Transcript MLN9708 in Relapsed and/or Refractory MM

Experimental Agents for Relapsed/Refractory
Myeloma - Current Trials in Context
Kenneth C. Anderson, M.D.
Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Harvard Medical School
Conflict of Interest: Kenneth C. Anderson, M.D.
Consultancy: Celgene, Onyx, Sanofi Aventis, and
Gilead
Scientific Founder: Acetylon, Oncopep
Integration of Novel Therapy
Into Myeloma Management
Bortezomib, Lenalidomide, Thalidomide, Pegylated
Liposomal Doxorubicin, Carfilzomib, Pomalidamide
Target MM in the BM microenvironment to overcome
conventional drug resistance in vitro and in vivo
Effective in relapsed/refractory, relapsed,
induction, consolidation, and
maintenance therapy
Eight FDA approvals and median survival prolonged
from 3-4 to 6-7 years, with additional prolongation
from maintenance
New approaches needed to treat and ultimately
prevent relapse
Targeting Growth, Survival, and Drug Resistance of MM
MM
in BM Microenvironment
migration
CD40
Cell surface
targets
BAFF-R
GSK-3
FKHR
PKC
Survival
Caspase-9
Anti-apoptosis
Akt
NF-B
Cell cycle
mTOR
PI3-K
Bad
Survival
Bcl-xL
JAK/STAT3
Anti-apoptosis
Mcl-1
Raf
VEGFR
NF-B
Cytokines
IL-6, VEGF
IGF-1, SDF-1
BAFF, APRIL
BSF-3
TNF
TGF
VEGF
MEK/ERK
Bcl-xL
IAP
Cyclin-D
MEK/ERK
p27Kip1
proliferation
Survival
Anti-apoptosis
Cell cycle
Proliferation
Anti-apoptosis
Smad, ERK
cytokines
BMSC
Adhesion
NF-B
NF-B
NF-B
Hideshima T and Anderson KC. Nat Rev Cancer 2007,
adhesion
molecules
LFA-1
ICAM-1
VCAM-1
Fibronectin
MUC-1
VLA-4
SC
Overview of Phase III Trials with Len and
Bortezomib in Relapsed/Refractory MM
ORR, CR or ≥ VGPR,
%
nCR, %
%
Regimen
Trial
Len + dex
MM-009[1]
Len + dex
[2]
61
24
NE
DOR,
Mos
16
TTP or
PFS,
Mos
11
Median
OS,
Mos
35[5]
MM-010
60
25
NE
17
11
Bortezomib
APEX[3]
43
16
NE
8
6
30
Vdox
MMY3001[4]
44
13
27
10
9
NE
1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. 3. Richardson PG, et al. Blood.
2007;110:3557-3560. 4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-3901. 5. Weber D, et al. Blood. 2007;110:Abstract 412.
Efficacy and Toxicity by Bortezomib
schedule
VMP*
(VISTA)
VMP
twice weekly N=63
VMP
once weekly N=190
CR
30%
27%
23%
PFS @ 3 years
NA
32%
35%
Any grade
44%
43%
21%
Grade 3-4
13%
14%
2%
PN discontinuation
NA
16%
4%
Total planned dose
67.6
67.6 mg/m2
46.8 mg/m2
Total delivered dose
NA
41 mg/m2
40 mg/m2
Sensory PN
*Mateos et al. J Clin Oncol 2010; PN: peripheral neuropathy
Palumbo et al. ASH 2010 abstr 620
SC vs. IV Bortezomib for
Relapsed/Refractory Myeloma
Moreau et al. ASH 2010 abstr 312
EQUIVALENT EFFICACY
Bortezomib IV
(N=74)
Bortezomib SC
(N=148)
Pvalue*
Any PN event, %
53
38
0.04
Grade 2, %
41
24
0.01
Grade 3, %
16
6
0.03
Grade 1 PN at baseline
28
23
Diabetes at baseline
11
13
Exposure to prior neurotoxic agents
85
86
Peripheral Neuropathy
Risk factors for PN, %
*P-values are based on 2-sided Fisher’s exact test
When to Consider Retreatment
• Differences between biochemical relapse and symptomatic
relapse need to be considered
• Patients with asymptomatic rise in M-protein can be
observed to determine the rate of rise and nature of the
relapse
– Caveat: patients with known aggressive or high-risk disease
should be considered for salvage even in the setting of
biochemical relapse
• CRAB criteria are still listed as the indication to treat in the
relapsed setting
– C: Calcium elevation (> 11.5 mg/L or ULN)
R: Renal dysfunction (serum creatinine > 2 mg/dL)
A: Anemia (Hb < 10 g/dL or 2 g < normal)
B: Bone disease (lytic lesions or osteoporosis)
Considerations in Patients With
Relapsed/Refractory Myeloma
• Previous therapy
• Response to previous therapy
• Patient characteristics and other prognostic factors
– Older than 65 yrs of age
– Increased β2-M, decreased serum albumin, low platelet count
– Cytogenetic abnormalities: del(13q), t(4;14)
– Renal dysfunction
• Up to 50% of patients with MM have renal dysfunction
• Between 20% and 30% of patients have concomitant renal
failure
– Extensive bone disease; extramedullary MM
Kyle RA, et al. Mayo Clin Proc. 2003;78:21-33. Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874. Facon T, et al. Blood. 2001;97:1566-1571.
Barlogie B, et al. Blood. 2004;103:20-32. Fonseca R, et al. Cancer Res. 2004;64:1546-1558. Kyle RA. Stem Cells. 1995;13(suppl 2):56-63. Bladé J, et
al. Arch Intern Med. 1998;158:1889-1893.
Current and Future Directions
1. Development of immune therapies
2. Development of new oral proteasome inhibitors
3. Development of rationally based combination therapies
4. Identification of novel targets
MAb-Based Therapeutic Targeting of Myeloma
Antibody-dependent
Cellular cytotoxicity
(ADCC)
Complement-dependent
Cytotoxicity (CDC)
Apoptosis/growth
arrest
via targeting
signaling pathways
C1q
C1q
Effector cells:
CDC
MM
MM
ADCC
FcR
 Daratumumab (CD38)
MM




Lucatumumab or Dacetuzumab (CD40)
Elotuzumab (CS1)
Daratumumab (CD38)
XmAb5592 (HM1.24)
 huN901-DM1 (CD56)
 nBT062-maytansinoid
(CD138)
 1339 (IL-6)
 BHQ880 (DKK1)
 RAP-011 (activin A)
 Daratumumab (CD38)
Tai & Anderson Bone Marrow Research 2011
Phase II: Elotuzumab + Len + Low-Dose Dex in
Rel/Ref MM (Study 1703)
Phase 1*
N=28
Phase 2
N=73
R
A
N
D
O
M
I
Z
E
Elotuzumab 10 mg/kg IV
+ Len/dex
n=36
Elotuzumab 20 mg/kg IV
+ Len/dex
n=37
P
R
O
G
R
E
S
S
I
O
N†
• Phase 2: Pts (n=73) with relapsed and/or refractory MM with 1-3 prior therapies were
randomized to elotuzumab 10 or 20 mg/kg IV combined with
–
–
Lenalidomide 25 mg PO
Low-dose dexamethasone 40 mg PO
• Endpoints
–
–
Primary: ORR (≥PR per IMWG Criteria)
Key secondary endpoints: PFS and safety
Len/dex: lenalidomide plus low dose dexamethasone
†Progression defined by IMWG Criteria.
*Lonial et al. J Clin Oncol. 2012
Richardson et al. ASH 2012
Efficacy: Maximum Percent Reduction in
Serum M Protein*
60
10 mg/kg Elotuzumab (n=36)
50
50
40
40
30
30
20
10
0
-10
-20
-30
-40
-50
-60
-70
Percentage Change from Baseline
Percentage Change from Baseline
60
20 mg/kg Elotuzumab (n=29)†
20
10
0
-10
-20
-30
-40
-50
-60
-70
-80
-80
-90
-90
-100
-100
*Maximum percentage decrease from baseline to 60 d after permanent discontinuation of elotuzumab or
start of new line of MM therapy.
†Eight pts without measurable disease (baseline and all on-study serum M-protein levels <0.5 g/dL) were
not included.
Richardson et al. ASH 2012
ASH 2012: Progression Free Survival
Proportion of
Progression Free Patients (%)
100
90
80
70
60
10 mg/kg
50
40
20 mg/kg
30
Median Time to Progression/Death:
20
10 mg/kg (n=36): not yet reached
10
20 mg/kg (n=37): 18.6 mos (95% CI 12.9-29.7)
0
0
Number at Risk:
36
37
3
6
9
12
15
18
21
24
27
30
33
18
15
18
13
13
13
9
10
3
3
0
0
Mos
32
29
30
26
29
23
23
21
20
17
At a median follow-up of 20.8 mos, median PFS has not been reached in the 10 mg/kg arm
– Preliminary median PFS of 26.9 mos was reported in the abstract; after 2.7 mos of additional
follow-up, no new PD or death reported. These pts had an increased PFS duration, and in the
updated analysis, median PFS was not yet reached
Richardson et al. ASH 2012
Phase 2 Elotuzumab + Lenalidomide LowDose Dex in Relapsed/Refractory MM
• Elotuzumab plus lenalidomide and low-dose dexamethasone has a
high ORR in relapsed and relapsed/refractory MM
– 82% for all pts (91% in pts who had received only 1 prior therapy)
– 92% for pts treated with elotuzumab 10 mg/kg
Median PFS was 33 mos for patients receiving elotuzumab
10 mg/kg
• The combination was generally well tolerated
– Most common Grade 3/4 treatment-emergent AEs were neutropenia
(16%), thrombocytopenia (16%), and lymphopenia (16%)
– Premedication regimen decreased incidence and mitigated severity
of infusion reactions*
Richardson et al. ASH 2012, Lonial et al. ASCO 2013
Daratumumab
A human CD38 mAb with broad-spectrum killing activity
18 of 29 patients in phase I benefit (5PR,4MR,9SD)
Lokhorst et al. EHA 2012
Daratumumab Response
Maximal Change in Paraprotein
A: serum M-component
9
B: urine M-component
C: FLC
2
100
Reletive change in paraproteine from baseline (% )
< 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
8
A A B A C A A A A A A B A B A A C A C
13
C C A A A A A A B C A
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
Phase I/Ii Study of Daratumumab Cd38
Monoclonal Antibody in Relapsed/Refractory Mm
• Favorable safety profile as monotherapy
• In 15 of 32 (47%) showed benefit
– 4 patients achieving PR (13%)
– 6 patients achieving MR (19%)
– 5 patients achieving SD (16%)
• At doses 4mg/kg and above, 8 of the 12 patients had at least MR
(66%)
• To be combined with lenalidomide & dexamethasone
Plesner et al. ASH 2012 Abstr 73
Phase I Trial of Vaccination with DC/MM
Fusions in Relapsed Refractory MM
• Well tolerated, no
autoimmunity
• Induced tumor reactive
lymphocytes in a majority of
patients
• Induced humoral responses
to novel antigens (SEREX
analysis)
•
•
DC/MM fusions induce anti• Disease stabilization in 70%
MM immunity in vitro and
of patients
inhibit MM cell growth in
vivo in xenograft models
Vasir et al. Brit J Hematol 2005; 129: 687-700
Rosenblatt et al. Blood 2011; 117:393-402.
Proteasome: Present and Future Therapies
Potential
Therapeutic Targets
UB enzymes E1, E2 and
E3-UB-Ligases
Deubiquitylating
Enzymes (DUBs))
Ub
Ub
ATPases/
Cdc48
Ub
P5091 target USP-7
ATP
Poly-ubiquitinated proteins
(proteasome substrates)
Immunoproteasome
ADP
PR-924
19S
Six Protease
activities
20S
 
20S
5, 5i
1, 1i
2, 2i
19S
Free
5
NPI-0052: 5, 1, 2
Ub
for re-cycling
Bortezomib,
Carfilzomib,
CEP-18770
ONX-0912
MLN 2238
Degraded protein
26S PROTEASOME
MLN2238/9708 Decreases Cell Viability in MM
Cells and Overcomes Bortezomib Resistance
24h
48h
Chauhan et al. Clin Cancer Res, 2011; 17: 5311-21.
MLN9708 (Ixazomib) in Relapsed/Refractory MM
Oral single-agent MLN9708 administered on days 1, 8, and 15 of a 28-day cycle,
for up to 12 cycles*
Doseescalation
cohorts
Dose-escalation: 3+3 schema, based on cycle 1 DLTs
(modified Fibonacci dose sequence)
0.24→0.48→0.8→1.2→1.68→2.23→2.97→3.95 mg/m2
MTD established
Expansion cohorts
Relapsed and
refractory
Bortezomibrelapsed
Proteasome
inhibitor-naïve
Prior carfilzomib
Refractory to most
recent therapy (PD
while on or within 60
days of last therapy)
Relapsed after
previous bortezomib
therapy but not
refractory
Relapsed after ≥1
therapy including an
IMiD compound, no
proteasome inhibitor
Received prior
carfilzomib and with
relapsed or refractory
disease
Kumar et al. ASCO 2013
Weekly MLN9708 in Relapsed/Refractory
Multiple Myeloma: Phase I Study
• Single-agent oral MLN9708 MTD 2.97 mg/m2 on a weekly (days 1,
8, and 15 every 28 days) schedule
• Oral MLN9708 generally well tolerated
– hematologic and gastrointestinal events generally manageable, low rate
of discontinuations
– Infrequent PN, only 1 grade 3 PN
• Pharmacokinetic profile supports weekly oral dosing
• Relapsed and/or refractory MM patients (median 4 prior lines of
therapy)
– ORR (≥PR) of 18%, plus 2% MR and 30% SD, including relapse post
Bortezomib
Kumar et al. ASCO 2013
MLN9708 in Relapsed and/or Refractory MM:
Expansion Cohorts of a Phase 1 Dose-Escalation Study
Richardson et al. ASH 2011
• 46 pts evaluable for response
– 21 in dose-escalation cohorts
– 30 in expansion cohorts (including 6 from dose-escalation cohorts)
• 6 pts have achieved ≥PR
– 1 CR, confirmed by bone marrow (PI-naïve expansion cohort)
– 5 PRs (1 each at 1.2 and 2.23 mg/m2 in dose-escalation cohorts; 1 in RRMM
and 2 in bortezomib-relapsed expansion cohorts)
• 1 pt achieved MR (bortezomib-relapsed expansion cohort; 40%
M-protein reduction)
• All 7 pts remain in response, with duration of disease control of
up to 15.9 months
• 28 pts have achieved SD
– 14 in dose-escalation cohorts
– 9, 5, and 2 in RRMM, bortezomib-relapsed, and PI-naïve expansion cohorts
– Durable, with disease stabilization for up to 12.9 months
Phase 1/2 Study of MLN9708 Lenalidomide and
Dex in Patients with Previously Untreated MM
•
Oral weekly MLN9708, lenalidomide, and dexamethasone is well
tolerated
– incidence of PN has been limited
At median drug exposure of 6 months, 92% PR or better, including
≥VGPR 55% and CR 23%
– Responses increased with number of cycles and deepened over
time
– 88% of patients achieving CR who were evaluable for MRD status
were confirmed as MRD-negative
•
A phase 3 trial of MLN9708 plus lenalidomide–dexamethasone versus
placebo plus lenalidomide–dexamethasone in patients with relapsed
and/or refractory MM is currently enrolling (NCT01564537) for new
drug approval
Kumar et al. ASH 2012 Abstr 332
In Vitro Anti-MM Activity of Oral
Chymotryptic Inhibitor ONX 0912 (Oprozomib)
Myeloma Cell Lines
Patient Tumor Cells
• Phase I clinical trials ongoing
Chauhan et al. Blood. 2010;116:490614.
Marizomib: A Non-Peptide Proteasome Inhibitor
Induces Rapid, Broad and Prolonged Inhibition
Marizomib (NPI-0052)
H
H
H
N
O
OH
O
O
H
CH3
Cl
•
Exhibits high levels of proteasome inhibition
without toxicities associated with bortezomib
•
Active in bortezomib and immunomodulatorresistant myeloma preclinically
Chauhan et al. Cancer Cell 2005; 8: 407-19.
Responses to Marizomib +/- Dexamethasone in Evaluable Pts at Full Dose
[ >0.4 mg/m2 ]* Twice Weekly (n=21**)
Richardson et al. ASH 2011
Pts Refractory to Bortezomib
All Pts
EBMT
≥ SD
MR + PR
Uniform Criteria
≥ SD
PR + VGPR
11/20
3/20
12/21
4/21
55%
15%
EBMT
≥ SD
MR + PR
8/12
2/12
67%
17%
57%
19%
Uniform Criteria
≥ SD
PR + VGPR
8/12
2/12
67%
17%
Median Duration of Response (all Pts) = 133 days (~ 5 mos)
Pts Exposed to Bortezomib
EBMT
≥ SD
MR + PR
Uniform Criteria
≥ SD
PR + VGPR
11/19
3/19
11/19
3/19
Pts Refractory to Lenalidomide
58%
16%
EBMT
≥ SD
MR + PR
8/13
3/13
62%
23%
58%
16%
Uniform Criteria
≥ SD
PR + VGPR
9/14
4/14
64%
29%
• Response criteria defined with baseline SPEP ≥ 0.5 g/dL or UPEP ≥ 200 mg/24h with
at least 2 assessments after treatment Day 1 for EBMT ; also by free lite for UC**.
*As of
05 Dec 11
• Refractory defined as having PD during or within 60 days of last regimen.
Additional Targeted Therapies in
Development
•
•
•
•
•
•
KSP inhibitors (ARRY-520)
AKT inhibitor (GSK2110183)
Nuclear transport inhibitors (KPT)
CDK inhibitors
BTK inhibitors
Bromodomain inhibitors
Development of Rationally based Combination
Therapies (HDAC and Proteasome Inhibitors)
Protein
Ub
Ub
Ub
protein aggregates
(toxic)
Ub
Ub
26S proteasome
Ub
HDAC6
Ub
Panobinostat,
Vorinostat, ACY1215
Ub
Bortezomib, Carfilzomib, NPI0052,
MLN9708, ONX 0912
HDAC6
dynein
Ub
HDAC6
dynein
Microtubule
Ub
Aggresome
Ub Ub
Lysosome
Ub Ub
Ub
Ub
Autophagy
Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:3441-9.
VANTAGE 088: An International, Multicenter,
Randomized, Double-Blind Study of Vorinostat
or Placebo with Bortezomib in Relapsed MM
• The combination of vorinostat + bortezomib is active in patients
with relapsed and refractory MM
– Significant improvement in response rate
– ORR 54% vs. 41% (P<0.0001); CBR 71% vs 53% (P<0.0001)
• PFS and TTP were prolonged in the combination arm compared
with bortezomib alone
PFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4)
versus 6.83 months (5.7–7.7)
• Diarrhea, fatigue, and thrombocytopenia limited tolerability.
Dimopoulos et al. ASH 2011, Lancet Oncology, in press
Bench to Bedside Translation
of HDAC 6 Selective Inhibitor ACY1215
Orally bioavailable, highly potent, selective
inhibitor of HDAC 6 synthesized in fall 2009
Synergistic MM cytotoxicity with bortezomib
in vitro and in vivo
Favorable PK/PD, toxicity profile
Phase Ia/Ib/II clinical trials of ACY1215, alone and
with bortezomib and with lenalidomide/dexamethasone, ongoing; trials
with pomalidomide and carfilzomib this year.
Santo et al. Blood 2012;119:2579-89
Mutations in Myeloma
19 Patients Each With Newly Diagnosed and Relapsed MM
Chapman et al. Nature 2011; 471: 467-72.
•
Protein homeostasis: 42% including FAM46C, RPL10, RPS6KA1,
EIF3B, XBP1, LRRK2
•
NF-kB signaling: 10 point mutations, 4 additional structural rearrangements affecting coding
Confers bortezomib sensitivity
•
Histone methylating enzymes: WHSC1, UTX, MLL
•
BRAF: 4% activating : Single patient MM response
Andrulis et al Cancer Discovery 2013; 3: 862-9.
•
PSMB5 b5 proteasome subunit mutation confers proteasome
inhibitor resistance in laboratory, not identified in clinic
Lichter et al. Blood 2012: 120: 4513-16.
Current and Future Directions
1. Development of immune therapies
2. Development of new oral proteasome inhibitors
3. Development of rationally based combination therapies
4. Identification of novel targets
United Nations Against Myeloma:
Bench to Bedside Research Team
USA
UK
India
Italy
Israel
Kenneth Anderson
Nikhil Munshi
Paul Richardson
Robert Schlossman
Irene Ghobrial
Steven Treon
Jacob Laubach
Deborah Doss
Kathleen Colson
Mary McKenney
Kim Noonan
Tina Flaherty
Kathleen Finn
Muriel Gannon
Stacey Chuma
Janet Kunsman
Diane Warren
Carolyn Revta
Andrea Freeman
Alexis Fields
Andrea Kolligian
John Feather
Farzana Masood
Nora Loughney
Heather Goddard
Tiffany Poon
Nicole Stavitzski
Ranjit Banwait
Shawna Corman
Heather Goddard
Meghan Marie Leahy
Caitlin O’Gallagher
Christina Tripsas
Karin Anderson
Shannon Viera
Katherine Redman
Amber Walsh
Samir Amin
Wanling Xie
Parantu Shah
Holly Bartel
Lisa Popitz
Jeffrey Sorrell
Japan
Canada
Germany
Austria
China
Teru Hideshima
Constantine Mitsiades
Dharminder Chauhan
Noopur Raje
Yu-Tzu Tai
Ruben Carrasco
James Bradner
Gullu Gorgun
Jooeun Bae
Francesca Cottini
Michele Cea
Antonia Cagnetta
Teresa Calimeri
Edie Weller
Ajita Singh
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Yiguo Hu
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Sun-Yung Kong
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Panisinee Lawasut
Niels van de Donk
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Jake Delmore
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Mariateresa Fulciniti
Jianhong Lin
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Michael Sellito
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Taiwan
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