DoseEscalation Study of Carfilzomib +
Lenalidomide + LowDose Dexamethasone
in Relapsed/Refractory Multiple Myeloma
William Bensinger, MD, Michael Wang, MD, Robert Z. Orlowski, MD, PhD, Melissa Alsina, MD, Tom
Martin, MD, Seema Singhal, MD, Nashat Gabrail, MD, Marcy Vallone, Michael Kauffman, MD, PhD,
Ruben Niesvizky, MD
Fred Hutchinson Cancer Research Center, Seattle, WA; MD Anderson Cancer Center, Houston, TX;
Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX; H. Lee Moffitt
Cancer Center, Tampa, FL; University of California San Francisco, San Francisco, CA; Northwestern
University, Chicago, IL; Gabrail Cancer Center, Canton, OH; Onyx Pharmaceuticals, Emeryville, CA; Weill
Cornell Medical College, New York, NY
Introduction
Carfilzomib is a next-generation, irreversible epoxyketone proteasome inhibitor
that is selective for the unique N-terminal threonine active sites within the
proteasome, the major N-terminal threonine protease in the cell. Consecutive-
day dosing of carfilzomib provides prolonged (>48 hours) and potent
(>80-90%) proteasome inhibition and confers greater antitumor activity than
intermittent dosing in animal models. Carfilzomib has shown a lack of
preclinical neurotoxicity and neutropenia. Further
Further, bortezomib-resistant cells
remain sensitive to carfilzomib.
Single-agent carfilzomib demonstrates robust and durable activity and
tolerability in p
ypatients with relapsed and/or refractory (R/R) multiple myeloma
(MM), including those who have received bortezomib and in patients with
baseline neuropathy or renal insufficiency. The tolerability profile of
carfilzomib allows for prolonged administration with minimal dose modification
and no observed clinically
clinically significant cumulative toxicity. Peripheral
neuropathy is infrequent and mild and does not limit therapy even in patients
with significant baseline neuropathy.
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Rationale
Rationale for the combination of carfilzomib +
lenalidomide/low dose-dexamethasone (CRd):
Carfilzomib is active as a single agent in R/R MM, and twice-weekly
dosing (QD
(QD x2 for 3 weeks on
on 28-
28 day cycles) is
is well
well-tolerated.
Lenalidomide/Dexamethasone (RD) is a current standard of care for
relapsed MM. Bortezomib + Len/Dex (VRD) is active in relapsed or
refractory MM but has toxicities that limit duration of therapy
ypy and use of
the combination at full dose.1 CRd should provide superior activity to Rd
alone. Lack of both overlapping toxicities (e.g., neutropenia) and
neuropathy should allow for long-term dosing of CRd at full doses of
C and R along with low-dose dexamethasone
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Methods
Study Design
Phase 1b, multi-center, dose escalation (Figure 1)
Primary obj
bj t
ec itives: saft
fety
d
an
i
max mum tl
tol
td
erated dose
Secondary objectives: efficacy and pharmacokinetics
Figure 1. Study design.
Eligible population
· Relapsed or progressive MM
after 13 prior therapies
Carfilzomib + Lenalidomide
· Neuropathy (Grade 1/2 without
and low-dose Dexamethasone
pai)
in) alllowed at baseliline
(6 dose escalation cohorts)
· Platelets 50,000/mm3
28-day cycles
· ANC 1000/mm3
· CrCl 50 mL/min
Expansion cohort at MTD or highest protocol
dose (if MTD not established)
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Methods (cont)
Study Treatment:
6 dose-escalation cohorts + expansion cohort at maximum
tolerated dose (MTD) or highest
protocol dose (if MTD not established)
CRd schedule (1
(1 cycle = 28 days) is shown in
in Table 1.
1.
Response criteria:
IMWG-URC, EBMT
Dose-limiting toxicity (DLT) defined as (per NCI-CTCAE v3.0):
Grade (G) 3 non-hematologic; G4 neutropenia for >7 d or any
neutropenic fever;
fever; G4
G4 thrombocytopenia
thrombocytopenia 7d
7 ;
d; G3
G3 G4
thrombocytopenia in association with bleeding; treatment
delay >21 days for drug-related toxicity
MTD = Dose l
l
eve
i
pr or to th t
a
l
resu ti
lting in 2/6
DLT
DLTs
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Methods (cont)
Dosing cohorts and schedules are shown in Table 1
Tb
Ta l
ble 1. Dosing C h
o orts
Cohort
Carfilzomib*
Lenalidomide
Dexamethasone
mg/m2
mg
mg
1(
1 n
(n=6)
15
10
40
2 (n=6)
15
15
40
3 (n=8)
15
20
40
4 (n=6)
()
20
20
40
5 (n=6)
20
25
40
6 (n=8)
20/27*
25
40
Expansion (n=44)
20/27*
25
40
Days of Administration
Cycles 112
1, 2, 8, 9, 15, 16
121
1, 8, 15, 22
Cycles 1318
1, 2, 15, 16
121
1, 8, 15, 22
*Carfilzomib 20 mg/m2 IV over 10 minutes on days 1 and 2 in cycle 1; 27 mg/m2 thereafter
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Results--Patient Baseline Characteristics
Table 2. Patient Baseline Characteristics*
Baseline characteristics
N=84
Md
Me i
dian age, years (
)
range
62 (43-86)
Median years from diagnosis (range)
3 (0.35-21.5)
Female/Male (%)
43/57
Immunoglobulin subclass (%)
IgG
81
IgA
19
Bl
Base iline
l
eva
t
ua ition (%)
History of neuropathy
82
*Data cutoff date 29 April 2010
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Results--Prior Therapies
Table 3. Prior Therapies
Prior therapies, n (%)
Cohorts 15
Cohort 6 + expansion
All patients
(N=32)
(N=52)
(N=84)
Number of prior therapies
1
5 (16)
13 (25)
18 (21)
2
27 (84)
39 (75)
66 (79)
Bortezomib (Bor)
23 (72)
()
39 (75)
()
62 (74)
()
Lenalidomide (Len)
20 (63)
36 (69)
56 (67)
Thalidomide (Thal)
15 (47)
22 (42)
37 (44)
Len or Thal
28 (88)
45 (87)
73 (87)
LT
Len + h
Th l
a
7 (22)
(22)
13 (25)
20 (24)
Bor + Len
17 (53)
28 (54)
45 (54)
Bor + Thal
9 (28)
16 (31)
25 (30)
Bor + Len + Thal
5 (16)
9 (17)
14 (17)
Other prior therapies included stem cell transplant (78% of patients in cohorts 15, 54% of patients in cohort 6 + the expansion), alkylating
agents (75% and 67%), anthracyclines (28% and 33%), immune therapies (6% and 6%), and corticosteroids (100% and 96%).
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Safety Results
Adverse events (AEs) are generally mild and manageable
Low rate of grade 3/4 AEs
AEs with full dose of
of all
all agents in
in CRd
combination
Serious adverse events (SAEs)
28/84 patients (33.3%) reported at least one SAE regardless of
relationship
9/84 patients (10.7%)
(10.7%) reported
reported SAEs considered possibly or
or probably
probably
related to carfilzomib, lenalidomide, and/or dexamethasone.
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Results (cont)
Table 4. Treatment Emergent AEs* Reported in 25% or G3/4 AEs
Reported in 5% of All Patients
All Grades
Grades 3 / 4
( 25%)
( 5%)
Adverse Events (N=84)
n (%)
Fatigue
38 (45)
4 (5)
Diarrhea
31 (37)
5 (6)
Neutropenia
25 (30)
19 (23)
Anemia
21 (25)
19 (12)
Thrombocytopenia
18 (21)
15 (18)
Hyperglycemia
7 (14)
4 (5)
*regardless of relationship
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Results--Efficacy (cont)
Responses ere
w
obser
obser ed
v
across all cohorts
cohorts (Fig r
u e
re 2)
2)
Figure 2. Responses to CRd treatment by cohort*
100%
3%
10%
8%
PD
SD
15%
80%
26%
44%
PR
s
VGPR
ts
VGP
60%
enti
42%
CR/sCR
33%
pa
19%
of
40%
%
20%
28%
27%
28%
6%
6%
6%
0%
5
+
n
ts
1
6
o
)
n
sio
8)
e
rts 1
32)
rt 6
n
ti
80)
o
=
o
a
=4
=
h
h
(n
p
(n
l pa
(n
Co
Co
ex
Al
*Data cutoff date 29 April 2010, N=84. Four patients were non-evaluable for efficacy due to lack of post-baseline assessment attime
of data cutoff
Includes 2 sCR in expansion; 3 unconfirmed CR (2 in C 1-5; 1 in expansion) due to lack of BM Bx at time of data cutoff
Includes 1 unconfirmed PR without confirmatory consecutive assessment at time of data cutoff
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Results--Efficacy (cont)
Responses were independent of cytogenetics, disease stage, or prior
therapies (Table 5)
Responses improve with long-term treatment2
Md
Me i
dian d
t
ura ition f
o response has
t
no
t
ye been
h
reac d
e ( 1
> 2
12
t
mon h
ths)
34.6% (9/26) patients have remained on study for >12 months (range
1423 months)
3) with SD;
S; all remain on study;
y; all of these patients
p
were in cohorts 14 and, therefore, received sub-maximal doses of
the study drugs carfilzomib and lenalidomide.
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Results - Efficacy (cont)
Table 5. Response Rates by Baseline Characteristics and Prior Therapies*
Tota
t l n
CR/sCR
CR/
VGPR
V
ORR (
( PR)
CBR (
( SD)
n (%)
n (%)
n (%)
n (%)
Number of prior therapies, n (%)
1
17
0 (0)
8 (47)
13 (77)
17 (100)
2
63
5 (8)
19 (30)
40 (64)
57 (91)
Prior therapies, n (%)
Bortezomib (Bor)
59
2 (3)
16 (27)
34 (58)
53 (90)
Lenalidomide (Len)
54
2 (4)
15 (28)
32 (59)
48 (89)
Thalid
id
om e (Th
l
a )
l)
34
3 (9)
12 (35)
27 (79)
33 (97)
Len or Thal
69
5 (7)
21 (30)
44 (64)
63 (91)
Len and Thal
19
0 (0)
6 (32)
15 (79)
18 (95)
Bor and Len
44
1 (2)
10 (23)
23 (52)
38 (86)
Bor and Thal
22
1 (5)
5 (23)
15 (68)
21 (96)
Bor, Len
, and
Thal
13
0 (0)
3 (23)
9 (69)
12 (92)
Cytogenetics, n(%)
Normal/favorable
40
2 (5)
15 (38)
28 (70)
38 (95)
Poor prognosis
31
3 (10)
9 (29)
17 (55)
27 (87)
Unknow
Unkno n/not done
9
0 (0)
3 (33)
8 (89)
9 (100)
ISS disease stage, n (%)
Stage I
34
2 (6)
13 (38)
25 (74)
34 (100)
Stage II
31
2 (7)
10 (32)
21 (68)
28 (90)
Stage III
9
0 (0)
2 (22)
4 (44)
6 (67)
*Data cutoff date 29 April 2010, N=84. Four patients were non-evaluable for efficacy due to lack of post-baseline assessment at time of data cutoff
Normal/favorable as defined by t(11;14) or normal cytogenetics by metaphase analysis
Poor prognosis as defined by t(4;14), t(14;16), del17p, del13q, gain 1q21, or other abnormality by metaphase analysis
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Conclusions
Full-dose CRd is well tolerated even in patients previously treated with bortezomib,
thalidomide, and/or lenalidomide.
The O
eORR for
o full-
u dose CRd
Cd com
co bin
b ati
a on
o was
as 75%
5% in these
ese very heavil
ea y pr
p etrea
eated
ed
patients (74% prior bortezomib, 87% prior lenalidomide or thalidomide).
Carfilzomib and lenalidomide can be combined at full doses, and no dose-limiting
toxicities were identified (MTD not reached).
CRd combination yielded
yielded responses in the majority
majority of
of patients, and prolonged
administration is possible (1423 months) with no new unexpected toxicities.
The ASPIRE* trial will commence in 2010.
This randomized, international, multi-center, phase 3 trial (N=700) will investigate
CRd vs Rd in relapsed MM (13 prior therapies) with full-dose Len (25 mg) + low-
dose Dex (40 mg) ± full dose carfilzomib (20/27 mg/m2).
*CArfilzomib, Lenalidomide, and DexamethaSone versus Lenalidomide and Dexamethasone for the treatment of PatIents with RelapsEd Multiple
Myeloma (ASPIRE)
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Acknowledgements
· We would like to thank all the patients and families that have contributed to
and participated in this study.
· Special thanks
thanks to
to participating co
co-investigators, research
research nurses, study
study
coordinators, support staff, Weill Cornell University, MD Anderson Cancer
Center, Fred Hutchinson Cancer Research Center, H. Lee Moffitt Cancer
Center; Gabrail Cancer Center; UCSF Cancer
Cancer Center; Northwestern
Northwestern
University, and Celgene Corporation.
· This study was supported by Onyx Ph
Pharmaceutiticals, Inc, Emeryville, CA.
· Editorial assistance provided by Onyx Pharmaceuticals, Inc. and Nexus
Communications, North Wales, PA.
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References
1. Anderson KC, Jagannath S, Jakubowiak A, et al. Lenalidomide, bortezomib, and dexamethasone in
relapsed/refractory multiple myeloma (MM):
(MM): Encouraging
Encouraging outcomes and tolerability in
in a phase IIII
study. ASCO Meeting Abstracts.2009;27(15S):8536.
2. Niesvizky R, et al. Phase Ib Multicenter Dose Escalation Study of Carfilzomib Plus Lenalidomide
and Low Dose Dexamethasone (CRd) in
in Relapsed
Relapsed and Refractory Multiple Myeloma (MM)
(MM). Blood
(ASH Annual Meeting Abstracts). 2009;114:304.
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