NEWLY DIAGNOSED MYELOMA>65 YEARS:
FACTS & QUESTIONS
Antonio Palumbo, MD
University of Torino, Torino, I, EU
On behalf of the
10m
Treatment strategies
1
Sensitive vs Resistant Disease
Diagnosis
1° Relapse
2° Relapse
3° Relapse
30 months
15 months
7 months
3 months
c
Single
Combination regimen
Single
Single
agent
agent
agent
Sensitive disease
Resistant disease
c
Low-risk SAE
High-risk SAE
Treatment strategy
Continuous therapy
Prolongs PFS
burden
ourmuT
Combinational therapy
Increases CR rate
Time
2
Clinical Impact of VTD Consolidation
in VGPR Patients After ASCT
Responses after ASCT
Responses after VTD
VGPR 85%
VGPR 49%
CR 15%
CR 49%
15%
49%
49%
85%
VGPR
CR
Ladetto M, et al. J Clin Oncol. 2010;28:2077-2084.
Complete Response
are all the same?
Tumor gene
Response Criteria
copy number
Diagnosis
25,000 - 500,000
PR
5,000 ­ 100,000
VGPR
1,500 ­ 20,000
Immunofixation-negative CR 1,000 ­ 10,000
Immunophenotypic CR*
10 ­ 100
Molecular CR^
5 ­ 20
*Paiva et al Blood 2009: 114;4369-72; ^Ladetto et al. J Clin Oncol . 2010;28(12):2077-84
3
MPR vs MEL200
CRD vs MEL200
Treatment schedule
402 patients (younger than 65 years) randomized from 62 centers
Patients: Symptomatic disease, organ damage, measurable disease
1°
2°
R
MPR
R
A
six 28-day courses
A
M: 0,18 mg/Kg/d, days 1-4
NO
N
N
P: 2 mg/Kg/d, days 1-4
MAINTENANCE
D
D
R: 10 mg/d, days 1-21
Rd*
O
O
four 28-day courses
M
M
R: 25 mg/d, days 1-21
I
I
d: 40 mg/d, days
1,8,15,22
Z
Z
A
A
MEL 200
T
T
MAINTENANCE
Two courses
I
M: 200 mg/m2 day -2
I
28-day courses until relapse
O
Stem cell support day 0
O
R: 10 mg/day, days 1-21
N
N
*Thromboprophylaxis randomization: aspirin vs low molecular weight
heparin
R, lenalidomide; M, melphalan; d, dexamethasone; P, prednisone
4
VMPT-T vs VMP
age > 65 years
5
Bortezomib-Melphalan-Prednisone-Thalidomide
VMPT-VT vs VMP
· 511 patients (older than 65 years) randomized from 61 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
VMP
R
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
MAINTENANCE
Cycles 1-9
Bortezomib 1.3 mg/m2 IV
Z
Bortezomib 1.3 mg/m2 IV Days 1,8,15,22*
Days 1,15
Melphalan 9 mg/m2 and prednisone 60 mg/m2 Days 1-4
E
Thalidomide 50 mg/day
Thalidomide 50 mg/day continuously
continuously
*66 VMP patients and 73 VMPT-VT patients were treated with twice weekly infusions of bortezomib
Palumbo A, et al. J Clin Oncol. 2010;Oct 12:[E-pub ahead of print].
11
Bortezomib-Melphalan-Prednisone-Thalidomide
Time to first response and time to CR
VMP
VMPT VT
100
PR: VMPTVT
80
PR: VMP
tsn
tie
60
pa
CR: VMPTVT
of% 40
CR: VMP
20
0
0
5
10
15
20
25
30
Months
Palumbo et al. JCO. 2010; [Epub ahead of print]
6
Bortezomib-Melphalan-Prednisone-Thalidomide
Median follow-up 32 months
Progression-Free survival
Time to next therapy
41% Reduced Risk of Progression
48% Reduced Risk of Progression
3-years PFS
Median PFS
3-years TNT
Median TTNT
VMPT
51%
37.2 months
VMPT
70%
Not reached
VMP
32%
27.4 months
VMP
51%
37.6 months
1.00
1.00
0.75
0.75
)
)
(%ts
(%
n
ts
0.50
HR 0.52
tie
0.50
a
tien
P
a
P < 0.0001
HR 0.59
P
0.25
P < 0.0001
0.25
0.00
0.00
0
1020
3040
5060
0
10
20
3040
5060
Time (months)
Time (months)
Palumbo A, et al. J Clin Oncol. 2010;Oct 12:[E-pub ahead of print].
Prognostic factors
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
tiea
tie
P
a
VMP
0.25
0.25
VMP
P
P=0.003
P<0.0001
0.00
0.00
0
1020
3040
5060
010
20
30
40
50
60
Time (months)
Time (months)
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
tie
tie
a
VMP
a
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)
Palumbo A, et al. J Clin Oncol. 2010;Oct 12:[E-pub ahead of print].
7
Age-adjusted therapies
Risk stratification
> 1 risk factor
Age > 75 years
Cardiac
Pulmonary
Renal
Liver
Grade 3-4 Adverse Event
Recommendations by EMNTG
8
Risk stratification
Risk Factors
Action required
Age over 75 years
At least one risk factor
Comorbidities:
Reduce to dose level -1
o Cardiac dysfunction
o Pulmonary dysfunction
o Hepatic dysfunction
If Grade 3-4 Non-Hemat AE
o Renal dysfunction
occurs
Reduce to dose level -2
Recommendations by EMNTG
Rd vs MPR vs CRP
age > 65 years
9
Treatment schedule
650 patients (older than 65 years) randomized from 5 countries
Patients: Symptomatic disease, organ damage, measurable disease
1°
Rd
2°
R
MAINTENANCE
Nine 28-day courses
R
A
28-day courses until relapse
R: 25 mg, d 1-21
A
N
R: 10 mg/day, days 1-21
d: 40 mg, d 1-8,15,22
N
D
D
O
O
MPR
M
M
Nine 28-day courses
I
M: 0.18 mg/kg, d 1-4
I
Z
P: 1.5 mg/kg, d 1-4
Z
A
R: 10 mg, d1-21
A
MAINTENANCE
T
T
28-day course until relpase
CRP
I
I
R: 10 mg/day, days 1-21
Nine 28-day courses
O
O
P: 25 mg; 3 times wk
C: 50 mg, 3 times wk
N
P: 25 mg, 3 times wk
N
R: 25 mg, d1-21
C, cyclophosphamide; R, lenalidomide; M, melphalan; P, prednisone
Subcutaneous
VP vs VMP vs VCP
age > 75 years
10
Treatment schedule
Treatment schedule
150 patients (> 75 years) randomized from 3 countries
Patients: Symptomatic disease, organ damage, measurable disease
1°
VP
R
MAINTENANCE
Nine 35-day courses
28-day course until relpase
A
Vsc: 1.3 mg/sqm, d 1,8,15,22
Vsc: 1.3 mg/sqm, d 1, 15
N
P: 50 mg, 3 times wk
P: 25 mg; 3 times wk
D
O
VMP
M
Nine 35-day courses
MAINTENANCE
I
Vsc: 1.3 mg/sqm, d 1,8,15,22
28-day course until relpase
Z
M: 2 mg, 3 times wk
Vsc: 1.3 mg/sqm, d 1, 15
P: 25 mg; 3 times wk
A
P: 50 mg, 3 times wk
T
VCP
I
MAINTENANCE
Nine 35-day courses
O
28-day course until relpase
Vsc: 1.3 mg/sqm, d 1,8,15,22
N
Vsc: 1.3 mg/sqm, d 1, 15
C: 50 mg, 3 times wk
P: 25 mg; 3 times wk
P: 50 mg, 3 times wk
Vsc, subcutaneous bortezomib, cyclophosphamide; M, melphalan; P, prednisone
We Are Grateful to All Patients, Nurses and
Physicians of the Participating Centers
1. ALESSANDRIA
Levis, Baraldi
39. GENOVA
Carella, Spriano
77. RIMINI
Pasquini, Fattori
2. ANCONA
Leoni, Offidani
40. GENOVA
Bacigalupo, Dominietto
78. RIONERO VULTURE
Musto
3. AOSTA
Di Vito
41. IVREA
Girotto, Aitoro
79. RIETI
Capparella
4. ASCOLI PICENO
Galieni
42. LATINA
De Blasio
80. ROMA
Foà, Petrucci
5. ASTI
Favro, Ciravegna
43. LATINA
Cimino
81. ROMA
De Fabritiis, Caravita
6. AVELLINO
Cantore, Volpe
44. LECCE
Di Renzo
82. ROMA
Andriani
7. AVIANO
Tirelli, Rupolo
45. MATERA
Fragasso
83. ROMA
Annino, Bongarzoni
8. BARI
Vacca, Ria
46. MESSINA
Brugiatelli
84. ROMA
Leone, De Stefano
9. BARI
Liso
47. MESSINA
Musolino
85. ROMA
Petti, Pisani
10. BELLUNO
Pianezze
48. MILANO
Corradini, Montefusco
86. ROMA
Majolino, De Rosa
11. BENEVENTO
Di Lonardo, Vallone
49. MILANO
Morra
87. ROMA
Amadori
12. BERGAMO
Rambaldi, Galli
50. MILANO
Ciceri
88. ROMA
Avvisati
13. BOLOGNA
Baccarani,Cavo
51. MILANO
Lambertenghi, Baldini
89. ROMA
Recine
14. BOLZANO
Cortellazzo, Pescosta
52. MILANO
Gianni
90. ROZZANO
Santoro, Nozza
15. BRA
Vanni, Stefani
53. MODENA
Marasca
91. S. G. ROTONDO
Cascavil a, Falcone
16. BRESCIA
Rossi, Crippa
54. MODENA
Sacchi
92. SASSARI
Dore, Podda
17. BRESCIA
Russo, Malagola
55. MONZA
Pogliani, Rossini
93. SIENA
Lauria, Gozzetti
18. BRINDISI
Quarta
56. NAPOLI
Pane,Catalano
94. TARANTO
Mazza, Casulli
19. CAGLIARI
Angelucci, Derudas
57. NAPOLI
Ferrara
95. TERNI
Liberati
20. CAGLIARI
La Nasa, Ledda
58. NAPOLI
Mettivier
96. TORINO
Boccadoro
21. CAMPOBASSO
Storti
59. NOCERA INF.
D'Arco, Califano
97. TORINO
Pregno, Benevolo
22. CANDIOLO
Aglietta, Capaldi
60. NOVARA
Gaidano, Rossi
98. TORINO
Tarella, Gottardi
23. CATANIA
Di Raimondo
61. NUORO
Gabbas
99. TREVISO
Gherlinzoni
24. CATANZARO
Peta, Piro
62. ORBASSANO
Saglio, Guglielmelli
100. TRICASE
Pavone
25. CATTOLICA
Pasquini
63. PADOVA
Semenzato, Zambello
101. TRIESTE
De Sabbata
26. CESENA
Guardigni
64. PALERMO
Mirto, Cangialosi
102. UDINE
Fanin, Patriarca
27. CIRIE'
Girotto, Freilone
65. PARMA
Rizzoli, Giuliani
103. VENEZIA
Chisesi
28. COSENZA
Morabito
66. PAVIA
Lazzarino, Corso
104. VERBANIA
Montanara, Luraschi
29. CREMONA
Lanza
67. PERUGIA
Martelli, Ballanti
105. VERCELLI
Santagostino
30. CUNEO
Gallamini, Grasso
68. PESARO
Visani, Leopardi
106. VERONA
Pizzolo, Meneghini
31. FIRENZE
Bosi/Nozzoli
69. PESCARA
Fioritoni, Spadano
107. VICENZA
Rodeghiero, Elice
32. FOGGIA
Capalbo
70. PIACENZA
Cavanna, Lazzaro
108. VITERBO
Montanaro
33. FORLI'
Amadori, Gentilini
71. PINEROLO
Griso
109. ISRAEL
Nagler
34. FROSINONE
Sala
72. PISA
Petrini/Benedetti
110. JERUSALEM
Ben Yehuda
35. GALLARATE
Mozzana, Ciambelli
73. POTENZA
Ricciuti, Vertone
111. KEFAR SABAH
Manor
36. GENOVA
Gobbi, Canepa
74. RAVENNA
Zaccaria, Cel ini
112. ZERIFIM
Kornberg
37. FORLI'
Amadori, Gentilini
75. REGGIO CALABRIA
Nobile, Callea
113. HAIFA
Attias
38. GENOVA
Gobbi, Canepa
76. REGGIO EMILIA
Gugliotta, Masini
11