Disclosures for
Palumbo Antonio, MD
Honoraria to disclose
Celgene
Janssen-Cilag
GIMEMA: Italian Myeloma Network
A Phase III Study of VMPT versus VMP
in newly diagnosed elderly
myeloma patients
Antonio Palumbo1, Sara Bringhen1, Davide Rossi2, Salvatore Berretta3,
Vittorio Montefusco4, Jacopo Peccatori5, Monica Galli6, Angelo Carella7,
Paola Omedč1, Mario Boccadoro1
1Divisione di Ematologia dell'Universitā di Torino, A.O.U. San Giovanni Battista, Torino, Italy;
2Universitā del Piemonte Orientale Amedeo Avogadro, Novara, Italy; 3Ospedale Ferrarotto,
Universitā 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.
Rationale: 3 drug combinations
MP1
MPT2
VMP1
(diagnosis)
(diagnosis)
(diagnosis)
No. patients
331
167
337
CR
4%
16%
33%
> VGPR
8%
29%
41%
> PR
39%
76%
74%
V = Bortezomib; M= Melphalan; P = Prednisone; T= Thalidomide
1 San Miguel JF et al. New Eng J Med 2008; 359: 906-17
2 Palumbo et al. Blood 2008;112: 3107-3114
Rationale: 4 drug combinations
VMPT3
RMPT4
VCRD5
(relapse)
(relapse)
(diagnosis)
No. patients
30
44
25
CR
17%
13%
56%
> VGPR
43%
33%
68%
> PR
66%
76%
100%
V=Bortezomib; M=Melphalan; P=Prednisone; T=Thalidomide; R=Lenalidomide;
C=Cyclophosphamide; D=Dexametasone
3 Palumbo et al. Blood 2007;109: 2767-2772
4 Palumbo ASH 2008; 112: 868
5 Kumar ASH 2008; 112: 93
Aims
VMPT: superior to VMP?
Weekly infusion of bortezomib: safety improvement?
Treatment schedule
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
VMP
NO
Cycles 1-9
R
MAINTENANCE
Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
A
N
D
9 x 5-week cycles in both arms
Until relapse
O
M
VMPT
I
MAINTENANCE
Cycles 1-9
Bortezomib 1.3 mg/m2 IV: days 1,15
Z
Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*
Thalidomide 50 mg/day
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
E
continuously
Thalidomide 50 mg/day continuously
* 64 VMP patients and 71 VMPT patients were treated with twice-weekly
infusions of Bortezomib
Patient Characteristics
VMPT
VMP
(n=221)
(n=229)
Age (median)
71
71
70 years
49%
43%
71­75 years
30%
35%
>75 years
21%
22%
2-microglobulin-mg/L (median)
3.7
4.0
Hemoglobin-g/dL (median)
10.5
10.8
Creatinine-mg/dL (median)
1.0
1.0
Calcemia-mmol/L (median)
2.32
2.32
Best Response
VMPT
VMP
N=221
N=229
70
Median No. of cycles 5
70
Median No. of cycles 5
60
60
51%*
P < 0.0001
50
50
* P = 0.06
40
40
35
35
patients
42%*
36
patients
33
of
of
% 30
% 30
21
21
21
20
18
16
20
9
10
10
1
1
0
0
CR
VGPR
PR
SD
PD
CR
VGPR
PR
SD
PD
Time to response
0
100
PR
CR
VMPT
0,1
90
80 0,2
VMP
ts 70 0,3
n 60 0,4
tieap 50 0,5
fo 40 0,6
%
VMPT
30 0,7
VMP
20
0,8
10 0,9
0
1
0123
45
67
89
10
11
Treatment cycle
Time to next therapy
Progression free survival
Median follow-up 16.1 months
Time to next therapy
Progression free survival
00
1.00
VMPT
75
VMP
VMPT
0.75
50
VMP
0.50
patients
of
25
%
0.25
VMPT: TTNT @ 36 months = 80%
VMPT: PFS @ 36 months = 71%
VMP: TTNT @ 36 months = 78%
VMP: PFS @ 36 months = 56%
00
0.00
0
P
5
= 0.30
10
15
20
25
30
35
40
45
0
P =
5
0.13
10
15
20
25
30
35
40
45
Months
Months
Progression free survival
Age: 75 years vs > 75 years
All patients
VMP
Age 75 years
Age 75 years
Age >75 years
Age >75 years
patients
patients
of
of
%
%
P=0.02
P=0.47
months
months
VMPT
gpp
1. 00
Age 75 years
0. 75
Age >75 years
0. 50
patients
of
0. 25
%
P=0.006
0. 00
0
5
10
15
20
25
30
35
40
45
months
Progression free survival
Response rate: CR vs VGPR vs PR
All patients
All patients
CR
CR
VGPR
PR
PR
patients
patients
of
of
%
%
P=0.005
months
months
All patients
VGPR
PR
patients
of%
P=0.0003
months
Progression free survival
FISH analisis: t(4;14) or t(14;16) or del17
All patients
VMP
1. 00
Standard Risk
0. 75
Standard Risk
High Risk
High Risk
0. 50
patients
patients
of
of
% 0.25
%
P=0.39
P=0.81
0. 00
0
5
10
15
20
25
30
35
months
months
VMPT
Standard Risk
High Risk
patients
of%
P=0.25
months
Progression free survival
International Staging System: ISS 1 vs ISS 2-3
All patients
VMP
gpp
1. 00
1. 00
ISS 1
ISS 1
0. 75
0. 75
ISS 2-3
ISS 2-3
0. 50
0. 50
patients
patients
of
of
0. 25
0. 25
%
%
P=0.30
P=0.04
0. 00
0. 00
0
5
10
15
20
25
30
35
40
45
0
5
10
15
20
25
30
35
40
months
months
VMPT
gpp
1. 00
ISS 2-3
0. 75
ISS 1
0. 50
patients
of% 0.25
P=0.45
0. 00
0
5
10
15
20
25
30
35
40
45
months
Progression free survival
FISH analisis t(4;14) or t(14;16) or del17 and ISS 2-3
All patients
VMP
1. 00
Standard Risk
0.75
Standard Risk
0.50
High Risk
High Risk
patients
patients
of 0.25
of
%
%
P=0.02
P=0.08
0.00
0
5
10
15
20
25
30
35
months
months
VMPT
1. 00
Standard Risk
0. 75
0. 50
High Risk
patients
0. 25
of%
P=0.06
0. 00
0
5
10
15
20
25
30
35
months
Grade 3-4 Hematologic Adverse Events
VMP vs VMPT
VMP
VMPT
Neutropenia
Thrombocytopenia
Anaemia
0
5
10
15
20
25
30
% of patients
Grade 3-4 Non-hematologic Adverse Events
VMP vs VMPT
VMP
VMPT
Sensory
neuropathy
Infections
Gastrointestinal
Cardiologic
Fatigue
Thrombosis
05
10
15
% of patients
Efficacy and Toxicity
bortezomib infusion schedule
VMPT
VMP
twice
twice
weekly
weekly
weekly
weekly
(N=150)
(N=165)
(N=71)
(N=64)
CR
38%
32%
27%
20%
Grade 3-4
18%
2%
14%
2%
Peripheral neuropathy
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
VMP
P value
(N=177)
(N=177)
CR
35%
21%
< 0.0001
PFS @ 3 years
71%
56%
0.13
OS @ 3 years
90%
89%
0.81
Grade 3-4
2%
2%
-
Peripheral neuropathy*
Discontinuation
3%
4%
-
*For patients (VMPT 150; VMP 165) who received weekly infusion of bortezomib,)
Due to peripheral neuropathy
We Are Grateful to All Patients, Nurses and
Physicians of the Participating Centers
1. ALESSANDRIA
Levis, Baraldi
32. FOGGIA
Monaco
65. PISA
Petrini/Benedetti
2. ANCONA
Leoni, Offidani
33. FORLI'
Amadori, Gentilini
66. POTENZA
Ricciuti, Vertone
3. AOSTA
Di Vito
34. GALLARATE
Ciambelli
67. RAVENNA
Zaccaria, Molinari
4. ASCOLI PICENO
Galieni, Bigazzi
35. GENOVA
Gobbi, Canepa
68. REGGIO CAL.
Nobile, Callea
5. ASTI
Scassa, Campa
36. GENOVA
Carella
69. REGGIO EMILIA
Gugliotta,Masini
6. AVELLINO
Cantore, Volpe
37. LATINA
Zapone
70. RIMINI
Pasquini, Fattori
7. AVIANO
Tirelli, Rupolo
38. LECCE
Pavone
71. ROMA
Annino, Bongarzoni
8. BARI
Dammacco, Lauta
39. MATERA
Ciancio
72. ROMA
Andriani
9. BARI
Liso
40. MESSINA
Brugiatelli, Mamone
73. ROMA 1
Foā, Petrucci
10. BERGAMO
Barbui, Galli
41. MESSINA
Musolino
74. ROMA Cattolica
Leone, De Stefano
11. BIELLA
Tonso
42. MILANO
Corradini, Montefusco
75. ROMA R.Elena
Petti, Pisani
12. BOLOGNA
Cavo, Tosi
43. MILANO
Morra
76. ROMA S. Camillo
Majolino, De Rosa
13. BOLZANO
Pescosta
44. MILANO
Bregni
77. ROMA T. Vergata
Amadori, Caravita
14. BRA
Vanni, Stefani
45. MODENA
Narni
78. ROZZANO
Santoro, Nozza
15. BRESCIA
Rossi, Crippa
46. MONTEFIASC.
Montanaro, Niscola
79. S. G. ROTONDO
Musto, Merla
16. CAGLIARI
Angelucci, Carubelli
49. MONZA
Pogliani, Rossini
80. SASSARI
Longinotti, Dore
17. CAGLIARI
Mantovani
50. NAPOLI
Rotoli,Catalano
81. SIENA
Lauria, Gozzetti
18. CAMPOBASSO
Storti
51. NAPOLI
Ferrara
82. TARANTO
Mazza, Casulli
19. CANDIOLO
Aglietta, Capaldi
52. NOCERA INF.
D'Arco, Califano
83. TORINO 1
Boccadoro
20. CATANIA
Giustolisi, Di Raimondo
53. NOVARA
Gaidano, Rossi
84. TORINO 2
Gallo, Pregno
21. CATANZARO
Piro
54. NUORO
Latte, Palmas
85. TORINO MAURIZ.
Poccardi, Gottardi
22. CATTOLICA
Pasquini
55. ORBASSANO
Saglio, Guglielmelli
86. TORINO S. VITO
Marinone, Ficara
23. CESENA
Guardigni
56. PADOVA
Semenzato, Zambello
87. TORINO VALD.SE
Bazzan, Rus
24. CHIOGGIA
Battista
57. PALERMO
Mirto, Cangialosi
88. TREVISO
Foscolo, Gherlinzoni
25. CIRIE'
Freilone, Beggiato
58. PARMA
Rizzoli, Giuliani
89. TRIESTE
De Sabbata
26. COSENZA
Morabito
59. PAVIA
Lazzarino, Corso
90. UDINE
Fanin, Patriarca
27. CREMONA
Passalacqua, Morandi
60. PERUGIA
Liberati, Nunzi
91. VARESE
Pinotti
28. CREMONA
Morandi
61. PESARO
Visani, Leopardi
92. VENEZIA
Chisesi
29. CUNEO
Gallamini, Grasso
62. PESCARA
Fioritoni, Spadano
93. VERBANIA
Montanara, Luraschi
30. FIRENZE
Bosi, Nozzoli
63. PIACENZA
Cavanna, Lazzaro
94. VERONA
Pizzolo, Meneghini
31. FOGGIA
Monaco, Ferrandina
64. PINEROLO
Griso
95. VICENZA
Rodeghiero, Elice