GIMEMA: Italian Myeloma Network A Prospective, Randomized

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,
Vincenzo Callea8, Giulia Benevolo9, Roberto Marasca10, Tommasina Guglielmelli11, Manuela
Rizzo12, Mariella Grasso13, Maria Teresa Petrucci14, Paola Omedè1, Gianluca Gaidano2,
Mario Boccadoro1
1Divisione
di Ematologia dell’Università di Torino, A.O.U. San Giovanni Battista, Torino, Italy; 2Divisione di Ematologia, Dipartimento
di Scienze Mediche & IRCAD e Dipartimento di Oncologia, Università 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,
Ematologia Azienda Ospedaliera San Giovanni Battista,
Battista Torino,
Torino Italy; 10Reparto di Ematologia,
Ematologia Policlinico di Modena,
Modena Modena,
Modena
11
Italy; S.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 - Università La Sapienza, Roma, Italy.
Rationale
MP1
MPT2
VMP1
VMPT3
(upfront)
(upfront)
(upfront)
(relapse)
No. p
patients
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
San Miguel JF et al. New Eng J Med 2008; 359: 906906-17; 2 Palumbo et al. Blood 2008;112: 31073107-3114
3 Palumbo et al. Blood 2007;109: 2767
2767--2772
1
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 myeloma/end organ damage with
measurable disease
 ≥65 yrs or <65 yrs and not transplant-eligible; creatinine ≤ 2.5 mg/dL
R
A
N
D
O
M
I
Z
E
VMP
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
y
in both arms
VMPT
Cycles 1-9
Bortezomib 1.3 mg/m2 IV: days 1,8,15,22*
M l h l 9 mg/m
Melphalan
/ 2 and
d prednisone
d i
60 mg/m
/ 2 days
d
1
1-4
4
Thalidomide 50 mg/day continuously
NO MAINTENANCE
Until relapse
p
MAINTENANCE
Bortezomib 1.3 mg/m2 IV: days 1,15
Thalidomide 50 mg/day continuously
* 61 VMP patients and 70 VMPT patients were treated with biweekly infusions of Bortezomib
Patient Characteristics
VMPT
(n=177)
VMP
(n=177)
Age
A ((median)
di )
71
72
≤70 years
49%
42%
71–
71
–75 years
31%
34%
>75 years
20%
25%
2-microglobulin
microglobulin--mg/L (median)
3.7
4.0
Hemoglobin--g/dL (median)
Hemoglobin
10.9
10.6
Creatinine--mg/dL (median)
Creatinine
1.0
1.1
Calcemia--mmol/L (median)
Calcemia
2.32
2.32
Best Response
70
VMPT
N=177
Median No. of cycles 5
70
60
40
55%*
% of patients
% of p
patients
60
50
VMP
N=177
Median No. of cycles 5
39
32
30
*P<0
0.001
001
50
40
45%*
30
21
20
6
CR
VGPR
24
20
16
10
0
37
PR
SD
16
10
2
PD
0
0
CR
VGPR
PR
SD
PD
Time to response
100
90
80
70
60
50
40
30
20
10
0
PR
0
CR
VMPT
0 ,1
0 ,2
VMP
0 ,3
0 ,4
0 ,5
0 ,6
VMPT
0 ,7
VMP
0 ,8
0 ,9
1
0
1
2
3
4
5
6
Treatment cycle
7
8
9
10
11
Time to next therapy
Progression free survival
Median followfollow-up 14.5 months
Time to next therapy
py
Progression
g
free survival
VMPT
VMPT
% of patie
ents
VMP
VMP
VMPT: TTNT @ 36 months = 80%
VMP: TTNT @ 36 months = 78%
P = 0.56
Months
VMPT: PFS @ 36 months = 74%
VMP: PFS @ 36 months = 70%
P = 0.28
Months
Overall survival
VMPT: OS @ 36 months = 88%
VMP: OS @ 36 months = 87%
VMPT
% of patients
VMP
P = 0.75
Months
PFS: VMPT + VMP
according to prognostic factors
% of patients
s
ISS
% of p
patients
CR
CR
P=0.99
months
VGPR + PR
t(11;14) or t(14;16) or del17
months
%o
of patients
s
P=0.0003
P=0.99
months
Grade 3
3--4 Hematologic Adverse Events
VMP
VMPT
Neutropenia
Thrombocytopenia
Anaemia
0
5
10
15
20
% of patients
25
30
35
Grade 3
3--4 Non
Non--hematologic Adverse Events
VMP
VMPT
Sensory
y
neuropathy
P 0 03
P=0.03
Infections
Gastrointestinal
Cardiologic
Fatigue
Thrombosis
0
5
10
Patients (%)
15
VMP weekly: toxicity according to age
VMP (N=165)
< 70 yr
70-74 yr
≥ 75 yr
N=61
%
N=61
%
N=43
%
6
9,8
8
13,1
3
7,0
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
N
Neuropatic
ti pain
i
1
16
1,6
3
49
4,9
0
00
0,0
sensory NP
1
1,6
1
1,6
1
2,3
At least 1 hematologic event
Grade 3-4 thrombocytopenia
At least 1 non-hematologic event
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
y p
10
6,06
,
7
4,24
,
At least 1 non-hematologic event
Cardiologic
Infective
Neuropatic
p
p
pain
sensory NP
5
9
3
1
33,03
03
5,45
1,82
0,61
3
1
1
2
11,82
82
0,61
0,61
1,21
Efficacy and Toxicity
biweekly
y – weekly*
y
VMPT
VMPT
VMP
VMP
biweekly
y
weekly
y
biweekly
y
weekly
y
(N=45)
(N=107)
(N=42)
(N=116)
CR
36%
39%
27%
20%
Peripheral sensory
neuropathy
24%
6%
14%
2%
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
(N=177)
VMP
(N=177)
P value
CR
39%
21%
<0
0.001
001
> VGPR
55%
45%
< 0.001
TTNT @ 3 years
80%
78%
0.56
PFS @ 3 years
74%
70%
0.28
0 28
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 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. BELLUNO
11. BENEVENTO
12. BERGAMO
13. BOLOGNA
14. BOLZANO
15. BRA
16. BRESCIA
17. BRESCIA
18 BRINDISI
18.
19. CAGLIARI
20. CAGLIARI
21. CAMPOBASSO
22. CANDIOLO
23. CATANIA
24. CATANZARO
25. CATTOLICA
26. CESENA
27. CIRIE'
28. COSENZA
29. CREMONA
30. CUNEO
31. FIRENZE
32. FOGGIA
33. FORLI’
34. FROSINONE
35. GALLARATE
36. GENOVA
Levis, Baraldi
Leoni, Offidani
Di Vito
Galieni,
Favro
Cantore, Volpe
Tirelli, Rupolo
Dammacco, Ria
Liso
Pianezze
Di Lonardo,, Vallone
Rambaldi, Galli
Baccarani,Cavo
Cortellazzo, Pescosta
Vanni, Stefani
Rossi, Crippa
Russo, Malagola
Quarta
Angelucci, Derudas
La Nasa, Ledda
Storti
Aglietta, Capaldi
Giustolisi,Di Raimondo
Peta, Piro
Pasquini
Guardigni
Girotto, Freilone
Morabito
Morandi
Gallamini, Grasso
Bosi/Nozzoli
Capalbo
Amadori, Gentilini
Sala
Ciambelli
Gobbi, Canepa
37. FORLI’
38. FROSINONE
39. GALLARATE
40. GENOVA
41. GENOVA
42. GENOVA
43. IVREA
44. LATINA
45. LATINA
46. LECCE
47. MATERA
48. MESSINA
49. MESSINA
50. MILANO
51. MILANO
52. MILANO
53. MILANO
54 MILANO
54.
55. MODENA
56. MODENA
57. MONZA
58. NAPOLI
59. NAPOLI
60. NAPOLI
61. NOCERA INF.
62. NOVARA
63. NUORO
64. ORBASSANO
65. PADOVA
66. PALERMO
67. PARMA
68. PAVIA
69. PERUGIA
70. PESARO
71. PESCARA
72. PIACENZA
Amadori, Gentilini
Sala
Ciambelli
Gobbi, Canepa
Carella, Spriano
Bacigalupo, Dominietto
Girotto, Aitoro
De Blasio
Cimino
Di Renzo
Fragasso
g
Brugiatelli
Musolino
Corradini, Montefusco
Morra
Ciceri
Lanbertenghi, Baldini
Gianni
Torelli
Sacchi
Pogliani, Rossini
Rotoli,Catalano
Ferrara
Mettivier
D’Arco, Califano
Gaidano, Rossi
Gabbas
Saglio, Guglielmelli
Semenzato, Zambello
Mirto, Cangialosi
Rizzoli, Giuliani
Lazzarino, Corso
Liberati, Nunzi
Visani, Leopardi
Fioritoni, Spadano
Cavanna, Lazzaro
73. PINEROLO
74. PISA
75. POTENZA
76. RAVENNA
77. REGGIO CAL.
78. REGGIO EMILIA
79. RIMINI
80. RIONERO VULTURE
81. RIETI
82. ROMA
83. ROMA
84. ROMA
85. ROMA
86. ROMA
87. ROMA
88. ROMA
89. ROMA
90 ROMA
90.
91. ROMA
92. ROZZANO
93. S. G. ROTONDO
94. SASSARI
95. SIENA
96. TARANTO
97. TORINO
98. TORINO
99. TORINO
100. TREVISO
101. TRIESTE
102. UDINE
103. VENEZIA
104. VERBANIA
105. VERCELLI
106. VERONA
107. VICENZA
108. VITERBO
Griso
Petrini/Benedetti
Ricciuti, Vertone
Zaccaria, Cellini
Nobile, Callea
Gugliotta, Masini
Pasquini, Fattori
Musto
Capparella
Foà, Petrucci
De Fabritiis,, Caravita
Andriani
Annino, Bongarzoni
Leone, De Stefano
Petti, Pisani
Majolino, De Rosa
Amadori
Avvisati
Recine
Santoro, Nozza
Cascavilla, Falcone
Dore, Podda
Lauria, Gozzetti
Mazza, Casulli
Boccadoro
Gallo, Pregno
Poccardi, Aragno
Foscolo, Gherlinzoni
De Sabbata
Fanin, Patriarca
Chisesi
Montanara, Luraschi
Santagostino
Pizzolo, Meneghini
Rodeghiero, Elice
Montanaro