Microsoft PowerPoint - Lacy-863-MC0789 ASH 2010 (4) [Compatibility Mode]

Pomalidomide plus low-dose dexamethasone
in myeloma refractory to both bortezomib and lenalidomide:
comparison of two dosing strategies in dual-refractory disease
MQ Lacy, SJ Mandrekar, MA Gertz, SR Hayman, K Detweiler Short, F Buadi,
A Dispenzieri, S Kumar, PR Greipp, JA Lust, SJ Russell, D Dingli,
S Zeldenrust, R Fonseca, PL Bergsagel, V Roy, AK Stewart,
K Laumann, JB Allred, C Reeder, SV Rajkumar, JR Mikhael, MD
Mayo Clinic
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center

Overall and Event-Free Survival in Patients Relapsing and Refractory
100%
to Bortezomib and Thalidomide/Lenalidomide
Median
Events / N in Months
Overall Survival
173 / 291 9 (7,11)
80%
Event-Free Survival
222 / 291
5 (4,6)
60%
40%
20%
0%
0
12
24
36
48
60
Months from Time Zero
Kumar S. EHA 2010

Background
· Pomalidomide (POM) is a distinct IMiD® immunomodulatory compound
derived from thalidomide
· Although structurally similar to thalidomide and lenalidomide, POM is
distinctively different clinical efficacy and side effects
O
O
H
N
O
N
O
NH2
Pomalidomide

Myeloma Pomalidomide Summary
Pom/Dex1
Pom/Dex2
Pom+/- dex3
1-3 reg
Len ref
MM-002
Pom dose
2 mg x 28d
2 mg x 28d
MTD = 4 mg 21
of 28
>PR
63%
32%
28%
>MR
82%*
47%
52%
Median 3 prior regimens
Median 4-6 prior regimens
1) Lacy JCO 2009, 27:5008-5014
2) Lacy Leukemia 2010 Nov; 24(11):1934-9
3) Richardson P, et al. Blood. 2009;114(22):126-127

Does starting with higher Pom dose
lead to better response rates?
4mg vs 2 mg
We opened two sequential phase II trials using
the Pom/dex regimen at differing doses to
study the efficacy of this regimen in patients
who have failed both lenalidomide and
bortezomib.

Comparison of 2 Phase II Trials of Pom/Dex
in Patients with Relapsed MM Refractory to
Both Lenalidomide and Bortezomib
2 sequential Phase II trials, 35 patients each,
· May 2009 - November 2009
· November 2009 - April 2010
· Responses were assessed according to
IWMG Uniform Response criteria.
· Goals:
· Assess response rate and duration of
remission in dual refractory MM
· Assess toxicity in this population

Treatment
Pomalidomide 2 or 4 mg daily continuous, days 1-28
28 day
cycle
Dexamethasone 40 mg days 1, 8, 15, 22
Aspirin 325 mg daily
After 2 cycles, if NR or if progression, pomalidomide dose could be
increased to 4 mg/day in the 2 mg cohort

Eligibility
· Previously treated, relapsed MM resistant/refractory to both
lenalidomide and bortezomib
· Refractory defined as progression on or within 60 days of
stopping RX
· > 1 prior regimen but no upper limit on prior regimens.
· Measurable disease (one of the following) :
· Serum M-spike 1.0 g/dL
· 24-hour Urine M-spike >200 mg
· Serum immunoglobulin FLC > 10 mg/dL with abnormal
ratio
· Measurable soft tissue plasmacytoma
· > 30% plasma cells in bone marrow
· ANC 1000/L and PLT 75,000/L
· Creatinine 2.5 mg/dL
· ECOG PS 0, 1, or 2.

Patient Characteristics
2mg
4mg
(N=35)
(N=35)
Age, median (range)
62.0 (39.0-77.0)
61.0 (45.0-77.0)
Gender
Male
27 (77.1%)
21 (60%)
Months from Diagnosis to On Study
57.0 (11.7-248.5)
71.6 (13.3-206.3)
median (range)
Beta2 Microglobulin, ug/mL
4.0 (1.9-9.6)
3.5 (2.2-13.4)
BM Labeling, %
2.6 (0.0-10.2)
1.8 (0.0-12.0)

Risk Assessment Markers
2mg
4mg
(N=35)
(N=35)
mSMART Risk
high
15 (56%)
21 (60%)
standard
12 (44%)
17 (40%)
FISH Results
17p-
5 (15%)
7 (23%)
t(11,14)
7 (21%)
6 (19%)
t(4;14)
3 (9%)
6 (19%)
t(14;16)
0 (0%)
2 (6%)
Cytogenetic Deletion 13
3 (9%)
9 (26%)
Plasma cell labeling index
> 3%
10 (29%)
9 (26%)

Prior Myeloma Treatment
Median 6, both cohorts
12
10
10
10
4mg Cohort
2mg Cohort
8
8
ts
7
6
6
atien 6
fP
.ooN
4
4
4
4
4
3
2
2
2
0
0
2
3
4
5
6
7
8+
2
3
4
5
6
7
8+
No. of Prior Regimens

Previous Regimens
2mg
4mg
(N=35)
(N=35)
Lenalidomide
35 (100%)
35 (100%)
Bortezomib
35 (100%)
35 (100%)
Thalidomide
22 (63%)
20 (57%)
Transplant
27(77%)
28 (80%)
auto
25
28
allo
2
0

Follow Up
2mg
4mg
(N=35)
(N=35)
Months of Follow-up median (range)
9.1 (1.0-15.7)
5.5 (1.2-9.4)
Progression Status
No Progression
11 (31.4%)
15 (42.9%)
Follow-up Status
Alive
25 (71.4%)
25 (71.4%)
Currently Receiving Treatment
6 (17%)
10 (29%)
Reason for Ending Treatment
Adverse Event
1 (3.4%)
4 (16%)
Disease Progression
24 (82.8%)
16 (64%)
Died on Study
2 (6.9%)
2(8%)
Other
2 (6.9%)
3 (12%)

Hematologic Toxicity,
regardless of attribution
2mg Cohort
Anemia
4mg Cohort
2mg Cohort
Thrombocytopenia
4mg Cohort
2mg Cohort
Neutropenia
4mg Cohort
Gr 1-2
2mg Cohort
Gr 3
Gr 4
Decreased Lymphocytes
4mg Cohort
0
5
10
15
20
25
30
35
40
Number of patients

Non-Hematologic Toxicity,
regardless of attribution
2mg Cohort
Fatigue
4mg Cohort
2mg Cohort
Peripheral Sensory
4mg Cohort
Neuropathy
2mg Cohort
Pneumonia
4mg Cohort
2mg Cohort
Hyperglycemia
4mg Cohort
2mg Cohort
Insomnia
4mg Cohort
2mg Cohort
Fracture
4mg Cohort
2mg Cohort
Back Pain
4mg Cohort
2mg Cohort
Hypercalcemia
4mg Cohort
Gr 1-2
Gr. 3
Atrial Fibrillation
2mg Cohort
Gr. 4
4mg Cohort
Febrile Neutropenia
2mg Cohort
Upper Resp. Infection
Renal Failure
2mg Cohort
0
5
10
15
20
25
30
35

Neuropathy
· 2mg:
· Seven (20%)
· 3 grade 1; 4 grade 2
· Five of the 7 patients had baseline
neuropathy; 5 had worsening grade during
treatment.
· 4mg:
· Ten (29%)
· 6 grade 1; 3 grade 2; 1 grade3
· Seven patients had baseline neuropathy; 6
had worsening grade during treatment.

Thromboembolic
· 2 mg:
· 2 DVT (6%)
· 1 MI (3%)
· 4 mg
· 1 DVT (3%)
· 1 MI (3%)

Response Rates
2 mg
4 Mg
N=35
N=35
Confirmed Response
9 (26%)
9 (26%)
Rate (>PR)
CR
01
VGPR
53
49%
40%
PR
45
MR
85
SD
13
12
PD
28
NE
31

Responses in High Risk
Risk group
2 mg
4 mg
>MR
>MR
High
47%
24%
Standard
42%
64%

Patient Outcomes
2mg (n=35)
4mg (n=35)
Confirmed Response Rate
26% (95%CI: 12-43)
26% (95%CI: 12-42)
Median time to response
1 mo (range: 0.8-3.9)
1.7mo (range: 0.9-6.4)
Duration of response*
12.2 mo (95%CI: 10.6-NA)
NA
Overall Survival*
NA
NA
-at 6 Months
78% (95%CI: 65-94)
69% (95%CI: 53-89)
CI: confidence interval; mo: month; NA: not attained
* Kaplan Meier

Progression Free Survival
100
2mg Cohort Median PFS: 6.5 mo (95%CI: 3.9-8.9)
e
4mg Cohort Median PFS: 3.3 mo (95%CI: 2.2-8.0)
e
80
Fr
ionsse 60
rogrP 40
ndae
2mg PFS
livA 20
%
4mg PFS
0
03
69
12
15
Time (months)

Patient 1, IgA M-spike
VRD
LD
VDT-PACE
TD
Pom/Dex
BZB
TD
SCT#2
SCT
Jan 03
Jan 07
Jan 11

Conclusions
· Pom/dex has significant activity in lenalidomide and
bortezomib refractory MM with response rates (>MR) 40-49%
and OS 69-78% at 6 months in this heavily pre-treated
resistant population.
· Responses are rapid with median time to response 1 - 2
month
· Toxicity is manageable at both dose levels and consists
primarily of neutropenia, but rate is higher at the 4 mg dose
· ORR is similar with both dose levels
· ORR is similar in standard and high risk patients
· Further studies ongoing to see if starting dose 4 mg for 21
of 28 days produces same response rates with less toxicity

Thanks for inviting me
Myeloma group at Mayo
·
Rochester
·Arizona
·
V. Rajkumar, MD
·Leif Bergsagel, MD
·
Francis Buadi, MD
·Rafael Fonseca, MD
·
David Dingli, MD
·Joseph Mikhael, MD
·
A Dispenzieri, MD
·Craig Reeder, MD
·
Morie Gertz, MD
·Keith Stewart, MD
·
Phil Greipp, MD
·Jacksonville
·
Suzanne Hayman, MD
·Vivek Roy, MD
·
Shaji Kumar, MD
·
Robert Kyle, MD
Special thanks to:
·
Nelson Leung, MD
Jake Allred, Kristina Laumann,
·
John Lust, MD
Melanie Thompson, Paula Orr, Lori
·
Greg Nowakowski, MD
Rhodes, Kris Liebfried, Nick Pirooz,
·
Steve Russell, MD
Rachel Hagerty, Michelle Maharaj
·
Tom Witzig, MD
·
S Zeldenrust, MD
·
Kristen Detweiler Short CNP
·
S Mandrekar, PhD