Novel Combination Therapies for Untreated Multiple Myeloma

Novel Combination Therapies for Untreated Multiple Myeloma Andrzej J. Jakubowiak, MD, PhD Director, Myeloma Program New York, NY, October 27, 201

Disclosures 2 Employee Consultant Major Stockholder Speakers Bureau Honoraria Advisory Board None Bristol-Myers Squibb, Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals None Celgene Bristol-Myers Squibb, Celgene, Millennium, Onyx Bristol-Myers Squibb, Millennium Pharmaceuticals, Onyx Pharmaceuticals Presentation may include agents that are not yet approved, and agents used for unapproved indications

Current Paradigm of Initial Treatment 3 Transplant eligibility Transplant Candidates Autotransplant Consolidation Initial therapy or Maintenance Continue initial therapy Non-transplant Candidates

4 Initial Treatment of Transplant Candidates Autotransplant Consolidation Initial therapy Maintenance Conventional VAD Novel Combinations 2-Drug: TD, VD, RD, Rd 3-Drug/1-Novel: TAD, PAD, VDD, CVD 3-Drug/2-Novel: VTD, RVD 4-Drug/2-Novel: CVDR, VTDC, RVDD

Pre-transplant Induction Response Rates 5 100 80 60 40 20 0 Composite Response Rates 50-60% 15-18% VGPR 60-75% 30-40% PR 90-100% 40-60% VAD 2-Drug 3-Drug 4-Drug 1. Lokhorst et al. Blood 2010;115(6):1113-1120. 2.Harousseau et al. J Clin Oncol. 2010;28(30):4621-4629. 3.Sonneveld et al. J Clin Onc. 2012;30:2946-55 95-100% 50-65% Randomized Comparisons % INDUCTION REGIMEN CR VGPR TAD vs 3 37* VAD 1 2 18* VD vs 6 38* VAD 2 1* 15* PAD vs NR 42* VAD 3 NR 15* VTD vs 19* 62* TD 4 5* 28* VTD vs 35* 60* TD 5 14* 29* vtd vs 13* 49* VD 6 12* 36* * P value statistically significant 4. Cavo et al. Lancet 2010;379(9758):2075-2085. 5. Rosiñol et al. Blood. 2012 Aug 23;120(8):1589-96 6. Moreau et al. Blood 2011;118(22):5752-8

Different Induction Regimens and Outcome after ASCT 6 Selection of initial regimen appears to impact posttransplant outcome Autotransplant Consolidation Initial therapy Maintenance Post-ASCT response rates further improve for all regimens Depth of response improves also in superior arms Statistical differences between two arms persist* *see for summary of data in supplemental slide Adopted from Cavo et al. Lancet 2010;379(9758):2075-2085.

Initial Treatment Strategy and Time to Event 7 TAD + Thal vs 34 mo* 73 mo VAD + IFN 1 22 mo* 60 mo VD+ Len ± Len vs 36 81% (3-yr) VAD+ Len ± Len 2 30 77% (3-yr) PAD + Bort vs 36 mo* HR = 0.73* VAD + Thal 3 27 mo* NR VTD + VTD vs TD + TD 4 Randomized Studies 68% (3-yr)* 86% (3-yr)* 56% (3-yr)* 84% (3-yr)* VTD vs 56 mo* NR TD 5 27 mo* NR vtd vs 26 NR VD 6 30 NR 1. Lokhorst et al. Blood 2010;115(6):1113-1120. 2. Harousseau et al. J Clin Oncol. 2010;28(30):4621-4629. 3. Sonneveld et al. J Clin Onc. 2012;30:2946-55 4. Cavo et al. Lancet 2010;379(9758):2075-2085. 5.Rosiñol et al. Blood. 2012 Aug 23;120(8):1589-96 6. Moreau et al. Blood 2011;118(22):5752-8 VTD vs TD Cavo et al. Blood 2010; 116(21). Abstract 42, Lancet 2011;376(9758):2075-85 * P value statistically significant

0.00 0.25 0.50 0.75 1.00 Post-Transplant Consolidation and Maintenance 8 Autotransplant Consolidation Initial therapy RVD Benefits of consolidation not established Bortezomib VTD Lenalidomide Lenalidomide PFS prolonged (2/2) OS prolonged (1/2) Bortezomib PFS and OS (1/1) Maintenance Thalidomide PFS prolonged (6/6) OS prolonged (3/6) 0 6 12 18 24 30 36 42 Placebo Revlimid Attal et al, ASH 2010.sequential approach including a proteasome inhibitor before and after ASCT improves the outcome in transplant-eligible patients Palumbo J Clin Onc 2012; 2012 vol. 30 no. 24 2935-2936

New Agents in Initial Treatment of Transplant Candidates 9 Carfilzomib regimens CYCLONE, CRd MLN9708 regimens MLN9708+Rd Initial therapy Autotransplant Consolidation Maintenance Conventional VAD Novel Combinations 2-Drug: TD, VD, RD, Rd 3-Drug/1-Novel: TAD, PAD, VDD, CVD 3-Drug/2-Novel: VTD, RVD 4-Drug/2-Novel: CVDR, VTDC, RVDD

Cyclophosphamide, Carfilzomib, Thalidomide, Dexamethasone (CYCLONE) Phase II: Schema 10 Newly Diagnosed MM Carfilzomib (20/27 mg/m 2 IV, days 1,2, 8,9, 15,16) Cyclophosphamide (300 mg/m 2 po, days 1, 8, 15) Thalidomide (100 mg po days 1-28) Dexamethasone (40 mg po days 1, 8, 15, 22) 28-day cycles x4 Response PFS Toxicity Stem cell harvest Mikhael et al, ASCO 2012, Courtesy J. Mikhael

CYCLONE Phase II: Efficacy (n=24) 11 27 patients treated in Phase II Median follow up 8.2 m (2.5-23.1) CR 7 VGPR 11 PR 5 MR 1 VGPR 75% 29% 46% CR VGPR PR MR > PR 96% 21% Toxicities manageable Extend Phase II with increasing doses of carfilzomib: Target CFZ 45mg/m 2 4% Mikhael et al, ASCO 2012, Courtesy J. Mikhael

New Agents in Initial Treatment of non-transplant Candidates 12 MP-based regimens MPT > MP VMP > MP VMP = VTP VMPT-VT > VMP MPR-R>MPR=MP Other regimens e.g. Rd, RVD Elotuzumab +/- Rd Carfilzomib +MP (CMP) Initial therapy Maintenance Continue initial therapy

Carfilzomib +MP (CMP): Treatment schedule 13 9 cycles / 42 days Dosing and schedule Carfilzomib C1: D1, D2, Carfilzomib 30 min-iv 20 mg/m²/day D8, D9, D22, D23, D29, D30 Carfilzomib 20, 27, 36 or 45 mg/m²/day (cohort 1, 2, 3, or 4) C2 to C9: Carfilzomib 20, 27, 36 or 45 mg/m²/day (cohort 1, 2, 3, or 4 D1, D2, D8, D9, D22, D23, D29, D30) Melphalan C1-9: PO 9 mg/m²day D1 to D4 Prednisone C1-9: PO 60 mg/m² day D1 to D4 Kolb et al, ASCO 2012, Courtesy P. Moreau

CMP: Results 14 43 patients have been enrolled : 6 + 6 + 6 + 6 + 19 Median age 74 years (66 86) EFS MTD defined at 36 mg/m2 80.7% After a median of 8 cycles (1 9): / 35 patients 1 CR > VGPR 40% 14 VGPR ORR: 89% 16 PR 1 MR 2 stable disease 1 progression No neurotoxicity!! (1 grade 1) OS 93.9% Median follow-up: 12 months Kolb et al, ASCO 2012, Courtesy P. Moreau

Changing Paradigm of Treatment of Transplant Candidates 15 Initial therapy Transplant Candidates Autotransplant or Continue initial therapy Maintenance Continue initial therapy Non-transplant Candidates

Rationale for Delayed Autotransplant in the Era of Novel Regimens 16 RVD Regimen PFS by ASCT status from 1-yr landmark Responses at 4 cycles: PR 75%, > VGPR 11%, CR/nCR 6% Best Response (all patients) > PR 100%, > VGPR 67%, CR/nCR 39% Richardson et al, Blood. 2010 Aug 5;116(5):679-86. Epub 2010 Apr 12 Main limitation of extended RVD treatment peripheral neuropathy Transplant eligible Autotransplant RVD Consolidation RVD vs R Maintenance Continue RVD

Frontline MLN9708 + Rd Treatment Schema Transplanteligible and - -ineligible patients MLN9708+Rd Induction Cycles 1 3/4 Cycles 4-12/5-16 Transplant-eligible Stem cell collection MLN9708 Maintenance Cycles 13/16+ Until disease progression or unacceptable toxicity ASCT after 6 (weekly) or 8 (twice-weekly) cycles Cycles 1 12 (weekly) or 1-16 (twice-weekly) MLN9708 weekly schedule D 1, 8, 15 in 28-d cycles, twice-weekly schedule D 1, 4, 8, 11 in 21-d cycles 1 LEN 25 mg Days 1 21 (weekly schedule 280day cycles), 1-14 (twice weekly schedule 21-day cycles) DEX 40 mg weekly Cycles 1-12 (weekly), 20/10 mg 1, 2, 4, 5, 8, 9, 11, Cycles 1 8/ 9-12 (twice-weekly) Cycles 12+ (weekly)/16+(twice-weekly) MLN9708 at last best tolerated dose 1 Based on Richardson et al. EHA 2012. 17

MLN9708 +Rd: Response Rates Response, % Weekly Schedule Best Response* (n=64) 4+ cycles (n=46) PR 91 98 Twice-weekly Schedule Response, % Best Response* (n=10) 4+ cycles (n=6) PR 90 100 VGPR 39 46 VGPR 60 83 CR 26 CR 10 17 *Median 4 cycles (range 1 15) *Median 4 cycles (range 1 8) Response appears to get better with time on treatment Toxicities manageable with rash or fatigue most common; peripheral neuropathy 18-33% 1 Based on Richardson et al. EHA 2012.

Frontline CRd Treatment Schema Transplanteligible and - -ineligible patients CRd Induction CRd Cycles 1 4 CRd Cycles 5 8 Transplant-eligible PR ASCT Stem cell collection CRd Maintenance CRd Cycles 9 24 Lenalidomide (off protocol) LEN Cycles 25+ Until disease progression or unacceptable toxicity Assessments on D1 and 15 of C1 and D1 thereafter using modified IMWG Criteria with ncr Cycles 1 8 CFZ 20-27-36 mg/m 2 Days 1 2, 8 9, 15 16 1 LEN 25 mg Days 1 21 DEX 40 mg weekly Cycles 1-4, 20 mg weekly Cycles 5 8 Jakubowiak AJ, et al. ASCO 2012., Blood 2012; 120(9):1801-9 Cycles 9 24 CFZ on Days 1 2 and 15 16 only CFZ, LEN, DEX at last best tolerated doses Cycles 25+ LEN at last best tolerated dose 19

Patients (%) Frontline CRd: Best Response Median 12 cycles (range 1 25) PR VGPR ncr scr 100 80 98 81 60 62 40 42 20 0 All patients N=53 There was no difference by disease stage and cytogenetics Jakubowiak AJ, et al. ASCO 2012., Blood 2012; 120(9):1801-9 20

M-protein level (% of baseline) Response (%) Frontline CRd Responses at Different Time Points 100 ncr scr M-protein 100 75 75 50 50 25 25 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Cycle 0 20/22 patients (91%) with suspected CR had no evidence of MRD by multiparameter flow cytometry 1. Jakubowiak AJ, et al. ASCO 2012. 21

Response (%) Frontline CRd Responses after Extended Treatment 100 ncr scr 80 78 60 62 67 61 40 42 45 20 0 Overall n=53 Median 12 cycles (range 1 25) 4+ Cycles n=49 Median 13 cycles (range 4 25) 8+ Cycles n=36 Median 16 cycles (range 8 25) Jakubowiak AJ, et al. ASCO 2012., Blood 2012; 120(9):1801-9 22

Frontline CRd Progression-free Survival 12-month rate 97% 24-month rate 92% Median follow-up of 13 months (range 4-25) 2 patients progressed All patients with scr have maintained response for median 9 months (range 1 20) Jakubowiak AJ, et al. ASCO 2012., Blood 2012; 120(9):1801-9 23

Will New Combinations Change a Strategy of Initial Treatment? 24 PRE-TRANSPLANT INDUCTION - Carfilzomib-based regimens (i.e. CYCLON or CRd) appear to provide superior rate of >VGPR than bortezomib +/- IMiD-based regimens - MLN9708+Rd regimen appears promising; awaiting more information on its role in pre-transplant setting - It is still not settled how critical is the choice of specific pretransplant regimen INITIAL THERAPY IN NON-TRANSPLANT CANDIDATES If MP-based regimens are to be used for primary treatment, then CMP (MP + Carfilzomib) is emerging as possibly most active Some of emerging new regimens (e.g. CRd) appear to be more active than any MP-based regimens and show extended tolerability All oral MLN9708+Rd is very active and maybe very appealing to use in non-transplant candidates provided it shows extended tolerability

Are new combinations changing the current paradigm of treatment of myeloma? 25 TRANSPLANT AND NON-TRANSPLANT CANDIDATES We can now achieve similar or better results after extended treatment without transplant of both transplant and non-transplant candidates( e.g. CRd) than with bortezomib-based induction, followed by transplant, followed by consolidation and maintenance in transplant candidates FUTURE DIRECTIONS Carfilzomib and MLN9708 will likely find their place in frontline therapy but we need longer follow-up and new data from ongoing and recent studies (including short and long term tolerability) Other agents, e.g. elotuzumab are likely to make further impact on treatment of new myeloma Increased focus on depth of response (scr, MRD) Likely shift to paradigms based on disease subtype-based individualized therapy rather than based on transplant versus non transplant status

Additional Slides

27 Different Induction Regimens followed by ASCT Induction with 4-drug vs 3-drug regimens Autotransplant Consolidation Initial therapy Maintenance RVD RVDD Induction Post-Transplant Attal et al. Blood ASH 2010/Richardson et al. Blood 2010 Studies not designed for comparison Jakubowiak et al. Blood 2011. Epub 2011

Different Induction Regimens followed by ASCT 28 Will adding 4 th drug to 3-drug regimen improve outcome? Autotransplant Consolidation Initial therapy Maintenance RVDD? VCRD not better than VRD or CVD After 4 cycles, % >PR >VGPR CR/nCR RVD* 75 11 6 RVDD* 96 57 29 Richardson et al., Blood 2010 Jakubowiak et al., Blood 2011 *Studies not designed for comparison

Is there are Role for Consolidation after ASCT? 29 Autotransplant Consolidation Initial therapy % post- ASCT % post- Consolidation REGIMEN CR VGPR CR VGPR Bortezomib vs 20 39 45* 71* observation 1 21 39 35* 57* VTD vs 55 NR 62* NR TD 2 41 NR 45 NR Len 3 14 58 20* 67* Bortezomib VTD vs TD Lenalidomide Depth of response improves MRD rates improve Maintenance 1. Mellqvist et al. Haematologica 2011; 96(suppl 1). Abstract 011 2. Cavo et al. Blood 2010;116(21). Abstract 42. 3. Attal et al. Blood 2009;114(22). Abstract 529. Terragna et al. Blood 2010; 116(21). Abstract 861

Patients (%) Maintenance in non-transplant candidates 30 MPR 100 75 50 Landmark Analysis 69% Reduced Risk of Progression Lenalidomide Continuous Therapy HR 0.314 P <.001 MPR-R MPR Lenalidomide PFS improved MPR-R > MPR Bortezomib-based VMPT-VT > VMP VT > VP? 25 0 0 5 10 15 20 25 30 Cycle 10 Time (months) Initial therapy 1 Maintenance Continue initial therapy 1. Palumbo et al, Blood 2010 (21); Abstract 620 2. Palumbo et al, Blood 2010; 116(21) Abstract 622. 3. Mateos et al. Lancet Oncology; 2010 Oct;11(10):934-41. Epub 2010 Aug 23

CYCLON: Results 31 27 patients treated in Phase II 4 sites: Mayo Arizona, Mayo Rochester, University of New Mexico and Medical University of South Carolina Median follow up 8.2 mths (2.5-23.1) 26/27 are still alive Pt died during cycle 3, felt to be unrelated to therapy Only one other pt elected to be removed from study Mikhael et al, ASCO 2012, Courtesy J. Mikhael

Carfilzomib + MP (CMP): Rationale 32 - MP + bortezomib, «VMP», is one of the standard of care in the treatment of patients with symptomatic myeloma not eligible for high-dose therapy - VMP (Vista) : 14% grade 3 / 4 peripheral neuropathy 71% Overall response rate - Carfilzomib: second-in-class proteasome inhibitor, without neurotoxicity, high response rate in relapsed/refractory MM - Carfilzomib MP: effective combination regimen in elderly patients? Kolb et al, ASCO 2012, Courtesy P. Moreau

33 CMP: Toxicity AE grade > 3 DVT : 6% Renal impairment: 3% Infections: 15% Pericardial effusion: 3% Fatigue: 3% Atrial fibrillation: 6% Cardiac failure: 3% Toxic death: 3% No neurotoxicity!! (1 grade 1) Kolb et al, ASCO 2012, Courtesy P. Moreau

MLN9708 + Rd: Study design Study Induction MLN9708 Lenalidomide Dexamethasone Weekly D 1, 8, 15 25 mg, D 1 21 Up to 12 x 28-day cycles Twice-weekly D 1, 4, 8, 11 25 mg, D 1 14 Up to 16 x 21-day cycles 40 mg, D 1, 8, 15, 22 20/10 mg (cycles 1 8/9 16), D 1, 2, 4, 5, 8, 9, 11, 12 MLN9708 maintenanc e D 1, 8, 15 28-day cycles D 1, 4, 8, 11 21-day cycles Phase 1: oral MLN9708 dose-escalation Standard 3+3 schema, 33% dose increments, based on cycle 1 DLTs Phase 2: oral MLN9708 at the RP2D from phase 1 Each protocol allows for stem cell collection after cycles 3 / 4, with autologous stem cell transplantation (ASCT) deferred until after 6 / 8 cycles in the weekly / twice-weekly studies, respectively MLN9708 maintenance continued until progression or unacceptable toxicity Richardson et al, EHA 2012, Courtesy P. Richardson

MLN9708 +Rd Drug-related* AEs, all grades ( 10% of total) in weekly dosing study AE, n (%) Phase 1 (n=15) Phase 2 (n=50) Total (n=65) Rash 6 (40) 17 (34) 23 (35) Fatigue 5 (33) 16 (32) 21 (32) Nausea 6 (40) 14 (28) 20 (31) Vomiting 7 (47) 9 (18) 16 (25) Thrombocytopenia 5 (33) 10 (20) 15 (23) Constipation 3 (20) 12 (24) 15 (23) Peripheral neuropathies 5 (33) 9 (18) 14 (22) Diarrhea 7 (47) 6 (12) 13 (20) Anemia 2 (13) 7 (14) 9 (14) Peripheral edema 2 (13) 6 (12) 8 (12) Muscle spasms 3 (20) 5 (10) 8 (12) Insomnia 2 (13) 6 (12) 8 (12) Dysgeusia 1 (7) 7 (14) 8 (12) Neutropenia 1 (7) 6 (12) 7 (11) Dizziness 4 (27) 3 (6) 7 (11) *Drug-related defined as related to any drug in the study drug combination, not specifically related to MLN9708 Pruritic, papular, maculo-papular, macular, erythematous, rash Includes peripheral neuropathy and peripheral sensory neuropathy Richardson et al, EHA 2012, Courtesy P. Richardson

Drug-related* AEs, grade 3 ( 2 pts overall) in weekly-dosing study AE, n (%) Phase 1 (n=15) Phase 2 (n=50) Total (n=65) Any grade 3 / 4 / 5 AE, % 60 / 0 / 0 30 / 2 / 2 37 / 1.5 / 1.5 Rash 2 (13) 5 (10) 7 (11) Blood and lymphatic system disorders 2 (13) 2 (4) 4 (6) Lymphopenia 1 (7) 1 (2) 2 (3) Thrombocytopenia 1 (7) 1 (2) 2 (3) Vomiting 3 (20) 0 3 (5) Nausea 2 (13) 1 (2) 3 (5) Syncope 2 (13) 0 2 (3) Fatigue 0 2 (4) 2 (3) One pt treated 2 dose levels above RP2D experienced grade 3 peripheral neuropathy with weekly MLN9708 in combination with lenalidomide and lowdose dexamethasone No grade 4 peripheral neuropathy *Drug-related defined as related to any drug in the study drug combination, not specifically related to MLN9708 Pruritic, papular, maculo-papular, macular, erythematous, rash Richardson et al, EHA 2012, Courtesy P. Richardson

Drug-related* AEs in twice-weekly dosing study AE n, % (N=11) All grades ( 10% pts) Fatigue 8 (73) Rash 7 (64) Constipation 3 (27) Insomnia 3 (27) Peripheral edema 2 (18) Anemia 2 (18) Peripheral neuropathies 2 (18) Tremor 2 (18) Hyperglycemia 2 (18) Hiccups 2 (18) Any grade 3 / 4 4 (11) / 0 Grade 3 ( 2 pts) Hyperglycemia 2 (18) *Drug-related defined as related to any drug in the study drug combination, not specifically related to MLN9708 Includes rash, rash maculo-papular, rash macular, rash pruritic, urticaria Includes peripheral neuropathy and peripheral sensory neuropathy; no grade 3/4 peripheral neuropathy Richardson et al, EHA 2012, Courtesy P. Richardson

MLN9708 +Rd Preliminary response in weekly-dosing study 64 of 65 pts received 1 cycle of treatment, and therefore were evaluable for response (response not confirmed by second assessment) 15 in phase 1, 49 in phase 2 Received median 4 cycles (range 1 15) Phase 1: median 6 (1 15), phase 2: median 3 (1 5) ORR: 91% 100% in phase 1, 88% in phase 2 CR+VGPR rate: 39% 53% in phase 1, 35% in phase 2 Richardson et al, EHA 2012, Courtesy P. Richardson

CRd Extended Treatment Tolerability 29 patients continue CRd maintenance (cycles 9 24) 5 pts patients initiated maintenance with single-agent lenalidomide (cycles 25+) Most common toxicities during maintenance were lymphopenia (30%), leukopenia (26%), and fatigue (25%) Limited dose modifications: 19% CFZ, 28% Len, and 31% Dex No discontinuations due to toxicity during maintenance phase Limited peripheral neuropathy (11%, all grade 1/2) No treatment related deaths during induction or maintenance Jakubowiak et al, ASCO 2012, Blood 2012; 120(9):1801-9 39