Management of Myeloma at Relapse
A. Keith Stewart
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Figure
100
90
80
70
60
ORR
50
VGPR
CR/nCR
40
30
20
10
0
VAD
TD
RD
PAD
VTD
CVD
RVD
CVRD VTD and
Tandem
Induction Regim
Approach to Treatment at Relapse
Must Be Individualized
Tempo of disease
Previous toxicities and response
Time of previous remission
Pragmatic concerns (access,
geography, age, preference)
To sequence or to combine existing
approved drugs ?
Increasing Response Rates With Combination Therapy
Treatment at Relapse
In general combinations outperform sequencing in
randomized trials (faster response, higher overall
response rates, improved progression free and /or
overall survival)
MPV versus MP
MPT versus MP
RD versus D
MPR versus MP
VTD versus TD
Conclusions
1.
In general combinations outperform sequencing in
randomized trials (faster response, higher overall
response rates, improved survival)
2.
In high risk disease multiple genomic clones
In rapidly relapsing, symptomatic or high genetic risk
patients favor combination therapy.
In indolent relapse, elderly and particularly in low
genetic risk disease more conservative therapy
sequencing otherwise reasonable.
What about New Drugs ?
180 drugs reported in preclinical
studies
~ 30 - 40 in trials
3 with known significant single
agent activity
Bendamustine
The efficacy and toxicity of bendamustine in
recurrent multiple myeloma after high-dose
chemotherapy.
S. Knop et al. Hematologica 9:1287, 2005
Patients (n = 31) relapse post transplant
Dose Escalation to MTD 100mg/m2 days 1, 2
of 28 day cycle
Bendamustine in Relapsed
Myeloma
ORR 55%
PR rate 12 of 31 (38%)
Median Duration of response 8
months
Toxicities mild nausea, emesis,
neutropenia, no neuropathy
Molecular Structure of Thalidomide,
Lenalidomide and Pomalidomide
O
O
O
O
O
H
O
H
N
N
N
N
O
N
O
N
O
O
NH
O
2
NH2
Lenalidomide
Thalidomide
Pomalidomide
15-25 mg/d
100-200 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)
Anti-inflammatory
activity against
+
+++++
monocytes
T cell/NK cell
+
+++++
costimulation
T regulatory cell
-
+++++
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 for Pomalidomide
N
Dose
MTD
ORR
Schey
24
1-10
2 mg
54%
mg
Streetly 20
1-10*
5 mg
50%
mg
QOD
QOD
* Nine patients also received dexamethasone
Pomalidomide (CC4047) plus low-dose dexamethasone (Pom/Dex)
is highly effective therapy in relapsed multiple myeloma
MQ Lacy, S Hayman, M Gertz, J Allred, S Mandrekar, A Dispenzieri,
S Zeldenrust, S Kumar, P Greipp, J Lust, S Russell, F Buadi, R Kyle,
PL Bergsagel, R Fonseca, V Roy, J Mikhael, AK Stewart, and SV Rajkumar
Mayo Clinic
Scottsdale, Arizona
Rochester, Minnesota
Jacksonville, Florida
Study design & treatment
· Phase II trial, 60 patients
· A confirmed response is defined to be a CR, PR or VGPR as
assessed by the International Myeloma Working Group
Uniform Response criteria.
· 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
Prior treatments
Total
(N=60)
Diagnosis to On Study, median
44 (9.1-192.5)
(months, range)
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%)
Hematologic Toxicity
Grade 1
Grade 3/4 neutropenia 32%
Grade 2
enia
Grade 3
cytop
Grade 4
mbo
ia
pen
Thro
eutro
N
Anemia
0
2040
6080
100
Percentage of patients
Non-Hematologic Toxicity
1 death due
ry
> Grade 3 = 28%
to
pneumonia
enso
Primarily fatigue
S
on
o-
while
itati
eur
a
N
Ag
ni
neutropenic
som
Grade 1
on
In
si
fu
Grade 2
n
ia
Co
Grade 3
ycem a
Grade 4
ergl
oni
yp
n
H
eum io
Pn ipat
st
ea
n
Co
arrh
No DVT/PE
Di
ue
ig
Fat
0
2040
6080
Percentage of Patients
Best Response
Response
N =60
CR
3 (5%)
ORR 63%
VGPR
17 (28%)
Median follow-up
PR
18 (30%)
CR +VGPR
7 months
SD
15 (25%)
33%
PD
6 (10%)
NE
1 (2%)
Responses in patients refractory
to other novel agents
Refractory to
N
CR
VGPR
PR
SD
PD
RR*
Bortezomib
10
1 (10%)
2 (20%)
3 (30%)
4 (40%)
0
6 (60%)
Lenalidomide
20
0
1 (5%)
7 (35%)
9 (45%)
3 (15%)
8 (40%)
Thalidomide
16
0
2 (12.5%)
4 (25%)
6 (37.5%)
4 (25%)
6 (37.5%)
Patient 2, 67 year old female
M-spike 3.5
CRD started
Bortezomib
M-spike 2.6
Pom/dex, M-spike 2.9
Bortezomib
Relapsing on
Melphalan,
CRD
Pred
Conclusions
· The combination of pomalidomide and low dose
dexamethasone is highly active in the treatment
of relapsed/refractory multiple myeloma.
· Toxicity has been manageable and consists
primarily of myelosuppression with neutropenia.
· Future directions include phase II trial of
pomalidomide and dexamethasone for
lenalidomide-refractory and bortezomib
refractory patients
Carfilzomib:
Carfilzomib is a new, selective and irreversible proteasome
inhibitor with preclinical antitumor activity.
Responses seen in Phase I Myeloma trials.
Tetrapeptide
Ketoepoxide
Mechanism of Binding
Selectivity and prolonged inhibition
Carfilzomib
O
O
H
H
H
O
O
N
N
O
N
N
N
N
H
H
H
O
O
O
O
Proteasome (Thr)
N
H
O
O
H
Irreversible
HO
Bortezomib
OH
HN
B
O
OH
H
O
R
N
N
B
CH
N
OH
H
CH
Thr or Ser protease
O
HN
N
O
Slowly reversible
PX-171-004 Carfilzomib Phase 2 Study Design
Population: Multiple Myeloma, relapsed after 1-3 prior therapies
CFZ administration: 20 mg/m2 IV bolus; maximum 12 cycles
Premedication: Hydration, Dexamethasone 4 mg during Cycle 1
D1 D2
D8 D9
D15 D16
28day
0
cycle
Rest period
(12 days)
proteasome
inhibition
%
80
Week:
12
3
4
QDx2 weekly for 3 weeks
Primary endpoint: Overall response rate (ORR = CR + VGPR + PR)*
Secondary endpoints: DOR, PFS, TTP, OS, Safety
*IMWG response criteria
Baseline Characteristics (N=31)
BTZ-Naïve (N=14)
BTZ-Exposed (N=17)
N (%)
N (%)
Peripheral Neuropathy
Prior History
9 (64)
14 (82)
Grade 1/2 Neuropathy at baseline
4 (29)
6 (35)
Prior Bortezomib Therapy
Single Agent
-
3 (18)
In Combination
-
14 (82)
Other Prior Therapies
Corticosteroid
16 (94)
14 (100)
Lenalidomide OR Thalidomide
13 (93)
12 (71)
Lenalidomide AND Thalidomide
3 (21)
4 (24)
Alkylator
16 (94)
13 (93)
Anthracycline
1 (7)
8 (47)
Stem Cell Transplant
15 (88)
12 (86)
Single Agent Anti-tumor Activity
100
6.5%
CR
14%
18%
VGPR
10%
PR
14%
MR
SD
ts
32%
c
14%
PD
47%
NE (TLS)
ubje 50
s
16%
36%
of%
ORR:
18%
26%
ORR:
57%
35.5%
14%
ORR:
6.5%
18%
18%
7%
0
3.2%
All
Bortezomib
Bortezomib
Subjects
Exposed
Naive
(N = 31)
(N = 17)
(N = 14)
> MR 71% for BTZ-Naïve
> MR 36% for BTZ-Exposed
PX-171-004: Time To Progression
100
e
80
-fre
on
60
ressi
40
g
rop 20
BTZ naive (N=14)
%
BTZ exposed (N=17)
0
0
100
200
300
400
Study Day
BTZ naïve
BTZ exposed (N=17)
(N=14)
Time to Progression (median)
11.1 months
8.3 months
Median follow up
10.8 months
12.5 months
PX-171-004: Time To Progression
100
8.3 months
e
80
-fre
on
60
ressi
40
g
rop 20
BTZ naive (N=14)
%
BTZ exposed (N=17)
0
0
100
200
300
400
Study Day
BTZ naïve
BTZ exposed (N=17)
(N=14)
Time to Progression (median)
11.1 months
8.3 months
Median follow up
10.8 months
12.5 months
PX-171-004: Time To Progression
100
11.1 months
e
80
-fre
on
60
ressi
40
g
rop 20
BTZ naive (N=14)
%
BTZ exposed (N=17)
0
0
100
200
300
400
Study Day
BTZ naïve
BTZ exposed (N=17)
(N=14)
Time to Progression (median)
11.1 months
8.3 months
Median follow up
10.8 months
12.5 months
PX-171-003: Response Summary (N=39)
Seven subjects excluded from response analysis:
*
· Serum free light chain only (4)
· Received < 1 cycle of therapy (2)
· No baseline value (1)
50
40
tsce 30 CBR=26%
ubjs 20
of% 10
0
PR
MR
SD
PD
50% of responses
occurred at 2 weeks
Most Common Non-Hematologic AEs (N=31)
Overall
> Grade 3
Adverse Event*, 1
n (%)
n (%)
Fatigue
23 (74.2)
0
Nausea
20 (64.5)
0
Vomiting
13 (41.9)
0
ALT increased
12 (38.7)
0
URI
12 (38.7)
1 (3.2)
Dyspnea
11 (35.5)
3 (9.7)
Headache
11 (35.5)
0
AST increased
10 (32.3)
0
Diarrhea
10 (32.3)
0
Hypoesthesia
10 (32.3)
0
Hypophosphatemia
9 (29.0)
1 (3.2)
Cough
9 (29.0)
0
Pyrexia
9 (29.0)
0
Increased creatinine
8 (25.8)
1 (3.2)
Hypomagnesemia
8 (25.8)
0
Insomnia
8 (25.8)
0
Non-Neuropathic Extremity Pain
8 (25.8)
0
*All AEs reported in >25% patients
1Includes both related and non-related
Data through March 2009
Increased Creatinine: Reversible and Non cumulative
Overall
> Grade 3
Adverse Event*, 1
n (%)
n (%)
Fatigue
23 (74.2)
0
Nausea
20 (64.5)
0
Vomiting
13 (41.9)
0
ALT increased
12 (38.7)
0
URI
12 (38.7)
1 (3.2)
Dyspnea
11 (35.5)
3 (9.7)
Headache
11 (35.5)
0
AST increased
10 (32.3)
0
Diarrhea
10 (32.3)
0
Hypoesthesia
10 (32.3)
0
Hypophosphatemia
9 (29.0)
1 (3.2)
Cough
9 (29.0)
0
Pyrexia
9 (29.0)
0
Increased creatinine
8 (25.8)
1 (3.2)
Hypomagnesemia
8 (25.8)
0
Insomnia
8 (25.8)
0
Non-Neuropathic Extremity Pain
8 (25.8)
0
*All AEs reported in >25% patients
1Includes both related and non-related
Data through March 2009
Low Rate of Treatment Emergent Peripheral
Neuropathy
· 73% had a prior history of drug or disease related neuropathy
· 32% had Grade 1/2 neuropathy at baseline*
30
No study discontinuations for
peripheral neuropathy
20
(N=31)
Peripheral Neuropathy does not
limit dose or duration of therapy
bjectsus 10
of%
6.5%
3.2%
0%
0
Gr1
Gr2
Gr3
(n=2)
(n=0)
(n=1)
Neuropathy AEs
*Grade Based on physical assessment at
screening (NCI-CTC scale)
Data through March 2009
Carfilzomib Conclusions: Ph 2 Relapsed MM
Single agent carfilzomib is highly active in relapsed patients
57% response rate in BTZ-naïve patients
26% CBR in Refractory disease
CFZ achieves durable disease control with continued dosing
Median TTP 11.1 mos in BTZ-naïve patients
Median TTP 8.3 mos in BTZ-exposed patients
Few > grade 3 Aes
Peripheral neuropathy is not a treatment-limiting toxicity with CFZ
Carfilzomib: Future Directions
Dose escalation to 27 mg/m2
Combination with Lenalidomide and Dexamethasone
Registrational Development
single arm monotherapy Phase 2 in refractory pts
completed
Randomized Phase 3 lenalidomide/dexamethasone +/- CFZ
planned for 2010
Many drugs in trials some current examples
AUY922
TAK901 / MLN8237
NPI-052 / CEP070 / MLN9708
TKI258 / MFGR1877S
PD0332991
Vorinostat
Tanespimycin
Perifosine
Conclusions
At relapse suggest combination therapy in rapid
relapsing, symptomatic or high genetic risk
patient
More conservative therapy otherwise reasonable
Three new active drugs with many more being
tested in clinical trials