Hypertension 5 4 (9) Cough 11 9 (20) Dyspnea 5 5 (11)

28 IRD Response Rates Kumar SK, et al. Lancet Oncol. 2014;15(13):

29 Ixazomib-Lenalidomide-Dexamethasone (IRd) combination before and after ASCT followed by Ixazomib maintenance in patients with newly diagnosed multiple myeloma: a phase 2 study from the Intergroupe Francophone du Myélome (IFM) P Moreau, C Hulin, D Caillot, G Marit, A Perrot, L Garderet, T Facon, L Benboubker, L Karlin, M Tiab, B Arnulf, JP Fermand, X Leleu, C Touzeau, M Roussel, L Planche, H Caillon, S Minvielle, MC Béné, H Avet-Loiseau, T Dejoie, M Attal

30 Study design 1- Induction: 3 cycles of Ixazomib RD, every 28 days - Ixazomib 4 mg/d; D1, 8, 15 - Lenalidomide 25 mg/d ; D1 to 21 - Dexamethasone 40 mg/d; D1, 8, 15, PBSC harvest Mobilization: Cyclophosphamide 3 g/m 2 and G-CSF 5 µg/kg 3- Peripheral stem cell transplantation Melphalan 200 mg/m 2 4- Early consolidation : 2 cycles of Ixazomib/Len/Dex, every 28 days 5- Late consolidation: 6 cycles of Ixazomib/Len (without Dex), every 28 days 6 Maintenance therapy for 1 year (13 cycles) Ixazomib weekly 4 mg D1, 8, 15, every 28 days

31 Responses intent-to-treat Post-induction N = 42 Post-ASCT N = 42 Post-early Conso N = 42 Post-late Conso N = 42 scr (%) CR (%) VGPR (%) PR (%) Stable (%) PD (%) NE (%) > PR (%) > VGPR (%) > CR (%)

32 Intent-to-treat / feasibility During induction : 2 PD, 1 Rash Feasibility ASCT: 37 / 42 (88%) ASCT: no toxic death, no PD Feasibility: 37 / 42 Early consolidation : no SAE, 1 PD Feasibility: 37 / 42 Late consolidation: 1 SAE (rash), 1 PD Feasibility 34 / 42 (81%) Maintenance ongoing : 1 thrombocytopenia precluding maintenance, 2 PD

33 Safety (excluding ASCT, and maintenance) AEs leading to exclusion - During induction : 1 rash - Late consolidation: 1 rash - Before maintenance: 1 thrombocytopenia 12 cases of non-hematologic grade 3-4 toxicities were reported: -infections (8 cases), -abdominal pain (2), -atrial fibrillation (1), -thrombosis (1) No cardiac failure, no ischemic heart disease, no renal impairment No grade 3-4 peripheral neuropathy

34 ELO+ RVD phase II study Screening Induction therapy and Transplant Maintenance 28-day cycles Follow Up Newly Diagnosed Multiple Myeloma 4 cycles Elo-RVD Stem Cell Mobilization ASCT NO ASCT YES 4 cycles Elo-RVD Autologous Stem Cell Transplantation High Risk: Elotuzumab Lenalidomide Bortezomib Dexamethasone Low Risk: Elotuzumab Lenalidomide Dexamethasone Follow Up Visits every 3 months Laubach et al, ASH 2016

35 Response After 4 Cycles Laubach et al, ASH 2016

36 On-study death and treatment discontinuations due to AEs One patient died on study Hospitalized due to respiratory failure and sepsis during cycle 2 and subsequently died as a result of these AEs One patient died > 30 days after discontinuing study therapy Patient became acutely ill during cycle 1, hospitalized for febrile neutropenia and hypotension related to sepsis, then developed renal failure. Participant was removed from study and died more than 30 days later. Five additional patients discontinued from treatment due to the following AEs: Grade 3 peripheral neuropathy, discontinues treatment after cycle 3 Grade 3 mood disturbance, discontinues treatment after cycle 3 Grade 4 hyperglycemia, discontinues treatment after cycle 2 Grade 3 orthostatic hypotension and demyelinating polyneuropathy, d/c s treatment after cycle 4 Grade 3 lung infection, discontinues treatment after cycle 2 Laubach et al, ASH 2016

37 Where are we? Risk stratify Smoldering IMID/PI combination is the standard of care Which PI? Bz has the most data, randomized trials in progress Role of HDT?

38 Registration RVD 1 Lenalidomide + Bortezomib + Dexamethasone 25mg/d (d1 to 14) 1.3mg/m 2 (d 1, 4, 8, 11) 20mg/d (d1,2,4,5,8,9,11,12) Randomization (stratified on ISS and FISH) ) IFM 2009 : Study Design. Arm A Arm B RVD 2 and 3 RVD 2 and 3 PBSC Collection (cyclophosphamide 3g/m 2 and G-CSF) 10mcg/kg/d) RVD 4 to 8 PBSC Collection (cyclophosphamide 3g/m 2 and G-CSF) ASCT HDM 200mg/m2 RVD 4 and 5 Lenalidomide Maintenance 12 months (10-15 mg/d) Lenalidomide Maintenance 12 months (10-15 mg/d)

39 IFM 2009: Best Response. RVD arm N=350 Transplant arm N=350 p-value CR 49% 59% VGPR 29% 29% 0.02 PR 20% 11% <PR 2% 1% At least VGPR 78% 88% Neg MRD by FCM, n (%) 228 (65%) 280 (80%) 0.001

40 IFM 2009: PFS (9/2015) HDT no HDT Patients (%) P< N at risk HDT no HDT Months of follow-up

41 IFM 2009: OS (9/2015) Patients (%) P NS 10 0 HDT no HD T N at risk HDT no HDT Months of follow-up

42 KRD outcomes by Transplant Status Jakubowiak et al, EHA 2016

43 Getting to Minimal Residual Disease (MRD): New Definitions for CR Newly diagnosed S.S. Patient Disease burden CR Stringent CR MRD Molecular/Flow CR Antibodies Maintenance Therapy?Cure? 0.0

44 Outcomes for patients are the same if they achieved MRD negativity MRD at post-maintenance 1.0 Patients without progression (%) /3 of these patients were from HDT, 1/3 from delayed HDT P-value (trend) : p< <10-6 [10-6;10-5[ [10-5;10-4[ >= N at risk (events) <10-6 [10-6 ;10-5 [ [10-5 ;10-4 [ [10-4 ;10-3 [ (0) 86 (0) 86 (0) 86 (0) 86 (5) 77 (3) 61 (5) 36 (0) (0) 29 (0) 29 (0) 29 (0) 28 (5) 22 (3) 16 (4) 4 (1) 1 23 (0) 23 (0) 23 (0) 23 (1) 22 (3) 19 (2) 14 (5) 3 (0) 2 40 (0) 40 (0) 40 (0) 40 (6) 33 (9) 23 (6) 15 (4) 4 (1) 2 30 Months since randomization

45 Where are we? Risk stratify Smoldering IMID/PI combination is the standard of care Which PI Bz has the most data, randomized trials in progress Role of HDT Continues to offer benefit in achievement of MRD- Role of consolidation/maintenance

46 Up-front single versus double autologous stem cell transplantation for newly diagnosed multiple myeloma: an intergroup, multicenter, phase III study of the European Myeloma Network (EMN02/HO95 MM Trial) Michele Cavo*, Maria Teresa Petrucci, Francesco Di Raimondo, Elena Zamagni, Barbara Gamberi, Claudia Crippa, Giulia Marzocchi, Mariella Grasso, Stelvio Ballanti, Donatella Iolanda Vincelli, Paola Tacchetti, Massimo Offidani, Giampietro Semenzato, Anna Marina Liberati, Anna Pascarella, Giulia Benevolo, Rossella Troia, Angelo D. Palmas, Nicola Cantore, Rita Rizzi, Fortunato Morabito, Mario Boccadoro, and Pieter Sonneveld On behalf of EMN02/HO95 MM Trial participants * Seragnoli Institute of Hematology, Bologna University School of Medicine, Italy

47 PFS by randomization 1 (HDM-1 vs HDM-2) 1.00 % Probability 0.50 HDM-2 HDM-1 PFS median, mos NR NR PFS at 3 yrs, % Number at risk HDM2 HDM1 HR (95% CI): 0.70 ( ); p = months HDM2 HDM1 Median follow-up: 32 months (IQR 26-41)

48 PFS by high-risk cytogenetics 1.00 % Probability Number at risk HDM2 HDM1 HDM-2 HDM-1 PFS median, mos PFS at 3 yrs, % HR (95% CI): 0.49 ( ); p = months HDM2 HDM1

49 EMN02 / HOVON 95 MM A randomized phase III study to compare Bortezomib, Melphalan, Prednisone (VMP) with High Dose Melphalan followed by Bortezomib, Lenalidomide, Dexamethasone (VRD) consolidation and Lenalidomide maintenance in patients with newly diagnosed multiple myeloma (NTR2528, Eudract ) The European Intergroup Trial of the European Myeloma Network EMN

50 Sonneveld et al. ASH 2016 Design of EMN02 trial 4 VCD + Stem cell apheresis R1 4 VMP HDM 1/2 R2 2 VRD None Registration Induction Stem cell mobilization in all pts Early or late ASCT, once or twice Consolidation MRD Lenalidomide Lenalidomide Maintenance until relapse HDM/ASCT at 1 st relapse [Accessed March 2015]

51 100 Progression-free free survival Cumulative percentage no consolidation VRD N 435 F 137 no consolidation VRD Cox LR P=0.045 (adjusted for 1st random.) At risk: no consolidation VRD HR = 0.78 ( ) months Sonneveld et al. ASH 2016 EMN02 / HO95 MM 51

52 Stadtmauer et al. ASH 2016

53 Stadtmauer et al. ASH 2016

54 Stadtmauer et al. ASH 2016

55 Where are we? Risk stratify Smoldering IMID/PI combination is the standard of care Which PI Bz has the most data, randomized trials in progress Role of HDT Continues to offer benefit in achievement of MRD- Role of consolidation Limited role, tandem transplant does not offer benefit Role of Maintenance

56 Overall Survival: Median Follow-Up of 80 Months There is a 26% reduction in risk of death, representing an estimated 2.5- year increase in median survival a yr OS Survival Probability Patients at risk N = 1209 LENALIDOMIDE CONTROL Median OS (95% CI), mos HR (95% CI) P value NE (NE-NE) 0.74 ( ) ( ) Overall Survival, mos 50% 62% a Median for lenalidomide treatment arm was extrapolated to be 116 months based on median of the control arm and HR (median, 86 months; HR = 0.74). HR, hazard ratio; NE, not estimable; OS, overall survival.

57 Overall Survival: Subgroup Analysis Age Sex ISS stage Response after ASCT Prior induction therapy < 60 yrs 60 yrs M a le F e m a le I o r II III CR CR/VGPR PR/SD/PD LEN Non-LEN Yes No LEN a CONTROL a HR (95% CI) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) < 5 0 m L /m in ( ) Adverse-risk cytogenetics b 5 0 m L /m in ( ) ( ) CrCl after ASCT c HR Favors LEN Favors control ( )

58 Suggested Approach for Newly Diagnosed MM Transplant Eligible Yes No RVD Std RIsk High RIsk Failure to achieve VGPR Car/Pom/Dex Maintenance High RIsk Early Transplant Del 17p Other high risk features RVD Maintenance t(4:14) Std RIsk Bz Maintenance Early vs Delayed Transplant Len Maintenance Rd, Vd, RVD-lite MPV Del 17p Other high risk features RVD Maintenance t(4:14) Bz Maintenance Nooka et al, JOP 2016

59 Emory OS by Genetics N= 256 all patients received RVD High risk all received 3 drug maintenance Minimal exposure to alkylators Nooka et al, Leukemia 2013

60 New directions IMID/PI is the standard of Care for Newly diagnosed MM, question on optimal PI remains the subject of trials Transplant continues to have an important role in quest to achieve MRD negativity Tandem in US patients not standard Maintenance is not one size fits all 4 drug induction is on the way

61 Thanks to: Jonathan Kaufman Charise Gleason Danni Cassabourne Melanie Watson Donald Harvey Renee Smith Colleen Lewis Amelia Langston L.T. Heffner Ebeneezer David Claire Torre S-Y Sun Jing Chen Fadlo Khuri Leon Bernal Larry Boise IMS Golfers Against Cancer T.J. Martell Foundation And Many Others who are part of the B-cell Team