novel therapies for myeloma a. keith stewart scottsdale, arizona rochester, minnesota jacksonville,...
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Novel Therapies for Myeloma
A. Keith Stewart
Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida
Disclosure of Potential Conflicts of Interest
Honoraria: Celgene, MilleniumResearch grants: Millenium
Consultant: Proteolix
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A “Gold Rush” in Myeloma Pre-clinical Drug Testing
>200 drugs reported in preclinical studies (~$30,000,000)
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>200 drugs reported in preclinical studies
~30 - 40 trial results reported
3 agents with known significant single agent activity – all arise from
known active drug classs
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Single Agent Activity (>PR) 39 Drugs in Multiple Myeloma
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
PomalidomideBortezomib
BendamustineTenoposide
LenalidomideThalidomide
Taxol
Dexamethasone
CarfilzomibDaunorubicin
PD332991InterferonHCD122
BT062RAD001
VincristineTanespimycinTemsirolimus
ArsenicLBH589Etoposide
2CDA
Vorinostat
VEGF Pazopanib
TipifarnibSF1126
PerifosinePentostatinITF2357Imatinib
IGF inhibitor CP751IGF inhibitor AVE1642
huLuc63FludarabineFlavoperidolDenosumab
Dasatinib
Clarithromycin
Atacicept
Single Agent Activity of 39 Drugs Tested in Myeloma
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Single Agent Activity (>PR) 39 Drugs in Multiple Myeloma
0
0.05
0.1
0.15
0.2
0.25
0.3
0.35
0.4
PomalidomideBortezomib
BendamustineTenoposide
LenalidomideThalidomide
Taxol
Dexamethasone
CarfilzomibDaunorubicin
PD332991InterferonHCD122
BT062RAD001
VincristineTanespimycinTemsirolimus
ArsenicLBH589Etoposide
2CDA
Vorinostat
VEGF Pazopanib
TipifarnibSF1126
PerifosinePentostatinITF2357Imatinib
IGF inhibitor CP751IGF inhibitor AVE1642
huLuc63FludarabineFlavoperidolDenosumab
Dasatinib
Clarithromycin
Atacicept
Active Drugs
Single Agent Activity of 39 Drugs Tested in Myeloma
Inactive Drugs
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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, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida
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Molecular Structure of Thalidomide, Lenalidomide and Pomalidomide
Molecular Structure of Thalidomide, Lenalidomide and Pomalidomide
Lenalidomide15-25 mg/d
MyelosuppressionSkin rash
DVT
NNHO O
O
NH2
Structurally similar, but functionally different both qualitatively
and quantitatively
N
N
O
O
O
O
Thalidomide100-200 mg/d
NeuropathyConstipation
SedationDVT
Pomalidomide 1-4 mg/d
N
O
O
NH
O
O
NH2
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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
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Response N =60
CR 3 (5%)
VGPR 17 (28%)
PR 18 (30%)
SD 15 (25%)
PD 6 (10%)
NE 1 (2%)
ORR 63%
CR +VGPR 33%
Best Response
Median follow-up 7 months
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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%)
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M-spike 3.5
CRD started
Relapsing on CRD
BortezomibM-spike 2.6
BortezomibMelphalan, Pred
Pom/dex, M-spike 2.9
Patient 2, 67 year old female
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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
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Updated Results of Bortezomib-Naïve Patients in PX-171-004, An Open-Label, Phase 2 Study of
Single-Agent Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma
Luhua Wang, MD, David Siegel, MD, Jonathan L. Kaufman, MD, Keith Stewart, MD, Andrzej J. Jakubowiak, MD, PhD, Melissa Alsina, MD, Vishal Kukreti, MD, FRCPC, Nizar J Bahlis, MD, Kevin T. McDonagh, MD,
Andrew Belch, MD, Michael Sebag, MD, PhD, Nashat Gabrail,MD, Mai H. Le, MD, Mark K Bennett, PhD, Lori Kunkel, MD,
Michael Kauffman, MD, PhD, Robert Z Orlowski, M.D., Ph.D., Ravi Vij, MD and The Multiple Myeloma Research Consortium (MMRC)
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Carfilzomib:
Carfilzomib is a new, selective and irreversible proteasome inhibitor with pre-clinical anti-tumor activity.
Responses seen in Phase I Myeloma trials.
Ketoepoxide
Tetrapeptide
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% p
rote
asom
e in
hibi
tion
D8 D9
0
Week:
D15 D16
1 2 3
28-daycycle
80
D1 D2
Rest period (12 days)
4
*IMWG response criteria
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
Primary endpoint: Overall response rate (ORR = CR + VGPR + PR)*
Secondary endpoints: DOR, PFS, TTP, OS, Safety
QDx2 weekly for 3 weeks
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Carfilzomib: Dose Escalation to 27 mg/m2
0
20
40
60
80
100
VGPRPRMRSD
BortezomibNaive
(N = 19)
PD
47.4
31.6
5.3%
15.8
% o
f su
bje
cts
N (%)
Evaluable population 19 (100)
CR 0 (0)
VGPR 1 (5)
PR 9 (47)
MR 0 (0)
SD 6 (32) ≥SD : 84%
≥MR : 53%
≥PR : 53%
ORR (> PR) = 53%
Disease Control in 84%
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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)
*
0
10
20
30
40
50
CBR=26%
PR MR SD PD
% o
f s
ub
jec
ts
50% of responses occurred at 2 weeks
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*All AEs reported in >25% patients1Includes both related and non-related
Most Commonly Reported Adverse Events
Adverse Event*, 1 Overalln (%)
> Grade 3n (%)
Fatigue 40 (68) 7 (12)Nausea 27 (46) 0 (0)Dyspnea 25 (42) 3 (5)Cough 22 (37) 0 (0)Anemia 21 (36) 4 (7)Diarrhea 18 (31) 1 (2)Pyrexia 18 (31) 0 (0)Peripheral Edema 18 (31) 1 (2)Thrombocytopenia 15 (25) 7 (12)Upper Respiratory
Infection15 (25) 1 (2)
Data through Oct 2009
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Peripheral Neuropathy is Infrequent and Mild
0
10
20
30
40
50
Neuropathy AEs
All Grades(n=11)
Gr 1 or 2(n=0)
2%
Gr3(n=1)
12%10%%
of
sub
ject
s (N
=90
)
Data through October 2009
There were no reports of Grade 4 peripheral neuropathy
*Grade Based on physical assessment at screening (NCI-CTC scale)
Only 1 patient was discontinued for peripheral neuropathy
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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
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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
Carfilzomib: Future Directions
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Many drugs in trials – some current examples
AUY922
TAK901 / MLN8237
CEP070 / MLN9708
TKI258 / MFGR1877S
SCH727965
Panobinostat
Monoclonals : CD38
BHQ880
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t(4;14) 15% of Myeloma
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Hypothesis
Pharmacologic abrogation of tyrosine kinase signaling by FGFR3 in MM cells will result in a tumour-specific
cytotoxicity
TKI-258 (Dovitinib)
MFGR1877S
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BM restricted plasmacytosis in Vk*MYC mice
CD
138
B220
wt Vk*MYC
spleen spleenBM BM
Chesi et al, Cancer Cell, February 2008
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Monoclonal Protein%
decr
ease
from
d=
0
Day 0 14 0 14 0 14 0 14 0 14
MelphalanDexamethasone BortezomibPlacebo
{
Revlimid
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Conclusions
Three new active drugs with many more being tested in clinical trials
New Mouse models and target selection may result in higher success rate in clinic
Future trials will likely focus on individualized therapy for different types of myeloma