Myeloma Updates ASH 2011 Annual Meeting Steve Smith OHSU Knight Cancer Institute Center for Hematologic Malignancies

What was new is now old… long-term data on novel agent + chemo combinations 2 nd generation immunomodulators, proteasome inhibitors Will chemotherapy combinations be replaced by multitargeted therapies?

Overview: Progress in MM  Overall survival rates improving in younger patients  Almost 800 ASH abstracts in multiple myeloma about 10x more than a decade ago  understanding of pathbiology of the malignant plasma cell and microenvironment ASH 2011: nontransplant (elderly) regimens: longer follow-up second generation novel agents “multitargeted” strategies

MM Survival Trends 1950 – – – – – – O v e r a l l S u r v i v a l ( p r o p o r t i o n ) TimeSinceDiagnosis(months) O v e r a l l S u r v i v a l ( p r o p o r t io n ) TimeSinceDiagnosis(months) Patients < 65 years at Diagnosis* Patients > 65 years at Diagnosis* Turesson I, et al. J Clin Oncol. 2009;28: *Swedish Registry data.

MPT 1 N = 129 VMP 2 N = 337 MPR 3 N = 153 MPR-R 4 N = 152 VTP 5 N = 130 CR16%30%11%16%27% > VGPR29%Not reported33%32%37% > PR69%71%68%77%81% PFS21.8 moTTP: 24.0 mo14 mo31 mo23 mo Median follow-up31.8 mo36.7 mo25 mo 22 mo 1 Palumbo A, et al. Blood. 2008;112: ; 2 Mateos MV, et al. Blood. 2009;114(22). Abstract 3859; 3,4 Palumbo A, et al. Blood. 2010;116(21). Abstract 622 and Abstract 566; 5 Mateos MV, et al. Blood. 2009;114(22). Abstract 3. MPT: melphalan, prednisone, thalidomide; VMP: bortezomib, melphalan, prednisone; MPR: melphalan, prednisone, lenalidomide; MPR-R: MPR with maintenance lenalidomide; VTP: bortezomib, thalidomide, prednisone. Newly Diagnosed, Patients SCT Ineligible

VISTA Final Analysis  (Velcade) as Initial Standard Therapy in Multiple Myeloma= VISTA  updated OS analysis of VISTA after 5 years median follow-up  randomized, international, phase III clinical trial Newly Diagnosed/SCT ineligible

VISTA Final Analysis Newly Diagnosed/SCT ineligible

VISTA Final Analysis  5-year OS VMP vs MP: 46.0% vs 34.4% 13.3-month increase in OS  OS benefit in most subgroups sex, race, geographic region, β 2 -microglobulin level, and albumin level  OS benefit not observed for high-risk cytogenetics OS benefit initially observed in VMP arm diminished when patients received second-line therapy (included bortezomib in 60% of MP pts) Newly Diagnosed/SCT ineligible

MPR  R: Italian intergroup study MM-015 ASH 2011: 41 month f/u  MM-015: MPR with or without maintenance lenalidomide, vs MP in upfront SCT ineligible pts Newly Diagnosed/SCT ineligible

Italian Intergroup MM-015 PFS benefit to lenalidomide maintenance MPR-R vs MPR Landmark Analysis: PFS After Cycle 9 Palumbo A, et al. Blood. 2009;114(22). Abstract 613; Palumbo A, et al. European Hematology Association 15th Congress Abstract Time(months) P a t i e n t s ( % ) 30 HR0.314 Logrank P < Newly Diagnosed/SCT ineligible

MM-015: Outcomes in Overall Population  Continued lenalidomide significantly improves PFS vs placebo PFS benefit extended through patient subgroups in landmark analysis ⁻ Age (65-75 vs > 75 yrs), response (PR vs ≥ VGPR), ISS stage (I/II vs III) No effect on OS or TTP with maintenance lenalidomide Palumbo A, et al. ASH Abstract 475. OutcomeMPR-R (n = 152) MPR (n = 153) MP (n = 154) Median PFS, mos  HR vs MP  P value vs MP < yr OS, %  HR vs MP  P value vs MP TTP  HR vs MP

MM-015: Grade 4 Toxicities during induction and maintenance 1. é J et al. Br J Haematol. 1998;102: Palumbo A, et al. ASH 2011 Abstract 475 Adverse Events, %* Induction Therapy Maintenance Therapy MPRMPMPR-RMPR Grade 4 hematologic events Neutropenia32720 Thrombocytopenia7443 Anemia2231 Febrile neutropenia0000 Newly Diagnosed/SCT ineligible

MM-015: Second Malignancies 1. é J et al. Br J Haematol. 1998;102: Palumbo A, et al. ASH 2011 Abstract 475 Second Malignancies, Incidence Rate/100 Patients/Yr MPR-R (n = 150) MPR (n = 152) MP (n = 153) Total invasive second primary malignancies Hematologic malignancies Solid tumors Nonmelanoma skin cancer Newly Diagnosed/SCT ineligible

Kumar, et al. Haematologica. 2010;95(suppl 2). Abstract 376. Patients Relapsing and Refractory to Bortezomib and Thalidomide or Lenalidomide Relapsed / Refractory Disease NEvents (n)Median Overall Survival months Event-Free Survival months

The Next Generation…  2nd generation immunomodulatory agents  2nd generation proteasome inhibitors  HDAC Inhibitors  Monoclonal antibodies  Alkylating agents  Other proteasome inhibitors  Heat shock protein inhibitors  PI3K / AKT inhibitor  mTOR inhibitors

Carfilzomib: second-generation proteasome inhibitor  Administered IV First 2 days of each week, for 3 weeks (repeated monthly)  Active in heavily pretreated MM patients  Mild neuropathy seen but uncommon (< 20%) Severe neuropathy (grade 3-4): <2% Toxicity ⁻ Myelosuppression, fatigue, URI/ PNA, infusion reactions  ≈ 15% grade 3-4 anemia, thrombocytopenia, and neutropenia PX A1: Siegel DS, et al. Blood. 2010;116(2). Abstract 985; PX Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099; Wang ASH 2009 Abstract 302. Niesvizky R, et al. Blood. 2010;116(2). Abstract 619.

Carfilzomib: Phase II Rel/Ref MM ASH 2011: Single-Agent Carfilfzomib, rel/ref MM (PX ): Final results from the bortezomib-naive group  n = 129  Treated for up to 12 cycles  Data from 2 cohorts presented 1- Carfilzomib 20 mg/m 2 (n=59) 2- Carfilzomib 20 mg/m 2 for cycle 1, then  to 27 mg/m 2 for cycles 2-12 (n=70) Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813 Rel/Ref MM

Carfilzomib phase II PX : Baseline characteristics Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813 Characteristic Carfilzomib 20 mg/m 2 (n = 59) Carfilzomib 20/27 mg/m 2 (n = 70) Median age, yrs (range)65 (38-82)65.5 (45-85) Median yrs from diagnosis (range) 3.5 ( )3.6 ( ) Neuropathy, %4955 Median previous treatments, n (range) 2 (1-4) Refractory to most recent therapy, % 6664 Prior Stem cell transplantation (%) 8067 Cyto or FISH = Unfavorable (%) 1514 Rel/Ref MM

Carfilzomib phase II PX : Response Data Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813 Outcome Carfilzomib 20 mg/m 2 (n = 59) Carfilzomib 20/27 mg/m 2 (n = 67)* ORR, %4252 CR32 VGPR1427 PR2524 Median time to response, mos Median PFS, mos8.2NR Median duration of f/u, mos Rel/Ref MM

Carfilzomib phase II PX : Conclusions  In bortezomib-naïve rel/ref MM pts, combined ORR 48% Potential dose-response relationship  No increase in neuropathy risk with carfilzomib in pts with history of, or pre-existing, neuropathy PNP is ⁻ Mostly mild to moderate severity, not dose limiting  Grade 3/4 adverse events in 80% of patients- primarily hematologic ⁻ Generally reversible  AE’s led to treatment discontinuation in 16% of patients Vij R, Kaufman JL, Jakubowiak AJ, et al. Abstract 813 Rel/Ref MM

ASH 2011: Phase 2 results  Carfilzomib + len + dex Upfront, SCT-eligible

MLN9708 Phase I Study: ASH 2011  MLN9708, PO proteasome inhibitor  Phase I study  relapsed/refractory MM (N = 56) ⁻ Dose-escalation phase (n = 26) ⁻ Expansion phase (n = 36; 6 from dose-escalation cohort) ⁻ 27% to 32% refractory to bortezomib on last previous therapy  MLN9708 dosing ⁻ Starting 0.24 mg/m 2, increased to 2.23 mg/m 2 on Days 1, 4, 8, 11 of a 21-day cycle for up to 12 cycles 46 patients evaluable for response Richardson PG, et al. ASH Abstract 301. Rel/Ref MM

MLN9708 Phase I Study: Safety and Response  MTD 2.0 mg/m 2 32% of patients required dose reductions due to adverse events ⁻ Mainly thrombocytopenia, neutropenia, and rash ⁻ 9% of patients discontinued treatment due to adverse events  Grade 3/4 adverse events: thrombocytopenia (34%), neutropenia (14%), fatigue (9%), rash (9%) No grade 3 /4 neuropathy  15% (n = 7) patients achieved response Durable disease control up to 15.9 mos Majority (61%) of remaining patients reached SD, durable for up to 12.9 mos Richardson PG, et al. ASH Abstract 301. Rel/Ref MM

MLN Len + Dex: Phase I/II Combination  Open-label, multicenter, dose-escalation phase I/II trial Primary endpoints: safety, MTD, recommended phase II dose ⁻ Secondary endpoints: MLN2238 pharmacokinetics, treatment response  Previously untreated MM (n = 15 to date)  Treatment: 28-day cycles for up to 12 mos ⁻ MLN9708: started at 1.68 mg/m 2, increased in 33% increments based DLT ⁻ Dex: 40 mg/day on Days 1, 8, 15, 22 ⁻ Lenalidomide: 25 mg/day on Days 1-21 Berdeja JG, et al. ASH Abstract 479. Upfront, SCT-eligible

MLN Len + Dex Phase I/II: outcomes  Responses observed in all patients (N =15), generally in cycle 1 CR (n = 4), VGPR (n = 5), and PR (n = 6)  No DLT observed up to 2.23 mg/m 2 MLN9708 Recommended phase II dose: 2.23 mg/m 2 /wk  Well tolerated Grade 1 peripheral neuropathy (n = 3) Grade 3: vomiting (n = 2), deep vein thrombosis (n = 2), anemia (n = 2), rash (n = 2) Grade 4: thrombocytopenia (n = 1) Berdeja JG, et al. ASH Abstract 479. Upfront, SCT-eligible

Final topic… Relapsed/novel agents: Multitargeted combinations

clinicaloptions.com/oncology Update on Multiple Myeloma VANTAGE 088: Study Design  International, multicenter, double-blind, randomized phase III trial [1] –Vorinostat: HDAC inhibitor active when combined with bortezomib in phase I and II trials [2-4] 1. Dimopoulos MA, et al. ASH Abstract Weber D, et al. ASCO Abstract Badros A, et al. Clin Cancer Res. 2009;15: Siegel DS, et al. ASH Abstract 480. Relapsed/ refractory MM patients with PD following most recent therapy (N = 637) 1-3 previous therapies; bortezomib sensitive PD or unacceptable toxicity Bortezomib 1.3 mg/m 2 on Days 1, 4, 8, 11 + Vorinostat 400 mg/day on Days 1-14 (n = 317) Bortezomib 1.3 mg/m 2 on Days 1, 4, 8, 11 + Placebo (n = 320) 21-day cycles Primary endpoint: PFS Secondary endpoints: OS, TTP, ORR, safety Rel/Ref MM

clinicaloptions.com/oncology Update on Multiple Myeloma VANTAGE 088: PFS, OS, and Response  PFS significantly prolonged with addition of vorinostat to bortezomib –No difference in median OS (data not yet mature) Dimopoulos MA, et al. ASH Abstract ORRCRVGPRPR Response Type Response Rate (%) MR SD Bortezomib + vorinostat (n = 315) Bortezomib + placebo (n = 320) 7.63 vs 6.83 mos HR: (95% CI: ; P =.01) P < Patients With PFS (%) Mos PFS (IAC) Response (IAC) Rel/Ref MM

clinicaloptions.com/oncology Update on Multiple Myeloma PANORAMA-2: Study Design  Panobinostat: potent, investigational HDAC inhibitor –Combination with bortezomib active in relapsed/refractory MM –ORR: 80% (overall population); 50% (bortezomib-refractory subset) [1]  Current study evaluated efficacy of panobinostat with bortezomib plus dexamethasone in relapsed bortezomib-refractory MM patients (N = 55) [2] –Single-arm phase II trial –Primary endpoint: ORR 1. San Miguel J, et al EHA. Abstract Richardson PG, et al. ASH Abstract 814. Phase I: 8 x 3-wk cycles Panobinostat 20 mg on Days 1, 3, 5, 8, 10, 12 + Bortezomib 1.3 mg/m 2 on Days 1, 4, 8, 11 + Dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, 12 Phase II (for patients with clinical benefit after phase I): 6-wk cycles until PD Panobinostat 20 mg on Days 1, 3, 5, 8, 10, 12, 22, 24, 26, 29, 31, 33 + Bortezomib 1.3 mg/m 2 on Days 1, 8, 22, 29 + Dexamethasone 20 mg on Days 1, 2, 8, 9, 22, 23, 29, 30 Rel/Ref MM

clinicaloptions.com/oncology Update on Multiple Myeloma PANORAMA-2: Response and Safety  Responses were rapid, often within 1-2 cycles  Most frequent grade 3/4 events: thrombocytopenia (53%), anemia (16%), neutropenia (12%) –Peripheral neuropathy (24%) was grade 3/4 in only 1 patient (2%) –Fatigue (63%) was grade 3/4 in 16%; generally manageable with dose reduction Response Rate, %Panobinostat + Bortezomib + Dexamethasone (n = 55) ORR (CR + nCR + PR)29  CR0  nCR4  PR25 Clinical benefit (ORR + MR)49  MR20 VGPR6 Richardson PG, et al. ASH Abstract 814. Rel/Ref MM

clinicaloptions.com/oncology Update on Multiple Myeloma PANORAMA-2: Conclusions  Combination of investigational HDAC inhibitor panobinostat with bortezomib active [1] –Effective even in this heavily pretreated, bortezomib- refractory MM patient set  Treatment relatively well tolerated [1] –Grade 3/4 myelosuppression manageable with dose reduction or interruption –Infrequent grade 3/4 peripheral neuropathy  Lower toxicity with this dose schedule (1 wk rest period between cycles) vs previously observed in phase I trial [2] 1. Richardson PG, et al. ASH Abstract San Miguel J, et al EHA. Abstract Rel/Ref MM

On the horizon  Improving outcomes for lenalidomide/bortezomib- refractory patients  maximizing clinical benefit disease control using maintenance? drug holiday? Multitargeted combinations?  Active clinical trials: Novel agents, orally administered MLN+rev+dex upfront optimal ASCT regimen? CTN 0702: ⁻ tandem  len maintenance ⁻ single  len+bort+dex consolidation  len maintenance ⁻ single  len maintenance

Acknowledgements Myeloma Program at OHSU: Emma Scott, MD Anne Kratz, RN Richard Maziarz, MD All other MD, RN, PA/NP, admin staff at OHSU Slides Rachid Baz, MD (Moffitt Cancer Center, Tampa, FL) Clinical Care Options (clinicaloptions.com) educational concepts group (

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(Extra slides) Consolidation after ASCT- already presented in Paris 2011…  CALGB OS benefit to len maintenance after ASCT (90 vs 83% OS at 28 months, p=.02) TTP benefit 48 mo vs 31 mo second malignancies higher (n=15 vs 6)  IFM clear PFS benefit (42 vs 22 mo), second malignancies higher, study halted  both: higher cumulative grade 3-4 PMN with maintenance, more 2 nd malignancies…

clinicaloptions.com/oncology Update on Multiple Myeloma QuiRedex: Study Design  Multicenter, open-label, randomized phase III trial –Evaluated new treatment regimen for smoldering MM vs current standard of care Mateos MV, et al. ASH Abstract 991. Patients with high-risk smoldering MM (N = 126) Lenalidomide 25 mg/day on Days Dexamethasone 20 mg/day on Days 1-4, No Treatment Lenalidomide 10 mg/day on Days 1-21 (Low-dose dexamethasone added at time of biologic progression) Induction 9 x 28-day cycles Maintenance 28-day cycles 2 yrs Primary endpoint: TTP to symptomatic MM Secondary endpoints: response, duration of response, safety and tolerability, PFS, OS

clinicaloptions.com/oncology Update on Multiple Myeloma QuiRedex: TTP to Symptomatic MM and OS  Significant increase in TTP with vs without treatment  Significantly prolonged OS with vs without treatment –Median 3-yr OS (from study inclusion): 93% vs 76%; P =.04 –Median 5-yr OS (from diagnosis): 94% vs 79%; P =.03 Mateos MV, et al. ASH Abstract 991. Median TTP Lenalidomide/dexamethasone: NR No treatment: 23 mos HR: 6.0 (95% CI: ; P <.0001) Median follow-up: 32 mos (range: 12-49) Proportion of Patients Alive Mos From Inclusion Lenalidomide + dexamethasone No treatment

clinicaloptions.com/oncology Update on Multiple Myeloma QuiRedex: Safety  3 cases of second primary malignancies reported in treatment arm Mateos MV, et al. ASH Abstract 991. Adverse Event, %Lenalidomide + Dexamethasone (n = 57) No Treatment (n = 62) Grade 1/2Grade 3Grade 1/2 Anemia282-- Neutropenia205-- Thrombocytopenia132-- Asthenia20711 Constipation18--2 Diarrhea2424 Rash334-- Paresthesias5-- Tremor13--2 Infection46626 Deep vein thrombosis5--

Alternative Bortezomib Regimens Reeder CB, et al. ASH Annual Meeting Abstracts. 2009;114(22):616; Palumbo A, et al. ASH Annual Meeting Abstracts. 2010;116(21):620. RegimenNORRCRGrade 1/2 PN > Grade 3 PN CyBorD Twice weekly btz Once weekly btz % 93% 39% 40% 64% 56% 6% 0% VMPT-VT Twice weekly btz Once weekly btz % 85% 35% 30% 29% 19% 14% 2% Btz: bortezomib; PN: peripheral neuropathy; CyBorD: cytarabine, bortezomib, dexamethasone; VMPT-VT: bortezomib, melphalan, prednisone, thalidomide followed by maintenance bortezomib and thalidomide.

Bort- Alternative Modes of Administration Moreau P, et al. Blood. 2010;116(21). Abstract 312. IV Bortezomib N = 73 SC Bortezomib N = 145 P ORR after 8 cycles CR > VGPR 52% 12% 25% 52% 10% 25% NS NS NS Median TTP9.4 months10.4 months year OS77%73%NR Any grade 3/4 AE70%57%NR PN Any grade > grade 3 53% 16% 38% 6% IV: intravenous; SC: subcutaneous; CR: complete response; VGPR: very good partial response; TTP: time to progression; OS: overall survival; AE: adverse event; PN: peripheral neuropathy.