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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
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
Study Design
Analysis After Relapse
90
Lenalidomide
Placebo
80
Median 2nd PFS
Placebo
24 Months
Lenalidomide 13 Months
Patients (%)
70
60
50
P<0.001
40
30
20
10
0
0
12
24
36
48
60
1
11
1
2
Months of follow-up
N at risk
Lenalidomide 165
Placebo 241
77
161
26
90
11
45
OS from Relapse
100
Lenalidomide
90
Placebo
80
70
Patients (%)
• Primary analysis: len
had better PFS, same
OS
• Current data suggest
len may cause
myeloma
chemoresistance
• BUT …
PFS from Relapse
100
60
50
P<0.001
40
Median survival
Placebo
48 Months
Lenalidomide 29 Months
30
20
10
0
0
12
24
36
48
60
7
44
3
7
Months of follow-up
N at risk
Lenalidomide 165
Placebo 241
122
209
67
161
36
101
Choice of Second Line Therapy Matters
2nd line bortezomib-based
2nd line IMiD-based
1.00
Kaplan-Meier survival estimates
0.75
0.75
1.00
Kaplan-Meier survival estimates
P=0.28
0.50
0.50
P<0.003
0.25
0.25
Placebo
Placebo
LEN
0.00
0.00
LEN
0
20
40
analysis time
60
0
10
20
30
analysis time
40
50
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. Dex
78% improvement in median time-to-progression
1.0
Median TTP
Bortezomib
Dexamethasone
Proportion of patients
0.9
0.8
0.7
All Pts Post-1st relapse
6.2 mos
7.0 mos
3.5 mos
5.6 mos
0.6
0.5
0.4
P = .0001
0.3
Bortezomib
Dexamethasone
0.2
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
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
25
25
n=39
n=82
PR  CR
2/15 (13%)
4/31 (13%)
<PR  PR
7/23 (30%)
14/47 (30%)
≥VGPR (CR + nCR + VGPR)
Response improvement (cycle 4  8)
in patients who received dex, n/N (%)
Moreau, P et al. Lancet Oncol. 12:431, 2011.
Patients without PD (%)
TTP of SC vs. IV Vd
100
90
80
70
60
50
40
30
20
10
0
ORR identical
after 4 cycles
IV : 9.4 months
SC: 10.4 months (0.839 HR; P-value 0.38657)
0
50
100
150
200
No. patients at risk Days from randomization
IV
74
60
56
50
36
SC
148
126
109
93
72
250
300
350
400
450
500
550
600
24
51
16
32
10
18
7
13
5
8
4
5
3
2
1
1
Moreau, P et al. Lancet Oncol. 12:431, 2011.
100
Bortezomib/PLD vs. Bortezomib
Percent of Patients Progression-Free
20
40
60
80
PLD + Bortezomib
9.3 months
Bortezomib
6.5 months
0
Statistical analysis:
HR (95% CI) 1.82 (1.41-2.35)
p = 0.000004
0
100
200
300
400
Orlowski, RZ et al. J. Clin. Oncol. 25:3892, 2007.
500
Len/Dex vs. Dex
Weber, DM et al. N. Engl. J. Med. 357:2133, 2007.
Carfilzomib : Approved in July, 2012
• Results from PX-171003-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
Siegel, DS et al. Blood 120:2817, 2012.
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
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
• Cycle 1-6: 28 day cycle
Carfilzomib
1 2
8 9
15
16
Pomalidomide
1
21
Dexamethasone
1
8
15
22
Response Data
Best overall response
VGPR
PR
MR
SD
PD
N=79
21 (27%)
34 (43%)
10 (13%)
13 (16%)
1 (1%)
ORR = 70%
CBR =
83%
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
Time to Progression
del17p
del17p
t(4;14)
t(4;14)
All All
• Response rate
with pom/dex
comparable in
patients ± del
17p
• Pom may
overcome this
poor risk lesion
Pomalidomide/Bortezomib/Dex
3 + 3 Design (21-day cycles)
POM
BORT
LoDEX
(D1-14)
(D1, 4, 8, 11*)
(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‡
Cohort
Evaluation
Every 21 Days
(± 3 Days)
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
Richardson, PG et al. ASH Abstract 727, 2012.
Follow-Up for
OS and SPM
Until 5 Years
Post-enrollment
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.
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 Disease
N = 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/Dex
Elotuzumab
10 mg/kg
Elotuzumab
20 mg/kg
Total
31
32
63
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)
Pts, n
≥ PR, n (%)
Richardson, PG et al. 2010 ASH Abstract 986.
Other Antibodies : Daratumumab
Part 1
Doseescalation
cohorts
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
Part 2
Open label, single arm, i.v. infusion
Expansion
cohort
weekly: 8 weeks
every other week: 16 weeks
every fourth week: up to 96 weeks
8 mg/kg, 16 patients
Plesner, T et al. ASH Abstract 73, 2012.
Paraprotein Responses
9
2
Reletive change in paraproteine from baseline (% )
100
< 1 mg/kg
50
2 mg/kg
4 mg/kg
8 mg/kg
16 mg/kg
24 mg/kg
5
1
20
19 10 12
31
16 29
0
C C A A A A A A B C A
8
13
A C
A A B A C A A A A A A B A B A A C A C
4
26
15
3
7
11
17
14
33
27
-50
21
6
30
18
34
23
32
-100
22 28
Patient number
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 MalignanciesData 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 Data
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
5 mg/kg Q2W
10 mg/kg Q2W
10 mg/kg QW
20 mg/kg Q2W
PD
NA
0
5
10
15
20
25
30
35
40
45
50
55
60
65
70
Week
• Binds different epitope than daratumumab
75
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
Dose
N
Cohort
Best Unconfirmed Response
N
E
PD SD
MR
PR VGPR
Part 1 34
2
3
10
2
13
3
Part 2 37
7
1
2
3
14
8
1
5
3
1
PK/PD 10
CR
sCR
1
2
ORR
(>PR )
CBR
(>MR)
50%
56%
65%
73%
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
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
O
O
NH
N
O
O
Thalidomide
LEN
O
O
NH
DDB1
O
NH
N
O
NH2
Lenalidomide
O
O
NH2
Teratogenicity
?
?
Roc1
Proteasomal
Degradation
Multiple Myeloma
E3 Ubiquitin Ligase
NH
N
O
NH2
Cul4A
O
N
O
O
Pomalidomide
Ito et al, Science 2010
Zhu et al, Blood 2011
Lopez-Girona et al, Leukemia
2012
Courtesy of Monica Schenone
Ikaros & IMiDs
O
O
NH
N
O
•First drug described to increase ubiquitin ligase activity – by
inducing ubiquitination of IKZF1 and IKZF3
O
Thalidomide
O
O
•Might help to develop new drugs that similarly target other
“undruggable” proteins
NH
N
O
LEN
NH2
O
Lenalidomide
O
NH
N
NH
DDB1
Cul4A
O
O
Roc1
NH2
O
O
N
O
Multiple
Myeloma/ B-NHL
NH2
IKZF1/
3
IKZF1/3
Pomalidomide
Jan Krönke and Investigators from Brigham and Women’s, Broad Institute and Dana-Farber Institute, ASH 2013
LBA-5
IL2 release
Strategy : Combos or Single Agents?
Garderet, L et al. J Clin Oncol. 30:2475, 2012.
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
• 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