Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT)

Followed

by Maintenance with Bortezomib and Thalidomide (VT) for

Initial Treatment of Elderly Multiple Myeloma Patients

GIMEMA: Italian Multiple Myeloma Network

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 Group1.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.

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

• 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

Treatment schedule

VMPCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4

VMPTCycles 1-9Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4Thalidomide 50 mg/day continuously

RANDOMIZE

9 x 5-week cycles in both arms

MAINTENANCEBortezomib 1.3 mg/m2 IV: days 1,15Thalidomide 50 mg/day continuously

NO MAINTENANCE

Until relapse

* 66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of Bortezomib

Patient Characteristics

27%27% > 75 years

3.842 microglobulin-mg/L (median)

Chromosome abnormalities

17%14% t(4;14)

5%3% t(14;16)

68%71% 65–74 years5%2% < 65 years

7171Age (median)

17%13% Del 17

VMPT VT

(N=254)

VMP

(N=257)

% o

f p

atie

nts

% o

f p

atie

nts

CRCR VGPRVGPR PRPRCRCR VGPRVGPR PRPR

% o

f p

atie

nts

% o

f p

atie

nts

SDSD PDPD SDSD PDPD

89%

59%

38%

VMPT VT (N=250)

0.01

0.03

0.0008

P value

81%> PR

50%> VGPR

24%CR

VMP (N=253)

VMPT VTVMP

2 42 6

3 1

1 7

1

0

5

1 0

1 5

2 0

2 5

3 0

3 5

4 0 3 8

2 1

3 0

6

1

0

5

1 0

1 5

2 0

2 5

3 0

3 5

4 0

Best Response Rate

% o

f p

atie

nts

Months

VMP VMPTVT

CR: VMPTVT

PR: VMPTVT

CR: VMP

PR: VMP

100

80

60

40

20

0

Time to first response and time to CR

0 5 10 15 20 25 300 5 10 15 20 25 30

Time to next therapy Progression free survival

% o

f p

atie

nts

Time to next therapy Progression free survival

Median follow-up 26.5 months

VMP: PFS @ 3 years = 40%VMPT VT: PFS @ 3 years = 54%

P = 0.006

VMP: TTNT @ 3 years = 55%VMPT VT: TTNT @ 3 years = 69%

VMPTVT

VMP

Months

VMPT VT

VMP

P = 0.0060.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Overall survival

Months

VMP: OS @ 3 years = 84%

VMPTVT: OS @ 3 years = 86%

% o

f p

atie

nts

VMP

VMPTVT

P = 0.60

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

Grade 3-4 Hematologic Adverse Events

Patients (%)

VMPTVTVMP

0 5 10 15 20 25 30 35 40

Anaemia

Thrombocytopenia

Neutropenia P=0.02

Grade 3-4 Non-hematologic Adverse Events

Patients (%)

VMPTVTVMP

0 5 10 15 20 25

Drop Out for PN

Drop Out for AE

DVT/PE

Cardiologic

Infections

Sensory neuropathy

P=0.04

P=0.05

Efficacy and Toxicity by Bortezomib schedule

46.8 mg/m267.6 mg/m267.6Total planned dose

4%16%NAPN discontinuation

57%57%48%PFS @ 2 years

2%14%13% Grade 3-4

NA

44%

30%

VMP* (VISTA)

40 mg/m2

21%

23%

VMP once weekly N=190°

Sensory PN

43% Any grade

41 mg/m2Total delivered dose

25%CR

VMP twice weekly N=63°

*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

PFS according to Bortezomib schedule

Twice weekly: PFS @ 3 years =45%

Once weekly: PFS @ 3 years = 50%

% o

f p

atie

nts

Months

Once weekly

Twice weekly

P = 0.870.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50 60

0.00669%55%TTNT @ 3 years

86%

54%

38%

VMPT VT

(N=250)

0.60

0.006

0.0008

P value

40%PFS @ 3 years

84%OS @ 3 years

24%CR

VMP

(N=253)

Conclusions 1

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

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