Treatment strategies for non-transplant-eligible patients

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1 Treatment strategies for non-transplant-eligible patients Thierry FACON, MD Professor of Hematology Service des Maladies du Sang University of Lille Lille, France

2 An average elderly MM patient.. 74 year old female patient who was otherwise heathly, presented in Oct with a vertebral compression fracture Work up revealed IgA K symptomatic MM, ISS3, creatinine 1.5, multiple bone lesions, no cytogenetics The patient family asked for several opinions Paris (2 KOL) ; MPT DFCI/USA (2 KOL) ; VRD MDACC/USA ; CVRD, discuss ASCT eligibility Florida/USA ; Rd, add V if poor response Beyrouth American University ; MPT or Rd or VMP Beyrouth Rafik Hariri University ; VCD Beyrouth Al-Zahraa Hospital ; Thal or R with Dex Courtesy to Dr Tarek Wehbe, Lebanon

3 Both MPV and MPT are recognised standards of care in TNE NDMM patients 2014: IMWG guidelines 1 Recommended treatments for patients not eligible for high-dose therapy, or in case the transplant procedure is not available, include MPT, MPV and CTD" 2014: EMN guidelines 2 Bortezomib-melphalan-prednisone or melphalan-prednisone-thalidomide are the standards of care for transplant-ineligible patients" 2014: NCCN guidelines 3 MPT is one of the five preferred primary regimens for non-transplant candidates with multiple myeloma 1. Ludwig H et al., Leukemia 2013, in press. 2. Engelhardt M, et al. Haematologica. 2014;99: NCCN Guidelines Multiple Myeloma. Version

4 MPT and VMP over time MPT: a stable standard of care thalidomide 100 (or 200 mg/day) MPV: an evolving standard of care from twice weekly to weekly 1,2 (2010) from i.v. to s.c. 3 (2012) subcutaneous weekly likely the current standard of care for VMP and other bortezomib-based regimens in the elderly 1. Palumbo A, et al. J Clin Oncol. 2010;28: Mateos MV, et al. Lancet Oncol. 2010;11: Moreau P, et al. Lancet Oncol. 2011;12:

RANDOMIZATION 1:1:1 PD or Unacceptable Toxicity PD, OS and Subsequent anti-mm Tx FIRST Trial: Study Design 5 Screening Active Treatment + PFS Follow-up Phase LT Follow-Up Arm A Continuous Rd LEN +

5 RANDOMIZATION 1:1:1 PD or Unacceptable Toxicity PD, OS and Subsequent anti-mm Tx FIRST Trial: Study Design 5 Screening Active Treatment + PFS Follow-up Phase LT Follow-Up Arm A Continuous Rd LEN + Lo-DEX Continuously LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm B Rd18 LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28 Lo-DEX 40mg D1,8,15 & 22/28 Arm C MPT MEL + PRED + THAL 12 Cycles 1 (72 wks) MELPHALAN PREDNISONE THALIDOMIDE 0.25mg/kg D1-4/42 2mg/kg D1-4/42 200mg D1-42/42 Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL 2 (100 mg D1-42/42); MEL mg/kg D1 4 Stratification: age, country and ISS stage ISS, International Staging System; LT, long-term; PD, progressive disease; OS, overall survival 1 Facon T, et al. Lancet 2007;370: ; 2 Hulin C, et al. JCO. 2009;27: Facon T, et al. Blood. 2013;122:abstract 2.

6 FIRST Trial: Patient Disposition Median follow-up of 37 months as of May 24, RANDOMIZATION 1:1:1 (N=1,623) Continuous Rd (n=535) Rd18 (72 weeks) (n=541) MPT (72 weeks) (n=547) Continuous Rd Rd18 MPT Pts still on study Tx, n (%) 121 (23) 0 (0) 0 (0) Pts reaching 72 wks of Tx, n (%) 293 (55) 283 (52) 242 (45) Pts treated > 2 yrs, n (%) 208 (39) 0 (0) 0 (0) Study discontinuation due to AEs, n (%) 56 (11) 71 (13) 76 (14) AEs, adverse events; pts, patients; Tx, treatment; wks, weeks; yrs, years Facon T, et al. Blood. 2013;122:abstract 2.

7 FIRST Trial: Baseline Characteristics 7 Patient characteristics were well balanced across all treatment arms Characteristic Continuous Rd (n=535) Rd18 (n=541) MPT (n=547) Median age, yrs (range) 73 (44 91) 73 (40 89) 73 (51 92) > 75 yrs (%) Male (%) ECOG PS grade 0/1/2 (%) 29/48/22 30/49/21 29/50/20 ISS III (%) CrCl < 30 ml/min (%) High-risk cytogenetics a (%) a Complete cytogenetics profile for 762 pts (248 in Rd, 261 in Rd18 and 253 in MPT), High-risk including t(4;14), t(14;16), del(17p) CrCl, creatinine clearance; ECOG, Eastern Cooperative Oncology Group; ISS, international scoring system; PS, performance status; yrs, years Facon T, et al. Blood. 2013;122:abstract 2.

8 72 wks Patients (%) FIRST Trial: Final Progression-free Survival Median PFS Rd (n=535) 25.5 mos Rd18 (n=541) MPT (n=547) Hazard ratio Rd vs. MPT: 0.72; P = Rd vs. Rd18: 0.70; P = Rd18 vs. MPT: 1.03; P = mos 21.2 mos Time (months) Rd Rd MPT mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone. Facon T, et al. Blood. 2013;122:abstract 2.

9 Patients (%) FIRST Trial: Final Progression-free Survival Median PFS Rd (n=535) 25.5 mos Rd18 (n=541) MPT (n=547) Hazard ratio Rd vs. MPT: 0.72; P = Rd vs. Rd18: 0.70; P = Rd18 vs. MPT: 1.03; P = mos 21.2 mos 40 42% (Rd) 20 23% (Rd18) 23% (MPT) Time (months) Rd Rd MPT mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, lenalidomide plus low-dose dexamethasone. Facon T, et al. Blood. 2013;122:abstract 2.

10 Patients (%) FIRST Trial: Overall Survival Interim Analysis deaths (35% of ITT) 4-year OS Rd (n= 535) 59.4% Rd18 (n= 541) 55.7% MPT (n= 547) 51.4% Hazard ratio Rd vs. MPT: 0.78; P = Rd vs. Rd18: 0.90; P = Rd18 vs. MPT: 0.88; P = Rd Rd18 MPT Overall survival (months) Facon T, et al. Blood. 2013;122:abstract 2.

11 FIRST Trial: Response Endpoints 11 Response a (%) Continuous Rd (n=535) Rd18 (n=541) MPT (n=547) ORR ( PR) b CR VGPR PR SD VGPR or better Time to response (median, mos) Duration of response (median, mos) a IMWG Criteria; CR, complete response; mos, months ORR, overall response rate; PR, partial response; SD, stable disease; VGPR, very good PR. b Response assessment for Rd obtained every 4 wks and for MPT every 6 wks; Response and progression rate based on IRAC assessment. a Durie et al. Leukemia 2006; 20: Facon T, et al. Blood. 2013;122:abstract 2.

12 FIRST Trial: Safety Selected Grade 3 4 TEAEs 12 Hematological (%) Continuous Rd (n=532) Rd 18 (n=540) MPT (n=541) Anemia Neutropenia Thrombocytopenia Febrile neutropenia Non-hematological (%) Infections Pneumonia Diarrhea Constipation Peripheral sensory neuropathy DVT and/or PE Cataract Severity of AEs graded according to NCI CTCAE v3.0. DVT, deep-vein thrombosis; PE, pulmonary embolism; TEAEs, treatment-emerging adverse events. Facon T, et al. Blood. 2013;122:abstract 2.

13 FIRST Trial: Conclusions 13 Continuous Rd significantly extended PFS, with an OS benefit vs. MPT PFS: HR= 0.72 (P= ) Consistent benefit across most subgroups Rd better than Rd18 (HR= 0.70, P= ) 3 yr PFS: 42% Rd vs 23% Rd18 and MPT Planned interim OS: HR= 0.78 (P= ) Rd was superior to MPT across all other efficacy secondary endpoints Safety profile with continuous Rd was manageable Hematological and non-hematological AEs were as expected for Rd and MPT Incidence of hematological SPM was lower with continuous Rd vs. MPT In NDMM transplant-ineligible patients, the FIRST Trial establishes continuous Rd as a new standard of care Facon T, et al. Blood. 2013;122:abstract 2.

14 Balancing efficacy and safety in TNE NDMM patients Study design Randomized phase 3 study of MPR, CPR, or Rd induction (9 cycles) R or 660 patients have been randomized RP maintenance in elderly SCT ineligible pts. Median follow-up: 21 months. Symptomatic multiple myeloma patients not transplant-eligible 1 R A N D O M I Z A T I O N Rd 1 Nine 28-day courses R: 25 mg, d 1-21 d: 40 mg, d 1,8,15,22 MPR 2 Nine 28-day courses M: 0.18 mg/kg, d 1-4 P: 1.5 mg/kg, d 1-4 R: 10 mg, d1-21 CRP 3 * Nine 28-day courses C: 50 mg, d1-21 P: 25 mg, 3 times wk R: 25 mg, d R A N D O M I Z A T I O N MAINTENANCE 28-day courses until relapse R: 10 mg/day, days 1-21 MAINTENANCE 28-day course until relpase R: 10 mg/day, days 1-21 P: 25 mg; 3 times wk >75 years: 1 Dexamethasone 20 mg/week; 2 Melphalan 0.13 mg/kg; 3 Cyclophosphamide: 50 mg qod on days 1-21 Palumbo A et al. Blood. 2013:abstract 536. Updated data presented at ASH 2013.

15 CPR vs MPR vs Rd: summary of efficacy and safety Efficacy outcomes CPR MPR Rd Response rates, % VGPR PR Long-term outcomes 2-yr PFS yr OS Grade 3-4 AEs, % CPR MPR Rd ANC PLT Infection SPM Discontinuation due to AE Palumbo A et al. Blood. 2013:abstract 536. Updated data presented at ASH 2013.

16 Randomization MM026: phase IIIb trial of Len vs placebo maintenance following VMP SCT-ineligible NDMM patients N =351 Lenalidomide (10 mg/day), Day 1-21 For 24 months PR following 6-9 cycles of VMP Placebo, Day 1-21 For 24 months

17 Lenalidomide as the backbone of therapy in elderly patients Proteasome inhibitors Rd + carfilzomib in RRMM, phase 3 (US/EU), phase 1/2 (US) Rd + MLN9708 in RRMM: phase 3 (USA, Canada, EU) Rd + MLN9708 in NDMM: phase 3 (USA, Canada, EU, Australia) HDAC inhibitors Rd + vorinostat in RRMM: multiple phase 1/2 (US, EU), 1 phase 3 (USA) Rd + panobinostat in RRMM: 2 phase1/2 (USA, Australia, EU) Rd + ACY-1215 in RRMM: phase 1 (USA) Monoclonal antibodies Rd + elotuzumab in RRMM: multiple phase 1/2 (EU, USA, Japan), 1 phase 3 (ELOQUENT-2) Rd + elotuzumab in NDMM: phase 3 (ELOQUENT-1) Rd + daratumumab in RRMM: 2 phase 1/2 (USA, Canada, EU) Rd + SAR in RRMM: phase 1 (USA) Rd + IPH2101 in RRMM: phase 1 (USA)

Randomization Phase 3 trial: oral MLN9708 plus Len/Dex vs placebo plus Len/Dex in NDMM MillenniumC16014 / IFM 2013-07 N ~ 700 Placebo + Lenalidomide (25 mg) + Dex (40 mg)* Treat for 18 months Placebo

18 Randomization Phase 3 trial: oral MLN9708 plus Len/Dex vs placebo plus Len/Dex in NDMM MillenniumC16014 / IFM N ~ 700 Placebo + Lenalidomide (25 mg) + Dex (40 mg)* Treat for 18 months Placebo + Lenalidomide (10 mg) Until progression MLN9708 (4.0 mg) + Lenalidomide (25 mg) + Dex (40 mg) Treat for 18 months MLN9708 (3.0 mg) + Lenalidomide (10 mg) Until progression Primary endpoint: PFS Key secondary endpoints: CR, OS, pain relief * 20 mg for patients > 75 years of age. NCT Available from:

19 Front-line regimens in elderly patients The Melphalan issue A different approach in the US and in other countries? SV Rajkumar, IMW Paris 2011 No melphalan No thalidomide Some other non-us countries Melphalan and cyclophosphamide: effective and low cost (MPV, CTD) Thalidomide: effective and affordable in many countries No high-dose dexamethasone No twice weekly or i.v. bortezomib Target CR only in high-risk patients Agree Agree Low-risk patients are still not cured and may benefit more from combination regimens

20 Different strategies for NDMM in elderly patients Carf-MP 1 (IFM, Carmysap) MLN 9708-Rd 2 Phase 1/2 Phase 1/2 Enrolment Oct March 2012 Nov 2010 Feb 2012 Cycles (N) 9 12, then maintenance Patients (N) years 64 Age not specified ORR (%) VGPR (%) Safety profile Tolerable No neurotoxicity Tolerable No significant neurotoxicity Phase 3 CMP vs VMP MLN9708-Rd vs Rd Carf-CycloDex results in elderly patients are also promising 3 1. Kolb et al. J Clin Oncol. 2012;[abstract 8009]. 2. Kumar S, et al. Blood. 2012;[abstract 332]. 3. Palumbo A, et al. Blood. 2012;[abstract 730].

Probability of OS Probability of OS Cytogenetic abnormalities are a major prognostic factor in elderly patients with MM the IFM experience 1,890 patients (median age 72, range 66 94), including 1,095

21 Probability of OS Probability of OS Cytogenetic abnormalities are a major prognostic factor in elderly patients with MM the IFM experience 1,890 patients (median age 72, range 66 94), including 1,095 patients with updated data on treatment modalities and survival 1.00 OS according to t(4:14) 1.00 OS according to del(17p) 0.75 p < 10.4 p < t(4:14) neg t(4:14) pos Time (years) Whatever the treatment, t(4;14) and del(17p) were associated with shorter PFS and OS; similar results were achieved in the subgroup of 335 patients > 75 years del(17p) < 60 del(17p) Time (years) Avet-Loiseau H, et al. JCO 2013;31:

22 Are all 'elderly' people alike?

23 Frailty is stronger predictor of OS than ISS or FISH (GIMEMA) Larocca A, et al. Blood. 2013;122:abstract 687.

24 IMWG consensus statement on the treatment of TNE NDMM patients Newly diagnosed, symptomatic MM patients NOT eligible for high dose therapy (MEL200) and SCT Assessment of patient status: Presence of comorbidities and/or limits in mental or mobility functions Specific index and scores can be used Very fit Fit Unfit Reducedintensity ASCT (MEL 100) MPT MPV/VMPT-VT VCD/VRD MPR-R/Rd Low-dose MPT/MPV Vd/Rd MPR-R, melphalan, prednisone, lenalidomide followed by lenalidomide maintenance; MPT, melphalan, prednisone, thalidomide; MPV, bortezomib, melphalan, prednisone; Rd, lenalidomide, low-dose dexamethasone; Vd, bortezomib, low-dose dexamethasone; VMPT-VT, bortezomib, melphalan, prednisone, thalidomide followed by bortezomib plus thalidomide maintenance Palumbo A, et al. J Clin Oncol Epub January 13.

25 Proportion surviving Continued Improvement in Survival Since the Introduction of Novel Agents 1,056 patients grouped into and cohorts Survival improved over time, particularly in patients aged > 65 years (p = 0.001) 1.0 Diagnosed Diagnosed Follow-up from diagnosis (years) Survival Median OS, years 4.6 NR year survival, % year estimated OS, % Overall > 65 years < 65 years NS p Kumar SK, et al. Blood. 2012;120:[abstract 3972]. Updated data presented at ASH 2012.

26 Targets in MM plasma cells & agents in development Approved agents Agents in phase 3 trials Ocio et al. Leukemia 2013 Nov 20 [Epub]

Acknowledgments: 27 Our Patients and Families Investigators, Nurses, Coordinators, DSMB and IRAC members Australia: C. Forsyth, P. Presgrave, J. Szer, S. Durrant, P. Campbell, P. Mollee, D.

27 Acknowledgments: 27 Our Patients and Families Investigators, Nurses, Coordinators, DSMB and IRAC members Australia: C. Forsyth, P. Presgrave, J. Szer, S. Durrant, P. Campbell, P. Mollee, D. Coghlan, J. Wellwood, P. Cannell, M. Prince, R. Eek, J. Catalano, N. Horvath, S. Harrison, W. Renwick; Austria: J. Thaler, A. Petzer, H. Kasparu, T. Bauernhofer, J. Meran, M. Fridrik, P. Balcke, H. Ludwig, H. Gisslinger, R. Greil; Belgium: C. Doyen, N. Meuleman, P. Pierre, M. Vekemans, H. Demuynck, K. Wu, J. Van Droogenbroeck, R. Schots, M. Delforge, F. Offner, A. Van de Velde; Canada: R. Leblanc, N. Bahlis, A. Tosikyan, A. Belch, C. Shustik, K. Song, C. Chen, B. Lemieux, L. Minuk, M. Lalancette, M. Cheung, D. White, M. Noble, R. Vanderjagt, P. Desjardins, N. Aucoin, G. Dueck, A. Yee, A. Reiman, T. Kouroukis, S. Assouline, A. Al-Tourah; China: J. Lu, L. Qiu, W. Chen, T. Liu, Z. Shen; France: M. Alexis, D. Assouline, M. Attal, B. Audhuy, I. Azais, A. Banos, K. Belhadj, L. Benboubker, R. Benramdane, A. Tempescul, F. Boue, C. Rose, J. Bourhis, D. Bouscary, D. Caillot, P. Casassus, B. De Renzis, P. Genet, T. De Revel, M. Dib, V. Dorvaux, G. Etienne, E. Gabriel, J. Eisenmann, T. Facon, J. Fermand, O. Fitoussi, L. Garderet, M. Gaspard, C. Sebban, S. Glaisner, I. Griffoul, O. Decaux, P. Moreau, R. Herbrecht, C. Hulin, A. Jaccard, H. Jardel, R. Kaphan, B. Kolb, M. Escoffre Barbe, K. Laribi, P. Lenain, M. Macro, H. Maisonneuve, S. Pavy, G. Marit, M. Michallet, O. Allangbam, L. Mosser, B. Pegourie, S. Rigaudeau, P. Rodon, J. Rossi, B. Royer, J. Eschard, A. Stoppa, E. Suc, A. Thyss, G. Salles, J. Vilque, L. Voillat, E. Voog, M. Wetterwald, C. Zarnitsky; Germany: C. Junghanss, U. Dührsen, R. Fenk,. M. Rummel, H. G. Derigs, M. Zeis, L. Mügge, O. Ottmann, H. Ostermann, M. Kropff, D. Niederwieser, K. Weisel, C. Langer, C. Röllig Greece: M. Dimopoulos, P. Panagiotidis Italy: M. Cavo, A. Corso, N. Di Renzo, R. Foa, A. Fragasso, L. Canepa, G. Martinelli, B. Gamberi, M. Musso, M. Petrini, A. Pinto, F. Pisani, G. Quarta, S. Sacchi, P. Tassone, A. Lazzaro, F. Ciceri; New Zealand: P. Browett, K. Romeril, A. Butler; Portugal: J. Parreira, A. Martins, C. Geraldes, M. Herlander, C. Gonçalves; South Korea: J. H. Lee, S. Yoon, H. Eom, J. Lee, D. Jo, J. Kwak, H. Ryoo, J. Lee, S. J. Kim, C. K. Min, C. Suh, K. Kim, W. Lee, Y. Mun, H. J. Kim; Spain: J. J. Lahuerta-Palacios, J. Bargay Lleonart, M. S. Gonzalez, A. Bermudez-Rodriguez, F. De Arriba de la Fuente, M. Mateo-Morales, Y. Gonzalez-Montes, D. Hernandez Maraver, A. Oriol Rocafiguera, V. Clapés, F. Prosper-Cardoso, G. Ramírez, A. Teruel Casasus, M. Granell, J. De la Rubia Comos, P. Giraldo-Castellano, A. Echeveste Gutierrez, L. Palomera-Bernal; Sweden: H. Nahi, A. Gruber, F. Sjöö; Switzerland: S. Leyvraz (former Dr. Ketterer), T. Pabst, D. Heim, M. Bargetzi, R. Cathomas, D. Binder; Taiwan: S. Huang, S. Yeh, T. Chiou; United Kingdom: J. Cavenagh, Y. Ezaydi, T. Littlewood, C. Knechtli, G. McQuaker, C. Fegan, A. Mehta, J. Bird, J. Ashcroft, M. Kazmi, H. Hunter, M. Cook, C. Crawley, S. Basu, R. Hall, J. Seale; United States: A. Dispenzieri, W. Bensinger, S. Coutre, V. Priego, T. Martin, H. Kaplan, N. Tirumali, S. Dakhil, M. Gupta, R. Jacobson, D. Vogl, M. Moezi, D. Gravenor, F. Yunus, T. Guthrie, F. Reu, R. Catchatourian, N. Gabrail, J. Nieva, M. De la Puerta, H. Ryan Facon T, et al. Blood. 2013;122:abstract 2.

28 Dexamethasone-based regimens vs MP in elderly NDMM patients 28

Dexamethasone-based regimens versus MP for elderly NDMM patients Proportion Proportion 1.0 1.0 0.8 0.8 0.6 0.4 0.2 0.

29 Dexamethasone-based regimens versus MP for elderly NDMM patients Proportion Proportion Time from inclusion (month) Treatment O/N Survival time median±se (month) MP 106/ ± 3.6 M + DEX 97/ ± 3.1 DEX 110/ ± 2.0 DEX + IFN 102/ ± Time from inclusion (month) Progression-free Treatment O/N survival time median±se (month) MP 120/ ± 1.7 M + DEX 112/ ± 2.0 DEX 123/ ± 1.0 DEX + IFN 118/ ± 2.7 Facon T, et al. Blood. 2006;107:

30 Dexamethasone-based regimens versus MP for elderly NDMM patients: toxicity 30 Toxicity Total, n (%) MP, n M-Dex, n Dex, n Dex-IFN, n Severe pyogenic infections 59 (12) Pulmonary 25 (5) Septicemia 18 (4) Other 16 (3) Severe hemorrhage Perforated diverticulum Psychiatric complications 10 (2) (2) (2.5) * Severe diabetes 16 (3) DVT/PE 21 (4) Any severe toxicity 121 (25) Facon T, et al. Blood. 2006;107:

31 MP vs MPT Studies : Patient characteristics and MPT regimens 31 GIMEMA 1,2 IFM IFM NMSG 5 HOVON 6 No.pts (MPT) 331 (167) 447 (125) 232 (113) 363 (182) 333 (165) Age median (mean) 72 range NA WHO 3/4 (%) MPT regimen No. Cycles Until plateau Until plateau M dosing 4 mg/m mg/kg 0.2 mg/kg 0.25 mg/kg 0.25 mg/kg d1-7 d1-4 d1-4 d1-4 d1-5 Thal. dosing 100 up to up to Maintenance Palumbo et al, Lancet 2006;367: Palumbo et al. Blood 2008;112: Facon et al. Lancet 2007;370: Hulin et al. JCO 2009 ;27: Waage et al. Blood 2010 ;116: Wijermans et al. JCO 2010;28:

32 MP vs MPT : PFS and OS 32 PFS (med,mo.) MP MPT P OS (med,mo.) MP MPT P * Event-free survival GIMEMA 1,2 IFM IFM NMSG 5 HOVON NS < NS NS 9 * 13 < In 4/5 studies, MPT was superior to MP in terms of PFS. In 3/5 studies, MPT was superior to MP in terms of OS. 1. Palumbo et al, Lancet 2006;367: Palumbo et al. Blood 2008;112: Facon et al. Lancet 2007;370: Hulin et al. JCO 2009 ;27: Waage et al. Blood2010 ;116: Wijermans et al. JCO 2010;28:

33 MPT vs MP for previously untreated elderly patients with MM: Meta-analysis of 1685 individual-patient data from 6 randomized trials Survival proportion PFS HR=0.67 in favor of MPT, p< Median 14.9 mos ( ) Median 20.3 mos ( ) MPT MP months OS HR=0.83 in favor of MPT, p=0.005* Median 39.3 mos ( ) Median 32.7 mos ( ) MPT MP months *Cox model for treatment, with analysis stratified by study using a random effects (frailty) model Fayers et al. Blood 2011;118:

Higher risk of mortality in patients 75 years of age Retrospective meta-analysis of 4 EU phase III trials (N = 1,435) with MP, MPT, VMP, and VMPT Median follow up 33 months Median OS in total

34 Higher risk of mortality in patients 75 years of age Retrospective meta-analysis of 4 EU phase III trials (N = 1,435) with MP, MPT, VMP, and VMPT Median follow up 33 months Median OS in total population 50 months Estimated 3-year OS 68% in patients < 75 years of age vs 57% in patients 75 years of age (HR 1.44, CI , p < 0.001) HR (95% CI) p value All 1.44 ( ) < MP 1.21 ( ) 0.21 MPT 1.12 ( ) 0.49 VMP 1.62 ( ) 0.03 VTP/VMPT 3.02 ( ) < Higher mortality in patients < 75 years of age 1 10 Higher mortality in patients 75 years of age Bringhen S, et al. Haematologica. [Epub ahead of print 26 February 2013].

35 Factors associated with shorter survival Advanced age, renal failure, severe cardiac/infective AEs and drug discontinuation were associated with shorter OS PN was associated with longer OS HR (95% CI) p value Male 1.13 ( ) 0.17 Age 75 years 1.36 ( ) Serum creatinine 2 mg/dl 1.59 ( ) Grade 3/4 haem AEs 1.24 ( ) 0.21 Grade 3/4 non-haem AEs 1.72 ( ) cardiac 2.61 ( ) infections 2.46 ( ) < GI 1.89 ( ) 0.08 VTE 1.14 ( ) 0.79 PN 0.29 ( ) 0.08 Drug discontinuation 1.61 ( ) Lower mortality 1 10 Higher mortality Bringhen S, et al. Haematologica. [Epub ahead of print 26 February 2013].

36 Proportion Proportion Dexamethasone-based regimens versus MP for elderly multiple myeloma patients ineligible for highdose therapy 1.0 T.Facon et al. Blood 2006,107, Time from inclusion (month) Time from inclusion (month) Treatment O/N Survival time median±se (month) MP 106/ ± 3.6 M + DEX 97/ ± 3.1 DEX 110/ ± 2.0 DEX + IFN 102/ ± 5.3 Progression-free Treatment O/N survival time median±se (month) MP 120/ ± 1.7 M + DEX 112/ ± 2.0 DEX 123/ ± 1.0 DEX + IFN 118/ ± 2.7

The challenge of high-risk CA [t(4;14), del(17p), t(14;16)] in NDMM elderly patients Study No of patients with high-risk CA Outcome of high-risk CA patients MPT/MP 1 NR NR CTDa/MP 1 (MRC Myeloma IX)

37 The challenge of high-risk CA [t(4;14), del(17p), t(14;16)] in NDMM elderly patients Study No of patients with high-risk CA Outcome of high-risk CA patients MPT/MP 1 NR NR CTDa/MP 1 (MRC Myeloma IX) NR CTDa does not overcome the effect of high-risk CA and not significantly better than MP in highrisk CA RD/Rd 2 (E4A03) 21 2y OS=76% for high-risk CA vs 91% VMP/MP 3 (VISTA) VMP/VTP VT/VP 4 (GEM-05) Absence of OS benefit, median OS 44.1mo. VMP vs 50.6 mo., MP Adverse prognosis of both t(4;14) and del (17p) regardless of induction and maintenance. Median OS t(4;14)=29 mo., del(17p) = 27mo. First generation novel agents do not overcome the negative prognosis of highrisk CA in newly diagnosed elderly patients with MM 1. Bergsagel PL, et al. Blood 2013;121: Rajkumar SV, et al. Lancet Oncology 2010;11: San Miguel J, et al. JCO 2013;31: Mateos MV, et al. Blood 2011; 118:

38 The challenge of high-risk CA in elderly patients: improving OS is a priority which requires an international effort Design phase 2 exploratory studies with 2 nd /3 rd generation novel agents focused on elderly population Carefully assess cytogenetics/genomics in phase 3 trials for approval Pool data and studies Try to work on clonal evolution Investigate innovative therapeutic approaches alternating schedules, continuous therapy, 4-drug tolerable regimens; for example: IMiD/PI/Mab/Steroid with tolerable doses of each drug CA = cytogenetic abnormalities

39 Old and new challenges with transplant-ineligible patients Median TTP/PFS of months is sub-optimal Establish the role of maintenance therapy High-risk patients still have a very poor outcome with first generation novels agents combination therapy including non cross resistant drugs need to be investigated (IMiD/PI/Dex/MoAb) Frail patients remain a challenge It will be more challenging to have new therapies approved for newly diagnosed elderly patients more difficult to achieve OS benefit required by regulators We have some challenges ahead, but we have made progress already 1,2 1. Pulte D, et al. Oncologist. 2011;16: Libby E, et al. IMW Paris, May 2011 [abstract O-14].

40 What is the next step forward?

41 High doses of drugs are suboptimal in elderly patients a common finding Dexamethasone Thalidomide Bortezomib Lenalidomide Intermediate/High dose is associated with higher toxicity 1-3 and shorter OS 3 than low-dose dexamethasone Low-dose more tolerable than high-dose thalidomide Best MPT results in patients > 75 years of age achieved in IFM with thalidomide 100 mg/day (and melphalan 0.2 mg/kg) 4 Weekly more tolerable than twice weekly S.c. more tolerable than i.v. (less neurotoxicity) 5 S.c. weekly likely the current SOC 6 MPR (with melphalan 0.18 mg/kg and lenalidomide 10 mg/day) not tolerable in patients > 75 years of age 7 1. Hernandez JM, et al. Br J Haematol. 2004;127: Facon T, et al. Blood. 2006;107: Rajkumar SV, et al. Lancet Oncol. 2010;11: Hulin C, et al. J Clin Oncol. 2009;27: Palumbo A, et al. J Clin Oncol. 2010;28: Moreau P, et al. Lancet Oncol. 2011;12: Palumbo A, et al. New Engl J Med. 2012;366:

42 ASCO Plenary

43 Recommended starting doses and dose adjustments according to age groups and vulnerability status Agent Dexamethasone (mg/day, weekly) Melphalan (mg/kg, days 1 4) Thalidomide (mg/day) Lenalidomide** (mg/day, days 1 21) No risk factors* At least 1 risk factor At least 1 risk factor (+ grade 3/4 non-haem AE) (or prednisone) qod Bortezomib (mg/m 2, weekly, s.c.) * Risk factors; age> 75 years, frailty, comorbidities (cardiac, pulmonary, hepatic, renal); ** Dose also adapted according to renal function. Adapted from Palumbo A, et al. Blood. 2011;118:

44 MPT: melphalan, prednisone, thalidomide. Refresher on MPT and MPV data A journey back in time...

45 The challenge of high-risk CA in elderly patients: improving OS is a priority which requires an international effort Design phase 2 exploratory studies with 2 nd /3 rd generation novel agents focused on elderly population Carefully assess cytogenetics/genomics in phase 3 trials for approval Pool data and studies Try to work on clonal evolution Investigate innovative therapeutic approaches alternating schedules, continuous therapy, 4-drug tolerable regimens; for example: IMiD/PI/Mab/Steroid with tolerable doses of each drug CA = cytogenetic abnormalities

Treatment Strategies for Transplant-ineligible NDMM Patients

1 Treatment Strategies for Transplant-ineligible NDMM Patients Thierry Facon, MD Professor of Hematology Service des Maladies du Sang University of Lille Lille, France Multiple Myeloma affects primarily