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 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.
Rationale: 3 drug combinations
MP1
MPT2
(diagnosis) (diagnosis)
VMP1
(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)
30
44
25
CR
17%
13%
56%
> VGPR
43%
33%
68%
> PR
66%
76%
100%
No. patients
V=Bortezomib; M=Melphalan; P=Prednisone; T=Thalidomide; R=Lenalidomide;
C=Cyclophosphamide; D=Dexametasone
3
Palumbo et al. Blood 2007;109: 2767-2772
ASH 2008; 112: 868
5 Kumar ASH 2008; 112: 93
4 Palumbo
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
R
A
N
D
O
M
I
Z
E
Cycles 1-9
Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
9 x 5-week cycles in both arms
NO
MAINTENANCE
Until relapse
VMPT
MAINTENANCE
Cycles 1-9
Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
Thalidomide 50 mg/day continuously
Bortezomib 1.3 mg/m2 IV: days 1,15
Thalidomide 50 mg/day
continuously
* 64 VMP patients and 71 VMPT patients were treated with twice-weekly
infusions of Bortezomib
Patient Characteristics
VMPT
(n=221)
71
49%
30%
21%
VMP
(n=229)
71
43%
35%
22%
b2-microglobulin-mg/L (median)
3.7
4.0
Hemoglobin-g/dL (median)
Creatinine-mg/dL (median)
Calcemia-mmol/L (median)
10.5
1.0
2.32
10.8
1.0
2.32
Age (median)
≤70 years
71–75 years
>75 years
Best Response
70
VMPT
N=221
Median No. of cycles 5
70
60
40
§
51%*
% of patients
% of patients
60
50
VMP
N=229
Median No. of cycles 5
§
35
35
33
30
P < 0.0001
* P = 0.06
50
40
42%*
30
21
§
21
20
36
21
18
20
16
9
10
10
1
1
0
CR
VGPR
PR
SD
PD
0
CR
VGPR
PR
SD
PD
Time to response
100
PR
CR
VMPT
90
80
VMP
70
60
50
40
VMPT
30
VMP
20
10
0
0
1
2
3
4
5
6
Treatment cycle
7
8
9
10
11
Time to next therapy
Progression free survival
Median follow-up 16.1 months
Time to next therapy
Progression free survival
1. 00
1. 00
VMPT
VMP
% of patients
0. 75
0. 50
0. 25
0. 75
VMPT
0. 50
VMP
0. 25
VMPT: TTNT @ 36 months = 80%
VMP: TTNT @ 36 months = 78%
VMPT: PFS @ 36 months = 71%
VMP: PFS @ 36 months = 56%
0. 00
0. 00
0
5
P = 0.30
10
15
20
25
30
35
40
45
0
P = 0.13
5
t t nt
ST RAT A:
gr uppo=1
Months
Ce n s o r e d g r u p p o = 1
gr uppo=2
10
15
20
25
30
Months
35
40
ef s
Ce n s o r e d g r u p p o = 2
ST RAT A:
gr uppo=1
Ce n s o r e d g r u p p o = 1
gr uppo=2
Ce n s o r e d g r u p p o = 2
45
Progression free survival
Age: ≤ 75 years vs > 75 years
All patients
VMP
Age ≤75 years
% of patients
% of patients
Age ≤75 years
Age >75 years
Age >75 years
P=0.47
P=0.02
months
months
VMPT
gr uppo=1
1. 00
% of patients
Age ≤75 years
0. 75
Age >75 years
0. 50
0. 25
P=0.006
0. 00
0
5
10
15
20
25
30
35
40
ef s
S T RA T A :
ET A7 5 = 0
months
Ce n s o r e d E T A 7 5 = 0
ET A7 5 = 1
Ce n s o r e d E T A 7 5 = 1
45
Progression free survival
Response rate: CR vs VGPR vs PR
All patients
All patients
CR
CR
% of patients
PR
≥PR
P=0.005
months
All patients
≥VGPR
% of patients
% of patients
VGPR
≥PR
P=0.0003
months
months
Progression free survival
FISH analisis: t(4;14) or t(14;16) or del17
VMP
All patients
1. 00
Standard Risk
Standard Risk
% of patients
High Risk
0. 50
0. 25
P=0.39
High Risk
P=0.81
0. 00
0
5
10
15
20
25
30
35
months
ef s
S T RA T A :
v hr =0
months
Ce n s o r e d v h r = 0
v hr =1
Ce n s o r e d v h r = 1
VMPT
Standard Risk
% of patients
% of patients
0. 75
High Risk
P=0.25
months
Progression free survival
International Staging System: ISS 1 vs ISS 2-3
All patients
VMP
gr uppo=0
1. 00
1. 00
0. 75
% of patients
0. 75
ISS 2-3
0. 50
0. 25
ISS 2-3
0. 50
0. 25
P=0.30
P=0.04
0. 00
0. 00
0
5
10
15
20
25
30
35
40
S T RA T A :
I SS1 = 0
5
10
15
20
25
30
35
ef s
months
Ce n s o r e d I S S 1 = 0
0
45
ef s
I SS1 = 1
Ce n s o r e d I S S 1 = 1
VMPT
S T RA T A :
months
I SS1 = 0
Ce n s o r e d I S S 1 = 0
gr uppo=1
1. 00
% of patients
% of patients
ISS 1
ISS 1
ISS 2-3
0. 75
ISS 1
0. 50
0. 25
P=0.45
0. 00
0
5
10
15
20
25
30
35
40
ef s
S T RA T A :
I SS1 = 0
months
Ce n s o r e d I S S 1 = 0
I SS1 = 1
Ce n s o r e d I S S 1 = 1
45
I SS1 = 1
Ce n s o r e d I S S 1 = 1
40
Progression free survival
FISH analisis t(4;14) or t(14;16) or del17 and ISS 2-3
VMP
All patients
1. 00
Standard Risk
Standard Risk
% of patients
0. 50
High Risk
0. 25
High Risk
P=0.08
P=0.02
0. 00
0
5
10
15
20
25
30
35
ef s
S T RA T A :
r i s k 3=0
months
Ce n s o r e d r i s k 3 = 0
r i s k 3=1
Ce n s o r e d r i s k 3 = 1
months
VMPT
gr uppo=1
1. 00
Standard Risk
0. 75
% of patients
% of patients
0. 75
High Risk
0. 50
0. 25
P=0.06
0. 00
0
5
10
15
20
25
30
ef s
S T RA T A :
r i s k 3=0
months
Ce n s o r e d r i s k 3 = 0
r i s k 3=1
Ce n s o r e d r i s k 3 = 1
35
Grade 3-4 Hematologic Adverse Events
VMP vs VMPT
VMP
VMPT
Neutropenia
Thrombocytopenia
Anaemia
0
5
10
15
% of patients
20
25
30
Grade 3-4 Non-hematologic Adverse Events
VMP vs VMPT
VMP
VMPT
Sensory
neuropathy
Infections
Gastrointestinal
Cardiologic
Fatigue
Thrombosis
0
5
10
% of patients
15
Efficacy and Toxicity
bortezomib infusion schedule
VMPT
twice
weekly
(N=71)
VMP
twice
weekly
weekly
weekly
(N=150)
(N=165)
(N=64)
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
We Are Grateful to All Patients, Nurses and
Physicians of the Participating Centers
1. ALESSANDRIA
2. ANCONA
3. AOSTA
4. ASCOLI PICENO
5. ASTI
6. AVELLINO
7. AVIANO
8. BARI
9. BARI
10. BERGAMO
11. BIELLA
12. BOLOGNA
13. BOLZANO
14. BRA
15. BRESCIA
16. CAGLIARI
17. CAGLIARI
18. CAMPOBASSO
19. CANDIOLO
20. CATANIA
21. CATANZARO
22. CATTOLICA
23. CESENA
24. CHIOGGIA
25. CIRIE'
26. COSENZA
27. CREMONA
28. CREMONA
29. CUNEO
30. FIRENZE
31. FOGGIA
Levis, Baraldi
Leoni, Offidani
Di Vito
Galieni, Bigazzi
Scassa, Campa
Cantore, Volpe
Tirelli, Rupolo
Dammacco, Lauta
Liso
Barbui, Galli
Tonso
Cavo, Tosi
Pescosta
Vanni, Stefani
Rossi, Crippa
Angelucci, Carubelli
Mantovani
Storti
Aglietta, Capaldi
Giustolisi, Di Raimondo
Piro
Pasquini
Guardigni
Battista
Freilone, Beggiato
Morabito
Passalacqua, Morandi
Morandi
Gallamini, Grasso
Bosi, Nozzoli
Monaco, Ferrandina
32. FOGGIA
33. FORLI’
34. GALLARATE
35. GENOVA
36. GENOVA
37. LATINA
38. LECCE
39. MATERA
40. MESSINA
41. MESSINA
42. MILANO
43. MILANO
44. MILANO
45. MODENA
46. MONTEFIASC.
49. MONZA
50. NAPOLI
51. NAPOLI
52. NOCERA INF.
53. NOVARA
54. NUORO
55. ORBASSANO
56. PADOVA
57. PALERMO
58. PARMA
59. PAVIA
60. PERUGIA
61. PESARO
62. PESCARA
63. PIACENZA
64. PINEROLO
Monaco
Amadori, Gentilini
Ciambelli
Gobbi, Canepa
Carella
Zapone
Pavone
Ciancio
Brugiatelli, Mamone
Musolino
Corradini, Montefusco
Morra
Bregni
Narni
Montanaro, Niscola
Pogliani, Rossini
Rotoli,Catalano
Ferrara
D’Arco, Califano
Gaidano, Rossi
Latte, Palmas
Saglio, Guglielmelli
Semenzato, Zambello
Mirto, Cangialosi
Rizzoli, Giuliani
Lazzarino, Corso
Liberati, Nunzi
Visani, Leopardi
Fioritoni, Spadano
Cavanna, Lazzaro
Griso
65. PISA
66. POTENZA
67. RAVENNA
68. REGGIO CAL.
69. REGGIO EMILIA
70. RIMINI
71. ROMA
72. ROMA
73. ROMA 1
74. ROMA Cattolica
75. ROMA R.Elena
76. ROMA S. Camillo
77. ROMA T. Vergata
78. ROZZANO
79. S. G. ROTONDO
80. SASSARI
81. SIENA
82. TARANTO
83. TORINO 1
84. TORINO 2
85. TORINO MAURIZ.
86. TORINO S. VITO
87. TORINO VALD.SE
88. TREVISO
89. TRIESTE
90. UDINE
91. VARESE
92. VENEZIA
93. VERBANIA
94. VERONA
95. VICENZA
Petrini/Benedetti
Ricciuti, Vertone
Zaccaria, Molinari
Nobile, Callea
Gugliotta,Masini
Pasquini, Fattori
Annino, Bongarzoni
Andriani
Foà, Petrucci
Leone, De Stefano
Petti, Pisani
Majolino, De Rosa
Amadori, Caravita
Santoro, Nozza
Musto, Merla
Longinotti, Dore
Lauria, Gozzetti
Mazza, Casulli
Boccadoro
Gallo, Pregno
Poccardi, Gottardi
Marinone, Ficara
Bazzan, Rus
Foscolo, Gherlinzoni
De Sabbata
Fanin, Patriarca
Pinotti
Chisesi
Montanara, Luraschi
Pizzolo, Meneghini
Rodeghiero, Elice