GIMEMA: Italian Multiple Myeloma Network
Bortezomib, Melphalan, Prednisone and Thalidomide
followed by maintenance with Bortezomib and Thalidomide (VMPT-
VT) for initial treatment of elderly multiple myeloma patients:
updated follow-up and impact of prognosic factors
A. Palumbo1, S. Bringhen1, M. Cavalli2, R. Ria2, M. Offidani2, F. Patriarca2, C.
Nozzoli2, A. Levi2, T. Guglielmelli2, G. Benevolo2, V. Callea2, R. Zambello2, G.
Pietrantuono2,
L. De Rosa2, A.M. Liberati2, C. Crippa2, G. Perrone2, F. Ciambelli2, A.M. Carella2,
S. Palmieri2, M. Gilestro1, V. Magarotto1,
M.T. Petrucci2, P. Musto2, G. Gaidano2
and M. Boccadoro1.
1Myeloma Unit, Division of Hematology, University of Torino, A.O.U S.Giovanni Battista,Torino, Italy;
2Italian Multiple Myeloma Network, GIMEMA, Italy.
Treatment schedule
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
R
VMP
Cycles 1-9
A
Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*
NO MAINTENANCE
N
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
D
O
9 x 5-week cycles in both arms
Until relapse
M
VMPT
I
Cycles 1-9
MAINTENANCE
Z
Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*
Bortezomib 1.3 mg/m2 IV: days 1,15
Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4
E
Thalidomide 50 mg/day continuously
Thalidomide 50 mg/day continuously
* 66 VMP patients and 73 VMPT patients were treated with twice weekly infusions of Bortezomib
Patient Characteristics
VMP
VMPT-VT
(N=257)
(N=254)
Age (median)
71
71
< 65 years
2%
5%
6574 years
71%
68%
> 75 years
27%
27%
2 microglobulin-mg/L (median)
4
3.8
Chromosome abnormalities
t(4;14)
14%
17%
t(14;16)
3%
5%
Del 17
13%
17%
Best response rate
VMP (N=253)
VMPT-VT (N=250)
2
P value
CR
24%
42%
<0.000
<0
1
.000
> VGP
VG R
P
50%
64%
0.001
> PR
81%
90%
0.007
40
VMP
45
42
VMPT VT
35
40
31
35
30
ts
26
ts
24
30
25
26
tien
tien 25
22
pa 20
17
pa
f
f 20
o 15
o
%
% 15
10
10
6
5
5
1
1
0
0
CR
VGPR PR
SD
PD
CR
VGPR
PR
SD
PD
Time to first response and time to CR
VMP
VMPT
V
MPT VT
100
PR: VMPT-VT
80
PR: VMP
ents 60
pati
CR: VMPT-VT
of% 40
%
CR: VMP
20
0 0
1020
304050
60
Months
Progression-free survival / Time t next therapy
Median follow-up 32 months
Progression-Free survival
Time to next therapy
41% Reduced Risk of Progression
48% Reduced Risk of Progression
3-years
y
PFS
Med
Me i
d an
a PF
P S
F
3-years
y
TNT
N
Medi
e a
di n
a TTNT
VMPT
51%
37.2 months
1.00
VMPT
P
70%
Not reach
r
ed
VMP
32%
27.4 months
1.00
VMP
51%
37.6 months
0.75
)
0.75
(%
)
tsn
(%
0.50
ts
HR 0.52
atie
n
0.50
P
HR
H 0.59
0.
atie
P < 0.
0 0001
P
0.25
P < 0.0001
0.25
0.00
0.00
0
102
1
0
02
304
3
0
04
50
5
60
6
0
102
1
0
02
304
3
0
04
506
5
0
06
Ti
T me (months)
hs
Time
i
(months)
(months
Overall Survival
Median follow-up 32 months
3-ye
y ars OS
VMPT
85%
1.00
VMP
80%
0.75
)
(%
HR 0.81
ts
0.50
P = 0.35
Patien
0.25
0.00
010
01
20
2
30
3
40
4
50
5
60
6
70
7
Time (months)
Grade 3-4 Hematologic Adverse Events
VMP
VMPT
VMPT VT
Neutropenia
P=0.02
P = 0.02
Thrombocytopenia
Anaemia
0
5
10
15
20
25
30
35
40
Patients (%)
Grade 3-4 Non-hematologic Adverse Events
VMP
VMPT
VMPT VT
Sensory
or neuropa
ur
th
t y
Infe
f ctio
t ns
Card
r iologic
i
P=0.04
DVT/PE
/
P=0.05
Dro
r p Ou
O t for AE
A
Dro
r p Ou
O t for PN
0
5
10
15
20
25
Patients (%)
Efficacy and Toxicity by Bortezomib
schedule
VMP*
VMP
VMP
(VISTA)
twice weekly N=63
once weekly N=190
CR
30%
27%
23%
PFS @ 3 years
NA
32%
35%
Sensory PN
Any grade
44%
43%
21%
Grade 3-4
13%
14%
2%
PN discontinuation
NA
16%
4%
Total planned dose
46.8 mg/m2
67.6 mg/m2
67.6
NA
41 mg/m2
Total delivered dose
40 mg/m2
*Mateos et al. J Clin Oncol 2010; PN: peripheral neuropathy
Landmark Analysis
52% Reduced Risk of Progression
Median maintenance duration: 18 months
VMPT
VT Continuous Therapy
1.00
) 0.75
(%
ts
VMPT-VT
0.50
Patien
HR 0.48
0.25
P < 0.0001
HR 0.48, p < 0.0001
VMP
0.00
0
102
1
0
02
30
3
405
4
0
05
Time (month
(mon s)
th
Grade 3-4 Adverse Events After Cycle 9
Bortezomib and Thalidomide Continuous Therapy
Hematologic
DVT
Sensory neuropathy
Infection
Cardiologic
Drop out for AE
0246
8
10
12
Patients (%)
Newly occurring or worsening Grade 3/4 adverse events
Prognostic factors
PFS according response and age
< 75 years, p<0.0001
1.00
0.75
1.00
)
(%
VMPT
P -VT
(%
V
0.50
ts
0.75
)
n
(%
CR
atie 0.25
P
VMP
tsn 0.50
eti
0.00
aP
0
1020
30
4050
60
VGPR
0.25
Ti
T me (months)
hs
PR
75 years, p=0.68
0.00
1.00
0
10
2030
4050
60
0.75
)
Time (months)
(%
VMPT
P -VT
ts
V
ts 0.50
n
atie 0.25
P
VMP
0.00
0
1020
30
4050
60
Ti
T me (months)
hs
Treatment discontinuation
VMPT VT
VMP
Discontinuation ratea
rate ,
a %
65 - 75 years of age
27
16
> 75 years of age
37
18
Median cumulative doseb
dose -mg/m
b
2
-mg/m
65 - 75 years of age
61
42
> 75 years of age
31
37
a Discontinuation due to AEs
b Cumulative dose of bortezomib
Prognostic factors 2
PFS according ISS and cytogenetic
ISS 1 or 2
Absence of t(4;14) or t(14;16) or del17
1.00
1.00
)
)
(% 0.75
(% 0.75
tsn
VMPT-VT
ts
VMPT-VT
0.50
n 0.50
atieP
atie
VMP
0.25
VMP
P 0.25
P=0.003
P<0.0001
0.00
0.00
0
1020
3040
5060
010
20
30
40
50
60
Time (months)
Ti
T me (months)
hs
ISS 3
Presence of t(4;14) or t(14;16) or del17
1.00
1.00
)
)
(% 0.75
(%
0.75
ts
VMPT-VT
ts
n
n
VMPT-VT
0.50
0.50
atie
VMP
atie
VMP
P 0.25
P
0.25
P=51
P=0.49
0.00
0.00
0
1020
3040
5060
0
1020
3040
5060
Time (months)
Time (months)
Conclusion: VMPT-VT
CR rate
42%
median PFS
37 months
Survival
85% @ 3 years
More benefit
pts 65 75 years
good prognosis pts
We Are Grateful to All Patients, Nurses and
Physicians of the Participating Centers
1. AL
A ESSANDRI
A
A
Levis, Baraldi
37. FORLI'
Amadori, Gentilini
73. PINEROLO
Griso
2. ANCON
A
A
Leoni, Offidani
38. FROSINONE
Sala
74. PISA
Petrini/Benedetti
3. AO
A STA
Di Vito
39. GALLARATE
Ciambelli
75. POTENZA
Ricciuti, Vertone
4. AS
A COLI PICENO
Galieni,
40. GENOVA
Gobbi, Canepa
76. RAVENNA
Zaccaria, Cellini
5. AS
A TI
Favro
41. GENOVA
Carella, Spriano
77. REGGIO CAL.
Nobile, Callea
6. AVELLIN
A
O
Cantore, Volpe
42. GENOVA
Bacigalupo, Dominietto
78. REGGIO EMILIA
Gugliotta, Masini
7. AV
A IANO
A
Tirelli, Rupolo
43. IVREA
Girotto, Aitoro
79. RIMINI
Pasquini, Fattori
8. BAR
BA I
Dammacco, Ria
44. LATINA
De Blasio
80. RIONERO VULTURE
Musto
9. BAR
BA I
Liso
45. LATINA
Cimino
81. RIETI
Capparella
10. BELLUNO
Pianezze
46. LECCE
Di Renzo
82. ROMA
Foà, Petrucci
11. BENEVENTO
Di Lonardo, Vallone
47. MATERA
Fragasso
83. ROMA
De Fabritiis, Caravita
12. BERGAM
A O
Rambaldi, Galli
48. MESSINA
Brugiatelli
84. ROMA
Andriani
13. BOLOGNA
Baccarani,Cavo
49. MESSINA
Musolino
85. ROMA
Annino, Bongarzoni
14. BOLZAN
A O
Cortellazzo, Pescosta
50. MILANO
Corradini, Montefusco
86. ROMA
Leone, De Stefano
15. BRA
Vanni, Stefani
51. MILANO
Morra
87. ROMA
Petti, Pisani
16. BRESCIA
Rossi, Crippa
52. MILANO
Ciceri
88. ROMA
Majolino, De Rosa
17. BRESCIA
Russo, Malagola
53. MILANO
Lanbertenghi, Baldini
89. ROMA
Amadori
18. BRINDISI
Quarta
54. MILANO
Gianni
90. ROMA
Avvisati
19. CAGLI
A
ARI
A
Angelucci, Derudas
55. MODENA
Torelli
91. ROMA
Recine
20. CAGLI
A
ARI
A
La Nasa, Ledda
56. MODENA
Sacchi
92. ROZZANO
Santoro, Nozza
21. CAM
A POBAS
A SO
Storti
57. MONZA
Pogliani, Rossini
93. S. G. ROTONDO
Cascavil a, Falcone
22. CANDI
A
OLO
Aglietta, Capaldi
58. NAPOLI
Rotoli,Catalano
94. SASSARI
Dore, Podda
23. CAT
CA ANI
A A
Giustolisi,Di Raimondo
59. NAPOLI
Ferrara
95. SIENA
Lauria, Gozzetti
24. CAT
A ANZ
A
AR
A O
Peta, Piro
60. NAPOLI
Mettivier
96. TARANTO
Mazza, Casulli
25. CATTOLIC
A
A
Pasquini
61. NOCERA INF.
D'Arco, Califano
97. TORINO
Boccadoro
26. CESENA
Guardigni
62. NOVARA
Gaidano, Rossi
98. TORINO
Gallo, Pregno
27. CIRIE'
Girotto, Freilone
63. NUORO
Gabbas
99. TORINO
Poccardi, Aragno
28. COSENZA
Morabito
64. ORBASSANO
Saglio, Guglielmelli
100. TREVISO
Foscolo, Gherlinzoni
29. CREMONA
Morandi
65. PADOVA
Semenzato, Zambello
101. TRICASE
Pavone
30. CUNEO
Gallamini, Grasso
66. PALERMO
Mirto, Cangialosi
102. TRIESTE
De Sabbata
31. FIRENZE
Bosi/Nozzoli
67. PARMA
Rizzoli, Giuliani
103. UDINE
Fanin, Patriarca
32. FOGGIA
Capalbo
68. PAVIA
Lazzarino, Corso
104. VENEZIA
Chisesi
33. FORLI'
Amadori, Gentilini
69. PERUGIA
Liberati, Nunzi
105. VERBANIA
Montanara, Luraschi
34. FROSINONE
Sala
70. PESARO
Visani, Leopardi
106. VERCELLI
Santagostino
35. GAL
A LARATE
Ciambelli
71. PESCARA
Fioritoni, Spadano
107. VERONA
Pizzolo, Meneghini
36. GENOVA
Gobbi, Canepa
72. PIACENZA
Cavanna, Lazzaro
108. VICENZA
Rodeghiero, Elice
109. VITERBO
Montanaro