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