Bortezomib, dexamethasone, cyclophosphamide,
lenalidomide (VDCR) has high efficacy in frontline
multiple myeloma: Phase I results from the phase
I/II multi-center EVOLUTION study
Shaji Kumar,1 Ian Flinn,2 Stephen J. Noga,3 Parameswaran Hari,4 Robert Rifkin,5
Nli C l
d 6 Mi h Bhd i 7 Jff
W lf 8 Ci i
G
9
Natalie Callander,6 Manish Bhandari,7 Jeffrey Wolf,8 Cristina Gasparetto,
Amrita Krishnan,10 Daren Grosman,11 Jonathan Glass,12 Entezam Asim Sahovic,13
Hongliang Shi,14 Iain J. Webb,14 Paul Richardson,15 and S. Vincent Rajkumar1
1MC
Mayo li
Clinic, Rochester, MN 2
MN; Sarah Cannon Research Institute, Nashville, TN 3
TN; Sinai Hospital of Balti
ltimore,
Baltimore, MD; 4Medical College of Wisconsin, Milwaukee, WI; 5Rocky Mountain Cancer Centers, Denver, CO;
6University of Wisconsin Comprehensive Cancer Center, Madison, WI; 7The Christ Hospital, Cincinnati, OH;
8University of California Medical Center, San Francisco, CA; 9Duke University, Durham, NC; 10City of Hope,
Duarte, CA; 11
,; Memorial Healthcare Cancer Center, Holly
,ywood, FL; 12
; Louisiana State University Health Sciences
Center, Shreveport, LA; 13Western Pennsylvania Hospital, Pittsburgh, PA; 14Millennium Pharmaceuticals, Inc.,
Cambridge, MA; 15Dana-Farber Cancer Center, Boston, MA
Introduction
Combinations of bortezomib (VELCADE®, Vc),
dexamethasone (Dex), cyclophosphamide (Cy)
(Cy) and/or
lenalidomide (REVLIMID®, Rev) have substantial activity
in untreated multiple myeloma (MM)
The combination of all 4 agents (VDCR) may result in
even deeper responses in this patient population
The randomized Phase I/II EVOLUTION trial is
investigating VDR
VDR, VDC, and VDCR in both transplant
transplant
eligible and ineligible patients with previously untreated
MM
Objectives
Primary objectives:
Phase I: Determine the maximum tolerated dose
(MTD) f
o Cy in combi
bi t
na ition with
ith VDR
Phase II:
II Determine
Determine the combined
combined rate of complete
response (CR) plus very good partial response
(VGPR) for the VDR, VDC, and VDCR
bi
com
ti
na ons
Objectives
Secondary objectives:
Safety and tolerability of the combinations
Overall response rate (CR+VGPR+PR), stringent CR
(sCR) rate, and CR/ near-
near CR (nCR) rate
Time to response and duration of response (DOR)
Time to disease prog
pgression (TTP
(
),
) prog
pgression-free
survival (PFS), and overall survival (OS)
Feasibility of minimal residual disease (MRD) analysis by
flow cytometry
Exploratory objectives:
Frequency of flow cytometric remission and DNA-based
analysis of MRD
Patients
Inclusion criteria:
Previously untreated MM with measurable disease
Karnofsky Performance Status (KPS) 50%
Exclusion criteria:
Peripheral neuropathy Grade 2 (NCI CTCAE v3.0)
Renal insufficiency (serum creatinine >2.5 mg/dl)
ANC <1,000 cells/mm3
Platelets <70,000 cells/mm3
AST/ALT >2 x ULN
T t
o l
a bili
bilirubin 3
> x ULN
ULN
Phase I: Study design
Dose escalation of Cy: up to eight 21-day cycles
1
4
8
11
14 15
21
Vc
Vc
Vc
Vc
Dex
Dex
Dex
Cy
Cy
Rev
Maintenance therapy: up to four 42-day cycles
1
8
15
22
42
Vc
Vc
Vc
Vc
Eligible patients could undergo ASCT after 4 cycles
Ci
Concom tit t
an
d
me i
di t
ca itions:
Anticoagulants required: prophylactic aspirin (325 mg/day), or warfarin, or low molecular weight
heparin at the discretion of the investigator
Prophylactic antibiotics for Pneumocystis and acyclovir recommended
Phase I: Dosing and dose escalation
Dose level
Cy dose
1
100 mg/m2
Dose escalation of Cy PO plus:
2
200 mg/m2
Vc
1.3 mg/m2 IV
3
300 mg/m2
Dex 40 mg PO
4
400 mg/m2
Rev 15 mg PO
5
500 mg/m2
3+3 dose escalation design, 36 patients per dose level
Dose escalation based on dose-limiting toxicity (DLTs):
Platelet count <25,000/mm3 lasting >7 days or any platelet count <10,000/mm3
Grade 4 neutropenia lasting
lasting >7 days
Grade 3 non-hematologic toxicity related to Cy (except inadequately treated
nausea, vomiting, and diarrhea), or any toxicity resulting in >2 week treatment
delay
MTD was
was defined as the highest
highest dose of
of Cy
Cy in
in combination
combination with VDR
VDR
resulting in 1 DLT in 6 patients
Patients replaced if all drug doses not received in cycle 1
Assessments
Response assessed every other cycle using IMWG
Uniform Response Criteria with the addition of nCR
Assessments of serum and urine protein electrophoresis with
if
immuno ifi t
xa ition, and serum free lili h
g t
ht ch i
a ns th
th
h
roug
t
ou st d
u y
A central laboratory was used for M-protein and free-
light chain quantification, immunofixation
immunofixation, and MRD
Toxicities graded by NCI CTCAE v3.0
Cytogenetic data collected for all patients
Baseline characteristics
characteristics
Characteristic
N=25
Median age (range), years
years
61 (4979)
Male, n (%)
13 (52)
Myeloma type, n (%)
IgG / IgA
gg
15 (60)
() / 5 (20)
()
light-chain / light-chain
3 (12) / 2 (8)
ISS stage at diagnosis, n (%)
I / ll / lll
12 (48) / 12 (48) / 1 (4)
KPS 80%, n (%)
11 (44)
Cytogenetic abnormalities
del 13 (standard cytogenetics)
3 (12)
-13q14
7 (28)
t(4;14)
3 (12)
-17p13
5 (20)
Other
9 (36)
High risk
9 (36)
Eligible for ASCT at baseline, n (%)
22 (88)
Treatment assignment
Patients
Patients
Patients
Dose level
Enrolled
Treated
undergoing
entering
remaining on
ASCT
maintenance
treatment
1 (Cy 100 mg/m2)3
3
3
0
0
2 (Cy 200 mg/m2)4
4
1
2
0
3 (Cy 300 mg/m2)4
4
1
1
0
4 (Cy
(Cy 400 mg/m2
mg/m )
8
7*
7
5
2
1
5 (Cy 500 mg/m2)7
7
0
3
4
Total
26
25
10
8
5
*One patient excluded (did not receive study treatment due to a heart problem)
Patients who did not experience a DLT were replaced if they did not receive all
doses of each drug in cycle 1
MTD and
and DLTs
MTD not reached
One DLT at dose level 4 (Cy 400 mg/m2)
Grade 4 febrile
febrile neutropenia
One DLT at dose level 5 (Cy 500 mg/m2)
Grade 3 herpes zoster virus reactivation
reactivation despite antiviral
prophylaxis
Recommended Phase II dose of Cy was 500 mg/m2
Recommended Phase II dose of Cy was 500 mg/m
Most common non-hematologic
treatment emergent
-
AEs
AEs
N=25
AE
All Grades
Grades, n (%) Grade 3, n(
n %)
(%)
Peripheral neuropathy NEC
17 (68)
4* (16)
Constipation
p
17 (68)
()
0
Fatigue
16 (64)
1 (4)
Nausea
13 (52)
1 (4)
Diarrhea
10 (40)
1 (4)
Dizziness (excluding vertigo)
9 (36)
0
Vom
Vo i
m ting
n
8 (32)
(32)
1(
1 4)
(4)
Insomnia
8 (32)
0
* One patient had transient grade 3 sensory neuropathy and one patient had autonomic neuropathy
10 patients (40%) had 1 SAE
No deep-vein thrombosis/pulmonary embolism reported
Treatment-emergent hematologic
toxicities
N=25
Hematologic toxicity
toxicity
Grade 1/2
1/2
Grade 3
Grade 4
Anemia, n (%)
21 (84)
2 (8)
1 (4)
Nt
Neutropenia, n (%)
(%)
15 (60)
5 (20)
(20)
1(
1 4)
(4)
Thrombocytopenia, n (%)
18 (72)
0
3 (12)
No cumulative hematologic toxicity during
induction
Change in platelets for patients treated at dose level 5
300
250
eline
bas 200
efromg 150
g
chan 100
ercentP 50
0
Baseline
Cycle 2
Cycle 3
Cycle 4
Cycle 5
Cycle 6
Cycle 7
Cycle 8
day 1
day 1
day 1
day 1
day 1
day 1
day 1
Visit
Best confirmed response to
VDCR
Response rates to date (13 Feb 09) in 25 evaluable patients:
Response
n (%)
sCR
5 (20)
CR
9 (36)
ORR 96%
VGPR
16 (64)
PR
24 (96)
Median treatment duration: 6 cycles (range 3
3 12)
Response by
by cohort
cohort
Best confirmed response, N=25
Dose level
Patients
CR (sCR)
VGPR (nCR)
PR
1 (Cy 100 mg/m2)3
2 (2)
1
-
2 (Cy 200 mg/m2)4
1 (1)
-
2
3 (Cy 300 mg/m2)
4
2 (1)
2 (1)
-
4 (Cy
(Cy 400 mg/m2
mg/m )
7
2
2
3
5 (Cy 500 mg/m2)7
2 (1)
2
3
Total
Total patients
25
9(
9 5)
(5)
7(
7 1)
(1)
8
Median serum M-protein change by
cycle during induction
induction
Cohort
Cy 100
Cy 200
Cy 300
Cy 400
Cy 500
Oe
Ov rall
erall
110
100
aseline
90
b
80
70
from
60
ange
50
hc 40
30
percent
20
n
10
0
Media 10
Baseline
Cycle
Cy
3, day 1
Cycle
Cy
5, day 1
Cycle
Cy
7, day 1
Cycle
Cy
9, day 1
Phase I: Other endpoints
endpoints
Eligible patients
gp
could discontinue study therapy
py to
undergo ASCT after 4 cycles
12 patients have undergone stem cell mobilization
· Median CD34+ yield: 5.85 x 106/kg
· 2 patients required a second cycle of stem cell
mobilization
10 patients have discontinued treatment to undergo
ASCT
Phase I: Analysis of
of MRD
MRD
MRD is standard practice in other hematologic malignancies but is
still consid
d
ere investi ti
ga
l
ona in MM
A recent prospective study in MM patients who had undergone
HDT-ASCT showed that flow cytometry MRD status was
predictive of both PFS and OS
Data suggest that MRD status may be a better predictor of
outcome than immunofixation status
This study examined the feasibility of flow cytometry MRD analysis
within a multi-center clinical trial
Screen and suspected-CR marrow aspirates
aspirates sent to central lab
lab
(Mayo Rochester) for multi-parameter flow cytometry
92% (23 of 25) of baseline samples collected and successfully
analysed in
in Phase
Phase 1 cohort
Example of flow cytometry MRD negative sample from
patient
p
that had nCR
Sample at screening
Sample at nCR
59 1%
.
99.8%
kappa
kappa
0.2%
40.9%
lambda
lambda
· Kappa malignant clone
· Kappa/lambda ratio normalized
· 3.1% of total events
· Malignant clone < 0.01% of events
Phase I: Conclusions
Phase I: MTD was not reached
Rd
Recommended Ph
Phase IIII dose f
o Cy in
b
com i
bi
i
nat on
with VDR is 500 mg/m2, the highest dose level
tested
Confirmed responses show that VDCR is highly active
and well tolerated in patients with newly diagnosed MM
96% PR including 64% VGPR
36% CR including 20% sCR
No cumulative hematologic toxicities
No thrombotic events
Patients achieving high
gg response
p
rates in this study
included high-risk patients
Phase II: Study design
Enrollment to Phase II portion of the study is ongoing
VDR
(Vc, Dex, Rev)
Up to eight 21-day cycles
IONTAZ
VDCR
Z
Vc
(Vc, Dex, Cy, Rev)
Up to four 42-day cycles
Up to eight 21-day cycles
ANDOMI
VDC
R
(Vc, Dex, Cy)
Up to eight 21-day cycles
Induction
Maintenance
Eligible patients could undergo ASCT after 4 cycles
Phase II: Dosing and enrollment
enrollment
Vc 1.3 mg/m2
Dex 40 mg
Rev
Cy 500 mg/m2
Induction
Days 1, 4, 8, 11 Days 1, 8, 15 Days 114
Days 1, 8
VDR
x
x
x (25 mg)
VDCR
x
x
x (15 mg)
(g)
x
VDC
x
x
x
Maintenance
Vc 1.3 mg/m2 (days 1, 8, 15, 22)
Vc, Dex and Cy doses and schedules identical in all arms
Target enrollll
t
men is 39
39
lb
evalua l
ble
t
pa it
tients in each arm
87 patients enrolled in Phase II to date
Acknowledgements
All the
the patients who participated in the study
study
All the investigators, nursing staff and
research support staff
Research team at Millennium