novel therapies for myeloma a. keith stewart scottsdale, arizona rochester, minnesota jacksonville,...

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

A “Gold Rush” in Myeloma Pre-clinical Drug Testing

>200 drugs reported in preclinical studies (~$30,000,000)

>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

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

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

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

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

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

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

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%)

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

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

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)

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

% 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

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%

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

*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

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

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

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

Many drugs in trials – some current examples

AUY922

TAK901 / MLN8237

CEP070 / MLN9708

TKI258 / MFGR1877S

SCH727965

Panobinostat

Monoclonals : CD38

BHQ880

t(4;14) 15% of Myeloma

Hypothesis

Pharmacologic abrogation of tyrosine kinase signaling by FGFR3 in MM cells will result in a tumour-specific

cytotoxicity

TKI-258 (Dovitinib)

MFGR1877S

BM restricted plasmacytosis in Vk*MYC mice

CD

138

B220

wt Vk*MYC

spleen spleenBM BM

Chesi et al, Cancer Cell, February 2008

Monoclonal Protein%

decr

ease

from

d=

0

Day 0 14 0 14 0 14 0 14 0 14

MelphalanDexamethasone BortezomibPlacebo

{

Revlimid

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