New IMiD
IMiD Therapy
Martha Q Lacy, MD
Mayo Clinic
Scottsdale,
Scottsdale Arizona
Rochester,
Rochester Minnesota
Jacksonville,
Jacksonville Florida
Mayo Clinic College of Medicine
Mayo Clinic Comprehensive Cancer Center
IMiDs
Thalidomide Lenalidomide
+ dex
+ dex
Newly
diagnosed
60-75%
70-90%
MM
Relapsed MM
45-55%
60%
Molecular Structure of Thalidomide,
Lenalidomide and Pomalidomide
O
O
O
O
H
O
O
H
N
N
N
N
O
N
O
N
O
O
NH
O
2
NH2
Lenalidomide
Thalidomide
Pomalidomide
100-200 mg/d
15-25 mg/d
1-4 mg/d
Myelosuppression
Neuropathy
Skin rash
Constipation
DVT
Sedation
DVT
Structurally similar, but functionally different both qualitatively
and quantitatively
In vitro Pharmacology
Thalidomide Pomalidomide
Anti-angiogenic activity
(human explant model)
++++
++++
At
An i
ti-if
in l
flammatory
activity against
+
+++++
monocytes
T cell/NK cell
costimulation
+
+++++
T regulatory cell
inhibition
-
+++++
inhibition
Antibody-dependent
Cellular Cytotoxicity
-
++++
(ADCC)
List AF, et al. Semin Oncol. 2005;32 Suppl 5:S31-5.
+ = potency factor of 10
Teo ST, et al. Drug Discovery Today. 2005;10:107-14.
Phase I trials
trials for Pomalidomide
Pomalidomide
N
Dose
MTD
ORR
Schey
24
1-10
24
2mg
54%
mg
2 mg
1-10*
Streetly
20
mg
5 mg
QOD
QOD
50%
Q
* Nine patients also received dexamethasone
Phase II Trial of Pomalidomide +
Dexamethasone in Relapsed MM
St d
u y Goals:
· To assess the response rate and duration
f
o remission i
w th
ith Pom/d
/dex in patients with
ith
relapsed or refractory myeloma.
· Tt
To assess h
the toxicit
ity, overallll survival and
progression free survival of Pom/dex in
this patient population.
Study design
· Phase II t iral, 60
60
t
pa i
tients
· A confirmed response is defined to
be a CR, PR or VGPR as assessed by
the International Myeloma Working
Group Uniform Response criteria.
Eligibility
· Previously treated, relapsed multiple myeloma.
· > 1 and < 3 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 FLC
ratio
· Measurable soft tissue plasmacytoma, not previously
radiated
· > 30% plasma cells in bone marrow
· Age 18 years.
· ANC 1000/L and PLT 75,000/L
· Creatinine 2 5
. mg/dL
mg/dL
· ECOG PS 0, 1, or 2.
Patient Characteristics
Characteristics
N=60
Age, median
median (range)
(range)
65.5 (35-
(35 88)
Gender, male
36 (60%)
ISS Stage
Stage I
12 (28%)
Stage II
17 (40%)
Stage III
14 (32%)
-2 M
3.5 (1.5-14.0)
PC
PC Lbl
Labe iling I d
n ex, %
07
0.7 (0
(0.0-96
9. )
6)
Baseline neuropathy
Grade 1
24 (40%)
Grade 2
3 (5%)
Prior treatments
Total
(N=60)
Diagnosis to On Study,
median (months, range)
44 (9.1-192.5)
No. Prior Chemotherapies
1
17 (28%)
2
22 (37%)
3
21 (35%)
Transplant, yes
39 (65%)
Previous IMiD use, yes
36 (60%)
- Lenalidomide
21 (35%)
- Thalidomide
28 (47%)
Bortezomib
20 (33%)
Study treatment
· Starting Dose:
· Pomalidomide - 2mg p.o. daily days 1-
28
· Dexamethasone - 40mg p.o. days 1, 8,
15 & 22
· Aspirin - 325mg p.o. days 1-28
· G-
G CSF was
was not permitted
· Patients allowed to increase to 4 mg/day if
no grade 3/4
3/4 toxicity and if
if NR
NR or
or
progressing
Toxicity
Thrombocytopenia
35% > grade 3
Neutropenia
Anemia
5% gr
g ade
ade 3
DVT
2%
Neuro-Sensory
37%
Gr.1
Pneumonia
Gr.2
Constipation
Gr.3
Diarrhea
Gr.4
Nausea
Gr.5
Anorexia
Fatigue
17% grade 3
0
02
0.2
04
0.4
06
0.6
08
0.8
1
Percent of Patients
Neutropenia
· O
l
vera lll, 21
21 (35%)
(35%)
t
pa i
tients experience
grade 3/4 neutropenia.
· All patients first experienced the
neutropenia in cycle 1-3.
· No new patients experienced grade
3/4 neutropenia
neutropenia in
in cycle 4 or later.
Tr
T eatment
r
Administration
No. of Cycles Administered
399
Pomalidomide
# Patients
Patients with
with Reductions
Reductions
11
11 (18%)
Neutropenia
Neuropathy
Dexamethasone
# Patients with Reductions
24 (40%)
Edema
Hyperglycemia
Confusion/Mood Alteration
Muscle Weakness
W
Measurable parameter
parameter as
maximum % change from baseline
Waterfall Plot
200
At least 25%Increase
150
e
100
aselinBm
Fro
50
angehC
0
entrc
Pe
-50
At least 25%Decrease
-100
60 Patients
Best Responses
Confirmed
IMWG* response
it i
Response
criter a
N= 60
CR
3 (5%)
CR +VGPR
VGPR
17 (28%)
33%
Median
PR
18 (30%)
follow-up
ORR 63%
7 months
SD
18 (30%)
PD
3(
3 5%)
(5%)
NE
1 (2%)
*Kyle and Rajkumar Leukemia. January 2009
Dose Escalation
· E
l
sca ti
a on to 4 mg/day permitted if
NR or if progressing if no grade 3/4
toxicity
· 4 patients escalated the dose to 4
mg/d
· 1 VGPR
· 2 SD
· 1 Prog
Responses in p
ppatients treated
with other novel agents
Previously
Refractory >PR in
treated
refractory
patients
Bortezomib
20 (33%)
10
6 (60%)
(60%)
Lenalidomide
21 (35%)
20
8 (40%)
(40%)
Thalidomide
28 (47%)
16
6 (37%)
Refractory defined as progressing on therapy regardless of previous response
Patient 1, Lenalidomide refractory
refractory
69 year old male
IgG M-spike 3.0;
Progression on Len/dex; started
started Len/dex
Pom/dex; M-spike 2 5 labeling
started Len/dex
Pom/dex; M spike 2.5,
index was 2.2%.
PR; M-spike 1.5
M-spike 0.7
Patients refractory to
to both
Bortezomib and Lenalidomide
· 5t
5 pa i
tients
f
re
t
rac ory to both
th B t
or ez
and lenalidomide
· 2S
2 D
SD
· 3 > PR
Patient 2,
2, 67
67 year old female
female
M-spike 3.5
CRD started
Bortezomib
M-spike
p
2.6
Pom/dex, M-spike 2.9
Bortezomib
Relapsing on
Melphalan,
CRD
Pred
Follow-up
Continuation of treatment
Total
Currently Receiving Treatment
34 (57%)
Reason for Ending Treatment
Disease Progression
19 (73%)
Died on Study
2 (8%)
Other - MD Discretion
5 (19%)
Deaths (2 on-study; 2 off)
4
Disease Progression
2
Unrelated (valvular heart disease)
1
Neutropenic sepsis
1
Overall and Progression
Progression free
free
Survival
OS
PFS
100
80
60
11.6 mo
ccessuS% 40
20
0
02
46
8
10
12
14
Tim e (m onths)
Other Novel
Novel Agents for Relapsed
Relapsed
Myeloma
Regimen
Dex
DVT
ORR
dose/cycle
Dimopoulos
Thal/dex
480 mg
7%
55%
Anagnostopoulos
Thal/dex
480 mg
8%
47%
Weber
Len/dex
480 mg
14%
61%
Dimopoulos
Len/dex
480 mg
11%
60%
Palumbo
VMPT
-
0
67%
Current Study
Pom/Dex
160 mg
2%
63%
Conclusions
· The combination of Pom/dex is hi
highl
hly
active in relapsed/refractory MM.
· Ti
Toxicit
ity in our trial has been manageabl
ble
and consists primarily of
myelosuppression with neutropenia.
· Future directions include phase II trials
· Pom/dex for
for lenalidomide- and
bortezomib ­refractory patients
· trials using combination
combination therapy
Thanks for
for inviting me
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
Dispenzieri, MD
·Craig
·
Reeder
Reeder, MD
·
Morie Gertz, MD
·Keith Stewart, MD
·
Phil Greipp, MD
·Jacksonville
·
Suzanne Hayman, MD
·Vivek Roy, MD
·
Shaji Kumar
Kumar, MD
·
Robert Kyle, MD
·
Special thanks to:
Nelson Leung, MD
·
·Jake Allred, Kristina Laumann,
John Lust, MD
Melanie Thompson, Paula Orr
·
Greg Nowakowski, MD
MD
·
Steve Russell, MD
·Celgene
·
Tom Witzig, MD
·
S Zeldenrust, MD
·Our patients
·
Kristen Detweiler Short NP
·
S Mandrekar, PhD