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Advances in the Management of Relapsed/Refractory Multiple Myeloma. Robert Z. Orlowski, Ph.D., M.D. Director, Myeloma Section Florence Maude Thomas Cancer Research Professor Departments of Lymphoma/Myeloma & Experimental Therapeutics

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advances in the management of relapsed refractory multiple myeloma

Advances in the Management of Relapsed/Refractory Multiple Myeloma

Robert Z. Orlowski, Ph.D., M.D.

Director, Myeloma Section

Florence Maude Thomas Cancer Research Professor

Departments of Lymphoma/Myeloma & Experimental Therapeutics

Principal Investigator, MD Anderson SPORE in Multiple Myeloma

Chair, Southwest Oncology Group Myeloma Committee

slide2

2013 ASH Abstract 406Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma: Follow-up Analysis of the IFM 2005-02 Trial Michel Attal, ValérieLauwers-Cances, GéraldMarit, Denis Caillot, Thierry Facon, CyrilleHulin, Philippe Moreau, Claire Mathiot, Murielle Roussel, Catherine Payen, Pascale Olivier, and HervéAvet-Loiseau

analysis after relapse
Analysis After Relapse

PFS from Relapse

  • Primary analysis: len had better PFS, same OS
  • Current data suggest len may cause myeloma chemoresistance
  • BUT …

Median2nd PFS

Placebo 24 Months

Lenalidomide 13 Months

OS from Relapse

Mediansurvival

Placebo 48 Months

Lenalidomide 29 Months

choice of second line therapy matters
Choice of Second Line Therapy Matters

2nd line bortezomib-based

2nd line IMiD-based

P<0.003

P=0.28

Placebo

Placebo

LEN

LEN

outline
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
Types of Relapse

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

outcomes after relapse from sct
Outcomes After Relapse From SCT

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

apex bortezomib vs dex
APEX : Bortezomib vs. Dex

78% improvement in median time-to-progression

1.0

Median TTP

All Pts

Post-1st relapse

0.9

6.2 mos

7.0 mos

Bortezomib

0.8

3.5 mos

5.6 mos

Dexamethasone

0.7

0.6

Proportion of patients

0.5

0.4

P = .0001

0.3

Bortezomib

0.2

Dexamethasone

0.1

0.0

0

30

60

90

120

150

180

210

240

270

300

330

360

390

420

450

Time (days)

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

sc vs iv bortezomib dex
SC vs. IV Bortezomib ± Dex

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

ttp of sc vs iv vd
TTP of SC vs. IV Vd

100

90

80

70

60

50

40

30

20

10

0

ORR identical

after 4 cycles

Patients without PD (%)

IV : 9.4 months

SC: 10.4 months (0.839 HR; P-value 0.38657)

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

Days from randomization

No. patients at riskIVSC

74 60 56 50 36 24 16 10 7 5 4 3 1 148 126 109 93 72 51 32 18 13 8 5 2 1

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

bortezomib pld vs bortezomib

100

PLD + Bortezomib

9.3 months

80

60

Bortezomib

6.5 months

Percent of Patients Progression-Free

40

Statistical analysis:

HR (95% CI) 1.82 (1.41-2.35)

p = 0.000004

20

0

0

100

200

300

400

500

Bortezomib/PLD vs. Bortezomib

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

len dex vs dex
Len/Dex vs. Dex

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

carfilzomib approved in july 2012
Carfilzomib : Approved in July, 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

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

long term outcomes
Long-term Outcomes

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

toxicities
Toxicities
  • 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

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

len carfilzomib dex
Len/Carfilzomib/Dex

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

pomalidomide approved in february 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
PomalidomideEfficacy Data

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

durability data
Durability Data

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

slide21

2013 ASH Abstract 690Phase I/II Dose Expansion of a Multi-Center Trial of Carfilzomib and Pomalidomidewith Dexamethasone (Car-Pom-d) in Patients with Relapsed/Refractory Multiple MyelomaJatin J. Shah, Edward A. Stadtmauer, RafatAbonour, 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
Car/Pom/Dex
  • Cycle 1-6: 28 day cycle

Carfilzomib

Pomalidomide

Dexamethasone

response data
Response Data

ORR = 70%

CBR =

83%

slide25

2013 ASH Abstract 689Pomalidomide +Low-dose Dexamethasone in Relapsed or Refractory Multiple Myeloma with Deletion 17p and/or Translocation t(4;14) Xavier Leleu, Lionel Karlin, Margaret Macro, CyrilleHulin, Laurent Garderet, Murielle Roussel, Bertrand Arnulf, Brigitte Pegourie, Brigitte Kolb, Anne-Marie Stoppa, Sabine Brechiniac, MauricetteMichallet, Gerald Marit, Claire Mathiot, Anne Banos, Laurence Lacotte, MouradTiab, Mamoun Dib, Jean-Gabriel Fuzibet, Marie-OdilePetillon, Philippe Rodon, Marc Wetterwald, Bruno Royer, Laurence Legros, LotfiBenboubker, Olivier Decaux, Denis Caillot, Martine Escoffre-Barbe, Jean Paul Fermand, Philippe Moreau, Michel Attal, HervéAvet-Loiseau, and Thierry Facon

pomalidomide and deletion 17p

del17p

All

t(4;14)

Pomalidomide and Deletion 17p
  • Response rate with pom/dex comparable in patients ± del 17p
  • Pom may overcome this poor risk lesion

Time to Progression

del17p

All

t(4;14)

pomalidomide bortezomib dex
Pomalidomide/Bortezomib/Dex

3 + 3 Design (21-day cycles)

Evaluation Every 21 Days (± 3 Days)

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

*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

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

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

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

len thal dex
Len/Thal/Dex

Clinical Benefit Ratio (≥ MR) of 64%

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

outcomes in len refractory disease
Outcomes in Len Refractory Disease

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.

outline1
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 dex
Novel Agents : Elotuzumab + Len/Dex

Richardson, PG et al. 2010 ASH Abstract 986.

other antibodies daratumumab
Other Antibodies : Daratumumab

Part 1

Open label, weekly i.v. infusion, 8 weeks

Dose-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

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

Expansion cohort

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

paraprotein responses
Paraprotein Responses

< 1 mg/kg

2 mg/kg

4 mg/kg

8 mg/kg

16 mg/kg

24 mg/kg

A

A

A

B

A

B

A

C

A

B

C

A

A

A

A

A

A

A

C

A

C

A

C

C

A

A

B

A

C

A

A

A

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

slide35

2013 ASH Abstract 1986Preliminary Safety and Efficacy Data of Daratumumabin Combination with Lenalidomide and Dexamethasone in Relapsed or Refractory Multiple MyelomaTorbenPlesner, Tobias Arkenau, HenkLokhorst, Peter Gimsing, JakubKrejcik, Charlotte Lemech, Monique C. Minnema, UlrikLassen, Andrew Cakana, Nikolai ConstantinBrun, Linda Basse, Antonio Palumbo, and Paul G. Richardson

slide38

2013 ASH Abstract 284SAR650984, a CD38 Monoclonal Antibody in Patients with Selected CD38+ Hematological Malignancies- Data from a Dose-Escalation Phase I StudyThomas G Martin III, Stephen A. Strickland, Martha Glenn, Wei Zheng, Nikki Daskalakis, and Joseph R. Mikhael

response data2
Response Data

CR

PR

  • Binds different epitope than daratumumab

MR

Median prior therapies = 6

Patients treated > 10 mg/kg Q2W >PR 30.8%

SD

1 mg/kg Q2W

3 mg/kg Q2W

5 mg/kg Q2W

PD

10 mg/kg Q2W

10 mg/kg QW

20 mg/kg Q2W

NA

0

5

10

15

20

25

30

35

40

45

50

55

60

65

70

75

Week

slide40

2013 ASH Abstract 283Novel AKT Inhibitor Afuresertibin 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, AjaiChari, Michael Rosenzwieg, Ajay K. Nooka, Cara A Rosenbaum, Craig C Hofmeister, Deborah A Smith, Joyce M Antal, Ademi Santiago-Walker, Jennifer Gauvin, Joanna B Opalinskaand Suzanne Trudel

activity by prior bortezomib exposure
Activity by Prior Bortezomib Exposure
  • Akt inhibition may be attractive in myeloma!
slide43

2013 ASH Abstract 285Prolonged 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 SagarLonial, JatinJ. 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

slide48

2013 ASH Abstract 123Identification of Tight Junction Protein (TJP)-1 as a Modulator and Biomarker of Proteasome Inhibitor Sensitivity in Multiple Myeloma Xing-Ding Zhang, VerrabhadranBaladandayuthapani, Heather Lin, George Mulligan, Bin Li, Dixie-Lee Esseltine, Lin Qi, Jian-Liang Xu, Walter Hunziker, Bart Barlogie, SaadUsmani, Qing Zhang, John Crowley, Bing-ZongLi, Hui-Han Wang, Jie-XinZhang, Isere Kuiatse, Jin-Le, Tang, HuaWang, Richard Eric Davis, Wen-CaiMa, Zhi-QiangWang, Lin Yang, and Robert Z. Orlowski

tjp1 sensitizes to bortezomib
TJP1 Sensitizes to Bortezomib
  • High TJP1 = Good response to bortezomib
crbn and imids
CRBN and IMiDs

Thalidomide

LEN

DDB1

Teratogenicity

CRBN

Cul4A

?

Multiple Myeloma

Roc1

Lenalidomide

E3 Ubiquitin Ligase

Zhu et al, Blood 2011

Lopez-Girona et al, Leukemia 2012

Ito et al, Science 2010

Pomalidomide

?

Proteasomal Degradation

Courtesy of Monica Schenone

ikaros imids
Ikaros & IMiDs
  • 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

Thalidomide

LEN

Multiple Myeloma/ B-NHL

Lenalidomide

IKZF1/3

IL2 release

DDB1

IKZF1/3

CRBN

Cul4A

Roc1

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
Strategy : Combos or Single Agents?

Garderet, L et al. J ClinOncol. 30:2475, 2012.

advances in the management of relapsed refractory myeloma summary

Advances in the Management of Relapsed/Refractory Myeloma : Summary

Robert Z. Orlowski, Ph.D., M.D.

Director, Myeloma Section

Florence Maude Thomas Cancer Research Professor

Departments of Lymphoma/Myeloma & Experimental Therapeutics

Principal Investigator, MD Anderson SPORE in Multiple Myeloma

Chair, Southwest Oncology Group Myeloma Committee

relapsed and or refractory myeloma
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 myeloma1
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
MDACC Myeloma Center

Referral Line : 1-855-MYELOMA (toll-free)

Drs. ElisabetManasanch, Robert Orlowski (rorlowsk@mdanderson.org), Jatin Shah, Sheeba Thomas, Michael Wang, Donna Weber

E-mail: myelomatrial@mdanderson.org

Twitter: @Myeloma_Doc