Novel Three- and Four-Drug Combinations of
Bortezomib, Dexamethasone,
Cyclophosphamide, and Lenalidomide, for
Newly Diagnosed Multiple Myeloma: Results
from the Multi-Center, Randomized, Phase 2
EVOLUTION Study
Shaji Kumar,1 Ian Flinn,2 Parameswaran Hari,3 Natalie Callander,4
Stephen J Noga,5 A Keith Stewart,6 Jonathan Glass,7 Noopur Raje,8
Robert Rifkin,9 Hongliang Shi,10 Iain J Webb,10
Paul G Richardson,11 S Vincent Rajkumar1
1Division of Hematology, Mayo Clinic, Rochester, MN; 2Sarah Cannon Research Institute, Nashville, TN;
3Medical College of Wisconsin, Milwaukee, WI; 4University of Wisconsin Comprehensive Cancer Center,
Madison, WI; 5Sinai Hospital of Baltimore, Baltimore, MD; 6Mayo Clinic Arizona, Scottsdale, AZ;
7Louisiana State University Health Sciences Center, Shreveport, LA; 8Massachusetts General Hospital,
Boston, MA; 9Rocky Mountain Cancer Centers, Denver, CO; 10Millennium Pharmaceuticals, Inc.,
Cambridge, MA; 11Dana-Farber Cancer Institute, Boston, MA

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Introduction
Three-drug regimens adding bortezomib (VELCADE®, V) and
dexamethasone (D), to either cyclophosphamide (C), or
lenalidomide (Revlimid®, R) have shown significant activity in
untreated multiple myeloma (MM)1­3
Combining these agents in a novel 4-drug regimen, VDCR, may
result in even greater activity, with improved depth and duration
of response
The randomized Phase 1/2 multi-center EVOLUTION trial
designed to investigate VDCR, VDR, and VDC in patients with
previously untreated MM
1.
Richardson PG et al. Clin Lymphoma Myeloma 2009;9:S38 (abstract)
2.
Reeder et al, Leukemia, 2008
3.
Kumar S et al. Blood 2008;112:40a (abstract).

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Phase I
In the phase 1 dose-escalation portion,1 the
MTD of cyclophosphamide in combination
with VDR was tested
­ Recommended phase 2 dose of C was 500 mg/m2,
the highest dose tested
VDCR was highly active and generally well
tolerated
1. Kumar S et al. Clin Lymphoma Myeloma 2009;9:S43­44 (abstract).

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Phase 2 objectives
Primary objective
­ Determine the combined rate of complete response (CR) plus
very good partial response (VGPR) for VDCR, VDR, and VDC
Secondary objectives include:
­ Safety and tolerability
­ Overall response rate (CR+VGPR+partial response [PR]),
stringent CR (sCR) rate, and CR/near-CR (nCR) rate
­ Time to response and duration of response
­ Feasibility of minimal residual disease (MRD) analysis by flow
cytometry

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Phase 2 treatment schedule
Induction
V 1.3 mg/m2
D 40 mg
C 500 mg/m2
R
x 8 3-wk cycles
days 1, 4, 8, 11
days 1, 8, 15
days 1, 8
days 1­14
VDCR
x
x
x
x (15 mg)
VDR
x
x
x (25 mg)
VDC
x
x
x
VDC-mod
x
x
x (+ day 15)
Maintenance
x 4 6-wk cycles
V 1.3 mg/m2 (days 1, 8, 15, 22)
Patients received prophylactic antibiotics, acyclovir, transfusion
support, and anticoagulants as required

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Patients
Previously untreated MM with measurable disease
and Karnofsky Performance Status (KPS) 50%
Patients included regardless of eligibility for ASCT
­ Stem cell mobilization allowed any time after cycle 2 and
ASCT any time after cycle 4
Exclusion criteria included:
­ ANC <1 x 109 cells/L
­ Platelets <70 x 109 cells/L
­ Renal insufficiency (serum creatinine >2.5 mg/dl)
­ AST/ALT >2 x ULN
­ Total bilirubin >3 x ULN
­ Peripheral neuropathy Grade 2 (NCI CTCAE v3.0)

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Assessments
Response assessed every other cycle by IMWG
Uniform Response Criteria1 plus nCR2
­ Central laboratory used for serum and urine M-protein and
free-light chain quantification, immunofixation, and MRD
Responses determined using an automated
computer algorithm to assure consistent, rigorous
assessment of response across all patients
Toxicities graded by NCI CTCAE v3.0
Data cut-off: December 1, 2009
­ Median duration of follow-up: 7.3 months
1. Durie BG et al. Leukemia 2006;20:1467­73.
2. Richardson PG et al. N Engl J Med 2003;348:2609­17.

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Baseline characteristics
VDCR
VDR
VDC
VDC-mod
Characteristic
(N=48)
(N=42)
(N=33)
(N=15)
Median age, years
61.5
60
62
63
(range)
(41­81)
(42­85)
(40­75)
(46­72)
Myeloma type*, %
IgG / IgA
69 / 19
64 / 21
67 / 21
47 / 13
Light chain/ Other
12 / 0
14 / 0
9 / 3
33 / 7
ISS stage, %
I
33
38
36
47
II
46
43
30
40
III
21
19
33
13
KPS 80%, %
31
38
30
47
Eligible for ASCT, %
96
98
94
80
*Myeloma type unknown in 6 patients in the VDCR arm; these patients not included in response-
evaluable population

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Cytogenetics / FISH
VDCR
VDR
VDC
VDC-mod
Abnormality, %
(N=48)
(N=42)
(N=32)
(N=15)
del 13 / -13q14
55
4
7
(metaphase cytogenetics)
t(4;14)
6
2
6
7
t(14;16)
0
0
0
0
-17p13
6
10
16
7
Total high risk
15
17
22
20

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Dose intensity of each agent, by treatment arm
(% maximum planned dose; cycles 1­8)
VD
C
R
80
(%)
maximum
60
1­8)
versus
(cycle
40
intensity
dose
20
dose
planned
0
Median
VDCR
VDR
VDC
VDC-mod
Median cycles
4
6
6
5
(range)
(1-12)
(1-12)
(3-12)
(2-8)

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Best unconfirmed response (algorithm)
to date
VDCR
VDR
VDC
VDC-mod
Response, %
(N=41)
(N=42) (N=32)
(N=15)
CR
20
24
22
40
sCR
2
10
3
0
VGPR
39
31
25
20
nCR
12
14
3
0
VGPR (sCR + CR + nCR + VGPR)
59
55
47
60
nCR (sCR+CR+nCR)
32
38
25
40
PR
93
93
91
93
Stable disease
7
5
6
7
Progressive disease
0
2
3
0
Patients categorized as VGPR include those who have no measurable M-protein but have not yet had bone marrow
assessments to confirm CR/nCR status

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Stem cell mobilization and ASCT
VDCR
VDR
VDC
VDC-mod
Patients undergoing stem cell
13
18
13
2
mobilization with data available, n
Median CD34+ cells yield, x
8.50
6.05
7.70
7.30
106/kg (range)
(0.3­11.7)
(0­26.0)
(3.1­17.6)
(4.5­10.1)
Number of patients with <2.5 x
106/kg CD34+ cells during first
2 (15%)
3 (17%)
0
0
attempt, n (%)
Patients undergoing ASCT with
11
13
8
0
data available, n
Only 2 patients required a second mobilization cycle, both on VDCR arm

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Safety profile
AE, %
VDCR
VDR
VDC
VDC-mod
(N=48)
(N=42)
(N=33)
(N=15)
At least one AE
98
100
100
100
At least one grade 3 AE
75
76
76
73
At least one serious AE
40
40
21
47
AE resulting in
17
17
12
7
discontinuation
On-study deaths
2*
0
0
0
*n=1, due to renal failure considered treatment-related

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Most common non-hematologic AEs
Grade 1/2 3/4
VDCR
VDR
70
VDC
VDC-mod
60
50
(%)
40
30
Incidence
20
10
0
Fatigue
Nausea
PN NEC
Constipation
Diarrhea
PN NEC, peripheral neuropathy not elsewhere classified: high-level term including peripheral sensory neuropathy,
peripheral motor neuropathy, and peripheral neuropathy not otherwise specified

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Hematologic toxicity
Grade 1/2
3
4
VDCR
VDR
VDC
100
VDC-mod
80
(%)
60
40
Incidence
20
0
Anemia
Neutropenia
Thrombocytopenia
Neutropenia data missing for 2 patients in each of the VDCR and VDR arms
Febrile neutropenia reported in 3 (6%), 1 (2%), 2 (6%), and 0 patients in the VDCR, VDR, VDC, and VDC-mod arms,
respectively (all grade 3/4 except 1 in VDCR arm)

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Detection of minimal residual disease
Flow cytometry based assessment on marrow
aspirates
Aspirates collected at screening and at time of
suspected CR
Samples collected in fixative, shipped to central lab
for analysis in <48 hr
Multi-color flow cytometry using antibodies to CD38,
CD45, CD138, CD19, CD56, kappa and lambda

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MRD assay feasibility in a multicenter study
Patients enrolled on
Enrolled pts that submitted Percentage
study
screening samples
159
154
97%
# post-screen marrows
# post-screen marrows
Percentage
on study
submitted for MRD
84
62
74%
IF negative that submitted
IF negative patients
Percentage
`unscheduled' sample
49
27
55%

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Conclusions: Efficacy
VDCR, VDR, and VDC (initial and modified) are highly
active and generally well-tolerated regimens in
previously untreated MM
­ Best response rates to date, including rates of CR+VGPR, did
not appear higher in VDCR than VDR arm
­ A number of patients in each arm remain on treatment, and
several pts require marrow assessments to evaluate nCR/CR;
so response rates are likely to improve with time, particularly
in the VDC-mod arm
Early responses in the VDC-mod arm, especially
CRs and VGPRs are encouraging
Long term follow up required to assess the MRD status
and durability of response

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Conclusion: Safety
Rates of the most common non-hematologic AEs appear
generally similar between treatment arms
Overall rates of most hematologic AEs also appear
similar between arms
­ Grade 3/4 neutropenia appeared more frequent with C-
containing regimens
Overall rate of serious AEs appeared to be lower in the
initial VDC arm

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Participating Centers
D Avigan, Beth Israel Deaconess Hospital
S Kumar, Mayo Clinic Rochester
M Bar, Hematology Oncology PC
S Noga, Sinai Hospital Baltimore
E Bengston, Dartmouth Hitchcock Medical
K Osman, Mount Sinai School of Medicine
Center
M Bhandari, The Christ Hospital Research
L Popplewell / A Krishnan, City of Hope
N Callandar, University of Wisconsin
N Raje, Mass General Hospital
J Catlett, Med Star Institute
P Richardson, DFCI
I Flinn, Sarah Cannon Research Institute
R Rifkin, Rocky Mountain Cancer Center
J Glass, Louisiana State University Health
E Sahovic, Western Pennsylvania Hospital
Sciences Center
C Gasparetto, Duke University
S Smith, Loyola University Chicago
D Grosman, Memorial Cancer Institute
K Stewart, Mayo Clinic Arizona
N Haideri, University of Kansas Medical
J Wolf, UCSF
Center
P Hari, Medical College of Wisconsin

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