GIMEMA: Italian Multiple Myeloma Network

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1 GIMEMA: Italian Multiple Myeloma Network Overall Survival Benefit for Bortezomib-Melphalan- Prednisone-Thalidomide Followed by Maintenance with Bortezomib-Thalidomide (T-VT) Versus Bortezomib- Melphalan-Prednisone () in Newly Diagnosed Multiple Myeloma Patients Antonio Palumbo, MD 1, Sara Bringhen 1, Davide Rossi, MD 2, Maide Cavalli, MD 2, Roberto Ria, MD 2, Silvia Gentilini, MD 2, Francesca Patriarca 2, Chiara Nozzoli, MD 2, Anna Levi, MD 2, Tommasina Guglielmelli, MD 2, Giulia Benevolo, MD 2, Donatella Vincelli, MD 2, Luca Baldini 2, Fortunato Morabito, MD 2, Mariella Grasso, MD 2, Roberto Marasca, MD 2, Manuela Rizzo, MD 2, Chiara Pautasso, Pharm D 1, Antonietta Pia Falcone, MD 2, Daniela Gottardi, MD 2, Vittorio Montefusco, MD 2, Caterina Musolino, MD 2, Clotilde Cangialosi, MD 2, Giovanna Mansueto, MD 2, Anna Marina Liberati, MD 2, Valeria Magarotto, MD 1, Paola Omedè, PhD 1, Pellegrino Musto, MD 2, Maria Teresa Petrucci, MD 2 and Mario Boccadoro, MD 1 1 Myeloma Unit, Division of Hematology, University of Torino, Torino, Italy 2 Italian Multiple Myeloma Network, GIMEMA, Italy

2 Disclosures for Palumbo Antonio, MD Research Support/P.I. Employee Consultant Major Stockholder Speakers Bureau Honoraria Scientific Advisory Board No relevant conflicts of interest to declare No relevant conflicts of interest to declare Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx No relevant conflicts of interest to declare No relevant conflicts of interest to declare Amgen, Bristol-Myers Squibb, Celgene, Janssen, Millenium, Onyx No relevant conflicts of interest to declare Presentation includes discussion of the off-label use of a drug or drugs

3 Aims Best experimental therapy: synergy bortezomib + IMID 4 drug induction T 2 years maintenance VT Best standard of care 3 drug induction No maintenance median follow-up of 54 months Initial report: Palumbo A. et al. J Clin Oncol, 2010, 28(34):

4 Treatment schedule 511 patients (older than 65 years) randomized from 58 Italian centers Patients: Symptomatic multiple myeloma/end organ damage with measurable disease 65 yrs or <65 yrs and not transplant-eligible; creatinine 2.5 mg/dl R A N D O M I Z E Cycles 1-9 Bortezomib 1.3 mg/m 2 IV: days 1,8,15,22* Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days x 5-week cycles in both arms T Cycles 1-9 Bortezomib 1.3 mg/m 2 IV: days 1,8,15,22* Melphalan 9 mg/m 2 and prednisone 60 mg/m 2 days 1-4 Thalidomide 50 mg/day continuously NO MAINTENANCE Until relapse MAINTENANCE Bortezomib 1.3 mg/m 2 IV: days 1,15 Thalidomide 50 mg/day continuously * 66 patients and 73 T patients were treated with twice weekly infusions of Bortezomib

5 Patient Characteristics T-VT (N=254) (N=257) Median age (range) years 27% 27% ISS stage I 23% 22% II 39% 34% III 22% 19% Chromosome abnormalities t(4;14) 17% 14% Del17p 17% 13% t(14;16) 5% 3% Unfavorable profile* 31% 26% * Defined as t(4;14) or or Del17 or or t(14;16)

6 Progression-Free Survival Time to Next Therapy Median follow-up 54 months 42% Reduced Risk of Progression 48% Reduced Risk of Next Therapy PFS TTNT* Patients (%) Median 35.3 months Median 46.6 months Median 24.8 months Median 27.8 months HR 0.58 (95% CI, , P < 01 HR 0.52 (95% CI, , P < Time (months) * Time to next therapy

7 Progression-free survival Landmark analysis T VT Maintenance 4-years PFS Median PFS T-VT 33% 31.5 months 16% 17.8 months Patients (%) Time (months)

8 Progression-Free Survival Time to Next Therapy T Bort resistant VT maint. No maint. IMID sensitive Delayed clonal evolution T Bort resistant VT maint. No maint. IMID sensitive Delayed clonal evolution Patients (%) Faster clonal evolution Faster clonal evolution HR 0.58, 95% CI, , P < 01 HR 0.52, 95% CI, , P < Time (months) Time (months) Median follow-up 54 months 42% Reduced Risk of Progression 48% Reduced Risk of Next Therapy

9 Overall Survival (OS) 30% Reduced Risk of Death T VT Maintenance 5-years OS Median OS T-VT 61% Not reached 51% 60.6 months Patients (%) HR 0.70, 95% CI, , P = Time (months)

10 Overall survival Landmark analysis T VT Maintenance Patients (%) 4-years OS Median OS T-VT 67% Not reached 55% 54.2 months HR 0.63, 95% CI, , p = Time (months)

11 Age < 75 years Overall survival Landmark analysis ISS 1-2 CR HR 0.60, 95% CI, , p= HR 0.66, 95% CI, 0.43-, p = HR 0.45, 95% CI, , p = Age 75 years ISS 3 VGPR/PR HR 0.76, 95% CI, , p =.36 HR 0.64, 95% CI, , p =.22 HR 0.80, 95% CI, , p = T VT maint. No maint. T VT maint. No maint. T VT maint. No maint.

12 Overall survival from relapse 3-years OS Median OS T-VT 47% 27.8 months 46% 27.3 months Patients (%) HR 0.92, 95% CI, , p = Time (months)

13 Grade 3-4 Adverse Events During VT maintenance Hematologic DVT Sensory neuropathy Infection Cardiologic Drop out for AE Newly occurring or worsening Grade 3-4 adverse events Patients (%)

14 Treatment discontinuation T VT Discontinuation rate a, % years of age > 75 years of age Bortezomib dose intensity, % years of age > 75 years of age a Discontinuation due to AEs

15 Conclusion T-VT P value 5-year PFS 29% 13% <01 5-year TNT 41% 19% <01 5-year OS 61% 51% year OS from relapse 47% 46% 0.63

16 We Are Grateful to All Patients, Nurses and Physicians of the Participating Centers 1. ALESSANDRIA Levis, Baraldi 2. ANCONA Leoni, Offidani 3. AOSTA Di Vito 4. ASCOLI PICENO Galieni, 5. ASTI Favro 6. AVELLINO Cantore,, Volpe 7. AVIANO Tirelli, Rupolo 8. BARI Dammacco, Ria 9. BARI Liso 10. BELLUNO 11. BENEVENTO Pianezze Di Lonardo, Vallone 12. BERGAMO Rambaldi, Galli 13. BOLOGNA Baccarani,Cavo 14. BOLZANO Cortellazzo, Pescosta 15. BRA Vanni, Stefani 16. BRESCIA Rossi, Crippa 17. BRESCIA Russo, Malagola 18. BRINDISI Quarta 19. CAGLIARI Angelucci, Derudas 20. CAGLIARI La Nasa, Ledda 21. CAMPOBASSO Storti 22. CANDIOLO Aglietta, Capaldi 23. CATANIA Giustolisi,Di Raimondo 24. CATANZARO Peta, Piro 25. CATTOLICA Pasquini 26. CESENA Guardigni 27. CIRIE' Girotto, Freilone 28. COSENZA Morabito 29. CREMONA Morandi 30. CUNEO Gallamini, Grasso 31. FIRENZE Bosi/Nozzoli 32. FOGGIA Capalbo 33. FORLI Amadori, Gentilini 34. FROSINONE Sala 35. GALLARATE Ciambelli 36. GENOVA Gobbi, Canepa 37. FORLI Amadori, Gentilini 38. FROSINONE Sala 39. GALLARATE Ciambelli 40. GENOVA Gobbi, Canepa 41. GENOVA Carella, Spriano 42. GENOVA Bacigalupo, Dominietto 43. IVREA Girotto, Aitoro 44. LATINA De Blasio 45. LATINA Cimino 46. LECCE Di Renzo 47. MATERA Fragasso 48. MESSINA Brugiatelli 49. MESSINA Musolino 50. MILANO Corradini, Montefusco 51. MILANO Morra 52. MILANO Ciceri 53. MILANO Lanbertenghi, Baldini 54. MILANO Gianni 55. MODENA Torelli 56. MODENA Sacchi 57. MONZA Pogliani, Rossini 58. NAPOLI Rotoli,Catalano 59. NAPOLI Ferrara 60. NAPOLI Mettivier 61. NOCERA INF. D Arco, Califano 62. NOVARA Gaidano, Rossi 63. NUORO Gabbas 64. ORBASSANO Saglio, Guglielmelli 65. PADOVA Semenzato, Zambello 66. PALERMO Mirto, Cangialosi 67. PARMA Rizzoli, Giuliani 68. PAVIA Lazzarino, Corso 69. PERUGIA Liberati, Nunzi 70. PESARO Visani, Leopardi 71. PESCARA Fioritoni, Spadano 72. PIACENZA Cavanna, Lazzaro 73. PINEROLO Griso 74. PISA Petrini/Benedetti 75. POTENZA Ricciuti, Vertone 76. RAVENNA Zaccaria, Cellini 77. REGGIO CAL. Nobile, Callea 78. REGGIO EMILIA Gugliotta, Masini 79. RIMINI Pasquini, Fattori 80. RIONERO VULTURE Musto 81. RIETI Capparella 82. ROMA Foà, Petrucci 83. ROMA De Fabritiis, Caravita 84. ROMA Andriani 85. ROMA Annino, Bongarzoni 86. ROMA Leone, De Stefano 87. ROMA Petti, Pisani 88. ROMA Majolino, De Rosa 89. ROMA Amadori 90. ROMA Avvisati 91. ROMA Recine 92. ROZZANO Santoro, Nozza 93. S. G. ROTONDO Cascavilla, Falcone 94. SASSARI Dore, Podda 95. SIENA Lauria, Gozzetti 96. TARANTO Mazza, Casulli 97. TORINO Boccadoro 98. TORINO Gallo, Pregno 99. TORINO Poccardi, Aragno 100. TREVISO Foscolo, Gherlinzoni 101. TRICASE Pavone 102. TRIESTE De Sabbata 103. UDINE Fanin, Patriarca 104. VENEZIA Chisesi 105. VERBANIA Montanara, Luraschi 106. VERCELLI Santagostino 107. VERONA Pizzolo, Meneghini 108. VICENZA Rodeghiero, Elice 109. VITERBO Montanaro