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Advances in the Management of Relapsed/Refractory
Multiple MyelomaRobert 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
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
Analysis After Relapse
P<0.001
0
10
20
30
40
50
60
70
80
90
100
Patie
nts
(%
)
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
Patie
nts
(%
)
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
0.0
00
.25
0.5
00
.75
1.0
0
0 20 40 60analysis time
Kaplan-Meier survival estimates
P<0.003
Placebo
LEN
0.0
00
.25
0.5
00
.75
1.0
0
0 10 20 30 40 50analysis time
Kaplan-Meier survival estimates
Placebo
LEN
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
APEX : Bortezomib vs. Dex78% improvement in median time-to-progression
Time (days)
P = .0001
Pro
por
tion
of
pat
ien
ts
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
30 60 90 120 150 180 210 240 270 300 330 360 390 420 450
Median TTPBortezomibDexamethasone
Bortezomib
Dexamethasone
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 52
CR* 12 10
PR 40 42
nCR 10 10
VGPR 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.
100
90
80
70
60
50
40
30
20
10
0
Pat
ien
ts w
ith
out
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.
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
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
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
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%)
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/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 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 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
Paraprotein Responses9 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
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
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
NBest Unconfirmed Response
NE
PD SD MR PR VGPR CR sCRORR (>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 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 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
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
CRBN and IMiDs
Courtesy of Monica Schenone
Multiple Myeloma
TeratogenicityDDB1
Cul
4A
CR
BN
Roc1
? ?
Proteasomal Degradation
Lenalidomide
Thalidomide
Pomalidomide
LEN
E3 Ubiquitin Ligase
Ito et al, Science 2010Zhu et al, Blood 2011Lopez-Girona et al, Leukemia 2012
Ikaros & IMiDs
DDB1
Cul
4A
CR
BN
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
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
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
([email protected]), Jatin Shah, Sheeba Thomas, Michael Wang, Donna Weber– E-mail: [email protected]– Twitter: @Myeloma_Doc