OV
Once Versus T i
w ce Weekl
kly Bortezomib
ib
in CyBorD for Newly Diagnosed Myeloma
CB Reeder, DE Reece, V Kukreti, JR Mikhael, C. Chen, S
Trudel, K Laumann, J Hentz, NA Pirooz, JG Piza, VHJ Zepeda,
R Fonseca, PL Bergsagel, JF Leis, R Tiedemann, AK Stewart
Scottsdale, Arizona
Rochester,
Rochester Minnesota
Jacksonville, Florida
MAYO CLINIC
Background
CyBorD
· Phase II single arm trial MCA + PMH
· Untreated symptomatic multiple myeloma
· 12-06 to 10-08
· Role of novel agents
· Bortezomib, lenalidomide, thalidomide
· Role of alkylating agents
· Mlhl
Melphalan
· Cyclophosphamide
· Three drug combinations of an alkylator,
gy
bortezomib and corticosteroid active in relapsed
MM (Reece et al)
· Goal - Increase the depth
depth and speed
speed of response
prior to stem cell transplantation
Background
Cyclophosphamide
300 mg/m2 po
Days 1, 8, 15, 22
Bortezomib
1.3 mg/m2
Days 1, 4, 8, 11
Dexamethasone
40 mg po
Days 1-4, 9-12, 17-20
Cycle = 28 days
· CyBorD
·Rapid response 80% drop in sentinel
protein after
after 2 cycles
·All patients electing transplant had
successful SC collection
Reeder, Leukemia 2009;23:1337-1341
Phase II CyBorD Trial
Response Rates
Rates
PR
VGPR
CR/nCR
100
96%
100%
88%
80
39%
46%
72%
60
40
22%
25%
6%
20
27%
25%
22%
0
ITT
Post 4
- cyc
cy le
cl s
es
Post SCT
-
N=33
n=28
N=18
Rapid response:
response: mean M-
M protein reduction
reduction of 80% after 2 cycles
Reeder C, et al. ASCO 2008, abstract #8517.
CyBorD Toxicity Cohort 1
Thrombocytopenia
25%
9% did not complete
all 4 cycles due to
toxicity
Neutropenia
13%
Dose reductions:
Hyperglycemia
13%
Dose
13%
33% for Dex
Anemia
12%
27% for Bortez
21% for Cyclo
Cyclo
Hypokalemia
9%
Gr 3 AE's in 48%
Thrombosis
7%
Gr 3 PN in 6%
Diarrhea
6%
PN 64% all grades
PN
6%
Modified CyBor-
CyBor D
· Ch
Cohort 2 (
d
mo ifi
dified)
d)
·Bortezomib once weekly
·Dexamethasone weekly after
after cycle 2
Cyclophosphamide
300 mg/m2
mg/m po
Days 1, 8, 15, 22
Bortezomib
1.5 mg/m2 IV
Days 1, 8, 15, 22
Days 1-4, 9-12, 17-20
(cycles 1, 2)
Dexamethasone
40 mg po
Days 1,
y, 8, 15, 22 (c
( ycles
y
3, 4)
Cyclophosphamide 300 mg/m2
SCHEMA Cohort 2 (weekly bortezomib)
Bortezomib 1.5 mg/m2
Dexamethasone 40 mg
Cy
Cy
Cy
Cy
Bor
Bor
Bor
Bor
Dex
1-4
9-12
17-20
day
1
8
15
22
28
Modified CyBorD cycles 1, 2
Cy
Cy
Cy
Cy
Bor
Bor
Bor
Bor
Dex
Dex
Dex
Dex
day
1
8
15
22
28
Modified CyBorD
CyBorD cycles
cy
3, 4
CyBorD Methods
· 63 patients enrolled
· Cohort 1 (standard bortezomib dosing) (n=33
(
)
n=33
· Cohort 2 (weekly bortezomib)
(n=30)
· 1° goal 40% VGPR
2° - safety, survival, stem cell collection
· Newly diagnosed, symptomatic MM
· ECOG 2
· Platelets 100,000, ANC 1000, Cr < 3.5
· Acyclovir, quinolone antibiotic
Transplant
4 cycles
Stem cell harvest
(16 wks)
wks)
Continue CyBorD
(12 max)
Results - Patient Characteristics
n = 63
Cohort 1 and 2
Median Age
61 (36-74)
matched for age,
Female
gender and ECOG
48%
PS
D-S stage II
47%
III
50%
ISS Stage I
43%
ISS stages higher in
cohort 1 vs. 2
II
36%
II/III 67% vs. 44%
III
21%
High risk
25%
t(4;14), del 17
CyBorD
ITT Response
Response
ORR
88%
93%
90%
100
90
80
CR/
CR/
CR/
70
CR
nCR
n
60
nCR
50
40
VGPR
40
VGPR
VGPR
VGPR
30
20
PR
PR
PR
10
0
Cohort 1
Cohort 2
ALL = 63
(Twice
(T
weekly Bor)
(Weekly
(W
Bor)
(n = 33)
(n = 30)
CyBorD
Response after
after 4 cycles
ORR
96%
93%
95%
100
90
80
CR/
CR/
CR/
70
CR
nCR
nCR
n
60
50
40
VGPR
VGPR
VGPR
30
20
10
PR
PR
PR
0
Cohort 1
Cohort 2
ALL = 55
(Twice
(T
weekly Bor)
(Weekly
(W
Bor)
(n = 28)
(n = 27)
Results - Response
ITT
Cohort 1
Cohort 2
All (n=63)
(n=63)
ORR
88% (29/33)
93% (28/30)
90% (57/63)
CR/nCR
39% (13/33)
43% (13/30)
41% (26/63)
VGPR
61% (20/33)
60% (18/30)
60% (38/63)
After 4 cycles
Cohort 1
Cohort 2
All (n=55)
ORR
96% (27/28)
93% (25/27)
95% (52/55)
CR/nCR
46% (13/28)
48% (13/27)
47% (26/55)
VGPR
71% (20/28)
63% (17/27)
67% (37/55)
CyBorD Toxicity
Weekly Bortezomib less toxic despite higher total dose per
cycle = 5 2
. standard
standard vs
vs. 6 0
. weekly
weekly (cohort 2)
2)
100
90
80
70
64%
60
56%
48%
Cohor
C
t
ohor 1
50
40
37%
Cohort 2
30
20
12%
10
6%
3%
0
0%
Grade 3
Grade 4
PN
PN Gr 3
Any adverse event
Peripheral neuropathy
CyBorD Toxicity
Grade 3
Cohort 1
Cohort 2
Thrombocytopenia
25%
0%
Neutropenia
13%
6%
Anemia
12%
3%
PN
6%
0%
Thrombosis
7%
0%
Diarrhea
6%
3%
Bortezomib # cycles
116
137
% dose reduced
21%
13%
Cyclo # cycles
116
138
% dose reduced
9%
13%
Dex # cycles
116
138
% dose reduced
30%
20%
CyBorD Survival
OS
PFS
100
OS
80
PFS
60
essc
uc
%S
40
20
0
0
5
10
15
20
25
30
35
Time (months)
PFS High Risk
del17 or t(4;14
(;
)
all others
100
80
ee
Fr
All others
60
essionr
rog
Del 17
Pdn 40
t(4;14)
liveaA% 20
0
0
5
10
15
20
25
30
35
Tim e (m onths)
Conclusions
· Weekly Bortezomib in CyBorD
· Retains the high activity of standard dose
bortezomib in CyBorD
· Lt
Less toxic
· More convenient
· CyBorD
· Allows stem cell harvest
· Favorable overall survival
· Does not protect high risk patients from
relapse
Thank You
MCA
PMH
J Mikhael
D Reece
K Laumann
V Kukreti
J Hentz
C Chen
N Pirooz
S Trudel
R Fonseca
J Piza
P Bergsagel
V Zepeda
J Leis
R Tiedemann
K Stewart