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Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed

GIMEMA: Italian Multiple Myeloma Network. Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed by Maintenance with Bortezomib and Thalidomide (VT) for Initial Treatment of Elderly Multiple Myeloma Patients.

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Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed

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  1. GIMEMA: Italian Multiple Myeloma Network Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed by Maintenance with Bortezomib and Thalidomide (VT) for Initial Treatment of Elderly Multiple Myeloma Patients Boccadoro M(1), Bringhen S(1), Gaidano G(2), Ria R(3), Offidani M(4), Patriarca F(5), Nozzoli C(6), Musto P(7), Petrucci MT(8), Palumbo A(1). Italian Multiple Myeloma Group 1.Divisione di Ematologia dell’Università di Torino, A.O.U. San Giovanni Battista, Torino, Italy; 2.Divisione di Ematologia, Università del Piemonte Orientale Amedeo Avogadro e Ospedale Maggiore della Carità, Novara, Italy; 3.Dipartimento di Scienze Biomediche e Oncologia Umana, Sezione di Medicina Interna e Oncologia Clinica, Università di Bari, Bari, Italy; 4.Clinica di Ematologia, A.O.U. Ospedali Riuniti, Ancona, Italy; 5.Divisione di Ematologia, Istituto Nazionale Tumori, Milano, Italy; 6.Clinica Ematologica, Università di Udine, Udine, Italy; 7.Dipartimento di Ematologia, Università di Firenze, A.O.U. Careggi, Firenze, Italy; 8.Dipartimento di Oncoematologia, IRCCS CROB Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy; 9.Dipartimento di Biotecnologie Cellulari ed Ematologia, Università La Sapienza, Ospedale Umberto I, Roma, Italy.

  2. Aims • Best experimental therapy: • 4 drug combo  VMPT • Maintenance  VT • Best standard of care • 3 drug combo  VMP • Safety and efficacy of weekly infusion of bortezomib

  3. 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 VMP Cycles 1-9 Bortezomib 1.3 mg/m2 IV: days 1,8,15,22* Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4 R A N D O M I Z E NO MAINTENANCE 9 x 5-week cycles in both arms Until relapse VMPT Cycles 1-9 Bortezomib 1.3 mg/m2 IV: days 1,8,15,22* Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4 Thalidomide 50 mg/day continuously MAINTENANCE Bortezomib 1.3 mg/m2 IV: days 1,15 Thalidomide 50 mg/day continuously * 66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of Bortezomib

  4. Patient Characteristics VMP (N=257) VMPT  VT (N=254) Age (median) 71 71 < 65 years 2% 5% 65–74 years 71% 68% > 75 years 27% 27% 4 3.8 2 microglobulin-mg/L (median) Chromosome abnormalities t(4;14) 14% 17% t(14;16) 3% 5% Del 17 13% 17%

  5. VMP (N=253) VMPT  VT (N=250) P value CR 24% 38% 0.0008 > VGPR 50% 59% 0.03 > PR 81% 89% 0.01 Best Response Rate VMP VMPT  VT % of patients % of patients CR VGPR PR SD PD CR VGPR PR SD PD

  6. Time to first response and time to CR VMP VMPTVT 100 80 60 40 20 0 PR: VMPTVT PR: VMP % of patients CR: VMPTVT CR: VMP 0 5 10 15 20 25 30 Months

  7. 1.00 1.00 0.75 0.75 VMPT VT 0.50 0.50 0.25 VMP 0.25 P = 0.006 0.00 0 10 20 30 40 50 60 0.00 0 10 20 30 40 50 60 Time to next therapy Progression free survival Median follow-up 26.5 months Time to next therapy Progression free survival VMP: TTNT @ 3 years = 55% VMPT VT: TTNT @ 3 years = 69% VMP: PFS @ 3 years = 40% VMPT VT: PFS @ 3 years = 54% VMPTVT % of patients VMP P = 0.006 Months

  8. 1.00 VMPTVT VMP 0.75 % of patients 0.50 0.25 P = 0.60 0.00 0 10 20 30 40 50 60 Overall survival VMP: OS @ 3 years = 84% VMPTVT: OS @ 3 years = 86% Months

  9. VMP VMPTVT P=0.02 Neutropenia Thrombocytopenia Anaemia 0 5 10 15 20 25 30 35 40 Grade 3-4 Hematologic Adverse Events Patients (%)

  10. VMPTVT VMP Sensory neuropathy Infections Cardiologic P=0.04 P=0.05 DVT/PE Drop Out for AE Drop Out for PN 0 5 10 15 20 25 Grade 3-4 Non-hematologic Adverse Events Patients (%)‏

  11. Efficacy and Toxicity by Bortezomib schedule VMP* (VISTA) VMP twice weekly N=63° VMP once weekly N=190° CR 30% 25% 23% PFS @ 2 years 48% 57% 57% Sensory PN Any grade 44% 43% 21% Grade 3-4 13% 14% 2% PN discontinuation NA 16% 4% Total planned dose 67.6 67.6 mg/m2 46.8 mg/m2 Total delivered dose NA 41 mg/m2 40 mg/m2 *San Miguel JF et al. New Eng J Med 2008; 359: 906-17; ° 3 patients in twice weekly and 1 patient in once weekly group are not evaluable because they never start therapy; PN: peripheral neuropathy

  12. 1.00 0.75 0.50 0.25 0.00 0 10 20 30 40 50 60 PFS according to Bortezomib schedule Twice weekly: PFS @ 3 years =45% Once weekly: PFS @ 3 years = 50% % of patients Twice weekly Once weekly P = 0.87 Months

  13. Conclusions 1 VMP (N=253) VMPT  VT (N=250) P value CR 24% 38% 0.0008 TTNT @ 3 years 55% 69% 0.006 PFS @ 3 years 40% 54% 0.006 OS @ 3 years 84% 86% 0.60

  14. Conclusions 2 • Best available treatment option for elderly patient • VMPT  VT improves PFS in comparison with VMP • VMPT  VT improves response rate and PFS • VMPT increases CR rate • VT maintenance improves PFS • Once-weekly bortezomib reduces peripheral neuropathy

  15. 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 Pianezze 11.BENEVENTO 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 Lambertenghi, 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 Martelli, Ballanti 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. TERNI Liberati 98. TORINO Boccadoro 99. TORINO Pregno, Benevolo 100. TORINO Tarella, Gottardi 101. TREVISO Gherlinzoni 102.TRICASE Pavone 103. TRIESTE De Sabbata 104. UDINE Fanin, Patriarca 105. VENEZIA Chisesi 106. VERBANIA Montanara, Luraschi 107. VERCELLI Santagostino 108. VERONA Pizzolo, Meneghini 109. VICENZA Rodeghiero, Elice 110. VITERBO Montanaro

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