Disclosures for Palumbo Antonio, MD

Honoraria to disclose

CelgeneJanssen-Cilag

A Phase III Study of VMPT versus VMP

in newly diagnosed elderly

myeloma patientsAntonio Palumbo1, Sara Bringhen1, Davide Rossi2, Salvatore Berretta3, Vittorio Montefusco4, Jacopo Peccatori5, Monica Galli6, Angelo Carella7,

Paola Omedè1, Mario Boccadoro1

1Divisione di Ematologia dell’Università di Torino, A.O.U. San Giovanni Battista, Torino, Italy; 2Università del Piemonte Orientale Amedeo Avogadro, Novara, Italy; 3Ospedale Ferrarotto, Università di Catania, Catania, Italy; 4Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; 5Istituto Scientifico San Raffaele, Milano, Italy; 6Ospedali Riuniti, Bergamo, Italy; 7A.O.U. San Martino, Genova, Italy.

GIMEMA: Italian Myeloma Network

Rationale: 3 drug combinations

1 San Miguel JF et al. New Eng J Med 2008; 359: 906-172 Palumbo et al. Blood 2008;112: 3107-3114

V = Bortezomib; M= Melphalan; P = Prednisone; T= Thalidomide

MP1

(diagnosis)

MPT2

(diagnosis)

VMP1

(diagnosis)

No. patients

331 167 337

CR 4% 16% 33%

> VGPR 8% 29% 41%

> PR 39% 76% 74%

VMPT3 (relapse)

RMPT4

(relapse)VCRD5

(diagnosis)

No. patients

30 44 25

CR 17% 13% 56%

> VGPR 43% 33% 68%

> PR 66% 76% 100%

3 Palumbo et al. Blood 2007;109: 2767-27724 Palumbo ASH 2008; 112: 8685 Kumar ASH 2008; 112: 93

V=Bortezomib; M=Melphalan; P=Prednisone; T=Thalidomide; R=Lenalidomide; C=Cyclophosphamide; D=Dexametasone

Rationale: 4 drug combinations

Aims

VMPT: superior to VMP?

Weekly infusion of bortezomib: safety improvement?

511 patients (older than 65 years) randomized from 58 Italian centers

Patients: Symptomatic disease, organ damage, 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

* 64 VMP patients and 71 VMPT patients were treated with twice-weekly infusions of Bortezomib

VMPT(n=221)

VMP(n=229)

Age (median)

≤70 years

71–75 years

>75 years

2-microglobulin-mg/L (median)

Hemoglobin-g/dL (median)

Creatinine-mg/dL (median)

Calcemia-mmol/L (median)

71

49%

30%

21%

3.7

10.5

1.0

2.32

71

43%

35%

22%

4.0

10.8

1.0

2.32

Patient Characteristics

Best Response

35

16

33

9

10

10

20

30

40

50

60

70

CR VGPR PR

VMPTN=221Median No. of cycles 5

51%*

% o

f p

atie

nts

SD PD

35§ 42%*

21 21

36

18

10

10

20

30

40

50

60

70

% o

f p

atie

nts

CR VGPR PR

§ P < 0.0001

* P = 0.06

VMPN=229Median No. of cycles 5

SD PD

21 §

Time to response0

0 ,1

0 ,2

0 ,3

0 ,4

0 ,5

0 ,6

0 ,7

0 ,8

0 ,9

1

0 1 2 3 4 5 6 7 8 9 10 11

VMPT

VMP

VMP

VMPT

% o

f p

atie

nts

Treatment cycle

100

90

80

70

60

50

40

30

20

10

0

PR CR

Time to next therapy Progression free survival

P = 0.30 P = 0.130. 00

0. 25

0. 50

0. 75

1. 00

t t nt

0 5 10 15 20 25 30 35 40 45

STRATA: gr uppo=1 Censor ed gr uppo=1 gr uppo=2 Censor ed gr uppo=2

% o

f p

atie

nts

Months Months

Time to next therapy Progression free survivalMedian follow-up 16.1 months

0. 00

0. 25

0. 50

0. 75

1. 00

ef s

0 5 10 15 20 25 30 35 40 45

STRATA: gr uppo=1 Censor ed gr uppo=1 gr uppo=2 Censor ed gr uppo=2

VMPT

VMP

VMPT: PFS @ 36 months = 71%VMP: PFS @ 36 months = 56%

VMPT

VMP

VMPT: TTNT @ 36 months = 80%VMP: TTNT @ 36 months = 78%

Progression free survivalAge: ≤ 75 years vs > 75 years

P=0.47

VMP

% o

f p

atie

nts

months

Age ≤75 years

Age >75 years

All patients

% o

f p

atie

nts

months

P=0.02

Age ≤75 years

Age >75 years

gr uppo=1

0. 00

0. 25

0. 50

0. 75

1. 00

ef s

0 5 10 15 20 25 30 35 40 45

STRATA: ETA75=0 Censor ed ETA75=0 ETA75=1 Censor ed ETA75=1

P=0.006

VMPT

% o

f p

atie

nts

months

Age ≤75 years

Age >75 years

Progression free survival Response rate: CR vs VGPR vs PR

CR

VGPR

PR

% o

f p

atie

nts

months

% o

f p

atie

nts

months

CR

≥PR

P=0.005

All patients All patients

≥VGPR

≥PR

P=0.0003

% o

f p

atie

nts

months

All patients

Progression free survivalFISH analisis: t(4;14) or t(14;16) or del17

% o

f p

atie

nts

months

All patients

0. 00

0. 25

0. 50

0. 75

1. 00

ef s

0 5 10 15 20 25 30 35

STRATA: vhr =0 Censor ed vhr =0 vhr =1 Censor ed vhr =1

P=0.39

% o

f p

atie

nts

months

VMP

P=0.81

% o

f p

atie

nts

months

VMPT

P=0.25

Standard Risk

High Risk

Standard Risk

High Risk

Standard Risk

High Risk

Progression free survivalInternational Staging System: ISS 1 vs ISS 2-3

% o

f p

atie

nts

months

All patients

0. 00

0. 25

0. 50

0. 75

1. 00

ef s

0 5 10 15 20 25 30 35 40 45

STRATA: I SS1=0 Censor ed I SS1=0 I SS1=1 Censor ed I SS1=1

P=0.30

ISS 1

ISS 2-3

% o

f p

atie

nts

months

VMPgr uppo=0

0. 00

0. 25

0. 50

0. 75

1. 00

ef s

0 5 10 15 20 25 30 35 40

STRATA: I SS1=0 Censor ed I SS1=0 I SS1=1 Censor ed I SS1=1

P=0.04

ISS 1

ISS 2-3%

of

pat

ien

ts

months

VMPTgr uppo=1

0. 00

0. 25

0. 50

0. 75

1. 00

ef s

0 5 10 15 20 25 30 35 40 45

STRATA: I SS1=0 Censor ed I SS1=0 I SS1=1 Censor ed I SS1=1

P=0.45

ISS 1

ISS 2-3

Progression free survivalFISH analisis t(4;14) or t(14;16) or del17 and ISS 2-3

% o

f p

atie

nts

months

VMP

Standard Risk

High Risk

P=0.08

months

gr uppo=1

0. 00

0. 25

0. 50

0. 75

1. 00

ef s

0 5 10 15 20 25 30 35

STRATA: r i sk3=0 Censor ed r i sk3=0 r i sk3=1 Censor ed r i sk3=1

% o

f p

atie

nts

VMPT

Standard Risk

High Risk

P=0.06

0. 00

0. 25

0. 50

0. 75

1. 00

ef s

0 5 10 15 20 25 30 35

STRATA: r i sk3=0 Censor ed r i sk3=0 r i sk3=1 Censor ed r i sk3=1

% o

f p

atie

nts

months

All patients

Standard Risk

High Risk

P=0.02

Grade 3-4 Hematologic Adverse Events VMP vs VMPT

0 5 10 15 20 25 30

Anaemia

Thrombocytopenia

Neutropenia

% of patients

VMPTVMP

Grade 3-4 Non-hematologic Adverse Events

VMP vs VMPT

0 5 10 15

Thrombosis

Fatigue

Cardiologic

Gastrointestinal

Infections

Sensoryneuropathy

% of patients

VMPTVMP

Efficacy and Toxicity bortezomib infusion schedule

VMPT VMP

twice weekl

y (N=71

)

weekly

(N=150)

twice weekl

y (N=64

)

weekly

(N=165)

CR 38% 32% 27% 20%

Grade 3-4 Peripheral neuropathy

18% 2% 14% 2%

Dose reduction* 42% 11% 35% 13%

Discontinuation* 10% 3% 15% 4%25 VMPT and 19 VMP patients received both twice- and once-weekly

*Due to peripheral neuropathy

Conclusion

VMPT (N=177)

VMP (N=177

)P value

CR 35% 21%<

0.0001

PFS @ 3 years 71% 56% 0.13

OS @ 3 years 90% 89% 0.81

Grade 3-4 Peripheral neuropathy*

2% 2% -

Discontinuation§ 3% 4% -

*For patients (VMPT 150; VMP 165) who received weekly infusion of bortezomib,)

§ Due to peripheral neuropathy

1. ALESSANDRIA1. ALESSANDRIA Levis, BaraldiLevis, Baraldi

2. ANCONA2. ANCONA Leoni, OffidaniLeoni, Offidani

3. AOSTA3. AOSTA Di VitoDi Vito

4. ASCOLI PICENO4. ASCOLI PICENO Galieni, BigazziGalieni, Bigazzi

5. ASTI5. ASTI Scassa, CampaScassa, Campa

6. AVELLINO6. AVELLINO Cantore, VolpeCantore, Volpe

7. AVIANO7. AVIANO Tirelli, RupoloTirelli, Rupolo

8. BARI8. BARI Dammacco, LautaDammacco, Lauta

9. BARI9. BARI LisoLiso

10. BERGAMO10. BERGAMO Barbui, GalliBarbui, Galli

11. BIELLA11. BIELLA TonsoTonso

12. 12. BOLOGNA Cavo, TosiCavo, Tosi

13. BOLZANO13. BOLZANO PescostaPescosta

14. BRA14. BRA Vanni, StefaniVanni, Stefani

15. BRESCIA15. BRESCIA Rossi, CrippaRossi, Crippa

16. CAGLIARI16. CAGLIARI Angelucci, CarubelliAngelucci, Carubelli

17. CAGLIARI17. CAGLIARI MantovaniMantovani

18. CAMPOBASSO18. CAMPOBASSO StortiStorti

19. CANDIOLO19. CANDIOLO Aglietta, CapaldiAglietta, Capaldi

20. CATANIA20. CATANIA Giustolisi, Di RaimondoGiustolisi, Di Raimondo

21. CATANZARO21. CATANZARO PiroPiro

22. CATTOLICA22. CATTOLICA Pasquini Pasquini

23. CESENA23. CESENA GuardigniGuardigni

24. CHIOGGIA24. CHIOGGIA BattistaBattista

25. CIRIE'25. CIRIE' Freilone, BeggiatoFreilone, Beggiato

26. COSENZA26. COSENZA MorabitoMorabito

27. CREMONA27. CREMONA Passalacqua, MorandiPassalacqua, Morandi

28. CREMONA28. CREMONA MorandiMorandi

29. CUNEO29. CUNEO Gallamini, GrassoGallamini, Grasso

30. FIRENZE30. FIRENZE Bosi, NozzoliBosi, Nozzoli

31. FOGGIA31. FOGGIA Monaco, Ferrandina 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

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

We Are Grateful to All Patients, Nurses and Physicians of the Participating Centers