Multiple Myeloma:2013 Update

Genomies

A. Keith Stewart MB.ChB., MBAAnna Maria and Vasek Polak Professor of

Cancer Research Dean for Research Mayo Clinic in Arizona

Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida

Ongoing advances especially in elderly

Survival in Myeloma

376 pre clinical studies, 117 single-agent trials, 9 FDA approved drugs

All Approved Drugs Best Reported Response of at Least 20%

MelphalanDexamethasoneThalidomideFotemustinePomalidomideCarfilzomibBortezomibLenalidomidePrednisoneInterferonIdarubicinPaclitaxelCyclophosphamideBendamustineTeniposideDoxorubicin

Mayo Myeloma Pomalidomide/Dex Trials, 345 patients

Cohort Group Dose mg/day

N Accrual dates

1 Relapsed< 4 prior reg

2, 28/28 60 Nov 2007 - Aug 2008

2 Len refractory 2, 28/28 34 Nov 2008 - April 2009

3 Bortez/Len refractory 2, 28/28 35 May 2009 - Nov 2009

4 Bortez/Len refractory 4, 28/28 35 Nov 2009 - April 2010

5 Len refractory<4 prior reg

4, 28/28 61 May 2010 – Nov 2010

6 Len refractory 4, 21/28 120 April 2011 – March 2012

Change in the measurable parameter from baseline (serum, urine, FLC)

MM-003 Design: POM + LoDEX vs HiDEXMM-003 Design: POM + LoDEX vs HiDEXRefractory MM Pts Who Have Refractory MM Pts Who Have FailedFailed BORT and LEN BORT and LEN

(n = 302)POM: 4 mg/day D1-21 +LoDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1, 8, 15, 22

Follow-Up for OS and SPM

Until 5 Years Post Enrollment

(n = 153)HiDEX: 40 mg (≤ 75 yrs) 20 mg (> 75 yrs) D1-4, 9-12, 17-20

28-day cycles

PD* orintolerable AE

PD* Companion trialMM-003C

POM 21/28 days

Stratification•Age (≤ 75 vs > 75 yrs)•Number of prior Tx ( 2 vs > 2)•Disease population

Thromboprophylaxis was indicated for those receiving POM or with DVT history

*Progression of disease was independently adjudicated in real-time

MM-003: Ongoing Evaluation of Response MM-003: Ongoing Evaluation of Response ITT PopulationITT Population

POM + LoDEX HiDEX

Response, %IRAC

Randomized ≥ 6 months(n = 204)

IRAC Randomized ≥ 6

months(n = 99)

P value

ORR (≥ PR) 24 3 < .001VGPR 3 0 —

≥ MR 38 7 —≥ SD 79 55 —

Median DOR*, m (95% CI)

10.1(6.2 – 12.1)

NE —

As of Nov 9, 2012

Based on adjudicated data; IMWG criteria

MM-003: Progression-Free SurvivalMM-003: Progression-Free SurvivalITT PopulationITT Population

0 4 8 12 160.0

0.2

0.4

0.6

0.8

1.0

Progression-Free Survival (months)

Prop

ortio

n of

Pat

ient

s

Median PFSPOM + LoDEX (n = 302) 3.6 monthsHiDEX (n = 153) 1.8 months

HR = 0.45P < .001

MM-003: Overall SurvivalMM-003: Overall SurvivalITT PopulationITT Population

NE, not estimable

Overall Survival (months)

0.0

0.2

0.4

0.6

0.8

1.0

0 4 8 12 16

Prop

ortio

n of

Pat

ient

sMedian OS (95% CI)

POM + LoDEX (n = 302) Not Reached (11.1-NE)HiDEX (n = 153) 7.8 months (5.4-9.2)

HR = 0.53P < .001

• 29% of pts received POM after progression on HiDEX

ConclusionsConclusions• POM + LoDEX significantly improved PFS and OS vs HiDEX

– Median PFS: 3.6 vs 1.8 months • HR = 0.45; P < .001

– Median OS: not reached vs 7.8 months • HR = 0.53; P < .001

• Equal benefit in pts refractory to both LEN and BORT

• In these heavily pre-treated pts, POM + LoDEX was generally well tolerated

• POM + LoDEX should be considered as a new treatment option for these pts

NNHO O

O

NH2

NN

O

O

O

O

Thalidomide

100–200 mg/d

NeuropathyConstipationSedation

DVT

Molecular Structure of Thalidomide, Lenalidomide, and Pomalidomide

Cereblon knockdown confers completeLenalidomide and Pomalidomide resistance In

Myeloma

0

0.1

0.2

0.3

0.4

0.5

0.6

Pomalidomide

OP M1/ NT

OP M1/ CRBN#13

OPM2 MTT (day6 post treatment)

0

0.2

0.4

0.6

0.8

1

1.2

0 5uM 10uM 20uM 40uM 80uM 120uM

Viab

ility

(orm

aliz

ed to

unt

reat

ed c

ontr

ol)

OPM2 NT

OPM2 #13

LenalidomidePomalidomide

Control

Cereblon knockdown

Gene expression levels of Cereblon predict response to Pomalidomide

N =

CRBN % of mean MM

0%

19%

33%

N = N =

Gene expression levels of Cereblon predict Overall Survival of Pomalidomide Treated Patients

P=0.01 P=0.005

9.1 months versus 27 months

All Approved Drugs Average Response of at Least 15%

MLN9708 GSK0183 ARRY520

All Approved Drugs Average Response of at Least 15%

MLN9708 GSK0183 ARRY520 \

No single agent activityElotuzumabPanabinostatVorinostatPerifosineSiltuximab (anti-IL6)

22

Elotuzumab 10 mg/kg

Elotuzumab 20 mg/kg Total

Patients, n 36 37 73

ORR (≥PR), n (%) 33 (92) 27 (73) 60 (82)

CR/stringent CR, n (%) 5 (14) 4 (11) 9 (12)

VGPR, n (%) 14 (39) 12 (32) 26 (36)

PR, n (%) 14 (39) 11 (30) 25 (34)

No confirmed response, n (%) 3 (8) 10 (27) 13 (18)

EfficacyBest Confirmed Response (IMWG Criteria)

CR = complete response; IMWG = International Myeloma Working Group; PR = partial response; VGPR = very good partial response

• Median time to response, months (range): 1 (0.7-5.8)

• Median time to best response, months (range): 2.2 (0.7-17.5)

Dinaciclib (SCH727965)

• Dinaciclib is a novel, potent, small molecule inhibitor of cyclin dependent kinases (cdk).

• It inhibits cdk1, cdk2, cdk5 and cdk9 with 50% inhibitory concentrations (IC50) of 4nM, 1nM, 1nM and 4nM respectively.

• Cyclin D/CDK4 complexes are inhibited with an IC50 of 100nM.

Best Response across all cycles

 

30 mg/m2

(N=3)

40 mg/m2

(N=6)

All 50 mg/m2

(N=18)

All

(N=27)

VGPR 0 1 1 2

PR 0 1 1 2

MR 0 0 2 2

SD 1 4 8 13

PD 2 0 6 8

NA 0 0 1 1

6/27 or 22% response rate ≥MR

Serum M-protein responses

Conclusions• Doing better overall - drug combinatons given for longer

• High risk disease a major problem

• MOA of Lenalidomide better understood

• New Agents

– Pomalidomide

– Carfilzomib

– Other investigational