Experimental Agents for Relapsed/Refractory Myeloma - Current Trials in Context

Kenneth C. Anderson, M.D.

Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute

Harvard Medical School

Conflict of Interest: Kenneth C. Anderson, M.D.

Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead

Scientific Founder: Acetylon, Oncopep

Integration of Novel Therapy

Into Myeloma Management Bortezomib, Lenalidomide, Thalidomide, Pegylated Liposomal Doxorubicin, Carfilzomib, Pomalidamide

Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo

Effective in relapsed/refractory, relapsed,induction, consolidation, and maintenance therapy

Eight FDA approvals and median survival prolonged from 3-4 to 6-7 years, with additional prolongation from maintenance

New approaches needed to treat and ultimately prevent relapse

VCAM-1Fibronectin

ICAM-1LFA-1

MUC-1

VLA-4

CytokinesIL-6, VEGFIGF-1, SDF-1BAFF, APRILBSF-3

TNFTGFVEGF

NF-B

NF-BBMSC

adhesion molecules

NF-B

Smad, ERK

JAK/STAT3

MEK/ERK

PI3-K

GSK-3FKHRCaspase-9NF-BmTORBad

PKC

Bcl-xLMcl-1

MEK/ERKp27Kip1

NF-BBcl-xLIAPCyclin-D

MM

SurvivalAnti-apoptosisCell cycle

SurvivalAnti-apoptosisCell cycle

proliferation

SurvivalAnti-apoptosis

Akt

migration

ProliferationAnti-apoptosis

cytokines

Raf

FGFR3

Adhesion

Targeting Growth, Survival, and Drug Resistance of MM in BM Microenvironment

Hideshima T and Anderson KC. Nat Rev Cancer 2007,

SC

CD40

CS1

BAFF-R

Cell surfacetargets

VEGFR

Overview of Phase III Trials with Len and Bortezomib in Relapsed/Refractory MM

1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. 3. Richardson PG, et al. Blood. 2007;110:3557-3560. 4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-3901. 5. Weber D, et al. Blood. 2007;110:Abstract 412.

Regimen Trial ORR, %

CR or nCR, %

≥ VGPR, %

DOR, Mos

TTP or PFS, Mos

Median OS, Mos

Len + dex MM-009[1] 61 24 NE16 11

35[5]

Len + dex MM-010[2] 60 25 NE 17 11

Bortezomib APEX[3] 43 16 NE 86

30

VdoxMMY-3001[4] 44 13 27

109 NE

Efficacy and Toxicity by Bortezomibschedule

46.8 mg/m267.6 mg/m267.6Total planned dose

4%16%NAPN discontinuation

35%32%NAPFS @ 3 years

2%14%13%Grade 3-4

NA

44%

30%

VMP*(VISTA)

40 mg/m2

21%

23%

VMP once weekly N=190

Sensory PN

43%Any grade

41 mg/m2Total delivered dose

27%CR

VMP twice weekly N=63

**MateosMateos et al. J et al. J ClinClin OncolOncol 2010; 2010; PN: peripheral neuropathyPalumbo et al. ASH 2010 abstr 620

SC vs. IV Bortezomib for Relapsed/Refractory Myeloma

EQUIVALENT EFFICACY

Peripheral Neuropathy Bortezomib IV

(N=74)

Bortezomib SC (N=148)

P-value*

Any PN event, % 53 38 0.04

Grade 2, % 41 24 0.01

Grade 3, % 16 6 0.03

Risk factors for PN, %

Grade 1 PN at baseline 28 23

Diabetes at baseline 11 13

Exposure to prior neurotoxic agents 85 86

*P-values are based on 2-sided Fisher’s exact test

Moreau et al. ASH 2010 abstr 312

When to Consider Retreatment

• Differences between biochemical relapse and symptomatic relapse need to be considered

• Patients with asymptomatic rise in M-protein can be observed to determine the rate of rise and nature of the relapse– Caveat: patients with known aggressive or high-risk disease

should be considered for salvage even in the setting of biochemical relapse

• CRAB criteria are still listed as the indication to treat in the relapsed setting– C: Calcium elevation (> 11.5 mg/L or ULN)

R: Renal dysfunction (serum creatinine > 2 mg/dL)A: Anemia (Hb < 10 g/dL or 2 g < normal)B: Bone disease (lytic lesions or osteoporosis)

Considerations in Patients With Relapsed/Refractory Myeloma

• Previous therapy • Response to previous therapy• Patient characteristics and other prognostic factors

– Older than 65 yrs of age– Increased β2-M, decreased serum albumin, low platelet count

– Cytogenetic abnormalities: del(13q), t(4;14)– Renal dysfunction

• Up to 50% of patients with MM have renal dysfunction• Between 20% and 30% of patients have concomitant renal

failure– Extensive bone disease; extramedullary MM

Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874. Facon T, et al. Blood. 2001;97:1566-1571. Barlogie B, et al. Blood. 2004;103:20-32. Fonseca R, et al. Cancer Res. 2004;64:1546-1558. Kyle RA. Stem Cells. 1995;13(suppl 2):56-63. Bladé J, et

al. Arch Intern Med. 1998;158:1889-1893.

1. Development of immune therapies

2. Development of new oral proteasome inhibitors

3. Development of rationally based combination therapies

4. Identification of novel targets

Current and Future Directions

Antibody-dependentCellular cytotoxicity

(ADCC)

ADCC

Effector cells:

MM

FcR

Complement-dependentCytotoxicity (CDC)

CDC

MM

C1q

C1q

Apoptosis/growth arrest

via targetingsignaling pathways

MM

Lucatumumab or Dacetuzumab (CD40) Elotuzumab (CS1) Daratumumab (CD38) XmAb5592 (HM1.24)

huN901-DM1 (CD56) nBT062-maytansinoid

(CD138) 1339 (IL-6) BHQ880 (DKK1) RAP-011 (activin A) Daratumumab (CD38)

Daratumumab (CD38)

MAb-Based Therapeutic Targeting of Myeloma

Tai & Anderson Bone Marrow Research 2011

Phase II: Elotuzumab + Len + Low-Dose Dex in Rel/Ref MM (Study 1703)

Len/dex: lenalidomide plus low dose dexamethasone†Progression defined by IMWG Criteria.

• Phase 2: Pts (n=73) with relapsed and/or refractory MM with 1-3 prior therapies were randomized to elotuzumab 10 or 20 mg/kg IV combined with– Lenalidomide 25 mg PO – Low-dose dexamethasone 40 mg PO

• Endpoints– Primary: ORR (≥PR per IMWG Criteria)– Key secondary endpoints: PFS and safety

Phase 2N=73

RANDOMIZE

Elotuzumab 10 mg/kg IV+ Len/dex

n=36

Elotuzumab 20 mg/kg IV + Len/dex

n=37

Phase 1*N=28

PROGRESSION†

*Lonial et al. J Clin Oncol. 2012Richardson et al. ASH 2012

Efficacy: Maximum Percent Reduction in Serum M Protein*

10 mg/kg Elotuzumab (n=36) 20 mg/kg Elotuzumab (n=29)†

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

Pe

rce

nta

ge

Ch

an

ge

fro

m B

as

eli

ne

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

30

40

50

60

Pe

rce

nta

ge

Ch

an

ge

fro

m B

as

eli

ne

*Maximum percentage decrease from baseline to 60 d after permanent discontinuation of elotuzumab or start of new line of MM therapy. †Eight pts without measurable disease (baseline and all on-study serum M-protein levels <0.5 g/dL) were not included.

Richardson et al. ASH 2012

ASH 2012: Progression Free Survival

At a median follow-up of 20.8 mos, median PFS has not been reached in the 10 mg/kg arm – Preliminary median PFS of 26.9 mos was reported in the abstract; after  2.7 mos of additional

follow-up, no new PD or death reported. These pts had an increased PFS duration, and in the updated analysis, median PFS was not yet reached

Median Time to Progression/Death:

10 mg/kg (n=36): not yet reached

20 mg/kg (n=37): 18.6 mos (95% CI 12.9-29.7)

0

10

20

30

40

50

60

70

80

90

100

0 3 6 9 12 15 18 21 24 27 30 33

Mos

Pro

po

rtio

n o

f P

rog

ress

ion

Fre

e P

ati

en

ts (

%)

36 32 30 29 23 20 18 18 13 9 3 0Number at Risk:

37 29 26 23 21 17 15 13 13 10 3 0

10 mg/kg

20 mg/kg

Richardson et al. ASH 2012

Phase 2 Elotuzumab + Lenalidomide Low-Dose Dex in Relapsed/Refractory MM

• Elotuzumab plus lenalidomide and low-dose dexamethasone has a high ORR in relapsed and relapsed/refractory MM

– 82% for all pts (91% in pts who had received only 1 prior therapy)

– 92% for pts treated with elotuzumab 10 mg/kg

Median PFS was 33 mos for patients receiving elotuzumab 10 mg/kg

• The combination was generally well tolerated

– Most common Grade 3/4 treatment-emergent AEs were neutropenia (16%), thrombocytopenia (16%), and lymphopenia (16%)

– Premedication regimen decreased incidence and mitigated severity of infusion reactions*

Richardson et al. ASH 2012, Lonial et al. ASCO 2013

Daratumumab A human CD38 mAb with broad-spectrum killing activity

Lokhorst et al. EHA 2012

18 of 29 patients in phase I benefit (5PR,4MR,9SD)

9 2

5

1 20

19 10 12 31

16 29 8 13

4 2615 3 7 11

1714

33

27

21 6 3018 34

23

32

22 28-100

-50

0

50

100

Re

leti

ve

ch

an

ge

in p

ara

pro

tein

e f

rom

ba

se

line

(%

)

Patient number

Daratumumab ResponseMaximal Change in Paraprotein

A AA A AA AAA

AAA AA AA AA AAB

BB B

CA

C C CCC C

2 mg/kg 4 mg/kg 8 mg/kg 16 mg/kg 24 mg/kg< 1 mg/kg

A: serum M-component B: urine M-component C: FLC

Phase I/Ii Study of Daratumumab Cd38 Monoclonal Antibody in Relapsed/Refractory Mm

• Favorable safety profile as monotherapy

• In 15 of 32 (47%) showed benefit

– 4 patients achieving PR (13%)– 6 patients achieving MR (19%)– 5 patients achieving SD (16%)

• At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%)

• To be combined with lenalidomide & dexamethasone

Plesner et al. ASH 2012 Abstr 73

Phase I Trial of Vaccination with DC/MM Fusions in Relapsed Refractory MM

• Well tolerated, no autoimmunity

• Induced tumor reactive lymphocytes in a majority of patients

• Induced humoral responses to novel antigens (SEREX analysis)

• Disease stabilization in 70% of patients

Rosenblatt et al. Blood 2011; 117:393-402.

• DC/MM fusions induce anti-MM immunity in vitro and inhibit MM cell growth in vivo in xenograft models

• Vasir et al. Brit J Hematol 2005; 129: 687-700

20S20S

19S

19S

a b5, 5i1, 1i2, 2i

ATPases/Cdc48

PotentialTherapeutic Targets

26S PROTEASOME

ATP ADP

UB enzymes E1, E2 andE3-UB-Ligases

UbUb

Ub

Poly-ubiquitinated proteins (proteasome substrates)

Free for re-cycling

Six Proteaseactivities

Degraded proteinUb

Immunoproteasome

Proteasome: Present and Future Therapies

DeubiquitylatingEnzymes (DUBs))

Bortezomib, Carfilzomib, CEP-18770ONX-0912MLN 2238

NPI-0052: 5, 1, 2

5

PR-924P5091 target USP-7

MLN2238/9708 Decreases Cell Viability in MM Cells and Overcomes Bortezomib Resistance

24h 48h

Chauhan et al. Clin Cancer Res, 2011; 17: 5311-21.

MLN9708 (Ixazomib) in Relapsed/Refractory MM

Relapsed and refractory

Refractory to most recent therapy (PD

while on or within 60 days of last therapy)

Expansion cohorts

Dose-escalation

cohorts

Dose-escalation: 3+3 schema, based on cycle 1 DLTs

(modified Fibonacci dose sequence)

0.24→0.48→0.8→1.2→1.68→2.23→2.97→3.95 mg/m2

Bortezomib-relapsed

Relapsed after previous bortezomib

therapy but not refractory

Proteasome inhibitor-naïve

Relapsed after ≥1 therapy including an IMiD compound, no proteasome inhibitor

Prior carfilzomib

Received prior carfilzomib and with

relapsed or refractory disease

MTD established

Oral single-agent MLN9708 administered on days 1, 8, and 15 of a 28-day cycle,for up to 12 cycles*

Kumar et al. ASCO 2013

Weekly MLN9708 in Relapsed/Refractory Multiple Myeloma: Phase I Study

• Single-agent oral MLN9708 MTD 2.97 mg/m2 on a weekly (days 1, 8, and 15 every 28 days) schedule

• Oral MLN9708 generally well tolerated– hematologic and gastrointestinal events generally manageable, low rate

of discontinuations – Infrequent PN, only 1 grade 3 PN

• Pharmacokinetic profile supports weekly oral dosing

• Relapsed and/or refractory MM patients (median 4 prior lines of therapy)– ORR (≥PR) of 18%, plus 2% MR and 30% SD, including relapse post

Bortezomib

Kumar et al. ASCO 2013

MLN9708 in Relapsed and/or Refractory MM: Expansion Cohorts of a Phase 1 Dose-Escalation Study

Richardson et al. ASH 2011

• 46 pts evaluable for response– 21 in dose-escalation cohorts– 30 in expansion cohorts (including 6 from dose-escalation cohorts)

• 6 pts have achieved ≥PR– 1 CR, confirmed by bone marrow (PI-naïve expansion cohort)– 5 PRs (1 each at 1.2 and 2.23 mg/m2 in dose-escalation cohorts; 1 in RRMM

and 2 in bortezomib-relapsed expansion cohorts)

• 1 pt achieved MR (bortezomib-relapsed expansion cohort; 40% M-protein reduction)

• All 7 pts remain in response, with duration of disease control of up to 15.9 months

• 28 pts have achieved SD– 14 in dose-escalation cohorts– 9, 5, and 2 in RRMM, bortezomib-relapsed, and PI-naïve expansion cohorts– Durable, with disease stabilization for up to 12.9 months

Phase 1/2 Study of MLN9708 Lenalidomide and Dex in Patients with Previously Untreated MM

• Oral weekly MLN9708, lenalidomide, and dexamethasone is well tolerated

– incidence of PN has been limited

At median drug exposure of 6 months, 92% PR or better, including ≥VGPR 55% and CR 23%

– Responses increased with number of cycles and deepened over time

– 88% of patients achieving CR who were evaluable for MRD status were confirmed as MRD-negative

• A phase 3 trial of MLN9708 plus lenalidomide–dexamethasone versus placebo plus lenalidomide–dexamethasone in patients with relapsed and/or refractory MM is currently enrolling (NCT01564537) for new drug approval

Kumar et al. ASH 2012 Abstr 332

• Phase I clinical trials ongoing

In Vitro Anti-MM Activity of Oral Chymotryptic Inhibitor ONX 0912 (Oprozomib)

Myeloma Cell Lines Patient Tumor Cells

Chauhan et al. Blood. 2010;116:490614.

Marizomib: A Non-Peptide Proteasome Inhibitor Induces Rapid, Broad and Prolonged Inhibition

Chauhan et al. Cancer Cell 2005; 8: 407-19.

• Exhibits high levels of proteasome inhibition

without toxicities associated with bortezomib

• Active in bortezomib and immunomodulator-resistant myeloma preclinically

Marizomib (NPI-0052)

HN

O

O

O

CH3

OH

Cl

H

H

H

Responses to Marizomib +/- Dexamethasone in Evaluable Pts at Full Dose [ >0.4 mg/m2 ]* Twice Weekly (n=21**)

Richardson et al. ASH 2011

All PtsEBMT ≥ SD 11/20 55%MR + PR 3/20 15%

Uniform Criteria ≥ SD 12/21 57%PR + VGPR 4/21 19%

Pts Exposed to Bortezomib EBMT ≥ SD 11/19 58%MR + PR 3/19 16%

Uniform Criteria ≥ SD 11/19 58%PR + VGPR 3/19 16%

*As of 05 Dec 11

• Response criteria defined with baseline SPEP ≥ 0.5 g/dL or UPEP ≥ 200 mg/24h with at least 2 assessments after treatment Day 1 for EBMT ; also by free lite for UC**.

• Refractory defined as having PD during or within 60 days of last regimen.

Pts Refractory to BortezomibEBMT ≥ SD 8/12 67%MR + PR 2/12 17%

Uniform Criteria ≥ SD 8/12 67%PR + VGPR 2/12 17%

Pts Refractory to LenalidomideEBMT ≥ SD 8/13 62%MR + PR 3/13 23%

Uniform Criteria ≥ SD 9/14 64%PR + VGPR 4/14 29%

Median Duration of Response (all Pts) = 133 days (~ 5 mos)

Additional Targeted Therapies in Development

• KSP inhibitors (ARRY-520)• AKT inhibitor (GSK2110183)• Nuclear transport inhibitors (KPT)• CDK inhibitors • BTK inhibitors• Bromodomain inhibitors

Protein

protein aggregates(toxic)

UbUb

UbUb

26S proteasome

UbUb

Ub Ub

Ub

Aggresome

Panobinostat,Vorinostat, ACY1215

dynein

UbUb

dynein

MicrotubuleAutophagy

Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912

Ub Ub

Ub

Lysosome

HDAC6

HDAC6

HDAC6

Ub

Ub

Development of Rationally based Combination Therapies (HDAC and Proteasome Inhibitors)

Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:3441-9.

VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat

or Placebo with Bortezomib in Relapsed MM

• The combination of vorinostat + bortezomib is active in patients with relapsed and refractory MM– Significant improvement in response rate– ORR 54% vs. 41% (P<0.0001); CBR 71% vs 53% (P<0.0001)

• PFS and TTP were prolonged in the combination arm compared with bortezomib alone

PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4)versus 6.83 months (5.7–7.7)

• Diarrhea, fatigue, and thrombocytopenia limited tolerability.

Dimopoulos et al. ASH 2011, Lancet Oncology, in press

Bench to Bedside Translation of HDAC 6 Selective Inhibitor ACY1215

Orally bioavailable, highly potent, selective inhibitor of HDAC 6 synthesized in fall 2009

Synergistic MM cytotoxicity with bortezomib in vitro and in vivo

Favorable PK/PD, toxicity profile

Phase Ia/Ib/II clinical trials of ACY1215, alone and with bortezomib and with lenalidomide/dexamethasone, ongoing; trials

with pomalidomide and carfilzomib this year.

Santo et al. Blood 2012;119:2579-89

Mutations in Myeloma19 Patients Each With Newly Diagnosed and Relapsed MM

Chapman et al. Nature 2011; 471: 467-72.

• Protein homeostasis: 42% including FAM46C, RPL10, RPS6KA1,

EIF3B, XBP1, LRRK2

• NF-kB signaling: 10 point mutations, 4 additional structural re-arrangements affecting codingConfers bortezomib sensitivity

• Histone methylating enzymes: WHSC1, UTX, MLL

• BRAF: 4% activating : Single patient MM response Andrulis et al Cancer Discovery 2013; 3: 862-9.

• PSMB5 b5 proteasome subunit mutation confers proteasome inhibitor resistance in laboratory, not identified in clinic

Lichter et al. Blood 2012: 120: 4513-16.

1. Development of immune therapies

2. Development of new oral proteasome inhibitors

3. Development of rationally based combination therapies

4. Identification of novel targets

Current and Future Directions

United Nations Against Myeloma:

Bench to Bedside Research TeamKenneth AndersonNikhil MunshiPaul RichardsonRobert SchlossmanIrene GhobrialSteven TreonJacob LaubachDeborah DossKathleen ColsonMary McKenneyKim NoonanTina FlahertyKathleen Finn Muriel GannonStacey ChumaJanet KunsmanDiane WarrenCarolyn RevtaAndrea FreemanAlexis FieldsAndrea KolligianJohn FeatherFarzana MasoodNora LoughneyHeather GoddardTiffany PoonNicole StavitzskiRanjit BanwaitShawna CormanHeather GoddardMeghan Marie LeahyCaitlin O’GallagherChristina TripsasKarin AndersonShannon VieraKatherine RedmanAmber WalshSamir AminWanling XieParantu ShahHolly BartelLisa PopitzJeffrey Sorrell

Teru HideshimaConstantine MitsiadesDharminder ChauhanNoopur RajeYu-Tzu TaiRuben CarrascoJames BradnerGullu GorgunJooeun BaeFrancesca CottiniMichele CeaAntonia CagnettaTeresa CalimeriEdie WellerAjita SinghZe TianDiana CirsteaYiguo HuNaoya MimuraJiro MinamiSun-Yung KongWeihua SongDouglas McMillinCatriona HayesSteffen KlippelJana JakubikovaPanisinee LawasutNiels van de DonkEugen DhimoleaJake DelmoreHannah JacobsMasood ShammasMariateresa FulcinitiJianhong LinJagannath PalSamantha PozziLoredana SantoClaire FabreAnuj MahindraRao PrabhalaJake DelmorePuru NanjappaMichael SellitoAvani Vaishnav

USA

UK

India

Italy

Japan

Canada

Germany

China

Greece

Taiwan

Australia

IrelandIsrael

Turkey

Austria