THE WEEKLY INFUSION OF BORTEZOMIB REDUCES PERIPHERAL NEUROPATHY
Gay F. 1, Bringhen S. 1, Genuardi M.1, Rossi D.2, Ria R.2, Romano A.2, Ferrara F.2, Di Renzo N.2, Dominietto A.2, Andriani A.2, Rizzi R.2, Vallone R.2, Mele G.2, Storti S.2, Podda L.2, Aitoro G.2, Mettivier V.2,
Annibali O.2, Rossini F.2, Gentilini P.2, Pavone V.2, Giuliani N.2, Rauco A.M.2, Baraldi A.2, Capaldi A.2, Gherlinzini F.2, Gaidano G.2, Boccadoro M.1 and Palumbo A.1
1 Diii
Division of Hl
Hematology, Ui
University of Ti
Torino, A.O.U. San Giovanni Bi
Battista, Ti
Torino, Il 2
Italy; Il
Ita ilian Ml
Multil
iple Ml
Myeloma Nk
Network, GIMEMA, Il
Italy
ABSTRACT
BACKGROUND
AIMS
MATERIALS AND METHODS
SCHEDULE TREATMENT
Background. Peripheral neuropathy (PN) is a non-hematologic side effect frequently reported in elderly patients treated
511 newly diagnosed MM patients older than 65 years, were randomly assigned to
with bortezomib-melphalan-prednisone (VMP). To address this issue, both bortezomib-melphalan-prednisone-thalidomide
receive
Melphalan 9 mg/m2
(VMPT) and VMP dosing regimens were changed; and bortezomib schedule was modified from twice weekly to weekly
· In patients with Multiple Myeloma (MM), peripheral neuropathy (PN) is
nine 6-week cycles of VMP or VMPT:
administration.
disease-related and/or drug-related (Vincristine, Thalidomide, Bortezomib).
The aims of this subanalysis of VMP versus VMPT trial are:
Induction treatment:
Aims. To determine incidence and risk factors of bortezomib-associated PN in twice weekly or weekly bortezomib infusion
Prednisone 60 mg/m2
schedules.
· Bortezomib 1.3 mg/m2
on days 1,4,8,11,22,25,29,32 in cycles 1-4 and
Methods. Patients (N=511) older than 65 years were randomly assigned to receive VMPT fol owed by maintenance with
bortezomib and thalidomide or VMP. Initial y, patients were treated with nine 6-week cycles of VMPT (induction:
on days 1,8,22,29 in cycles 5-9
· Bortezomib is approved in Europe and USA as first line therapy in newly
- To analyze incidence, characteristics and risk factors of Bortezomib-related
+/- Thalidomide 50 mg
bortezomib 1.3 mg/m2 days 1,4,8,11,22,25,29,32 in cycles 1-4 and days 1,8,22,29 in cycles 5-9; melphalan 9 mg/m2 days
· Melphalan 9 mg/m
on days 1-4
1-4; prednisone 60 mg/m2 days 1-4 and thalidomide 50 mg days 1-42; maintenance: bortezomib 1.3 mg/m2 every 15 days
di
diagnos d
e MM
MM
t
pa iti t
en s, bas d
e on th
the I t
n ern ti
a on l
a VIS
VI T
S A
T
t
s d 1
· Melphalan 9mg/m2
on days 1-
udy1.
PN.
PRE-EMENDEMENT:
and thalidomide 50 mg/day as maintenance) or VMP (bortezomib, melphalan and prednisone at the same doses and
· Prednisone 60 mg/m2
on days 1-4
schedules previously described without maintenance). In March 2007, the protocol was amended: both VMPT and VMP
induction schedules were changed to nine 5-week cycles and bortezomib schedule was modified to weekly administration
· Thalidomide 50 mg/die continuously (only in VMPT arm)
(1.3 mg/m2 days 1,8,15,22 in cycles 1-9). Baseline grade 2 PN was an exclusion criteria.
· PN is a common and significant dose limiting adverse effect of Bortezomib
- To evaluate the relationship between PN and Bortezomib schedule,
Results. 254 VMPT patients
V
V
V
V
V
V
V
V
and 257 VMP patients were evaluated in intention-to-treat: 141 patients received twice weekly infusion of bortezomib and
based chemotherapy (> grade 3 PN = 22%)1.
according to protocol amendment.
Maintenance (only in VMPT arm):
370 once weekly. The overall incidence of PN was 37% in the VMPT patients and 27% in the VMP patients (p=0.01) while
1
4
8
11
22
25
29
32
the grade 3 was quite similar (8% and 5%. p=0.19). When VMPT and VMP groups were combined, the incidence of PN
· Bortezomib 1.3 mg/m2
every 15 days
was significantly higher in patients who received twice weekly infusion of bortezomib: the incidence of all grade PN was
- To evaluate whether the addition of Thalidomide to Bortezomib increases
45% in the twice weekly group and 27% in the once weekly group (p=0.0002), including a grade 3 PN incidence of 16%
· PN is typical y sensory and occurs within the first courses of Bortezomib,
· Thalidomide 50 mg/day continuously until progression.
and 3% (p<0.0001), respectively (table 1). In multivariate analysis, the weekly infusion of bortezomib was the only
the rate of PN.
predictive factor of lower incidence of PN (p<0.0001) whereas low-dose thalidomide did not affect PN rate (p=0.16). The
reaching a plateau at cycle 52.
In March 2007 the protocol was amended:
weekly infusion of bortezomib significantly reduced discontinuation rate and bortezomib dose reduction (table 1). The
· Nine 5-week cycles
weekly infusion of bortezomib slightly reduced the CR rate (p=0.07), but did not affect progression-free survival (p=0.31)
and overall survival (p=0.44) (table 1).
- To analyze response rate and PFS in patients treated with once weekly
· Weekly administration of Bortezomib: 1.3 mg/m2 on days 1,8,15,22 in
Conclusion. The weekly infusion of bortezomib significantly decreased incidence of PN, discontinuation rate and dose-
· In the GIMEMA trial VMP versus VMPT, the protocol was amended in March
POST-EMENDEMENT:
reduction rate without significant reduction of PFS. The addition of low-dose thalidomide to VMP did not increase the
versus twice weekly Bortezomib infusion.
cycles 1-9.
incidence of grade 3-4 PN. An update of these data and correlation between PN and clinical outcome wil be presented at
2007 and Bortezomib schedule was changed from twice weekly to once
V
V
V
V
the meeting.
weekly infusion to reduce PN3.
Patients with grade 2 PN or neuropathic pain (by National Cancer Institute Common Terminology
Criteria for Adverse Events [NCI CTCAE] version 3.0) were not enrol ed.
1
8
15
22
ASSESSMENT OF PN ACCORDING TO NATIONAL CANCER INSTITUTE
PATIENTS CHARACTERISTICS
RECOMMENDED DOSE MODIFICATIONS FOR
COMMON TOXICITY CRITERIA
STATISTICAL METHODS
INCIDENCE OF ADVERSE EVENTS AND NEUROPATHY
ACCORDING TO BORTEZOMIB SCHEDULE
BORTEZOMIB AND THALIDOMIDE-ASSOCIATED PN
(NCI CTC), VERSION 3.0
Baseline characteristics of the
Bortezomib twice weekly
Bortezomib once weekly
Bortezomib and Thalidomide-associated PN and neuropathic pain were managed
patients
N=139
N=372
with established dose-modification guidelines
· Data are reported from the analysis of VMP versus VMPT trial, updated to
Adverse event
Any grade toxicity
Pvalue
Grade 34 toxicity
Pvalue
Age median (range)
71(60-85)
71(56-86)
Grade
Bortezomib
Bortezomib
Bortezomib Bortezomib
October 2009.
Age No (%)
twice weekly
once weekly
twice weekly
once weekly
< 65 years
3(2)
15(4)
12
3
4
5
Sev erity of peripheral
Modific ation of Bortez omib
Modific ation of T halidomide
N = 134
N = 369
N = 134
N = 369
65-74 years
102(73)
254(68)
neuropathy sig ns and
dos e and reg imen
dos e and reg imen
75 years
34(24)
103(28)
Neuropathy
As imptomatic;
Sens ory
Sens ory
Dis abiling
Death
symptoms
· Time-to-event analyses were assessed by the Kaplan-Meier method.
Stage ISS No (%)
sens ory
los s of deep
alteration or
alteration or
Hematologic toxicity No(%)
114 (85)
306 (83)
0.68
60 (45)
161 (44)
0.84
I
35(25)
80(21)
tendon reflexes
pares thes ia
pares thes ia
II
55(39)
133(36)
Grade 1 neuropathic s ens ory or
No action
No action
or pares thes ia
(including
interfering with
III
31(22)
73(20)
pain
· P values were calculated with log-rank.
Non hematologic toxicity
124 (92)
307 (83)
0.009
68 (51)
131 (35)
0.0027
(including
tingling)
AD L
Variable missing No(%)
18(13)
86(23)
No (%)
tingling) but not interfering with
Chromosome abnormalities No (%)
Grade 1 with pain or
Reduce dos e to
Reduce by 50%
interfering with function but not
Non hematologic toxicity
111 (83)
290 (79)
0.29
47 (35)
108 (29)
0.23
del 13
46(48)
141(50)
Grade 2
1.0 mg/m2
function
interfering with
· The incidence of adverse events was compared by the chi-square or Fisher
(except neuropathy) No(%)
t (4;14)
20(21)
39(14)
t (11
(1 ;1
1; 4)
14)
19(20)
0
32(
32 1
( 1)
ADL
11)
exac
exa t
c tes
te t
s .
t (14;16)
2(2)
13(5)
Withhold until toxicity res olves ,
del 17
13(14)
42(15)
Neuropathy No (%)
Grade 2 with pain or Grade 3
then res tart at dos e of 0.7
Dis continue
Pain
Mild pain not
Moderate pain;
Severe pain;
Dis abiling
Death
Patients tested for FISH No / total No
95(68)
281(75)
interfering with
pain or
pain or
97 (72)
147 (40)
<0.0001
38 (28)
30 (8)
<0.0001
(%)
mg/m2
function
analges ics
analges ics
· The analyses were performed with SAS (version 8.2; SAS Institute, Cary, NC).
SensoryNo (%)
Presence of diabetes mel itus No (%)
9(6)
24(6)
interfering with
severely
PainNo (%)
62 (46)
97 (26)
<0.0001
22 (16)
11 (3)
<0.0001
Presence of hyperglycemia No(%)
51(37)
124(33)
Sensory and painNo (%)
17 (13)
27 (7)
0.07
6(7)
10 (3)
0.26
Grade 4 neuropathic s ens ory or
function, but
interfering with
Dis continue
Dis continue
not interfering
AD L
· Multivariate analysis was performed accounting for competing events (Fine &
18 (13)
21 (6)
0.0073
10 (7)
9(2)
0.01
Presence of cardiopatia - No (%)
42(30)
93(25)
pain
with ADL
Patients treated with VMP No (%)
66(47)
191(51)
Gray model).
Patients treated with VMPT No (%)
73(52)
181(49)
DISCONTINUATION RATE AND DOSE REDUCTION RATE
DISCONTINUATION RATE, DOSE REDUCTION RATE
CUMULATIVE INCIDENCE OF SENSORY PN,
RESPONSE RATE ACCORDING TO BORTEZOMIB
AND MEDIAN CUMULATIVE DOSE
MULTIVARIATE ANALYSIS
DUE TO TOXICITY ACCORDING TO BORTEZOMIB
ACCOUNTING FOR COMPETING EVENTS
Best
Best Re
R spon
espo
SC se
nHE (
D V
U ER
LE SI
VER ON
O E
N 2)
SCHEDU
SCHE
L
DU E
ACCORDING TO BORTEZOMIB SCHEDULE
LE
Association between patients characteristics and cumulative incidence of PN.
Analyses performed accounting for competing events (Fine & Gray model).
Bortezomib Twice weekly
Bortezomib once weekly
Twice weekly
Once weekly
P value
Ris k fac tor
Any Grade
Grade 3 to 4
(N=134)
1.00
(N=369)
Adverse event
Discontinuation
Dose reduction
HR
95% CI
pvalue
HR
95% CI
pvalue
due to toxicity
Pvalue
due to toxicity
Pvalue
60
60
0.90
CR
35%
30%
0.23
1.35
1.04, 1.74
0.023
1.25
0.75, 2.07
0.397
Bortezomib Bortezomib
Bortezomib Bortezomib
T halidomide
twice weekly
once weekly
twice weekly
once weekly
0.80
> VGPR
54%
55%
0.84
0.43
0.33, 0.56
<0.001
0.26
0.16, 0.42
<0.001
50
sq 50
Velc ade R educ tion
N = 134
N = 369
N = 134
N = 369
/m
ce
> PR
86%
85%
0.23
ts
g
0.70
0.98
0.96, 1.01
0.237
1.01
0.96, 1.06
0.675
n
m
en
Ag e < 75 / > 75
etia 40
e 40
s
cid 0.60
0.94
0.72, 1.21
0.615
1.7
0.7, 1.94
0.550
70
70
p
o
G ender :
Any cause No(%)
54 (40)
117 (32)
0.09
75 (56)
93 (25)
<0.0001
of
de
Male/F emale
Hematologic toxicity
2 (1)
11 (3)
0.53
9 (7)
11 (3)
n
0.50
iv
Any grade sensory PN twice weekly schedule
IS S Stag e
60
60
No(%)
0.07
30
30
tio
lat
I
1
1
u
lativeIn 0.40
m
u
50
50
Non hematologic
9 (7)
34 (9)
0.47
11 (8)
27 (7)
0.71
ropor
cu
m
II
0.74
0.55, 1.01
0.06
0.67
0.37, 1.2
0.175
ts
P 20
20
u 0.30
Any grade sensory PN once weekly schedule
toxicity except
n
40
tients
ian
C
III
0.87
0.58, 1.29
0.482
0.75
0.36, 1.56
0.436
35
40
neuropathy No(%)
d
0.20
Grade 34 sensory PN twice weekly schedule
32
30
30
10
Me
30
fpa 30
Peripheral
10
25
FIS H hig h ris k * :
fpatie
o
0.10
Grade 34 sensory PN once weekly schedule
o
neuropathy No(%)
20 (15)
17 (5)
0.0006
55 (41)
55 (15)
<0.0001
no
1
1
19
%
20
%
20
Sensory
13 (10)
8(2)
0.0006
38 (28)
38(10)
<0.0001
0
0.00
13
0
yes
1.04
0.73, 1.48
0.814
1.37
0.75, 2.53
0.306
9
Pain
2(1)
6(2)
0.69
12 (9)
16(4)
0.07
10
10
Both
4(3)
3(1)
0.085
5(4)
1(0.3)
0.006
DiscontinuationDosereduction
Median cumulative dose
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18
0.93
0.57, 1.52
0.763
0.47
0.11, 2.01
0.310
1
1
Mo nths
Diabetes
Other No(%)
23 (17)
54 (15)
0.47
0
0
0
0
0
Cardiopathy
0.93
0.68, 1.22
0.538
0.73
0.4, 1.33
0.305
CR
VGPR PR
SD
PD
CR
VGPR
PR
SD
PD
*Abnormalities cytogenetic: t(4;14) or t(14;16)or Del17
PROGRESSION FREE SURVIVAL ACCORDING TO
CONCLUSIONS 1
CONCLUSIONS 2
REFERENCES
DISCLOSURES
BORTEZOMIB SCHEDULE
PFS @ 2 years: 62% versus 61%
· The rate of PN is consistent with data from VISTA trial.
First author:
Bortezomib
Bortezomib
p value
1.
San Miguel J, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan
Francesca Gay, MD: No relevant conflict of interest to disclose
twic e weekly
onc e weekly
1. 00
· The incidence of PN, treatment discontinuation rate and dose reduction rate
and prednisone for initial treatment of mulriple myeloma. N Engl J Med,
N = 134
N = 369
are significantly lower in patients receiving once weekly Bortezomib infusion.
2008, 359: 906-917.
Co-authors:
Sens ory
0. 75
2.
Mateos MV, Richardson PG, Schlag R, et al. Peripheral neuropathy with
Sara Bringhen, MD: Honoraria from Celgene and Janssen-Cilag.
Peripheral NeuropathyNo(% )
· The addition of low dose Thalidomide did not significantly increase grade 3-4
VMP in the phase III VISTA study resolves in the majority of patients and
tients
Any grade PN
62 (46)
97 (26)
<0.0001
PN incidence.
shows a rate plateau. Clinical Lymphoma and myeloma, 2009, A172.
Mario Boccadoro, MD: Consultancy, advisory committee and reserch funding
Grade 34 PN
22 (16)
11 (3)
<0.0001
fpa 0. 50
o
· In multivariate analysis accounting for competing events, no consistent
from Celgene, Janssen-Cilag and Pharmion
Bes t res pons e rateNo(% )
baseline risk factor were outlined. The only significant factor influencing the
3.
Palumbo A et al, A prospective randomized phase III study of
rtion
CR
47 (35)
109 (30)
0.23
incidence of PN is the reduction of Bortezomib infusion from twice to once
0. 25
Bortezomib, Melphalan, Prednisone and Thalidomide (VMPT) versus
VG P R
76 (54)
202 (55)
0.84
weekly.
Antonio Palumbo, MD: Honoraria from Celgene and Janssen-Cilag
ropo
Bortezomib, Melphalan, Prednisone (VMP) in elderly newly diagnosed
PR
119 (86)
312 (85)
0.73
P
myeloma patients. Blood, 2008, 112: 652.
P=0.99
PF S at 2 years
61%
62%
0.99
· The weekly infusion of Bortezomib did not affect response rate and PFS.
The remaining co-authors declare that they have no conflict of interest to
0. 00
declare
0
1020
30
4050
Months