I nuovi scenari terapeutici TERAPIA DEL MIELOMA MULTIPLO NEL PAZIENTE ANZIANO. Antonio Palumbo Div. Hematology, University of Torino, Italy

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1 I nuovi scenari terapeutici TERAPIA DEL MIELOMA MULTIPLO NEL PAZIENTE ANZIANO Antonio Palumbo Div. Hematology, University of Torino, Italy

2 I nuovi scenari terapeutici TERAPIA DEL MIELOMA MULTIPLO NEL PAZIENTE ANZIANO Antonio Palumbo Div. Hematology, University of Torino, Italy

3 Multiple Myeloma ASL TORINO: people INCIDENCE: 1974: 5.9/ : 8.9/ Median age at diagnosis: 69.4 years years 36% 31% years 33% years Regione Piemonte, Assessorato Sanità 2006,15

4 Survival outcomes for multiple myeloma Age at diagnosis Years Mortality Ratio Increased ratio (ref.) % % % % % 60 years 4-year survival 70 years 3-year survival Kristinsson SY, et al. J Clin Oncol. 2007;25:

5 Transplant Transplant-Eligible Patients

6 Autologous stem cell transplant in elderly patients Survival advantage Age < 65 yr Survival advantage Age yr NO Survival advantage Age yr OS MP MPT MEL P= Time From Randomization, mo Tandem MEL200 Tandem MEL100 Tandem MEL100 Barlogie et al NEJM 2006;354:1021 Palumbo et al Blood 2004;104:3052 Facon T et al. ASCO 2006

7 Non-Transplant Elderly Untreated Patients

8 MP vs Dexamethasone-Based Regimens (IFM Trial) 488 patients aged yr randomized to MP, MD, D, or D- IFN (12 courses at 6-wk intervals) FU 82.8 mo, OS 35.0 mo (415/488), EFS 18.3 mo (473/488) for whole series Standard MP gold standard for treatment of older pts Regimen MP MD D D-IFN n PR (P<0.001) 51% 74% 40% 42% CR (P=NS) 1% 3% 1% 1% EFS (mo) 21.1 ± ± ± 1.0* 15.2 ± 2.7* OS (mo) 34.0 ± ,6 ± ± ± 5.3 *P<0.001 for pts not receiving Melphalan Facon T et al. Blood. 2006; 107:1292

9 Study and patients Thal/Dex vs MP in newly diagnosed MM Median age: 72 years Thal 200 mg/d, Dex 40 mg (odd: d 1 4, ; 18; even: d 1 4), 1 OR Melphalan 0.25 mg/kg/d (d 1 4) 1 + prednisone 2 mg/kg, d 1 4, 1 q wks Response > PR CR/nCR EFS (months) OS (months) Thal/Dex (n=136) 68% 30% MP (n=138) 51% 14% P value <0.004 < Ludwig, et al. Haematologica Ludwig, 2007;92: et (abstract al. IMW 0466) 2007

10 MPT vs MP in Elderly Patients With MM: Event-Free Survival and Overall Survival Age: : years Melphalan, 4 mg/m 2 (7 days/mo) Prednisone, 40 mg/m 2 (7 days/mo) Thalidomide, 100 mg/d (continuously) 50mg/month 6 cycles EFS 49% in risk of event for MPT MP MPT OS 65% in risk of death at >9 mo for MPT Proportion of Patients Proportion of Patients HR 0.51 (95% CI ) P= Months Palumbo A et al. Lancet. 2006;367: HR 0.68 (95% CI ) P= Months

11 MP vs MPT and MP vs MEL100/ASCT in Newly Diagnosed Elderly MM Patients: PFS and OS Age: : years Melphalan,, 0.25 mg/kg (4 days/1.5 mo) 50 mg/month Prednisone,, 2 mg/kg (4 days/1.5 mo) 12 cycles Thalidomide,, mg/day 1.0 PFS 1.0 OS MP MPT MEL100 Fraction Fraction P< P= Time From Randomization, mo Time From Randomization, mo Facon T et al. Presented at: ASCO Annual Meeting; June 2 6, 2006; Atlanta, GA

12 MP vs MPT in Newly Diagnosed Elderly MM Age: : years Melphalan,, 0.2 mg/kg (4 days/1,5 mo) 35 mg/month Prednisone,, 2 mg/kg (4 days/1.5 mo) 12 cycles Thalidomide,, mg/day Progression-free survival Overall survival MPT 24.1 mo MPT 45.3 mo MP 19 mo P= MP 27.7 mo P = 0.05 Hulin C et al. Presented at: ASCO Annual Meeting; June 2007; Chicago, IL

13 Proportion of patients Newly Diagnosed Patients MPR vs MPT: Response Rates Melphalan,, 0.18 mg/kg (4 days/mo) 50 mg/month Prednisone,, 2 mg/kg (4 days/mo) 9 cycles Lenalidomide,, 10 mg/d (21days/mo) 70 ASA,, 100 mg/day, continuously 48% MPR Cohort 3 ( ) Best Response n= CR VGPR PR MR SD PD Age: : years *Historical control Palumbo et al, Lancet % of response not available Proportion of patients % MPT Best Response n=129* 5 5 CR VGPR PR MR SD PD 8

14 MPR vs MPT: EFS and OS R-MP: median follow-up 14.6 months ( ) [N=53] MPT: median follow-up 17.6 months ( ) [N=129]* 1 EFS 1 OS RMP Proportion of patients 0,75 0,5 0,25 p=0.053 RMP MPT Proportion of patients 0,75 0,5 0,25 p=0.046 MPT Months Months Palumbo et al ASH 2006 *Historical control Palumbo et al, Lancet 2006

15 Newly Diagnosed Patients MPV vs MPT: Response Rates Age: : years Four 6-week cycles Bortezomib d 1,4,8,11,22,25,29,32 Melphalan, 9 mg/ ( m 2 (4 days) Prednisone, 60 mg/m 2 (4 days) Proportion of patients % 11 MPV Best Response n=53* CR ncr PR MR SD PD Mateos et al. Blood 2006; 108(7): Proportion of patients Five 5-week cycles Bortezomib day 1,8,15,22 Melphalan, 9 mg/m 2 (4 days) Prednisone, 60 mg/m 2 (4 days) % 21 Palumbo A et al. Lancet 2006;367:825 MPT Best Response n=129* CR VGPR PR MR SD PD 8

16 MPV vs MP: EFS and OS Event-free survival V-MP: 83% P= MP: 51% Median follow-up: 16 months (11 24) Overall survival V-MP: 90% P= MP: 62% Mateos et al. Blood 2006; 108(7):

17 Response rate VMPT RELAPSE MPV MPR MPT MP VAD-MEL200 TD-MEL200 ASCT VGPR (%)

18 Event-free survival Proportion of patients MPR MP MPT MEL200 MEL100 Months Palumbo et al Blood 2006; 108:55; Palumbo et al Lancet 2006; Palumbo et al Blood 2006;108:407

19 Diagnosis: MEL100 (age 70) Diagnosis: MEL200 (age 59) Relapse: VMPT (age 67) GR3 GR4 Fever Facon et al ASCO 2006; Attal et al. Blood 2006;108:3289; Palumbo et al Blood 2006;108:407 MEL100 MEL200 VMPT

20 Treatment Strategies

21 Prognostic factors MPT 2-microglobulin > 3.5 mg/dl MPR Del 13; t(4:14) MPV Del 13; t(4:14) Palumbo et al EHA 2006 Palumbo et al ASH 2006 Mateos et al Blood 2006

22 Therapeutic Algorithm Level of Evidence 1b (>( 1 Randomized Trial) Diagnosis > 65 years TD = MP 1 randomized trial MPT > MP 3 randomized trials MPV > MP 1 randomized trial MPR MP under evaluation

23 Salvage therapy

24 Relapsed salvage regimens Bortezomib Bortezomib PGL doxo Lenalidomide Dexamethasone p = Days p < (months) Richardson et al.. NEJM 2005 Orlowski et al ASH 2006 Dimopoulos MA. Blood. 2005

25 Age-adjusted corticosteroid dose < 65 years Dexamethasone 40 mg/day d 1 4, Prednisone 50 mg Every other day years Dexamethasone 40 mg/day d 1, 8, 15, 22 Prednisone mg Every other day > 75 years Dexamethasone 20 mg/day d 1, 8, 15, 22 Prednisone 12,5-25 mg Every other day Recommendations by A. Palumbo.

26 V-MPT at 1 Relapse MPT at Diagnosis Bortezomib, day 1,4,15,22 Melphalan, 0.18 mg/kg (4 days) 50 mg/month Prednisone, 2 mg/kg (4days) Thalidomide, 50 mg/daily, continuously 6 cycles 50 57% V-MPT [N=14] 45 39% MPT (N=129)^ % % 1 Relapse 21% 21% 21% % % 15% 21% Diagnosis 13% 10 0 CR- 0% VGPR PR MR SD-PD 5 0 5% CR- VGPR PR MR SD-PD Palumbo A et al. Lancet

27 VMPT MPT^ Grade Adverse Events VMPT (relapse) MPT (diagnosis)^ Anemia Thrombocytopenia Neutropenia Infection Peripheral neuropathy Thrombosis % Patients ^Historical controls Lancet 2006;367:825

28 Management of Adverse Events

29 Management of hematological toxicity Hematological toxicity Action During the cycle PLT <25-50,000/ L L or ANC < 500/ L Withhold, reinitiate at lower dose On the first day of a new cycle. PLT < 75,000/ L L or ANC > 1,500/ L Withhold until grade 1, reinitiate at lower dose

30 Management of non-hematological toxicity Thromboembolism: risk factors Diagnosis, high-tumor mass, doxorubicin, high-dose dexamethasone (> 160 mg/mo), Age (> 55 yrs), infection, immobilization, CVC, previous TE Action If one factor is present: Aspirin 100 mg/d If 2 or more factors are present: Enoxaparin 40 mg/d (4-6 months) Peripheral neurophaty symptoms Grade 1 (paresthesia( paresthesia). Grade 1 with pain or grade 2 (interfering with function) Grade 2 with pain or grade 3 (interfering with ADL) Action No action 50% dose reduction Withhold until grade 1, reinitiate at lower dose

31 Conclusion New combo or ASCT: similar response Data on PFS and OS are needed Better safety profile with new combo

32 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, Bigazzi 5. ASTI Scassa, Campa 6. AVELLINO Cantore, Volpe 7. AVIANO Tirelli, Rupolo 8. BARI Dammacco,, Lauta 9. BARI Liso 10. BERGAMO Barbui,, Galli 11. BIELLA Tonso 12. BOLOGNA Cavo, Tosi 13. BOLZANO Pescosta 14. BRA Vanni, Stefani 15. BRESCIA Rossi, Crippa 16. CAGLIARI Angelucci, Carubelli 17. CAGLIARI Mantovani 18. CAMPOBASSO Storti 19. CANDIOLO Aglietta, Capaldi 20. CATANIA Giustolisi,Di Raimondo 21. CATANZARO Piro 22. CATTOLICA Pasquini 23. CESENA Guardigni 24. CHIOGGIA Battista 25. CIRIE' Freilone, Beggiatto 26. COSENZA Morabito 27. CREMONA Passalacqua, Morandi 28. CREMONA Morandi 29. CUNEO Gallamini,, Grasso 30. FIRENZE Bosi/Nozzoli 31. FOGGIA Monaco, Ferrandina 32. FOGGIA Monaco 33. FORLI Amadori, Gentilini 34. GALLARATE Ciambelli 35. GENOVA Gobbi, Canepa 36. GENOVA Carella 37. LATINA Zapone 38. LECCE Pavone 39. MATERA Ciancio 40. MESSINA Brugiatelli, Mamone 41. MESSINA Musolino 42. MILANO Corradini, Montefusco 43. MILANO Morra 44. MILANO Bregni 45. MODENA Narni 46. MONTEFIASC. Montanaro, Niscola 49. MONZA Pogliani, Rossini 50. NAPOLI Rotoli,Catalano 51. NAPOLI Ferrara 52. NOCERA INF. D Arco, Califano 53. NOVARA Gaidano, Rossi 54. NUORO Latte, Palmas 55. ORBASSANO Saglio, Guglielmelli 56. PADOVA Semenzato, Zambello 57. PALERMO Mirto, Cangialosi 58. PARMA Rizzoli, Giuliani 59. PAVIA Lazzarino, Corso 60. PERUGIA Liberati, Nunzi 61. PESARO Visani, Leopardi 62. PESCARA Fioritoni, Spadano 63. PIACENZA Cavanna, Lazzaro 64. PINEROLO Griso 65. PISA Petrini/Benedetti 66. POTENZA Ricciuti, Vertone 67. RAVENNA Zaccaria, Molinari 68. REGGIO CAL. Nobile, Callea 69. REGGIO EMILIA Gugliotta,Masini 70. RIMINI Pasquini, Fattori 71. ROMA Annino, Bongarzoni 72. ROMA Andriani 73. ROMA 1 Foà, Petrucci 74. ROMA Cattolica Leone, De Stefano 75. ROMA R.Elena Petti, Pisani 76. ROMA S. Camillo Majolino, De Rosa 77. ROMA T. Vergata Amadori, Caravita, i 78. ROZZANO Santoro, Nozza 79. S. G. ROTONDO Musto, Merla 80. SASSARI Longinotti, Dore 81. SIENA Lauria, Gozzetti 82. TARANTO Mazza, Casulli 83. TORINO 1 Boccadoro 84. TORINO 2 Gallo, Pregno 85. TORINO MAURIZ. Poccardi, Gottardi 86. TORINO S. VITO Marinone, Ficara 87. TORINO VALD.SE Bazzan, Rus 88. TREVISO Foscolo, Gherlinzoni 89. TRIESTE De Sabbata 90. UDINE Fanin, Patriarca 91. VARESE Pinotti 92. VENEZIA Chisesi 93. VERBANIA Montanara, Luraschi 94. VERONA Pizzolo, Meneghini 95. VICENZA Rodeghiero, Elice