1. 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

2. 2013 ASH Abstract 406 Lenalidomide Maintenance after Stem-Cell Transplantation for Multiple Myeloma: Follow-up Analysis of the IFM 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

3. Study Design

4. Analysis After Relapse
Primary analysis: len had better PFS, same OS
Current data suggest len may cause myeloma chemoresistance
BUT …
PFS from Relapse
Median 2nd PFS
Placebo 24 Months
Lenalidomide 13 Months
OS from Relapse
Median survival
Placebo 48 Months
Lenalidomide Months

5. Choice of Second Line Therapy Matters
2nd line IMiD-based
2nd line bortezomib-based
P<0.003
P=0.28
Placebo
Placebo
LEN
LEN

6. Outline
Current standards of care and novel regimens that take advantage of them
Emerging agents showing activity in the relapsed and relapsed/refractory setting

7. Alegre, A et al. Haematologica. 87:609, 2002.
Types of Relapse
Alegre, A et al. Haematologica. 87:609, 2002.

8. Outcomes After Relapse From SCT
Zamarin, D et al. Bone Marrow Transplant. 48:419, 2013.

9. APEX : Bortezomib vs. Dex
78% improvement in median time-to-progression
1.0
Median TTP
All Pts
Post-1st relapse
0.9
Bortezomib
6.2 mos
7.0 mos
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 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.

10. SC vs. IV Bortezomib ± Dex
Response rate, %
Bortezomib IV ± dex (N=73)
Bortezomib SC ± dex (N=145)
ORR (CR + PR) 52
CR* 12 10 PR 40 42
nCR
VGPR 3 5
≥VGPR (CR + nCR + VGPR) 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%)
Moreau, P et al. Lancet Oncol. 12:431, 2011.

11. Moreau, P et al. Lancet Oncol. 12:431, 2011.
TTP of SC vs. IV Vd
100 90 80 70 60 50 40 30 20 10
ORR identical
after 4 cycles
Patients without PD (%)
IV : 9.4 months
SC: 10.4 months (0.839 HR; P-value )
Days from randomization
No. patients at risk IV SC
Moreau, P et al. Lancet Oncol. 12:431, 2011.

12. Bortezomib/PLD vs. Bortezomib
PLD + Bortezomib
9.3 months
Bortezomib
6.5 months
Statistical analysis:
HR (95% CI) 1.82 ( )
p =
Percent of Patients Progression-Free
100
200
300
400
500 20 40 60 80
Orlowski, RZ et al. J. Clin. Oncol. 25:3892, 2007.

13. Weber, DM et al. N. Engl. J. Med. 357:2133, 2007.
Len/Dex vs. Dex
Weber, DM et al. N. Engl. J. Med. 357:2133, 2007.

14. Carfilzomib : Approved in July, 2012
Results from PX 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.

15. Long-term Outcomes
Siegel, DS et al. Blood 120:2817, 2012.

16. 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.

17. Len/Carfilzomib/Dex
Wang, M et al. Blood 122:3122, 2013.

18. 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

19. Pomalidomide Efficacy Data
Richardson, P et al. Blood preprint online, 2014.

20. Richardson, P et al. Blood preprint online, 2014.
Durability Data
Richardson, P et al. Blood preprint online, 2014.

21. 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

22. Car/Pom/Dex Cycle 1-6: 28 day cycle Carfilzomib Pomalidomide9 15 16
Pomalidomide
Dexamethasone 1 8 15 22

23. Response Data Best overall response N=79 VGPR 21 (27%) PR 34 (43%) MR
10 (13%) SD
13 (16%) PD
1 (1%)
ORR = 70%
CBR =
83%

24. Long Term Outcomes

25. 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

26. Pomalidomide and Deletion 17p
Time to Progression
Response rate with pom/dex comparable in patients ± del 17p
Pom may overcome this poor risk lesion
del17p
t(4;14)
All
del17p
All
t(4;14)

27. Pomalidomide/Bortezomib/Dex
3 + 3 Design (21-day cycles)
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
3 (n = 3)
3 mg/day
4 (n = 3)
4 mg/day
5 (n = 3)
1.3 mg/m2
Expansion cohort (n = 6) at MTD/MPD
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.

28. Richardson, PG et al. ASH Abstract 727, 2012.
Response Summary
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
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.

29. Shah, JJ et al. ASH Abstract 75, 2012.
Len/Thal/Dex
N = 61
Overall Response Rate ( ≥ PR)
31 (51%)
Stable Disease
15 (25%)
Minimal Response
8 (13%)
Partial Response
19 (31%)
VGPR
4 (7%)
nCR/CR
Progressive Disease
7 (11%)
Clinical Benefit Ratio (≥ MR) of 64%
Shah, JJ et al. ASH Abstract 75, 2012.

30. Outcomes in Len Refractory Disease
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.

31. Outline
Current standards of care and novel regimens that take advantage of them
Emerging agents showing activity in the relapsed and relapsed/refractory setting

32. Novel Agents : Elotuzumab + Len/Dex
Elotuzumab 10 mg/kg
Elotuzumab 20 mg/kg
Total
Pts, n 31 32 63
≥ PR, n (%)
28 (90)
23 (72)
51 (81)
Stringent CR, n (%)
1 (3)
2 (3)
CR, n (%)
2 (7)
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)
Not evaluable, n (%)
2 (6)
Richardson, PG et al ASH Abstract 986.

33. 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.

34. Paraprotein Responses
< 1 mg/kg
2 mg/kg
4 mg/kg
8 mg/kg
16 mg/kg
24 mg/kg A A B A C A A A A A A B A B A A C A C C C A A A A A A B C A A C
Plesner, T et al. ASH Abstract 73, 2012.

35. 2013 ASH Abstract 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

36. Response Data

37. Adverse Events

38. 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

39. Response Data Binds different epitope than daratumumab CR PR MR
Median prior therapies = 6
Patients treated > 10 mg/kg Q2W >PR 30.8% SD
1 mg/kg Q2W
3 mg/kg Q2W PD
5 mg/kg Q2W
10 mg/kg Q2W
10 mg/kg QW
20 mg/kg Q2W NA 5 10 15 20 25 30 35 40 45 50 55 60 65 70 75
Week
Binds different epitope than daratumumab

40. 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

41. Analysis After Relapse
Dose
Cohort N
Best Unconfirmed Response NE PD SD MR PR
VGPR CR
sCR
ORR
(>PR )
CBR
(>MR)
Part 1 34 2 3 10 13 1
50%
56%
Part 2 37 7 14 8
65%
73%
PK/PD 5
40%

42. Activity by Prior Bortezomib Exposure
Naïve (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
4/9 (44%)
1/10 (10%)
Total
62%
61%
43%
Akt inhibition may be attractive in myeloma!

43. 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

44. Mechanism of Action

45. Study Design

46. Response Data

47. AAG and Outcomes

48. 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

49. TJP1 Sensitizes to Bortezomib
High TJP1 = Good response to bortezomib

50. Proteasomal Degradation
CRBN and IMiDs
Thalidomide
LEN
DDB1
Cul4A
CRBN ?
Proteasomal Degradation
Teratogenicity ?
Roc1
Multiple Myeloma
Lenalidomide
E3 Ubiquitin Ligase
Zhu et al, Blood 2011
Lopez-Girona et al, Leukemia 2012
Ito et al, Science 2010
Pomalidomide
Courtesy of Monica Schenone

51. Multiple Myeloma/ B-NHL
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
Lenalidomide
DDB1
Multiple Myeloma/ B-NHL
IL2 release
CRBN
Cul4A
IKZF1/3
IKZF1/3
Roc1
Pomalidomide
Jan Krönke and Investigators from Brigham and Women’s, Broad Institute and Dana-Farber Institute, ASH 2013 LBA-5

52. Strategy : Combos or Single Agents?
Garderet, L et al. J Clin Oncol. 30:2475, 2012.

53. 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

54. 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

55. 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

56. MDACC Myeloma Center Referral Line : 1-855-MYELOMA (toll-free)
Drs. Elisabet Manasanch, Robert Orlowski Jatin Shah, Sheeba Thomas, Michael Wang, Donna Weber 56