GIMEMA: Italian Myeloma Network
A Prospective, Randomized, Phase III Study
of Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT)
versus
Bortezomib, Melphalan and Prednisone (VMP)
in Elderly Newly Diagnosed Myeloma Patients
Antonio Palumbo1, Sara Bringhen1, Davide Rossi2, Valeria Magarotto1, Francesco Di
Raimondo3, Roberto Ria4, Massimo Offidani5, Chiara Nozzoli6, Francesca Patriarca7,
8
9
10
11
Vincenzo Callea8, Giulia Benevolo9, Roberto Marasca10, Tommasina Guglielmelli , Manuela
Rizzo12, Mariella Grasso13, Maria Teresa Petrucci14, Paola Omedč1, Gianluca Gaidano2,
Mario Boccadoro1
1Divisione di Ematologia dell'Universitā di Torino, A.O.U. San Giovanni Battista, Torino, Italy; 2Divisione di Ematologia, Dipartimento
di Scienze Mediche & IRCAD e Dipartimento di Oncologia, Universitā degli Studi del Piemonte Orientale, Amedeo Avogadro,
Novara, Italy; 3Cattedra di Ematologia, Ospedale Ferrarotto, Catania, Italy; 4Sezione di Medicina Interna e Oncologia Clinica,
Policlinico di Bari, Bari, Italy; 5Clinica di Ematologia, Azienda Ospedaliero-Universitaria Umberto I, Ancona, Italy; 6Day Hospital
Ematologia, Azienda Ospedaliera Universitaria Careggi, Firenze, Italy; 7Clinica Ematologica - Centro Trapianti e Terapia Cellulari
"Carlo Melzi", Policlinico Universitario di Udine, Udine, Italy; 8Divisione di Ematologia, Ospedali Riuniti, Reggio Calabria, Italy;
9Ematologia
Ematologi , Azienda Ospedaliera
Ospedal
San Giovanni
Gi
Battista
Batti
, Tor
To ino
n , Italy; 10
;
Reparto di Ematologia
Ematol
, Policlinico di Modena, Modena,
Italy; 11S.C. Medicina Interna II ed Ematologia, Azienda Ospedaliera San Luigi Gonzaga, Orbassano, Italy; 12Dipartimento di
Ematologia, Azienda Ospedaliera Universitaria Policlinico Tor Vergata, Roma, Italy; 13Divisione di Ematologia, Ospedale S. Croce e
Carle, Cuneo, Italy; 14Dipartimento di Bioteconologie e Ematologia, Policlinico Umberto I - Universitā La Sapienza, Roma, Italy.
Rationale
MP1
MPT2
MPT
VMP1
VMP
VMPT3
MP
VMPT
(upfront)
(upfront)
(upfront)
(relapse)
No. patients
p
331
167
337
30
CR
4%
16%
33%
17%
VGPR
8%
29%
41%
44%
PR
39%
69%
74%
67%
V = Velcade; M= Melphalan; P = Prednisone; T= Thalidomide
1 San Miguel JF et al. New
Ne Eng J Med 2008; 359: 906
906--17;
17; 2 Palumbo et al. Blood 2008;112:
2008;1
3107
3107--311
31 4
14
3 Palumbo et al. Blood 2007;109: 2767
2767--2772
2772
Aims
VMPT: superior
p
to VMP?
Bortezomib weekly infusion: safety improvement?
Treatment schedule
393 patients (older than 65 years) randomized from 58 Italian centers
Patients: Symptomatic multiple
multiple myeloma/end
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
NO MAINTENANCE
Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*
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
p
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
Mlhl
Melphalan 9 mg/ 2
/m andd
d pred i
n sone 60
60 mg/ 2
/m d1
days 1-4
Thalidomide 50 mg/day continuously
E
Thalidomide 50 mg/day
Thalidomide 50 mg/day continuously
* 61 VMP patients and 70 VMPT patients were treated with biweekly infusions of Bortezomib
Patient Characteristics
VMPT
VMP
(n=177)
(n=177)
A(
Age (medi
d
di
)
an
71
72
70 years
49%
42%
7175 years
31%
34%
>75 years
20%
25%
22--microglobulin
microglobulin--mg/L
mg/L (median)
3.7
4.0
4.0
Hemoglobin
Hemoglobin--g/dL
g/dL (median)
10.9
10.6
Creatinine
Creatinine--mg/dL
mg/dL (median)
1.0
1.1
Calcemia
Calcemia--mmol/L
mmol/L (median)
2.32
2.32
Best Response
VMPT
VMP
N=177
N=177
70
70
Median No. of cycles 5
Median No. of cycles 5
60
60
55%*
* P < 0 001
55%*
.
50
50
45%*
39
atients 40
patients 40
37
p
32
of
of
%
% 30
30
24
21
20
16
20
16
10
6
10
2
0
0
0
CR
VGPR
PR
SD
PD
CR
VGPR
PR
SD
PD
Time to response
100 0
PR
CR
90
VMPT
0,1
VM
80 0,2
VMP
70 0,3
60 0,4
50 0,5
40 0,6
VMPT
30 0,7
VMP
20 0,8
10 0,9
0
1
01
23
45
6
7
8
9
10
11
Tr
T eatment cycle
Time to next therapy
Progression free survival
Median follow
follow--up
up 14.5 months
Time to next therapy
Progression
g
free survival
VMPT
VMPT
VMP
ents
VMP
e
pati
of%
VMPT: TTNT @ 36 months = 80%
VMPT: PFS @ 36 months = 74%
VMP: TTNT @ 36 months = 78%
VMP: PFS @ 36 months = 70%
P = 0.56
P = 0.28
Months
Months
Overall survival
VMPT: OS @ 36 months = 88%
VMP: OS @ 36 months = 87%
VMPT
VMP
tients
pa
of%
P = 0.75
Months
PFS: VMPT + VMP
according to prognostic factors
ISS
s
CR
patientof
%
P=0.99
CR
months
atients
VGPR + PR
p
of%
t(11;14) or t(14;16) or del17
P=0.0003
s
months
fpatiento
%
P=0.99
months
Grade 33--44 Hematologic Adverse Events
VMP
VMPT
Neutropenia
Thro
Thr mb
m ocytope
t
nia
ni
Anaemia
0
5
10
15
20
25
30
35
% of patients
Grade 33--44 Non
Non--hematologic
hematologic Adverse Events
VMP
VMPT
Sensory
P0
P=0 0
. 3
03
neuropathy
Infections
Gastrointestinal
Cardiologic
Fatigue
Throm
Thr
bos
om
is
i
0
5
10
15
Patients (%)
VMP weekly: toxicity according to age
VMP (N=165)
< 70 yr
70-74 yr
75 yr
N=61
%
N=61
%
N=43
%
At least 1 hematologic event
Grade 3-4 thrombocytopenia
6
9,8
8
13,1
3
7,0
At least 1 non-hematologic event
Cardiologic
2
3,3
5
8,2
2
4,7
Gastrointestinal
2
3,3
2
3,3
3
7,0
Infective
4
6,6
6
9,8
0
0,0
Nt
Neuropa i
tic pain
1
16
1,6
3
49
4,9
0
00
0,0
sensory NP
1
1,6
1
1,6
1
2,3
VMP weekly: early or late toxicities
VMP (N=165)
()
1-4 cycles
5-9 cycles
N=
%
N=
%
At least 1 hematologic event
Grade 3-4 thrombocytopenia
yp
10
6,06
,
7
4,24
,
At least 1 non-hematologic event
Cardiologic
5
30
3, 3
03
3
18
1, 2
82
Infective
9
5,45
1
0,61
Neuropatic pain
pp
3
1,82
1
0,61
sensory NP
1
0,61
2
1,21
Efficacy and Toxicity
biweekly
biweekl weekl
weekly*
VMPT
VMPT
VMP
VMP
biweekly
weekly
biweekly
weekly
(N=45)
(N=107)
(N=42)
(N=116)
(N=1
CR
36%
39%
27%
20%
Peripheral sensory
neuropathy
24%
6%
14%
2%
neuropathy
24%
6%
14%
Neuralgia
g
4%
3%
12%
3%
Discontinuation
22%
10%
24%
10%
*25 VMPT and 19 VMP patients received both biweekly and weekly infusions
Conclusions
VMPT
VMP
(N=177)
(N=177)
P value
CR
39%
21%
< 0 001
.
> VGPR
55%
45%
< 0.001
TTNT @ 3 years
80%
78%
0.56
PFS @ 3 years
74%
70%
02
0.
0 8
0228
OS @ 3 years
88%
87%
0.75
Conclusions 2
VMPT improves response rates of VMP
Weekly infusion of bortezomib decreases peripheral
neuropathy
Longer follow-up is needed to assess PFS and OS
We
W Are Grateful to All Patients, Nurses and
Physicians of the Participating Centers
1. AL
A ESSANDRI
A
A
Levis, Bara
Bar ldi
37. FORLI'
Amadori, Gentilini
73. PINEROLO
Griso
2. AN
A CO
N
NA
CO
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
r
41. GENOVA
Carella, Spriano
77. REGGIO CAL.
Nobile, Callea
6. AV
A ELLINO
Cantore, Volpe
42. GENOVA
Bacigalupo, Dominietto
78. REGGIO EMILIA
Gugliotta, Masini
7. AV
A IANO
IA
Tirelli, Rupolo
43. IVREA
Girotto, Aitoro
79. RIMINI
Pasquini, Fattori
8. BARI
BA
Dammacco, Ria
44. LATINA
De Blasio
80. RIONERO VULTURE
Musto
9.
9. BARI
BA
Liso
45. LATINA
Cimino
81. RIETI
Capparella
10. BELLUNO
Pianezze
46. LECCE
Di Renzo
82. ROMA
Foā, Petrucci
11. BENEVENTO
Di Lonardo, Vallone
47. MATERA
Fragasso
83. ROMA
De Fabritiis, Caravita
12. BERGAM
BERGA O
Rambaldi, Galli
48. MESSINA
Brugiatelli
84. ROMA
Andriani
13. BOLOGNA
Baccarani,Cavo
49. MESSINA
Musolino
85. ROMA
Annino, Bongarzoni
14. BOLZAN
A O
Cort
Cor ellazzo, 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. MILAN
MILA O
Gianni
90. ROMA
Avvisati
19. CAGL
CA
IAR
A I
Angelucci, Derudas
55. MODENA
Torelli
91. ROMA
Recine
20. CAGL
CA
IAR
A I
La Nasa, Ledda
56. MODENA
Sacchi
92. ROZZANO
Santoro, Nozza
21. CAMP
CA
OBAS
A SO
Storti
57. MONZA
Pogliani, Rossini
93. S. G. ROTONDO
Cascavilla, Falcone
22. CANDI
CA
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
CA ANZ
A
AR
A O
Peta, Piro
60. NAPOLI
Mettivier
96. TARANTO
Mazza, Casulli
25. CATT
CA
OLICA
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. TRIESTE
De Sabbata
30. CUNEO
Gallamini, Grasso
66. PALERMO
Mirto, Cangialosi
102. UDINE
Fanin, Patriarca
31. FIRENZE
Bosi/Nozzoli
67. PARMA
Rizzoli, Giuliani
103. VENEZIA
Chisesi
32. FOGGIA
Capalbo
68. PAVIA
Lazzarino, Corso
104. VERBANIA
Montanara, Luraschi
33. FORLI'
Amadori, Gentilini
G
69. PERUGIA
Liberati, Nunzi
105. VERCELLI
Santagostino
34. FROSINONE
Sala
70. PESARO
Visani, Leopardi
106. VERONA
Pizzolo, Meneghini
35. GALLA
GA
RA
LLA
TE
RA
Ciambelli
71. PESCARA
Fioritoni, Spadano
107. VICENZA
Rodeghiero, Elice
36. GENOVA
Gobbi, Canepa
72. PIACENZA
Cavanna, Lazzaro
108. VITERBO
Montanaro