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1
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Background
Retrospecti
t ve
v
An
A alys
y is
SPMs/Total
% SPMs
NCI SEER 1973-2000
1219/23838
5.1%
ASCT1
CT 1982-2000
29/800
3.6%
Au
A stral
t
ian Cancer Registry 1982-20012
2-2001
134/2174
6.1%
Trials
Therapy
Patients in
SPMs/Total
% SPMs
Remission
Lenalidomide
60%
17/299
5.5%
IFM (4 yr
y s fr
f om
o
dg) 3
dg)
Plac
Pla ebo
33%
3/292
1.0%
Lenalidomide
15/231
6.5%
CAL
CA C
L GB4
GB
NA
Plac
Pla ebo
6/229
2.6%
24%/54%
11/535
3.1%
MM015 (2 yr
y s fr
f om
o
dg
d ) 5
MPR/MPR-R
) 5
Plac
Pla ebo
18.8%
2/154
1.3%
1. Forrest et al. 2003; 2. Youlden et al. 2011; 3. Attal M et al, ASH 2010; 4. McCarthy et al, ASH 2010; 5. Palumbo A et al, ASH 2010
SPM, secondary primary malignancy; ASCT, autologous stem cell transplantation; NA, not available
4
MM-015: Study Design
N = 459, 82 centers in Europe, Australia, and Israel
Double-Blind Treatment Phase
Open-Label
Extension Phase
Cycles (28-day) 1-9
Cycles 10+
MPR-R
Maintenance
M: 0.18 mg/kg, days 1-4
P: 2 mg/kg, days 1-4
Lenalidomide
R: 10 mg/day po, days 1-21
10 mg/day
days 1-21
MPR
Lenalidomide
M: 0.18 mg/kg, days 1-4
Disease
(25 mg/day)
P: 2 mg/kg, days 1-4
Placebo
Progression
+/-
R: 10 mg/day po, days 1-21
Dexamethasone
MP
M: 0.18 mg/kg, days 1-4
RANDOMIZATION
P: 2 mg/kg, days 1-4
Placebo
PBO: days 1-21
· Stratified by age ( 75 vs > 75 years) and stage (ISS I/II vs III)
· Primary comparison: MPR-R vs MP
ISS, International Staging System; MP, melphalan, prednisone; MPR, melphalan,
prednisone, lenalidomide; MPR-R, melphalan, prednisone, lenalidomide with
lenalidomide maintenance; NDMM, newly diagnosed multiple myeloma; PBO, placebo.
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5
Progression-Free Survival
All Patients
60% Reduced Risk of Progression
100
Median PFS
MPR-R
31 months
MPR
14 months
75
)
MP
13 months
(%
50
HR 0.395
Patients
P < .001
25
HR 0.796
P = .135
0
0
5
10
15
20
25
30
35
40
Time (Months)
Median follow-up 25 months
Data cutoff : May 11, 2010
5
6
MM-015: SPM
Data Cut-Off February 28, 2011
MPR-R
MPR
MP
SPM, n (%)
(n = 150)
(n = 152)
(n = 153)
Total Invasive SPMs
12 (8.0)
9 (5.9)
4 (2.6)
Hematologic Malignancies
7 (4.7)
5 (3.3)
1 (0.7)
AML
4 (2.7)
2 (1.3)
0
MDS to AML
1 (0.7)
1 (0.7)
0
MDS
0
2 (1.3)
T-ALL
1 (0.7)
0
0
CMML
1 (0.7)
0
0
B-cell malignancy
0
0
0
Solid tumors
5 (3.3)
4 (2.6)
3 (2.0)
Non-melanoma skin cancer
1 (0.7)
4 (2.6)
5 (3.3)
· Median follow-up: 30 months
AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; MDS,
myelodysplastic syndromes; T-ALL, T-cell acute lymphoblastic leukemia.
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MM-015: SPM
Incidence Rates
MPR-R
MPR
MP
(n = 150)
(n = 152)
(n = 153)
Total Invasive SPM
12
9
4
Person years
346
344
359
Incidence Rate*
3.5
2.6
1.1
95% CI
(1.97 - 6.11)
(1.36 - 5.03)
(0.42 - 2.97)
Hematologic SPMs, n
75
1
Person years
349
344
360
Incidence Rate*
2.0
1.5
0.3
95% CI
(0.96 - 4.21)
(0.60 - 3.49)
(0.04 - 1.97)
Solid tumor SPMs, n
54
3
Person years
348
346
360
Incidence Rate*
1.4
1.2
0.8
95% CI
(0.60 - 3.45)
(0.43 - 3.08)
(0.27 - 2.59)
*Incidence Rate per 100 person years
8
MM-015: Sensitivity Analysis
Effect of SPM on PFS
PFS
EFS
(Disease progression or death as event)
(Disease progression, death, or SPM as event)
MPR+R 31 months
MPR+R 29 months
100
100
MPR
14 months
MPR
15 months
MP
13 months
MP
13 months
75
75
)
(%tsn 50
50
tieaP
25
HR 0.494
HR 0.493
25
P < .001
HR 0.395
P < .001
HR 0.413
P < .001
P < .001
0
0
010
20
30
40
50
0
10
20
30
40
Time (months)
Time (months)
· Risk of death or disease progression at 2 years:
MPR-R: 45%; MP, 81%
· Risk of SPM at 2 years:
MPR-R: 3%; MP, 2%
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9
Risk for SPM vs PD/Death
(Safety Population)
MPR-R
MPR
MP
100
100
100
75
75
75
(%)
50
50
50
Patients
25
25
25
0
0
0
010
20
30
40
50
010
20
30
40
50
0
10
20
30
40
50
Time (Months)
Time (Months)
Time (Months)
PD/Death
Hematologic SPM
Solid Tumor
MP, melphalan, prednisone; MPR, melphalan, prednisone, lenalidomide; MPR-R, melphalan,
prednisone, lenalidomide with lenalidomide maintenance; PD, progressive disease.
Retrospective study design
9 EMN experimental trials1
2459 newly diagnosed MM patients
287 CRD/CPR
164 MP
685 MPR
328 MPT1
484 ASCT-R maintenance
257 VMP2
254 VMPT2
661 excluded patients
1798
analysed
patients
diagnosed in the last year (after
with at least 1 year of follow-up
March 15th, 2010)
Times of observation were censored on March 15th, 2011
1. Palumbo A. Blood. 2008 Oct 15; 2. Palumbo A. J Clin Oncol. 2010 Dec 1; Gay F Eur J Haematol. 2010 Sep; Clinical trial.gov.
CRD, cyclophosphamide, lenalidomide, dexamethasone; CPR, cyclophosphamide, prednisone, lenalidomide; MP, melphalan, prednisone; MPR,
melphalan, prednisone, lenalidomide; ASCT-R, autologus stem cell transplantation followed by lenalidomide maintenance; MPT, melphalan,
prednisone, thalidomide; VMP, bortezomib, melphalan, prednisone; VMPT, bortezomib, melphalan, prednisone, thalidomide.
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Patient characteristics
Al
A l analysed
y
patients
(N=1798)
Age - me
m d
e i
d an
a
69
< 65 years
32%
65-74 years
49%
75 ye
y a
e rs
r
19%
Male sex
51%
MM treatmen
m
t
Alkylating
Alky
agents plus
p
lenalidomide
lena
30%
ASCT follow
follo ed
w
by lenalidom
lenalido ide
20%
No lenalidomide
lenalid
50%
MP
9%
MPT
12%
VMP
14%
VMPT
14%
Alkylating agents, melphalan or cyclophosphamide; ASCT, autologous stem cell transplantation; MP, melphalan, prednisone; MPT,
melphalan, prednisone, thalidomide; VMP, bortezomib, melphalan, prednisone; VMPT, bortezomib, melphalan, prednisone, thalidomide.
Type of second primary malignancies
All
Al
A kyla
y tin
la
g
tin plus
plu
AS
A CT follow
lo ed
e
No
Patients
Lenalidomide
by lenalidomide
Lenalidomide
(N=1798)
(N=534)
(N=366)
(N=898)
SPMs
30 (1.66%)
%
6 (1.1%)
%
7 (1.9%)
%
17 (1.89%)
%
Hematolo
o gic SPMs
8 (0.44%)
%
1 (0.18%)
%
0
7 (0.77%)
%
ALL
1
1
0
0
AML
7
0
0
7
Solid SPMs
22 (1.22%)
%
5 (0.93%)
%
7 (1.91%)
%
10 (1.11%)
%
GI tract
tr
7
0
3
4
Lung
6
1
2
3
Breast
r
4
1
1
2
Skin
2
1
1
0
Gynecologic
olog
3
2
0
1
SPM, secondary primary malignancy; Alkylating agents, melphalan or cyclophosphamide; ASCT, autologous stem cell transplantation; ALL, acute
lymphocytic leukemia; AML, acute myeloid leukemia; GI, gastrointestinal.
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Incidence of second primary malignancies
per 100 per year
Median Follow
o -up
Incidence
Protocol
(mon
m
ths)
(%)
(%
All pa
p t
a ien
e ts
t
27.7
0.72
Al
A kyl
y at
a ing plus lenalidomide
20.4
0.66
0
AS
A CT follow
lo ed
e by lenalidomide
d
26.4
0.87
No lenalidomide
33.8
0.67
MP
34.4
0.21
MPT
39.0
1.38
VMP
34.8
0.54
VMPT
34.4
0.28
Alkylating agents, melphalan or cyclophosphamide; ASCT, autologous stem cell transplantation; MP, melphalan, prednisone; MPT,
melphalan, prednisone, thalidomide; VMP, bortezomib, melphalan, prednisone; VMPT, bortezomib, melphalan, prednisone, thalidomide.
Type of second primary malignancies
Type
y
of
Tim
Ti e
m
PFS
Therapy
Sex
Age
A
SPMs
(mo)
(mo)
Alkyl
y at
a ing
n +Le
L n
e
Breast
F
72
56
74
Prostate
M
66
6
9
68
Prostate
M
67
35
68
ALL
M
68
60
65
Lung
M
73
56
15
Skin
Sk
M
69
6
11
1
11
1
ASCT
C +Le
L n
e
Lung
F
60
8
9
GI
M
62
6
19
1
23
2
GI
M
65
30
24
Breast
F
47
32
33
Skin
Sk
M
69
28
45
Lung
M
61
6
41
4
46
4
GI
F
66
42
54
SPM, secondary primary malignancy; PFS, progression-free survival; Alkylating agents, melphalan or cyclophosphamide; ASCT,
autologous stem cell transplantation; ALL, acute lymphocytic leukemia; GI, gastrointestinal; M, male; F, female.
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Second primary malignancies
and MM progression risk
All patients
Lenalidomide
No Lenalidomide
1.00
1.00
1.00
ts
0.75
0.75
0.75
ien
patof 0.50
0.50
0.50
n
tioor
op
0.25
0.25
0.25
Pr
0.00
0.00
0.00
0
20
2
40
4
60
6
80
8
100
0
10
1
203
2
04
03
0
04
50
5
60
6
708
7
0
08
0
10
1
203
2
0
03
405
4
0
05
60
6
70
7
months
months
months
Progression or death
Solid SPMs
Hematologic SPMs
SPM, secondary primary malignancy.
Second primary malignancies
and MM death risk
All patients
Lenalidomide
No Lenalidomide
40
50
50
45
35
45
40
40
30
ts
35
35
ien 25
30
30
pat 20
of
25
25
n
tio 15
20
20
or
15
15
op 10
Pr
10
10
5
5
5
0
0
0
0
12
24
36
48
60
72
84
0
12
24
36
48
60
72
84
0
12
24
36
48
60
72
84
months
months
months
Death
Solid SPMs
Hem
H
atologi
g c SPMs
M
SPM, secondary primary malignancy.
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Comparison of observed to expected rate of second
primary malignancies
SMPs observed in Italian patients
SMPs expected from Italian Cancer Registry (age- and sex-adjusted)
Al
A l pat
p ients
t
Obser
O
ve
v d
Expected
SIR
95
9 % CI
All pa
p t
a ien
e ts
t
27
48.11
0.56
0.37-0.82
Male
16
30.25
0.53
0.30-0.86
Female
11
17.86
0.62
0.31-1.10
Lenalidomide
Observe
v d
Expected
SIR
95
9 % CI
patients
All pa
p t
a ien
e ts
t
11
15.69
0.70
0.35-1.25
Male
8
9.20
9
0.87
0
0.38-1
0
.71
Female
3
6.49
0.46
0.10-1.35
SPM, secondary primary malignancy; SIR, standardized incidence ratio; CI, confidence interval
Conclusions
· Longer follow-up is needed
· At present, observed and expected rates of SPMs are similar
· The risk of progression/death is higher than the risk of SPMs
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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
10