Advances in the Management of Relapsed/Refractory

Multiple MyelomaRobert Z. Orlowski, Ph.D., M.D.

Director, Myeloma SectionFlorence Maude Thomas Cancer Research Professor

Departments of Lymphoma/Myeloma & Experimental TherapeuticsPrincipal Investigator, MD Anderson SPORE in Multiple Myeloma

Chair, Southwest Oncology Group Myeloma Committee

2013 ASH Abstract 406

Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma: Follow-up

Analysis of the IFM 2005-02 Trial

Michel Attal, Valérie Lauwers-Cances, Gérald Marit, Denis Caillot, Thierry Facon, Cyrille Hulin, Philippe Moreau, Claire Mathiot, Murielle Roussel, Catherine Payen,

Pascale Olivier, and Hervé Avet-Loiseau

Study Design

Analysis After Relapse

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Pat

ient

s (%

)

241 161 90 45 11 2Placebo165 77 26 11 1 1Lenalidomide

N at risk

0 12 24 36 48 60

Months of follow-up

Lenalidomide

Placebo

Median 2nd PFSPlacebo 24 MonthsLenalidomide 13 Months

P<0.001

0

10

20

30

40

50

60

70

80

90

100

Pat

ient

s (%

)

241 209 161 101 44 7Placebo165 122 67 36 7 3Lenalidomide

N at risk

0 12 24 36 48 60

Months of follow-up

Lenalidomide

Placebo

Median survivalPlacebo 48 MonthsLenalidomide 29 Months

PFS from Relapse

OS from Relapse

• Primary analysis: len had better PFS, same OS

• Current data suggest len may cause myeloma chemoresistance

• BUT …

Choice of Second Line Therapy Matters

2nd line IMiD-based

0.00

0.25

0.50

0.75

1.00

0 20 40 60analysis time

Kaplan-Meier survival estimates

P<0.003

PlaceboLEN

0.00

0.25

0.50

0.75

1.00

0 10 20 30 40 50analysis time

Kaplan-Meier survival estimates

PlaceboLEN

P=0.28

2nd line bortezomib-based

Outline

• Current standards of care and novel regimens that take advantage of them

• Emerging agents showing activity in the relapsed and relapsed/refractory setting

Types of Relapse

Alegre, A et al. Haematologica. 87:609, 2002.

Outcomes After Relapse From SCT

Zamarin, D et al. Bone Marrow Transplant. 48:419, 2013.

APEX : Bortezomib vs. Dex78% improvement in median time-to-progression

Time (days)

P = .0001

Prop

ortio

n of

pat

ient

s

0.00.10.2

0.30.4

0.50.60.70.80.9

1.0

30 60 90 120 150 180 210 240 270 300 330 360 390 420 450

Median TTPBortezomibDexamethasone

BortezomibDexamethasone

0

All Pts Post-1st relapse6.2 mos3.5 mos

7.0 mos5.6 mos

Richardson, PG et al. N. Engl. J. Med. 352:2487, 2005.

SC vs. IV Bortezomib ± Dex

Moreau, P et al. Lancet Oncol. 12:431, 2011.

Response rate, %Bortezomib IV

± dex (N=73)Bortezomib SC ±

dex (N=145)

ORR (CR + PR) 52 52CR* 12 10PR 40 42

nCR 10 10VGPR 3 5

≥VGPR (CR + nCR + VGPR) 25 25

Response improvement (cycle 4 8) in patients who received dex, n/N (%)

n=39 n=82

PR CR 2/15 (13%) 4/31 (13%)<PR PR 7/23 (30%) 14/47 (30%)

TTP of SC vs. IV Vd

Moreau, P et al. Lancet Oncol. 12:431, 2011.

100908070605040302010

0

Patie

nts w

ithou

t PD

(%)

IV : 9.4 monthsSC: 10.4 months (0.839 HR; P-value 0.38657)

Days from randomization 74 60 56 50 36 24 16 10 7 5 4 3 1148 126 109 93 72 51 32 18 13 8 5 2 1

No. patients at riskIVSC

0 50 100 150 200 250 300 350 400 450 500 550 600

ORR identical after 4 cycles

Bortezomib/PLD vs. Bortezomib

PLD + Bortezomib9.3 months

Bortezomib6.5 months

Statistical analysis:HR (95% CI) 1.82 (1.41-2.35)

p = 0.000004

Per

cent

of P

atie

nts

Pro

gres

sion

-Fre

e

0 100 200 300 400 500

020

4060

8010

0

Orlowski, RZ et al. J. Clin. Oncol. 25:3892, 2007.

Len/Dex vs. Dex

Weber, DM et al. N. Engl. J. Med. 357:2133, 2007.

Carfilzomib : Approved in July, 2012

Siegel, DS et al. Blood 120:2817, 2012.

• Results from PX-171-003-A1 study of carfilzomib in patients with relapsed and refractory myeloma

• But, approved for patients who have had at least 2 prior lines of therapy

Long-term Outcomes

Siegel, DS et al. Blood 120:2817, 2012.

Toxicities

Siegel, DS et al. Blood 120:2817, 2012.

• Most notable for the lower risk of peripheral neuropathy overall, and especially for the low rates of grade 3 or 4 events in this category

Len/Carfilzomib/Dex

Wang, M et al. Blood 122:3122, 2013.

Pomalidomide : Approved in February, 2013

• Approval based on the results of the MM-002 study• For patients with at least two prior lines of therapy

Pomalidomide Efficacy Data

Richardson, P et al. Blood preprint online, 2014.

Durability Data

Richardson, P et al. Blood preprint online, 2014.

2013 ASH Abstract 690

Phase I/II Dose Expansion of a Multi-Center Trial of Carfilzomib and Pomalidomide with Dexamethasone

(Car-Pom-d) in Patients with Relapsed/Refractory Multiple Myeloma

Jatin J. Shah, Edward A. Stadtmauer, Rafat Abonour, Adam D. Cohen, William Bensinger, Cristina Gasparetto, Jonathan L. Kaufman, Suzanne Lentzsch, Dan T.

Vogl, Robert Z. Orlowski, Erica L. Kim, Natalia Bialas, David D. Smith, and Brian GM Durie

Car/Pom/Dex

1 2 8 9 15 16

1 8 15 22

1 21

Carfilzomib

Pomalidomide

Dexamethasone

• Cycle 1-6: 28 day cycle

Response Data

ORR = 70%CBR =

83%

Best overall response N=79

VGPR 21 (27%)PR 34 (43%)MR 10 (13%)SD 13 (16%)PD 1 (1%)

Long Term Outcomes

2013 ASH Abstract 689

Pomalidomide + Low-dose Dexamethasone in Relapsed or Refractory Multiple Myeloma with

Deletion 17p and/or Translocation t(4;14) Xavier Leleu, Lionel Karlin, Margaret Macro, Cyrille Hulin, Laurent Garderet, Murielle Roussel, Bertrand Arnulf, Brigitte Pegourie, Brigitte Kolb, Anne-Marie Stoppa, Sabine Brechiniac, Mauricette Michallet, Gerald Marit, Claire Mathiot,

Anne Banos, Laurence Lacotte, Mourad Tiab, Mamoun Dib, Jean-Gabriel Fuzibet, Marie-Odile Petillon, Philippe Rodon, Marc Wetterwald, Bruno Royer, Laurence Legros, Lotfi Benboubker, Olivier Decaux, Denis Caillot, Martine Escoffre-Barbe,

Jean Paul Fermand, Philippe Moreau, Michel Attal, Hervé Avet-Loiseau, and Thierry Facon

Pomalidomide and Deletion 17p

del17p

t(4;14) All

del17p

t(4;14) All

Time to Progression• Response rate

with pom/dex comparable in patients ± del 17p

• Pom may overcome this poor risk lesion

Pomalidomide/Bortezomib/Dex

Richardson, PG et al. ASH Abstract 727, 2012.

3 + 3 Design (21-day cycles)

Evaluation Every 21 Days (± 3 Days)

Follow-Up for OS and SPM Until 5 Years Post-enrollment

Cohort POM(D1-14)

BORT(D1, 4, 8, 11*)

LoDEX(D1-2, 4-5, 8-9, 11-12†)

1 (n = 3) 1 mg/day 1 mg/m2 20 mg‡

2 (n = 3) 2 mg/day 1 mg/m2 20 mg‡

3 (n = 3) 3 mg/day 1 mg/m2 20 mg‡

4 (n = 3) 4 mg/day 1 mg/m2 20 mg‡

5 (n = 3) 4 mg/day 1.3 mg/m2 20 mg‡

Expansion cohort (n = 6) at MTD/MPD*For cycles 1-8, then D1, 8 for cycles 9+; †For cycles 1-8, then D1-2, 8-9 for cycles 9+; ‡10 mg for pts aged > 75 yrs

Response Summary

• ORR (≥ PR): 73%; VGPR: 27%; SD: 27%• Median time to response: 1 cycle (range 1-2)• Most responses are ongoing

Cohort Best Response

Cohort 1 (n = 3) 1 VGPR, 1 PR, 1 SD

Cohort 2 (n = 3) 1 PR, 2 SD

Cohort 3 (n = 3) 2 VGPR, 1 PR

Cohort 4 (n = 3) 1 VGPR, 2 PR

Cohort 5 (n = 3) 2 PR, 1 SD

Richardson, PG et al. ASH Abstract 727, 2012.

Len/Thal/DexN = 61

Overall Response Rate ( ≥ PR) 31 (51%)

Stable Disease 15 (25%)

Minimal Response 8 (13%)

Partial Response 19 (31%)

VGPR 4 (7%)

nCR/CR 8 (13%)

Progressive Disease 7 (11%)

Clinical Benefit Ratio (≥ MR) of 64%

Shah, JJ et al. ASH Abstract 75, 2012.

Outcomes in Len Refractory DiseaseN = 41*

Overall Response 13 (34%)Stable Disease 12 (29%)Minimal Response 8 (20%)Partial Response 11 (27%)VGPR 1 (2%)CR / nCR 2 (5%)

Progressive Disease 7 (17%)

Lenalidomide Refractory: Clinical Benefit Ratio (≥ MR) of 51%

Lenalidomide Naïve: Overall Response (≥ PR) of 14/16 (88%)

Shah, JJ et al. ASH Abstract 75, 2012.

Outline

• Current standards of care and novel regimens that take advantage of them

• Emerging agents showing activity in the relapsed and relapsed/refractory setting

Novel Agents : Elotuzumab + Len/DexElotuzumab

10 mg/kgElotuzumab

20 mg/kg Total

Pts, n 31 32 63

≥ PR, n (%) 28 (90) 23 (72) 51 (81)

Stringent CR, n (%) 1 (3) 1 (3) 2 (3)

CR, n (%) 2 (7) 1 (3) 3 (5)

VGPR, n (%) 10 (32) 8 (25) 18 (29)

PR, n (%) 15 (48) 13 (41) 28 (44)

SD, n (%) 3 (10) 7 (22) 10 (16)

PD, n (%) 0 (0) 0 (0) 0 (0)

Not evaluable, n (%) 0 (0) 2 (6) 2 (3)

Richardson, PG et al. 2010 ASH Abstract 986.

Other Antibodies : Daratumumab

Plesner, T et al. ASH Abstract 73, 2012.

Expansion cohort

Dose-escalation

cohorts

Part 2

Open label, single arm, i.v. infusion

weekly: 8 weeks

every other week: 16 weeks

every fourth week: up to 96 weeks

8 mg/kg, 16 patients

Part 1

Open label, weekly i.v. infusion, 8 weeksDose-escalation: 3+3 scheme*

0.005→0.05→0.1→0.5→1.0 →2.0→4.0→8.0→16.0 →24.0 mg/kg

Paraprotein Responses9 2

5

1 20

19 10 12 3116 29 8 13

4 2615 3 7 11

1714

3327

21 6 3018 34

23

32

22 28-100

-50

0

50

100

Rel

etiv

e ch

ange

in p

arap

rote

ine

from

bas

elin

e (%

)

Patient number

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

Plesner, T et al. ASH Abstract 73, 2012.

2013 ASH Abstract 1986

Preliminary Safety and Efficacy Data of Daratumumab in Combination with Lenalidomide and

Dexamethasone in Relapsed or Refractory Multiple Myeloma

Torben Plesner, Tobias Arkenau, Henk Lokhorst, Peter Gimsing, Jakub Krejcik, Charlotte Lemech, Monique C. Minnema, Ulrik Lassen, Andrew Cakana, Nikolai

Constantin Brun, Linda Basse, Antonio Palumbo, and Paul G. Richardson

Response Data

Adverse Events

2013 ASH Abstract 284

SAR650984, a CD38 Monoclonal Antibody in Patients with Selected CD38+ Hematological Malignancies-

Data from a Dose-Escalation Phase I Study

Thomas G Martin III, Stephen A. Strickland, Martha Glenn, Wei Zheng, Nikki Daskalakis, and Joseph R. Mikhael

Response DataCR

PR

MR

SD

PD

NA0 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

Median prior therapies = 6 Patients treated > 10 mg/kg

Q2W >PR 30.8%

• Binds different epitope than daratumumab

2013 ASH Abstract 283

Novel AKT Inhibitor Afuresertib in Combination with Bortezomib and Dexamethasone Demonstrates

Favorable Safety Profile and Significant Clinical Activity in Patients with Relapsed/Refractory Multiple

Myeloma

Peter M Voorhees, Andrew Spencer, Heather J. Sutherland, Michael E O'Dwyer, Shang-Yi Huang, Keith Stewart, Ajai Chari, Michael Rosenzwieg, Ajay K. Nooka, Cara A Rosenbaum, Craig C Hofmeister, Deborah A Smith, Joyce M Antal, Ademi

Santiago-Walker, Jennifer Gauvin, Joanna B Opalinska and Suzanne Trudel

Analysis After Relapse

DoseCohort N

Best Unconfirmed ResponseNE PD SD MR PR VGPR CR sCR ORR

(>PR )CBR

(>MR)Part 1 34 2 3 10 2 13 3 1 50% 56%Part 2 37 7 1 2 3 14 8 2 65% 73%PK/PD 10 1 5 3 1 40% 40%

Activity by Prior Bortezomib Exposure

Bortezomib ExposureNaïve (n=13)

Relapsed (n=44)

Refractory (n=23)

Unk

Part 1 2/3 (67%) 10/18 (56%) 5/13 (38%) -Part 2 6/10 (60%) 17/26 (65%) 1/1 (100%) -PK/PD NA NA 4/9 (44%) 1/10 (10%)Total 62% 61% 43% 1/10 (10%)

• Akt inhibition may be attractive in myeloma!

2013 ASH Abstract 285

Prolonged Survival and Improved Response Rates with ARRY-520 in Relapsed/Refractory Multiple Myeloma (RRMM) Patients with Low α-1 Acid

Glycoprotein (AAG) Levels: Results From a Phase 2 Study

Sagar Lonial, Jatin J. Shah, Jeffrey Zonder, William I. Bensinger, Adam D. Cohen, Jonathan L. Kaufman, Ajay K. Nooka, Donna M. Weber, Brandi Hilder, Selena A

Rush, Ann Ptaszynski, Duncan Walker, and Robert Z. Orlowski

Mechanism of Action

Study Design

Response Data

AAG and Outcomes

2013 ASH Abstract 123

Identification of Tight Junction Protein (TJP)-1 as a Modulator and Biomarker of Proteasome Inhibitor

Sensitivity in Multiple Myeloma

Xing-Ding Zhang, Verrabhadran Baladandayuthapani, Heather Lin, George Mulligan, Bin Li, Dixie-Lee Esseltine, Lin Qi, Jian-Liang Xu, Walter Hunziker, Bart Barlogie, Saad Usmani, Qing Zhang, John Crowley, Bing-Zong Li, Hui-Han Wang,

Jie-Xin Zhang, Isere Kuiatse, Jin-Le, Tang, Hua Wang, Richard Eric Davis, Wen-Cai Ma, Zhi-Qiang Wang, Lin Yang, and Robert Z. Orlowski

TJP1 Sensitizes to Bortezomib• High TJP1

= Good response to bortezomib

CRBN and IMiDs

Courtesy of Monica Schenone

Multiple Myeloma

TeratogenicityDDB1

Cul

4A

CRBN

Roc1

? ?

Proteasomal Degradation

Lenalidomide

Thalidomide

Pomalidomide

LEN

E3 Ubiquitin Ligase

Ito et al, Science 2010 Zhu et al, Blood 2011Lopez-Girona et al, Leukemia 2012

Ikaros & IMiDs

DDB1

Cul

4A

CRBN

Roc1IKZF1/3

Multiple Myeloma/ B-NHL

IL2 release

IKZF1/3

LEN

• First drug described to increase ubiquitin ligase activity – by inducing ubiquitination of IKZF1 and IKZF3

• Might help to develop new drugs that similarly target other “undruggable” proteins

Lenalidomide

Thalidomide

Pomalidomide

Jan Krönke and Investigators from Brigham and Women’s, Broad Institute and Dana-Farber Institute, ASH 2013 LBA-5

Strategy : Combos or Single Agents?

Garderet, L et al. J Clin Oncol. 30:2475, 2012.

Robert Z. Orlowski, Ph.D., M.D.Director, Myeloma Section

Florence Maude Thomas Cancer Research ProfessorDepartments of Lymphoma/Myeloma & Experimental TherapeuticsPrincipal Investigator, MD Anderson SPORE in Multiple Myeloma

Chair, Southwest Oncology Group Myeloma Committee

Advances in the Management of Relapsed/Refractory Myeloma : Summary

Relapsed and/or Refractory Myeloma

• Current portfolio of drugs includes 1st and 2nd generation PIs & IMiDs

• Novel combination regimens can be used that provide additional options

• Combining an IMiD with a PI probably results in greater benefit than relying on only one

• Select treatment based on past and most recent lines, since sequence of therapy really matters

Relapsed and/or Refractory Myeloma

• Monoclonal antibodies with single-agent activity (daratumumab, SAR650984) or in combinations (these and elotuzumab) are attractive approaches

• Novel agents with new mechanisms of action (filanesib, afuresertib) will be entering registration studies

• Better molecular understanding of myeloma will allow us to personalize therapy

MDACC Myeloma Center

• Referral Line : 1-855-MYELOMA (toll-free)• Drs. Elisabet Manasanch, Robert Orlowski

(rorlowsk@mdanderson.org), Jatin Shah, Sheeba Thomas, Michael Wang, Donna Weber– E-mail: myelomatrial@mdanderson.org– Twitter: @Myeloma_Doc