GIMEMA: Italian Multiple Myeloma Network
Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) Followed
by Maintenance with Bortezomib and Thalidomide (VT) for Initial
Treatment of Elderly Multiple Myeloma Patients
Boccadoro M(1), Bringhen S(1), Gaidano G(2), Ria R(3), Offidani M(4), Patriarca F(5),
Nozzoli C(6), Musto P(7), Petrucci MT(8), Palumbo A(1).
Italian Multiple Myeloma Group
1.Divisione di Ematologia dell’Università di Torino, A.O.U. San Giovanni Battista, Torino, Italy; 2.Divisione di
Ematologia, Università del Piemonte Orientale Amedeo Avogadro e Ospedale Maggiore della Carità, Novara, Italy;
3.Dipartimento di Scienze Biomediche e Oncologia Umana, Sezione di Medicina Interna e Oncologia Clinica,
Università di Bari, Bari, Italy; 4.Clinica di Ematologia, A.O.U. Ospedali Riuniti, Ancona, Italy; 5.Divisione di Ematologia,
Istituto Nazionale Tumori, Milano, Italy; 6.Clinica Ematologica, Università di Udine, Udine, Italy; 7.Dipartimento di
Ematologia, Università di Firenze, A.O.U. Careggi, Firenze, Italy; 8.Dipartimento di Oncoematologia, IRCCS CROB
Centro di Riferimento Oncologico della Basilicata, Rionero in Vulture, Italy; 9.Dipartimento di Biotecnologie Cellulari
ed Ematologia, Università La Sapienza, Ospedale Umberto I, Roma, Italy.
Aims
• Best experimental therapy:
• 4 drug combo  VMPT
• Maintenance  VT
• Best standard of care
• 3 drug combo  VMP
• Safety and efficacy of weekly infusion of bortezomib
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
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 in both arms
VMPT
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
NO MAINTENANCE
Until relapse
MAINTENANCE
Bortezomib 1.3 mg/m2 IV:
days 1,15
Thalidomide 50 mg/day
continuously
* 66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of Bortezomib
Patient Characteristics
VMP
VMPT  VT
(N=257)
(N=254)
71
71
2%
71%
27%
5%
68%
27%
4
3.8
t(4;14)
14%
17%
t(14;16)
3%
5%
Del 17
13%
17%
Age (median)
< 65 years
65–74 years
> 75 years
2 microglobulin-mg/L (median)
Chromosome abnormalities
Best Response Rate
VMP (N=253)
VMPT  VT (N=250)
P value
CR
24%
38%
0.0008
> VGPR
50%
59%
0.03
> PR
81%
89%
0.01
40
VMP
31
30
VMPT  VT
30
26
24
20
38
35
% of patients
% of patients
35
25
40
17
15
10
30
25
21
20
15
10
5
1
0
6
5
1
0
CR
VGPR PR
SD
PD
CR
VGPR
PR
SD
PD
Time to first response and time to CR
VMP
VMPTVT
100
PR: VMPTVT
% of patients
80
PR: VMP
60
CR: VMPTVT
40
CR: VMP
20
0
0
0
5
5
10
10
15
15
Months
20
20
25
25
30
30
Time to next therapy
Progression free survival
Median follow-up 26.5 months
Time to next therapy
Progression free survival
VMP: TTNT @ 3 years = 55%
VMPT VT: TTNT @ 3 years = 69%
VMP: PFS @ 3 years = 40%
VMPT VT: PFS @ 3 years = 54%
% of patients
1.00
1.00
VMPTVT
0.75
0.75
0.50
VMPT VT
0.50
VMP
0.25
0.25
VMP
0.00
0
P = 0.006
10
P = 0.006
0.00
20
30
40
50
60
0
Months
10
20
30
40
50
60
Overall survival
VMP: OS @ 3 years = 84%
VMPTVT: OS @ 3 years = 86%
1.00
VMPTVT
VMP
% of patients
0.75
0.50
0.25
P = 0.60
0.00
0
10
20
30
Months
40
50
60
Grade 3-4 Hematologic Adverse Events
VMP
VMPTVT
P=0.02
Neutropenia
Thrombocytopenia
Anaemia
0
5
10
15
20
25
Patients (%)
30
35
40
Grade 3-4 Non-hematologic Adverse Events
VMP
VMPTVT
Sensory neuropathy
Infections
Cardiologic
P=0.04
DVT/PE
P=0.05
Drop Out for AE
Drop Out for PN
0
5
10
15
Patients (%)
20
25
Efficacy and Toxicity by Bortezomib schedule
VMP* VMP twice weekly
(VISTA)
N=63°
VMP once weekly
N=190°
CR
30%
25%
23%
PFS @ 2 years
48%
57%
57%
Any grade
44%
43%
21%
Grade 3-4
13%
14%
2%
PN discontinuation
NA
16%
4%
Total planned dose
67.6
67.6 mg/m2
46.8 mg/m2
Total delivered dose
NA
41 mg/m2
40 mg/m2
Sensory PN
*San Miguel JF et al. New Eng J Med 2008; 359: 906-17; ° 3 patients in twice weekly and 1 patient in
once weekly group are not evaluable because they never start therapy; PN: peripheral neuropathy
PFS according to Bortezomib schedule
Twice weekly: PFS @ 3 years =45%
Once weekly: PFS @ 3 years = 50%
% of patients
1.00
0.75
0.50
Twice weekly
Once weekly
0.25
P = 0.87
0.00
0
10
20
30
Months
40
50
60
Conclusions 1
VMP
VMPT  VT
P value
(N=253)
(N=250)
CR
24%
38%
0.0008
TTNT @ 3
years
55%
69%
0.006
PFS @ 3
years
40%
54%
0.006
OS @ 3 years
84%
86%
0.60
Conclusions 2
• Best available treatment option for elderly patient
• VMPT  VT improves PFS in comparison with VMP
• VMPT  VT improves response rate and PFS
•VMPT increases CR rate
•VT maintenance improves PFS
• Once-weekly bortezomib reduces 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. BELLUNO
11. BENEVENTO
12. BERGAMO
13. BOLOGNA
14. BOLZANO
15. BRA
16. BRESCIA
17. BRESCIA
18. BRINDISI
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
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
Brugiatelli
Musolino
Corradini, Montefusco
Morra
Ciceri
Lambertenghi, 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
Martelli, Ballanti
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
91. ROMA
92. ROZZANO
93. S. G. ROTONDO
94. SASSARI
95. SIENA
96. TARANTO
97. TERNI
98. TORINO
99. TORINO
100. TORINO
101. TREVISO
102. TRICASE
103. TRIESTE
104. UDINE
105. VENEZIA
106. VERBANIA
107. VERCELLI
108. VERONA
109. VICENZA
110. 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
Liberati
Boccadoro
Pregno, Benevolo
Tarella, Gottardi
Gherlinzoni
Pavone
De Sabbata
Fanin, Patriarca
Chisesi
Montanara, Luraschi
Santagostino
Pizzolo, Meneghini
Rodeghiero, Elice
Montanaro