Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients

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Luciano Magni
6 anni fa
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1 GIMEMA: Italian Multiple Myeloma Network Carfilzomib, Cyclophosphamide and Dexamethasone (CCd) for Newly Diagnosed Multiple Myeloma (MM) Patients A. Palumbo 1, S. Bringhen 1, O. Villani 2, A. Siniscalchi 3, E. Russo 4, G. Uccello 5, C. Cerrato 1, M. Gilestro 1, D. Rossi 6 and M. Boccadoro 1. 1 Division of Hematology, University of Torino, Torino, I, EU; 2 Department of Onco-Hematology, IRCCS, Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture (PZ), Italy; 3 Division of Hematology, Sant Eugenio Hospital, Roma, Italy; 4 Hematology, Umberto I Hospital, University, Roma, Italy; 5 Hematology, Ospedale Ferrarotto, Catania, Italy; 6 Division of Hematology, BRMA Amedeo Avogadro Universtity of Eastern Piedmont, Novara, 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 Rationale 1 Efficacy Response CR/nCR VGPR Elderly MPT 27% 36% VMP 30%* 41% MPR-R 33% VMPT-VT 38%* 59% Young VRD 21% 57% VTD 31% 62% CyBorD 39% 61% * CR only, ncr not reported Palumbo at al, Lancet, 2006 ;367:825-31; San Miguel et al, N Eng J Med 2008;359:906-17; Palumboe et al, N Engl J Med 2012;366: ; Palumbo et al, J Clin Oncol 2010;28:5101-9; Richardson et al. Blood 2010; Cavo et al. Lancet 2010; 379(9758): ; Reader et at, Leukemia 2009;23:

4 Rationale 2 Safety Grade 3-4 AEs ANC Platelet PNP VTE Discontinuation Elderly MPT 16% 3% 6% 9% 35% VMP 40% 37% 14% 1% 33% MPR-R ~75% 46% 0% 5% 24% VMPT-VT 38% 22% 8% 5% 22% Young VRD 9% 6% 2% 6% VTD 0% 0% 10% 3% 4% CyBorD 13% 25% 7% 7% 9% ANC, Absolute neutrophils count; PNP, peripheral neuropathy; VTE, venous thromboembolism Palumbo at al, Lancet, 2006 ;367: Fayers et al, Blood 2011; 118: ; San Miguel et al, N Eng J Med 2008;359:906-17; Palumboe et al, N Engl J Med 2012;366: ; Palumbo et al, J Clin Oncol 2010;28:5101-9; Richardson et al. Blood 2010; Cavo et al. Lancet 2010; 379(9758): ; Reader et at, Leukemia 2009;23:

5 Primary objectives and Key Eligibility Criteria Primary objectives Safety: grade 4 neutropenia > 3 days grade 4 thrombocytopenia >7 days grade 3 non-haematologic toxicity. Efficacy: partial response (PR) Inclusion criteria Symptomatic newly diagnosed MM 65 years or ineligible for autologous stem cell transplantation Measurable disease Karnofsky performance status 60% Exclusion criteria Platelets < 50 x 109/L, ANC < 1 x 10 9 /L Creatinine clearance < 15 ml/minute Peripheral neuropathy > CTCAE grade 2 Serious co-morbidities Assessment of response was performed according to the International Myeloma Working Group criteria (Durie BGM et al, Leukemia 2006: 20: ) with the addition of ncr. Assessment of adverse events was performed according to the National Cancer Institute Common Terminology Criteria of Adverse Events (CTCAE version 4.0,

6 Phase II Multicenter (10 centres) Study design CCd Induction Cycles 1-9 C Maintenance Until progression Response Assessments Cycle day Carfilzomib Dose (mg/m 2 ) Dosing CYCLE 1 CYCLE 2 CYCLE 3 CYCLE 5 CYCLE 1 CYCLE 2 CYCLE 9 MAINTENANCE Cyphosphamide 300 mg/m 2 orally Dexamethasone 40 mg orally

7 Patient Characteristics No. of patients 58 Median age (range) 71 (55-86) 75 years 16 (28%) ISS stage I 16 (27%) II 19 (33%) III 23 (40%) Chromosome abnormalities t(4;14) 9/51 (18%) Del17p 8/51 (16%) t(14;16) 1/51 (2%) Unfavorable profile* 18/51 (35%) * Defined as t(4;14) or Del17 or t(14;16)

8 % of patients Response rate by treatment duration

9 % of patients Response rate by treatment duration

10 Time to response Median treatment duration, cycles (range): 5 (1-9) PR % of patients VGPR scr/cr/ncr Months

11 ISS stage Best Response* Subgroup analysis FISH risk % of patients *Assessed by modified IMWG Uniform Criteria with the addition of ncr ** Defined as presence of t(4;14) or t(14;16) or del17p

12 Hematologic Adverse Events All grades Percent of patients

13 Non-hematologic Adverse Events All grades Percent of patients No difference between patients younger and older than 75 years G3 cardiac AEs: IMA, FA; G4 gastrointestinal AEs: ileum perforation; G3 infections: pneumonia, bronchitis

14 Progression-Free and Overall Survival PFS OS Patients (%) year PFS year OS 88% 87% Time (months) Time (months)

15 Conclusions CCd MPT VMP Response rates VGPR 77% 36% 41% ncr/cr/scr 53% 27% 30%* scr 23% - - Grade 3-4 AEs ANC 15% 16% 40% Platelets 5% 3% 37% PNP 0% 6% 14% VTE 0% 9% 1% Discontinuation 12% 35% 33% * CR only, ncr not reported Palumbo at al, Lancet, 2006 ;367: Fayers et al, Blood 2011; 118: ; San Miguel et al, N Eng J Med 2008;359:906-17

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, Ciravegna 6. AVELLINO Cantore, Volpe 7. AVIANO Tirelli, Rupolo 8. BARI Vacca, 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 Di Raimondo 24. CATANZARO Peta, Piro 25. CATTOLICA Pasquini 26. CESENA Guardigni 27. CIRIE' Girotto, Freilone 28. COSENZA Morabito 29. CREMONA Lanza 30. CUNEO Gallamini, Grasso 31. FIRENZE Bosi/Nozzoli 32. FOGGIA Capalbo 33. FORLI Amadori, Gentilini 34. FROSINONE Sala 35. GALLARATE Mozzana, Ciambelli 36. GENOVA Gobbi, Canepa 37. FORLI Amadori, Gentilini 38. GENOVA Gobbi, Canepa 39. GENOVA Carella, Spriano 40. GENOVA Bacigalupo, Dominietto 41. IVREA Girotto, Aitoro 42. LATINA De Blasio 43. LATINA Cimino 44. LECCE Di Renzo 45. MATERA Fragasso 46. MESSINA Brugiatelli 47. MESSINA Musolino 48. MILANO Corradini, Montefusco 49. MILANO Morra 50. MILANO Ciceri 51. MILANO Lambertenghi, Baldini 52. MILANO Gianni 53. MODENA Marasca 54. MODENA Sacchi 55. MONZA Pogliani, Rossini 56. NAPOLI Pane,Catalano 57. NAPOLI Ferrara 58. NAPOLI Mettivier 59. NOCERA INF. D Arco, Califano 60. NOVARA Gaidano, Rossi 61. NUORO Gabbas 62. ORBASSANO Saglio, Guglielmelli 63. PADOVA Semenzato, Zambello 64. PALERMO Mirto, Cangialosi 65. PARMA Rizzoli, Giuliani 66. PAVIA Lazzarino, Corso 67. PERUGIA Martelli, Ballanti 68. PESARO Visani, Leopardi 69. PESCARA Fioritoni, Spadano 70. PIACENZA Cavanna, Lazzaro 71. PINEROLO Griso 72. PISA Petrini/Benedetti 73. POTENZA Ricciuti, Vertone 74. RAVENNA Zaccaria, Cellini 75. REGGIO CALABRIA Nobile, Callea 76. REGGIO EMILIA Gugliotta, Masini 77. RIMINI Pasquini, Fattori 78. RIONERO VULTURE Musto 79. RIETI Capparella 80. ROMA Foà, Petrucci 81. ROMA De Fabritiis, Caravita 82. ROMA Andriani 83. ROMA Annino, Bongarzoni 84. ROMA Leone, De Stefano 85. ROMA Petti, Pisani 86. ROMA Majolino, De Rosa 87. ROMA Amadori 88. ROMA Avvisati 89. ROMA Recine 90. ROZZANO Santoro, Nozza 91. S. G. ROTONDO Cascavilla, Falcone 92. SASSARI Dore, Podda 93. SIENA Lauria, Gozzetti 94. TARANTO Mazza, Casulli 95. TERNI Liberati 96. TORINO Boccadoro 97. TORINO Pregno, Benevolo 98. TORINO Tarella, Gottardi 99. TREVISO Gherlinzoni 100. TRICASE Pavone 101. TRIESTE De Sabbata 102. UDINE Fanin, Patriarca 103. VENEZIA Chisesi 104. VERBANIA Montanara, Luraschi 105. VERCELLI Santagostino 106. VERONA Pizzolo, Meneghini 107. VICENZA Rodeghiero, Elice 108. VITERBO Montanaro 109. ISRAEL Nagler 110. JERUSALEM Ben Yehuda 111. KEFAR SABAH Manor 112. ZERIFIM Kornberg 113. HAIFA Attias

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