Challenges and Novel Approaches to Treating Myeloma…

AZMN Roundtable

March 2014

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

Joseph Mikhael, MD, MEd, FRCPC, FACPStaff Hematologist, Mayo Clinic Arizona

Managing myeloma: the components

Supportive Care

Initial Therapy

Consolidation Maintenance

Treatment of Relapsed

disease

Transplant EligiblePatients

Transplant Ineligiblepatients

Consolidation/ Maintenance/ Continued therapy

Treatment sequence

Induction Consolidation

Front line treatment

Post consolidation

Maintenance

Rescue

Relapsed

OLD VADDEX

SCTNothing

PrednisoneThalidomide

Few options

NEW

Thal/Dex VD

Rev/DexCyBorD

VTDVRD

SCTVD/VRD

NothingThalidomide?Bortezomib?

Lenalidomide?

BortezomibLenalidomideThalidomideCarfilzomib

PomalidomideMonoclonal Ab (CD38)

ElotuzumabHDAC

Bendamustine

2006-2010 73% 56%

2001-2005 63% 31%

IMPACT OF NOVEL THERAPY 2012/2013

Median 7.3 years

5 YEAR SURVIVAL BY AGE

AGE≤ 65 YRS

AGE> 65 YRS

2012 ASH Abstract #3972 Kumar et al

Mayo Stratification for Myeloma And Risk-adapted Therapy

Newly Diagnosed Myeloma

Website: www.msmart.org

mSMART

mSMART 2.0: Classification of Active MM

FISH Del 17p t(14;16) t(14;20)

GEP High risk

signature

All others including: Hyperdiploid t(11;14) t(6;14)

FISH t(4;14)*

Cytogenetic Deletion 13 or hypodiploidy

PCLI >3%

High-Risk 20% Intermediate-Risk 20% Standard-Risk 60%

3 years 4-5 years 8-10 years

Mikhael et al Mayo Clinic Proceedings April 2013

mSMART – Off-StudyTransplant Eligible

a Bortezomib containing regimens preferred in renal failure or if rapid response neededb If age >65 or > 4 cycles of Rd Consider G-CSF plus cytoxan or plerixaforc Continue Rd for patients responding to Rd and with low toxicities; Dex is usually discontinued after first year* Consider risks and benefits; consider limited duration 12-24 months

Standard Risk

Autologous stem cell transplant

4 cycles of Rda or CyBorD

Collect Stem Cellsb

Continue Rd;

c or

CyBorD for ~12 months

High Risk

4 cycles of VRd

Intermediate Risk

Autologous stem cell transplant

Bortezomib based therapy for minimum of 1 year

4 cycles of CyBorD

Autologous stem cell transplant, especially if

not in CR

V or VCd for minimum of 1 year

2 cycles of Rd consolidation; Then Len maintenance if not in VGPR and Len responsive*

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v11 //last reviewed Dec 2013

mSMART – Off-StudyTransplant Ineligible

a Dex is usually discontinued after first yearb Bortezomib containing regimens preferred in renal failure or if rapid response needed*Clinical trials strongly recommended as the first option

Intermediate Risk Standard Risk*

MP + weekly Bortezomib or weekly CyBorD for

~12 months

Bortezomib based therapy for minimum of 1 year

High Risk

VRd* for ~12 months, Rda, b

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; Kumar et al. Mayo Clin Proc 2009 84:1095-1110; Mikhael et al. Mayo Clin Proc 2013;88:360-376. v11 //last reviewed Dec 2013

Continue VRd as maintenance for minimum

of 1 year

FIRST Design: Lenalidomide and Low-dose Dexamethasone (Rd/Rd18) vs. MPT

ARM A

Arm BRd18

Arm CMPT

N = 535

Arm ARd

LEN + Lo-DEX until Progressive DiseaseLENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

LEN + Lo-DEX: 18 Cycles (72 wks) LENALIDOMIDE 25mg D1-21/28Lo-DEX 40mg D1,8,15 & 22/28

MEL + PRED + THAL 12 Cycles1 (72 wks)MELPHALAN 0.25mg/kg D1-4/42PREDNISONE 2mg/kg D1-4/42THALIDOMIDE 200mg D1-42/42

Active Treatment + PFS Follow-up PhaseScreening LT Follow-Up

Pts > 75 yrs: Lo-DEX 20 mg D1, 8, 15 & 22/28; THAL2 100 mg D1-42/42, Melphalan2 0.2 mg/kg D1–4

• Stratification: age, country and ISS stage

1Facon T, et al. Lancet 2007;370:1209-18; 2Hulin C, et al. JCO. 2009;27:3664-70.

International Staging System; LT, long-term; PD, progressive disease; OS, overall survival

n= 1,623 - 18 countries from North America, Asia-Pacific, and Europe represented from 246 Centers

n=535

n=541

n=547

Facon T. et._ASH 2013: Abstract 2

FIRST Trial: Final PFSContinuous Rd the risk of PFS events (PD or death) by 28% vs. MPT

mos, months; MPT, melphalan, prednisolone, thalidomide; PFS, progression-free survival; Rd, Lenalidomide plus low-dose dexamethasone.

Median PFS

Rd (n= 535) 25.5 mos

Rd18 (n= 541) 20.7 mos

MPT (n= 547) 21.2 mos

Rd 535 400 319 265 218 168 105 55 19 2 0

Rd18 541 391 319 265 167 108 56 30 7 2 0

MPT 547 380 304 244 170 116 58 28 6 1 0

Hazard ratio

Rd vs. MPT: 0.72; P = 0.00006

Rd vs. Rd18: 0.70; P = 0.00001 Rd18 vs. MPT: 1.03; P = 0.70349

Time (months)

Pat

ien

ts (

%)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

72 w

ks

Facon T. et._ASH 2013: Abstract 2

FIRST Trial: Overall Survival Interim Analysis574 deaths (35% of ITT)

Pat

ien

ts (

%)

RdRd18MPT

535541547

488505484

457465448

433425418

403393375

338324312

224209205

121124106

434430

563

000

4-year OS

Rd (n= 535) 59.4%

Rd18 (n= 541) 55.7%

MPT (n= 547) 51.4%

Overall survival (months)

100

80

60

40

20

00 6 12 18 24 30 36 42 48 54 60

Hazard ratio Rd vs. MPT: 0.78; P = 0.0168 ( 22% risk of death with Rd)

Rd vs. Rd18: 0.90; P = 0.307 Rd18 vs. MPT: 0.88; P = 0.184

The pre-specified boundary (p<0.0096) was not crossed for Rd_continuous vs MPT_18 months

Facon T. et._ASH 2013: Abstract 2

FIRST Trial: Conclusions

• Continuous Rd significantly extended PFS, with an OS benefit vs. MPT• PFS:

• 3 yr PFS: 42% continuous Rd vs 23% Rd18 and MPT

• Planned interim OS: HR= 0.78 (P= 0.0168) but did NOT cross the pre-specified boundary (p<0.0096)

• Safety profile with continuous Rd was manageable • Hematological and non-hematological AEs were as expected for

Rd and MPT with more infections and cataract observed in the continuous Rd arm

• Incidence of hematological SPM was lower with continuous Rd vs. MPT

Facon T. et._ASH 2013: Abstract 2

Efficacy Comparisons

FIRST (Continuous Rd) (Facon)

FIRST (Rd for 72 wks)(Facon)

MM-015 (MPR-R) (Palumbo)

VISTA (VMP arm for 54 wks) (San Miguel)

VMP lite (for 45 wks) (Palumbo)

VMPT-VT (Palumbo)

VMP-VT(Mateos)

CR 15.1% 14.2% 9.9% 30% 24% 38% 46%

PFS 25.5 mo 20.7 mo 31 mo 21.7 mo 24.8 mo 35.3 mo 39 mo

OS 4-yr OS; 59.4%

4-yr OS: 55.7%

3-yr OS: 70%

5-yr OS: 46%

Med OS: 56.4 mo

5-yr OS: 51%

Med OS: 60.6 mo

5-yr OS: 61%

5-yr OS: 69%

Facon et al. ASH 2013 (Abstract 2), plenary presentation Palumbo et al. N Engl J Med 2012;366(19):1759-69 San Miguel et al. N Engl J Med 2008; 359: 906-917

San Miguel et al. J Clin Oncol 2013;31(4):448-55Palumbo et al. ASH 2012 (Abstract 200), oral presentation

Mateos et al. Blood 2012; 120: 2581-2588

Relapsed Disease

NEWER THERAPIES: ASH 2013

TOP 8

Anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284)

MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983) ARRY 520 (abstracts #285 and #1982) ACY-1215 (abstracts #759 and #3190) Selinexor (also known as KPT-330, abstract #279) Anti-CD 138 monoclonal antibody (BT062, indatuximab

ravatansine, abstract #758) Panabinostat (abstract #1970) Bendamustine (abstract #1971)

Anti-CD 38 monoclonal antibodies (MAb) daratumumab (abstracts #227 and #1986) and SAR 650984 (#284)

MLN 9708 (ixazomib citrate: abstracts #535, 1944, and 1983) ARRY 520 (abstracts #285 and #1982) ACY-1215 (abstracts #759 and #3190) Selinexor (also known as KPT-330, abstract #279) Anti-CD 138 monoclonal antibody (BT062, indatuximab

ravatansine, abstract #758) Panabinostat (abstract #1970) Bendamustine (abstract #1971)

Monoclonal antibodies in MMTarget mAb Stage of development

Surface molecules

CS1

CD38

CD74 CD40 CD56 CD138

Elotuzumab

Daratumumab SAR650984 MOR202 Milatuzumab Dacetuzumab Lorvotuzumab mertansine BT062

Phase 2/3

Phase 1/2/3 Phase 1/2 Phase 1/2 Phase 1/2 Phase 1 Phase 1 Phase 1

Signaling molecules IL-6 RANKL B cell activating factor (BAFF) VEGF DKK1

Siltuximab Denosumab Tabalumab

Bevacizumab BHQ880

Phase 3 Phase 3 Phase 2/3

Phase 2 Phase 2

Richardson et al. et al. IMW 2013 (Abstract P-214), poster presentation; Plesner et al. ASH 2013 (Abstract 1987), poster presentation; Martin et al. ASH 2013 (Abstract 284), oral presentation; http://www.clinicaltrials.gov/ct2/show/NCT00421525; http://www.clinicaltrials.gov/ct2/show/NCT00079716;

http://www.clinicaltrials.gov/ct2/show/NCT00346255; http://www.clinicaltrials.gov/ct2/show/NCT01001442; Wong et al. ASH 2013 (Abstract 505), oral presentation; Hageman et al. Ann Pharmacother 2013;47:1069-74;

Thomas G. Martin III1, Stephen A. Strickland2, Martha Glenn3,

Wei Zheng4, Nikki Daskalakis5 and Joseph R. Mikhael6

1University of California San Francisco, San Francisco, CA2Vanderbilt-Ingram Cancer Center, Nashville, TN 3University of Utah, Huntsman Cancer Institute, Salt Lake City, UT 4Sanofi Oncology, Cambridge, MA 5Sanofi US, Bridgewater, NJ 6Mayo Clinic in Arizona, Scottsdale, AZ

*NCT01084252 Trial Sponsored by Sanofi, Cambridge, MA

SAR650984, A CD38 Monoclonal Antibody in Patients with Selected CD38+

Hematological MalignanciesData From a Dose-Escalation Phase I Study

(TED10893)*

SAR650984: A Humanized IgG1 Monoclonal Antibody

Antibody

Fc Receptor

Complement

2. Complement-dependent

cytotoxicity (CDC)

2. Complement-dependent

cytotoxicity (CDC)3. Direct apoptosis induction without

crosslinking

3. Direct apoptosis induction without

crosslinking

1. Antibody-dependentcellular cytotoxicity (ADCC)

and phagocytosis (ADCP)

1. Antibody-dependentcellular cytotoxicity (ADCC)

and phagocytosis (ADCP)

NK cell,NK cell,MacrophageMacrophage

NK cell,NK cell,MacrophageMacrophage

NAD

4. CD38 enzymatic

activity inhibition

4. CD38 enzymatic

activity inhibition

cADPRADPR

SAR650984: Phase I Dose Escalation Study

Primary ObjectivePrimary Objective

● Determine maximum tolerated dose (MTD)/maximum administered dose (MAD)

Secondary ObjectiveSecondary Objective● Characterize safety profile

● Evaluate pharmacokinetic (PK) profile

● Assess pharmacodynamics, immunogenicity, and preliminary disease response

SAR650984: Baseline Characteristics

Accelerated Doses

0.3 mg/kgQ2W

1 mg/kgQ2W

3 mg/kgQ2W

5 mg/kgQ2W

10 mg/kgQ2W

10 mg/kg

QW

20 mg/kgQ2W

Overall

# of Patients (# of Myeloma patients) 6 (5) 7 (5) 3 (3) 6 (5) 3 (3) 7 (6) 2 (2) 5 (5) 39 (34)

# of Prior treatments,All pts - Median (range)

5(4 - 9)

6(1 - 12)

8(7 - 9)

7(3 -14)

4(4 - 10)

5(2 - 9)

8.5(4 -13)

5(4 - 7)

6(1- 14)

Prior carfilzomib 0 0 0 3 1 4 2 2 12

Prior pomalidomide 0 0 2 0 2 0 1 2 7

●39 treated patients● Median age = 65.0 (40 - 85)

●Prior therapies of myeloma patients (n=34)● Median = 6 (2 – 14)● At doses ≥ 0.3 mg/kg - all patients received prior lenalidomide and bortezomib● At doses ≥ 10 mg/kg - 69% of patient received carfilzomib and/or pomalidomide

SAR650984: Patients with Infusion ReactionsPatients treated at doses of 0.3 mg/kg Q2W or higher

Symptoms of Infusion Reactions (N; max severity): Nausea (5; G 2); Pyrexia (4; G 1); Drug hypersensitivity, Chills (3; G 2); Headache (3; G 1); Vomiting , Hypoxia (2; G 2); Cytokine release syndrome, Dyspnea, Flushing, Nasal congestion, Bronchospasm, Tracheal stenosis, Laryngospasm (1; G 2); Influenza-like illness, Abdominal pain, Blurred vision, Lacrimation increased, Rhinorrhea, Cough, Restlessness (1; G 1)

C1 C>11

C1 C>1 C1 C>1 C1 C>1 C1 C>1 C1 C>1 C1 C>1

7

6

5

4

3

2

1

Dose level 0.3 mg/kg 1 mg/kg 3 mg/kg 5 mg/kg 10 mg/kg 10 mg/kg QW 20 mg/kg

No infusion reaction

Grade 1

Grade 2

Mandatory Prophylaxis in All Patients*

C = Cycle

*methylprednisolone 100 mg IV, diphenhydramine 50 mg IV, ranitidine 50 mg IV, and acetaminophen 650-1000 mg po (or equivalents)

* Off study since 23May2013 due to patient decision. Ongoing

*CR

PR

MR

SD

PD

NA

0 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75

Week

5 mg/kg Q2W10 mg/kg Q2W10 mg/kg QW20 mg/kg Q2W

3 mg/kg Q2W1 mg/kg Q2W

SAR650984: Phase 1 Response Summary

ORR: 30.8%

CBR:38.5%

SAR650984: Phase 1 Response Summary

●Overall Response Rate (CR+PR)● Dosing cohorts ≥1mg/kg = 25% (2 CR, 4 PR of 24) ● Dosing cohorts ≥ 10 mg/kg = 31% (2 CR, 2 PR of 13)

● Clinical Benefit Rate (CR+PR+MR)● Dosing cohorts ≥ 1mg/kg = 33% (2 CR, 4 PR, 2 MR of 24) ● Dosing cohorts ≥ 10 mg/kg = 38% (2 CR, 2 PR, 1 MR of 13)

●Median Time to Initial Response (CR, PR, MR) = 6.1 weeks (3.4 – 12.3)

● In 8 responders the median duration of response 5.0 months (0 - 15.4)● 6 patients still on treatment

●Median duration of follow up is 6.5 months (1.9-16.3)