Rationale. Progression-free survival. Median: 38 vs 24 months P<.0001

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Eloisa Marra
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1 A PHASE III STUDY OF ASCT VS CYCLOPHOSPHAMIDE-LENALIDOMIDE- DEXAMETHASONE AND LENALIDOMIDE- PREDNISONE MAINTENANCE VS LENALIDOMIDE ALONE IN NEWLY DIAGNOSED MYELOMA PATIENTS Palumbo A. 1, Gay F. 1, Spencer A. 2, Di Raimondo F. 3, Zdenek A. 4, Larocca A. 1, Falcone A.P. 3, Catalano L. 3, Finsinger P. 3, Šcudla V. 5, Aschero S. 1, Offidani M. 3, Liberati A.M. 3, Carella A.M. 3, Maisnar V. 6, Donato F. 1, Caravita T. 3, Corradini P. 3, Ria R. 3, Pulini S. 3, Stocchi R. 3, Conticello C. 3, Petrucci M.T. 3, Hajek R. 7, Boccadoro M. 1 1 Myeloma Unit, Division of Hematology, University of Torino, Italy; 2 Alfred Health-Monash University, Melbourne, Australia; 3 Italian Multiple Myeloma Network, GIMEMA, Italy; 4 Department of Internal Medicine, Hematology and Oncology, University Hospital Brno, Jihlavska, Brno, Czech Republic; 5 3rd Department of Internal Medicine, University of Hospital Olomouk, Olomouk, Czech Republic; 6 Department of Medicine - Hematology, Charles University Faculty Hospital, Hradec Kralove, Czech Republic; 7 University Hospital Brno and Faculty of Medicine OU, Ostrava, Czech Republic.

2 N pts Rationale Progression-free survival Overall survival SCT vs Chemotherapy SCT vs CC+ novel agents vs 202 Median: 38 vs 24 months P< % vs 5 year P= NS Maintenance PDN 50 mg vs PDN 10 mg 2 61 vs 65 Thal-PDN vs PDN vs 129 Thal-PDN vs No maintenance vs 166 Median: 14 vs 5 months P= % vs 23%@ 3 year P< % vs 4 year P<.001 Median 37 vs 26 P=.05 86% vs 3 yr P= yr P=.18 SCT: stem cell transplant; CC: conventional chemotherapy; PDN:prednisone; Thal: thalidomide. 1 Palumbo ASCO 2013, 2Berenson JR, et al. Blood 2002;99: ; 3 Spencer A, et al. JCO 2009;27: ; 4 Stewart AK, et al. Blood 2013; 121: ;

3 Aims Efficacy and safety vs Median follow-up 36 months Efficacy and safety RP maintenance vs R maintenance Median follow-up 20 months : cyclophosphamide-lenalidomide-dexamethasone; : melphalan 200 mg/m2 and autologous stem cell transplant; RP: lenalidomide prednisone; R: lenalidomide.

4 Treatment schedule 389 patients (younger than 65 years) randomized from 59 centers Patients: Symptomatic disease, organ damage (CRAB), measurable disease *Randomisation (2x2 design) Rd four 28-day courses six 28-day courses six 28-day courses MEL 200 Two courses # MEL 200 Two courses # RP MAINTENANCE 28-day courses until PD R MAINTENANCE 28-day courses until PD RP MAINTENANCE 28-day courses until PD R MAINTENANCE 28-day courses until PD * vs MEL 200; RP maintenance vs R maintenance; Rd (R: 25 mg/d, days 1-21; d: 40 mg/d, days 1,8,15,22); (C: 300 mg/m2/d, days 1,8,15; d: 40 mg/d, days 1,8,15,22; R: 25 mg, d 1-21), MEL 200 (M: 200 mg/m2 day -2); RP maint (R: 10 mg/day, days 1-21; P: 50 mg every other day); R maint (R: 10 mg/day, days 1-21); # One course MEL 200 if patients achieves VGPR after cycle 1 R: lenalidomide; : melphalan 200 mg/m2 and autologous stem cell transplant; : cyclophosphamide-lenalidomide-dexamethasone; RP: lenalidomide prednisone; NDMM: newly diagnosed multiple myeloma.

5 vs 1 R A N D O M I Z A T I O N six 28-day courses C: 300 mg/m2/d, days 1,8,15 R: 25 mg/d, days 1-21 D: 40 mg/d days 1,8,15,22 two courses M: 200 mg/m2 day -2 Stem cell support day 0 C, cyclophosphamide; D, dexamethasone; R, lenalidomide;, melphalan 200 mg/m 2

6 Patient Characteristics (N=194) (N=195) Median age (years) ISS stage I 43% 44% II 38% 39% III 19% 17% Chromosome abnormalities t(4;14) 11% 10% t(14;16) 5% 5% del 17 7% 8% t(4;14) or t(14,16) or del17 21% 21% NA 29% 26%, cyclophosphamide-lenalidomide-dexamethasone;, melphalan 200 mg/m 2 ; ISS, International Staging System; NA, not available

7 vs Median follow-up 3 years Progression-free survival Overall survival 1.00 Rd Median PFS 27 months Not reached 1.00 Rd 3-year OS 81% 84% HR 1.46, 95% CI , P = HR 1.04, 95% CI , P = Months Months, cyclophosphamide-lenalidomide-dexamethasone;, melphalan 200 mg/m 2 ; PFS, progressionfree survival; OS, overall survival; ITT, intention to treat

8 Consolidation: Grade 3-4 Adverse events P<.0001 P<.0001 P=.0023 P=.0002 P=.326 % of patients, cyclophosphamide-lenalidomide-dexamethasone;, melphalan 200 mg/m 2 ; GI, gastrointestinal events

9 RP maintenance vs R maintenance 2 R A N D O M I Z A T I O N RP MAINTENANCE 28-day courses until relapse R: 10 mg/day, days 1-21 P: 50 mg every other day R maintenance 28-day courses until relapse R: 10 mg/day, days 1-21 R, lenalidomide; P, prednisone

10 Patient Characteristics RP maint (N=194) R maint. (N=195) Median age (years) ISS stage I 45% 43% II 41% 35% III 14% 22% Chromosome abnormalities t(4;14) 10% 11% t(14;16) 5% 5% del 17 8% 7% t(4;14) or t(14,16) or del17 22% 19% NA 25% 29% R, lenalidomide; P prednisone; ISS, International Staging System; NA, not available

11 RP maintenance vs R maintenance Median follow-up 20 months Progression-free survival Overall survival 2-year PFS 2-year OS RP maint. 69% RP maint. 92% R maint. 58% R maint. 90% vs RP maintenace R maintenace vs RP maintenace R maintenace HR 0.63, 95% CI , P = HR 0.93, 95% CI , P = Months R, lenalidomide, P, prednisone Months

12 Maintenance: Grade 3-4 Adverse events P=1.000 P=.456 P=.429 P=.338 P=.623 P=.248 P=.106 % of patients SPM: 7 patients in RP (including 4 skin cancer) and 7 patients in R (1 including skin cancer) DVT, deep venous thrombosis; GI, gastrointestinal events; R, lenalidomide, P, prednisone.

13 -RP vs -RP vs -R vs -R Median follow-up 3 years Progression-free survival Rd RP maintenace R maintenace Rd Overall survival RP maintenace R maintenace RP -R RP R -RP R RP R Months Months, cyclophosphamide-lenalidomide-dexamethasone;, melphalan 200 mg/m 2 ; R, lenalidomide, P prednisone; ITT, intention to treat

14 Conclusions vs P value 3-year PFS 39% 56% P= year OS 81% 84% P=.891 RP vs R maintenance RP maint. R maint. P value 2-year PFS from maint 69% 58% P= year OS from maint 92% 90% P=.879, cyclophosphamide-lenalidomide-dexamethasone;, melphalan 200 mg/m 2 ; R, lenalidomide, P prednisone; PFS, progression-free survival; OS, overall survival

15 We Are Grateful to All Patients, Nurses and Physicians of the Participating Centers ALESSANDRIA Levis, Baraldi GENOVA Gobbi, Canepa PISA Petrini/Benedetti BRATISLAVA Mistrík ANCONA Leoni, Offidani GENOVA Carella, Spriano POTENZA Ricciuti, Vertone BRNO Hàjek AOSTA Di Vito GENOVA Bacigalupo, Dominietto RAVENNA Zaccaria, Cellini BUDAPEST Masszi ASCOLI PICENO Galieni IVREA Girotto, Aitoro REGGIO CALABRIA Vincelli, Nobile, Callea HRADEC KRÁLOVÉ Maisnar ASTI Favro, Ciravegna LECCO Ferrando REGGIO EMILIA Gugliotta, Masini KOŠICE Tothová AVELLINO Cantore, Volpe LATINA De Blasio RIMINI Tosi OLOMOUC Ščudla AVIANO Tirelli, Rupolo LATINA Cimino RIONERO VULTURE Musto PLZEŇ Schützová BARI Vacca, Ria LECCE Di Renzo RIETI Capparella PRAZE Gregora BARI Liso MANTOVA Aitini Foà, Petrucci PRAZE Straub BELLUNO Pianezze MATERA Fragasso De Fabritiis, Caravita PRAZE Gregora BENEVENTO Di Lonardo, Vallone MELDOLA Ronconi Andriani PRAZE Straub BERGAMO Rambaldi, Galli MESSINA Brugiatelli Annino, Bongarzoni PLZEŇ Schützová BOLOGNA Cavo MESSINA Musolino Leone, De Stefano BRATISLAVA Mistrík BOLZANO Cortellazzo, Pescosta MILANO Corradini, Montefusco Petti, Pisani KOŠICE Tothová BRA Vanni, Stefani MILANO Cafro Majolino, De Rosa BUDAPEST Masszi BRESCIA Rossi, Crippa MILANO Ciceri Amadori ADELAIDE Lee BRESCIA Russo, Malagola MILANO Lambertenghi, Baldini Avvisati BRISBANE Mollee BRINDISI Quarta MILANO Gianni Recine GEELONG Campbell CAGLIARI Angelucci, Derudas MODENA Marasca ROZZANO Santoro, Nozza HAMILTON Goodman CAGLIARI La Nasa, Ledda MODENA Sacchi S. G. ROTONDO Cascavilla, Falcone HOBART Harrup CAMPOBASSO Storti MONZA Pogliani, Rossini SASSARI Dore, Podda MELBOURNE Grigg CANDIOLO Aglietta, Capaldi NAPOLI Pane,Catalano SIENA Lauria, Gozzetti MELBOURNE Roberts CATANIA Di Raimondo NAPOLI Ferrara TARANTO Mazza, Casulli MELBOURNE Spencer CATANZARO Piro NAPOLI Mettivier TERNI Liberati NEWCASTLE Rowlings CATTOLICA Pasquini NOCERA INF. D Arco, Califano TORINO Boccadoro, Palumbo PERTH Augustson CESENA Guardigni NOVARA Gaidano, Rossi TORINO Pregno, Benevolo PORT MACQUARIE Stark CIRIE' Girotto, Freilone NUORO Gabbas TORINO Tarella, Gottardi SOUTHPORT Bryson CIVITANOVA M. Centurioni ORBASSANO Saglio, Guglielmelli TREVISO Gherlinzoni SYDNEY Harrison COSENZA Morabito PADOVA Semenzato, Zambello TRICASE Pavone SYDNEY Joshua CREMONA Lanza PALERMO Cangialosi TRIESTE De Sabbata SYDNEY Kwan CUNEO Gallamini, Grasso PARMA Giuliani UDINE Fanin, Patriarca SYDNEY Milliken FIRENZE Bosi/Nozzoli PAVIA Lazzarino, Corso VENEZIA Chisesi SYDNEY Ramanathan FOGGIA Capalbo PERUGIA Martelli, Ballanti VERBANIA Montanara, Luraschi WODONGA Eek FORLI Amadori, Gentilini PESARO Visani, Leopardi VERCELLI Santagostino WOLLONGONG Warburton FROSINONE Sala PESCARA Fioritoni, Spadano VERONA Pizzolo, Meneghini GALLARATE Mozzana, Ciambelli PIACENZA Cavanna, Lazzaro VICENZA Rodeghiero, Elice FORLI Amadori, Gentilini PINEROLO Griso VITERBO Montanaro

16 Divisione di Ematologia 1 Azienda Ospedaliero Universitaria Citta della Salute e della Scienza Acknowledgments Prof. Mario Boccadoro Prof. Antonio Palumbo Dr.ssa Sara Bringhen Dr.ssa Federica Cavallo Dr.ssa Alessandra Larocca Dr.ssa Chiara Cerrato Dr.ssa Francesca Donato Dr.ssa Mariella Genuardi Dr.ssa Valeria Magarotto Dr. Roberto Mina Dr.ssa Stefania Oliva Dr.ssa Paola Omedé & Laboratory Staff Prof Massimo Massaia & Laboratory Staff Dr. Benedetto Bruno & Transplant Unit Nurses Data Managing Staff

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