Bortezomib in combination with pegylated
liposomal doxorubicin and thalidomide, an
effective steroid
steroid independent regimen for
previously untreated multiple myeloma patients
Roswell Park Cancer Institute Myeloma Team
T. Sher, K. Miller, S. Ailawadhi , D. Manfredi , M. Wood, W Tan, A.
Miller, H. Liu, M. Czuczman, F. Hernandez, F. Hong, R. Sood, S.
Soniwala, W. Lawrence, P. Kouides, K. Lee and A. Chanan-Khan.
Background of VDT
Bortezomib (V) in combination with PLD (D) is approved
ft
for h
the t
t
rea
t
men f
o
l
mye oma patitients progressing on 1
line of treatment1
Bortezomib (V) and thalidomide (T) has shown synergy
in pre-clinical and clinical studies2
VDT combination has high response rates (ORR 55%,
CR 22%) in relapsed/refractory myeloma patients3
1.
Orlowski et al J Clin Oncol. 2007 1:25(25):3892-901
2.
Zangari M et al Blood.2004;104:413a-414a
3.
Chanan-khan et al Leuk Lymphoma. 2009 Jul;50(7):1096-101.
Study Objectives
Primary:
y
1.
Determine Overall response rate ORR (CR+nCR+PR)
Secondary:
1.
Determine CR rate.
2.
Determine time to progression ()
(TTP)
3.
Determine toxicity of VDT regimen
Patient Selection
Selection
Inclusion criteria
Exclusion criteria
1.
Newly diagnosed MM
1.
Pregnant or lactating women
2.
No prior therapy
therapy
2.
Inability to
to provide
provide informed
3.
KPS 60%
consent
4.
Adequate hepatic and renal
3.
Failure to comply with birth
functions
control method(s)
functions
method(s)
5.
Adequate bone marrow
4.
Active, uncontrolled infection
function
5.
Hypersensitivity to study
EF 55% ithi 6
k
f
drug(s)
6.
EF 55% within 6 weeks of
study
6.
Uncontrolled cardiac disease
Study Design
Patients treated for 6* four week cycles
PLD 20 mg/m2
or until disease progression
progression hich
w
e e
v r
er
day 1 & 15
came first1
Thalidomide 200 mg
VTE prophylaxis with low dose
daily for 28 days
warfarin2
HZV prophylaxis with acyclovir3
Bortezomib 1.3 mg/m2
day 1,4, 15 & 18
* 2 additional cycles could be given to responding patients up
tf
to a max of 8
l
cyc es
1 Chanan-khan et al Leuk Lymphoma. 2009 Jul;50(7):1096-101
2 Miller KC et al Leuk Lymphoma. 2006; 47:2339-2343
3 DePaolo D et al Blood 110: 2007 abstr 3614
Disease Assessment and
and Follow up
up
Toxicities graded by
gy NCI CTCAE v 3.0
All patients were assessed for toxicity
Response assessed by modified EBMT criteria1
After treatment patients were followed every three
months until disease relapse
relapse, progression
progression, or initiation of
subsequent therapy (which ever came first)
1. Bladé, et al Br J of Haematology; 1998; 102:1115-23
Baseline Characteristics
Characteristics
N4
N= 0
40
Median age, years (range)
60 (40-81)
Male, n (%)
(%)
26 (65)
Myeloma type, n (%)
Ig G
27(67)
IA
IgA
12 (30)
Light chain only
1 (3)
Stage II/III, n (
g(%)
DSS
35 (85)
ISS
20 (50)
2 M, mg/l median (range)
37
3.7 (1
(1.6-16.5)
Albumin, mg/dl median (range)
4.2 (3.0-4.8)
LDH IU/L, median (
,(range
g )
443 (150-1230)
Skeletal disease, n (%)
30 (75)
Toxicity
Toxicity
All grade n (%)
Grade 3 n (%)
Hd f
d
11 (25)
3( )
Hand foot syndrome
11 (25)
3 (7)
Infections
19 (44)
9 (21)
Neuropathy
py
23 (53)
()
3 (7)
()
Hematological
Lymphopenia
28 (65)
11 (26)
Anemia
19 (44)
()
2 (5)
()
Neutropenia*
20 (46)
9 (21)
Thrombocytopenia**
11 (26)
2 (5)
Grade 4 events (n): confusion (1), hyperuricemia (1), respiratory
failure (1), pleural effusion (1) and neutropenia (1), pulmonary
embolism (1)
one patient discontinued treatment
one febrile neutropenia, one pneumococcal bacteremia and 7 cases of pneumonia
*1 grade 4 event. Neutropenia occurred more than once in 9 (21%) patients; only one grade 3 recurrence
**recurred in 3 (7%) of patients no grade 3 recurrence
Toxicity
No Treatment related death
Toxicity
All grade n (%)
Grade 3 n (%)
Cardiovascular
CHF
2 (5)
2 (5)*
Arrhythmia
6 (14)
_
Pulmonary
Pleural effusion
4 (9)
4 (9)
IP
1 (2)
1 (2)
Resp. failure
1(
1 2)
(2)
1(
1 2)
(2)**
Rash
29 (67)
3 (7)
DVT/PE
2 (5)
2 (5)
Diarrhea
10 (23)
_
Constipation
27 (63)
_
Fatigue
27 (63)
3 (7)
*Both had clinical CHF, no drop in EF. Bradycardia precipitated CHF in one patient and responded to
thalidomide dose reduction
All were para-pneumonic effusions
** grade 4 event, secondary to severe pneumonia
Efficacy
ORR (CR+nCR+PR)
() = 31/40 (78%
(
; 95% CI 62-89%)
CR + nCR = 14/40 (35%; 95% CI 21-52%)
CRIFE- = 9/40 (23%; 95% CI 11-38%)
No difference in ORR seen in patients with high risk
cytogenetic
cytogenetic
Cytogenetic results were available for 21 patients, 8 had high
risk (13q in 8; t4;14 in 3; 17p- in 2 and t14;16 in 2) and 13 had
standard risk cytogenetics by FISH analysis
TTP
Median 29.5 months
(95% CI 18 0
.
/)
-n/a)
Summary
VDT is a steroid independent regimen
pg
with high
g
response rates
The altered bortezomib schedule allows combination
with thalidomide
thalidomide without significantly increasing
neurotoxicity
VDT represents an effective alternative for treatment of
lt
myeloma pa iti t
en s i t
n l
o
t
eran to st
i
ero d
ids
Acknowledgements
Clinical research nurse: Debbie Manfredi & Dawn
Depaolo
Biostatistics: Wei Tan & Austin Miller
RPCI Myeloma Team
Team
Leukemia & Lymphoma
Lymphoma Society
Society (ACK)
All our Patients and their families