Lenalidomide, bortezomib and dexamethasone has
notable activity in the frontline treatment of
myeloma, including patients with high risk disease
Pl
Paul Ri
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dson, SL
Sagar L
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And
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akubowi k 3
ak, SdJ
Sundar J
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aganna h 4
th, Noopur
Raje,5 David Avigan,6 Irene Ghobrial,1 Robert Schlossman,1 Amitabha Mazumder,4 Nikhil
Munshi,1 David Vesole,4 Robin Joyce,6 Deborah Doss,1 Diane Warren,1 Laura Lunde,1
Rachel Lukas,1 Sarah Kaster ,5 Kathleen Shea ,5 Carol Delaney,6 Marisa Lauria,6
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Kenneth Anderson1
1Dana-Farber Cancer Institute, Boston, MA; 2Winship Cancer Institute, Atlanta, GA; 3University of
Michigan Comprehensive Cancer Center, Michigan, MI; 4St. Vincent's Comprehensive Cancer Center,
New York, NY; 5Massachusetts General Hospital, Boston, MA; 6Beth Israel Deaconess Medical Center,
Boston, MA; 7Celgene, Inc., Summit, NJ and 8Millennium Pharmaceuticals, Inc., Cambridge, MA.
Background
g
ˇ Bortezomib (Bz) as a single agent1,2 and lenalidomide
(Len)
() plus
p
dexamethasone (Dex
(
)3,4
)
are approved
pp
treatments for relapsed multiple myeloma (MM) pts who
have received 1 prior therapy
Ph III
d
ran
i
om zed st di
u es confirmed superiority of
Bz1,2 and Len/Dex3,4 versus high-dose Dex alone
ˇ Bz is also approved
pp
for the treatment of newly
diagnosed MM pts5
ˇ Bz/Dex6-8 and Len/Dex9,10 are active in frontline MM
1.
Richardson, et al. N Engl J Med 2005;352:2487-98.
6.
Jagannath, et al. Blood 2006;108:238-9a (abstract).
2.
Richardson, et al. Blood 2007;110:355760.
7.
Harousseau, et al. Haematologica 2006;91:14981505.
3.
Weber, et al. N Engl J Med 2007;357:2133-42.
8.
Harousseau, et al. J Clin Oncol 2008;26: 455s, Updated
4.
Dimopoulos, et al. N Engl J Med 2007;357:2123-
data presented at ASH2008 joint ASH-ASCO symposium.
2132.
9.
Rajkumar, et al. J Clin Oncol 2008;26:2171-2177.
5.
San Miguel, et al N Engl J Med 2008;359:906-17.
10. Lacy, et al. Mayo Clin Proc 2007;82:1179-84.
Rationale for Combination Therapy
in Multiple Myeloma
IMiDs, Bortezomib
Dex
Bortezomib
Alkylators
Anthracyclines
Mitochondria
NF-B
Cytochrome-c
Smac
Caspase-8
Caspase 9
Caspase-
Caspase 3
PARP
Tumor cell death
Tumor cell death
From Richardson PG , Mitsiades CS, Hideshima T, Anderson KC: Expert Review of AntiCancer Therapy. 2008;8:1053.
Background and Study
gy Aims
ˇ
Pre-clinical studies suggest synergy of Len and Bz1
ˇ
Ph II study of Len/Bz/Dex in relapsed/refractory MM pts2
yp
y
p
84% response rate (MR or better), including 68%
CR/nCR+VGPR+PR
Len/Bz/Dex well tolerated with
with only 1 pt with G3 peripheral
neuropathy (PNY) and 2 pts with deep vein thrombosis
(DVT)
Dd
Dex dose
d
re
t
uc i
tion was
i
requ red in 14
14 t
p s leadi
ding to
protocol amendment, using lower dose of Dex (20 mg)
ˇ
Update efficacy and ASCT data from the Ph l/ll study of
3
Len/Bz/Dex in frontline MM pts, including response in high-risk
pts
1.
Mitsiades, et al. Blood 2002;99:452530.
2.
Richardson, et al. ASH 2008; Abstract 1742.
3.
Richardson, et al. J Clin Oncol 2008;26:Abstract 8520.
Objectives
ˇ
Primary:
Define maximum tolerated dose (MTD) of Len/Bz/Dex
Response rate (CR+
(CR PR)
PR)
ˇ
Secondary:
CR+PR after
after 4 and 8 cycles
CR+nCR rate
TTP, DOR, PFS and OS
Ti
Toxi i
c t
ity
Surrogate markers
Cytogenetic analysis, gene expression profiling (GEP)
ˇ
Pts proceeding to ASCT:
Stem cell data (# CD34+ cells,
(, # days
y of harvest,
mobilization strategies)
Engraftment parameters
Patients
ˇ
Inclusion criteria:
Newly diagnosed
yg
MM
No previous systemic MM therapy (bisphosphonates
permitted)
Prior radiotherapy
radiotherapy completed
completed 2 wks
wks before study entry
Karnofsky performance score (KPS) 60%
ˇ
Exclusion criteria:
Concomitant corticosteroids
PNY G2 (NCI CTCAE v3.0)
Renal insufficiency (sCr >2.5 mg/dL)
Platelets <50,000 cells/mm3
ANC <1,000 cells/mm3
Hemoglobin <8.0 g/dL
gg
AST/ALT 2 × ULN
Study Design
Up to eight 21-day cycles*
1 2
4 5
8 9
11 12
14
21
Bz
Bz
Bz
Bz
Dex
Dex
Dex
Dex
Lenalidomide
*Dex, 40 mg/day days 1, 2, 4, 5, 8, 9, 11, and 12; 20 mg, cycles 58;
amended to 20 mg/10 mg cycles 14/58 based on safety data
ˇ Pts PR may proceed to ASCT after 4l
4 cycles
ˇ After 8 cycles, maintenance therapy permitted in responding
pts using wkly ( D1, 8) schedule of Bz and Dex on D1, 2, 8,
and 9
ˇ Antithrombotic therapy with daily aspirin (81 or 325 mg)
ˇ Antiviral therapy as prophylaxis against Herpes Zoster
Phase I Dose
Dose Levels
Levels
Dose level*
Len
Bz
Dex**
1
15 mg/day
1.0 mg/m2
40 mg
2
15 mg/day
1.3 mg/m2
40 mg
3
20 mg/day
1.3 mg/m2
40 mg
4
25 mg/day
1.3 mg/m2
40 mg
4M
25 mg/day
1.3 mg/m2
20 mg
*An additional dose level (DL) introduced based on safety data;
20 mg Dex, cycles 14, and 10 mg Dex, cycles 58 (DL 4M)
**40 mg, cycles 14; 20 mg, cycles 58 (DL 1-4)
Patient Accrual
Accrual
Phase I
ˇ
Successive cohorts of 36 pts per dose level
ˇ
Dose escalation proceeded depending on dose-limiting
toxicities (DLTs):
G3 non-hematologic toxicity
G4 thrombocytopenia with platelets <10,000/mm3 on
>1 occasion despite transfusion support
G4 neutropenia for >5 days and/or resulting
yg in
neutropenic fever
Inability to receive cycle 2 day 1 dose due to drug-related
toxicity
ˇ
MTD: dose level prior to that resulting in 2 DLTs
10 additional pts to be enrolled at the MTD
Phase II
ˇ
35 pts to be enrolled at MTD or maximum planned dose (MPD)
Assessments
ˇ Toxicities graded by
gy NCI CTCAE v3.0
ˇ Responses assessed by modified EBMT criteria1,2
and Uniform Criteria (UC)3
() (to include VGPR)
()
ˇ After cycle 2, then after every cycle
ˇ Response assessments for evaluable pts were
confirmed by 2 assessments, 6 wks apart as per
modified EBMT criteria
1.
Bladé ,et al. Br J Haematol 1998;102:1115-23.
2.
Richardson, et al. N Engl J Med 2003;348:2609-17.
3.
Durie, et al. Leukemia 2006;20:1467-73.
Baseline Characteristics
Characteristics Phase I/II
Characteristics
N=66*
N=66
Median age, years (range)
58 (2286)
Male, n (%)
36 (55)
Myeloma type, n (%)
IgG
44 (67)
IgA
14 (26)
light-chain
2 (4)
light-chain
1 (2)
ISS stage II/III at diagnosis, n (%)
33 (50)
Durie-Salmon stage II/III at diagnosis**, n (%)
41 (65)
* 68 pts enrolled; 2 pts with data pending
** Data based on 63 of 66 pts with available data
Disposition Phase I & ll (N=68)*
ˇ Ph I and ll enrollment is complete
Phase l enrollment
N=33
Dose level 1
3
Dose level 2
3
Dose level 3
4**
Dl
Dose l
l
eve 4
6
Dose level 4M
17
Phase ll
ll
enro
t
men
N3
N= 5
35
*as of November 2008
**1 pt did not receive treatment; not included in MTD determination
Phase I DLTs and MTD
MTD
ˇ Two DLTs seen at dose level 4:
G3 h
l
yperg ycemia* due to hi h
g dD
-dose Dex
ˇ MPD has been reached at dose level 4M:
Len 25 mg
Bz 1 3 mg/m2
Bz 1.3 mg/m
Dex 20 mg
*G3 hyperglycemia defined by NCI CTCAE v3.0 as serum glucose levels of
>250500 mg/dL (>13.927.8 mmol/L)
Treatment and disposition
to d t
a e (
66)
n=
ˇ Median treatment duration: 9 cycles (range 235)
Completed 8 cycles
46 (70%)
Proceeded to ASCT
15 (23%)
Pt choice (prior to completion)
3
PD
5
Discontinuation 2ary to PN
2
ˇ Dose reductions:
Len in 18 pts
Bz in 26 pts
Dex in 35 pts
Most Common Toxicities G3/4
DVT
Pneumonia
G3
Chest pain
G4
Neuropathy
Mental status
Dizziness
Metabolic
Renal
Liver
Infection
Insomnia
Cardiac
Thrombocyto...
Neutropenia
Lymphopenia
Leukopenia
Anemia
024
68
ˇ
Toxicities have been manageable:
Pts, n
ˇ all G3/4 hematologic toxicities (
g(315%)
ˇ G3 hypophosphatemia (8%)
ˇ G2-4 DVT/pulmonary embolism ( n=3, 4%)
ˇ G3 PNY (3%)
ˇ no treatment-related mortality
Overall Response
Response Rate
Rate (n=
(n 65)
ˇ Best response* (EBMT/UC) in 65 evaluable pts:
20 CR
(31%)
6 nCR (9%)
39 PR (60%)
- 23 VGPR (35%)
ˇ Overall response rate, PR: 100%
ˇ VGPR: 75%
ˇ CR/nCR: 40%
* As of Feb 2009
Best Response By Phase/Cohort
Response-evaluable
Dose level
CR
nCR
VGPR
PR
MR
pts
Phase I
31
7 (23%)
1 (3%)
14 (45%)
9 (29%)
0 (0%)
13
1
1
1
23
2
1
33
1
0
2
4
6
1
032
4M
16
2
0
9
5
Phase II
34
13 (38%)
5 (15%)
9 (26%)
7 (21%)
0 (0%)
TOTA
T L
65
20 (31%)
6(
6 9%)
(9%)
23 (35%) 16 (25%)
0(
0 0%)
(0%)
ˇ Duration of response for pts with confirmed best response;
Md
Me i
dian: 2 8
. mos (range 1 4
. 25
6
.
)
mos *
)*
* As of Nov 2008
Response Independent of Baseline
Cytogenetics or ISS Stage
Stage
No
With
Normal
Abnormal
No t(4;14)
With t(4;14)
Del 13q
Del 13q
n*
39
23
51
7
48
10
PR
100%
100%
100%
100%
100%
100%
P
0.108
0.454
.757
VGPR
72%
83%
75%
71%
73%
80%
P
0.337
.861
.642
ISS I
ISS II
ISS III
n*
33
22
9
PR
100%
100%
100%
P
0.368
VGPR
85%
64%
78%
P
0.926
*pts with available data, as of Feb 2009
Time to event (TTE) and
and SCT data
data
ˇ After median follow-up of 8 mos:
Median TTP, PFS, and OS have not yet been
reached
ˇ Stem cell collection has proceeded successfully
in 21/23 pts:
p
Median 6.2 x 106 CD34+ cells after a median
of 6 cycles of therapy
15 pts have proceeded to ASCT, with
unremarkable transplant
p
course
Conclusions
ˇ Len/Bz/Dex produces high-quality, durable
responses and is well tolerated in newly
py
diagnosed MM pts, irrespective of cytogenetic
status or ISS stage
ORR 100% across all
all cohorts and at
at MPD
MPD
ˇ MPD established: Len 25 mg, Bz 1.3 mg/m2, Dex
20 mg
ˇ Toxicities manageable 2 pts with G3 PNY (3%)
and 3 pts with DVT (4%)
ˇ Stem cell mobilization has been successful in
almost all pts, with transplant course
unremarkable to date
Future Directions
ˇ Additional analyses are under way for:
ˇ Time to events
ˇ Cytogenetics
ˇ Proteomics
ˇ Gene expression profiling
ˇ Mobilization strategies
ˇ Further Phase 3 studies
studies of RVD are
are in process and/or
planned (with or without ASCT)
ˇ Addition of other agents (e
g( g CRVD, RVDD, RVD + SAHA)
as part of Phase I/II trials ongoing
Acknowledgments
ˇ Dana-Farber Cancer Institute
ˇ Winship Cancer Institute
ˇ University of Michigan Comprehensive
Cancer Center
ˇ St Vincent's Comprehensive Cancer Center
ˇ Massachusetts General Hospital
ˇ Beth Israel Deaconess Medical Center
ˇ Research nurses, coordinators, and other
staff at
at all
all study sites
ˇ Celgene Corporation
ˇ Millennium
u
Pharmaceutica
cals,
s, Inc.
ˇ The patients and their families