The proteasome

Proteasome inhibitors in relapsed
multiple myeloma:
past, present and future
Michel Delforge
University Hospitals Leuven,
Belgium
Comy, Bangkok, 13 may 2014
Disclosures
• Advisory board: Janssen, Celgene
• Speaker’s honoraria: Janssen, Celgene, Novartis
2
Structure of the Proteasome
• The proteasome
– Cylindrical multi-protein
enzyme complex
– Present in cytoplasm and
nucleus of all eukaryotic
cells
– More than 30 different
proteins
– Complete structure 26S
proteasome
• Two 19S caps
• 20S catalytic core
19S cap
20S
core
19S cap
Structure of the Proteasome
•
19S cap serves 2 functions
–
–
•
•
Recognition of ubiquitinated proteins
Unfolding of target proteins
20S core contains catalytic domains
Peptides (3-22 amino acids) exit
proteasome by diffusion

3 different proteases
— Caspase-like

Cuts after acidic residues e.g. glutamyl
— Trypsin-like

protease
protease
Cuts after basic residues e.g. lysysl
— Chymotrypsin-like



protease e.g. tyrosyl
Cuts after large hydrophobic residues
Rate-limiting site of proteolysis
Site inhibited by bortezomib
Nobelprize Chemistry 2004
for the discovery of ubiquitin-mediated protein degradation
Aaron Chiechanover
Avram Hershko
Irwin Rose
The proteasome has a central rol in cell
proliferation and survival
Delforge M. Expert Opin Pharmacother 2011;12:2553
Proteasome inhibitors in myeloma
Drug
Class
Proteasomal target
caspase
bortezomib
(PS-341)
ixazomib
(MLN-9708)
delanzomib
(CEP-18770)
carfilzomib
(PR-171)
oprozomib
(ONX-0912)
marizomib
(NPI-0052)
trypsin
reversibility
Route of
Frequency
administration
of dosing
chymotrypsin
boronic acid
X
X
reversible
IV/SC
boronic acid
X
X
reversible
oral
boronic acid
X
X
Reversible
oral
days
1,4,8,11/21d
once/twice
per week
???
days
epoxyketone
X
irreversible
IV
1,2,8,9,15,16/
28d
epoxyketone
salinospore
X
X
X
irreversible
oral
X
reversible
IV
daily
days
1,4,8,11/21d
Richardson et al. N Engl J Med 2003;348:2609
Richardson et al. N Engl J Med 2005;352:2487
Better responses with bortezomib are associated
with longer response duration
subanalysis of APEX phase III trial
Niesvizky et al. Br J Haematol 2008;143:46
Retrospective matched-pairs analysis: bortezomib
+ dex versus bortezomib monotherapy as secondline treatment
• Patients (n=218)
– Patient-level data from 3 studies
• Patients treated with bortezomib-dex in phase 2 MMY-2045 study1
• Patients randomized to single-agent bortezomib in
– phase 3 APEX (bortezomib vs high-dose dex)2
– phase 3 DOXIL-MMY-3001 (bortezomib +/- Doxil)3
1.
2.
3.
TTP
13.6
7.0
0.003
PFS
11.9
6.4
0.051
2y OS
68.4
62.2
ns
Dimopoulos et al. Haematologica 2013;98:1264-72
Richardson et al. NEJM 2005;352:2487-98
Orlowski et al. JCO 2007;25:3892-901
Dimopoulos et al. ASH 2013 (Abstract 3177), poster presentation
Single agent or combination at relapse ?
other combinations
Study
Bortezomib/pegylated
liposomal doxorubicin
vs bortezomib1
n
CR+PR
CR+nCR
TTP
OS
318
44%
13%
9.3* months
15-month OS:
76%*
318
41%
10%
6.5 months
65%
Bortezomib + vorinostat vs
Bortezomib2
Bortezomib/thal/dex (VTD)
vs Thal/dex (TD)4
317
56%
28%
7.63* months
Not reached
320
41%
21%
6.83 months
28.1 months
135
86%
45%*
19.5* months
134
74%
25%
13.8 months
2-year OS:
71%
65%
* P < 0.05
1. Orlowski et al, J Clin Oncol 2007;25:3892
2. Dimopoulos et al. ASH 2011 (Abstract 811), oral presentation
3. Garderet et al, J Clin Oncol2012;30:2475
Retreatment: what are the arguments
• Many patients are currently treated at diagnosis with
bortezomib-containing regimens
• Although lenalidomide-dexa is a regimen of choice
for relapsed MM, later relapses will occur
• Therefor, retreatment with bortezomib can be a
valuable option when:
– the initial response duration was > 12 months
– the previous use of bortezomib did not result in
serious/irreversible toxicity
– especially when restrictions would limit the
availability/reimbursement of other new drugs
Retreatment with bortezomib
N = 130
Previous treatment with bortezomib resulting in: ≥ PR for ≥ 6 months
Petrucci et al, Br J Haematol 2013;160:649,
Bortezomib SC
Pharmacokinetic and pharmacodynamic parameters
Bortezomib Bortezomib
IV
SC
(n=14)
(n=17)
Plasma concentration-time profiles
Pharmacokinetics
Cmax (ng/mL),
mean (SD)
223 (101)
20.4 (8.87)
Tmax (min),
median (range)
2 (2–5)
30 (5–60)
AUClast (ngxh/mL),
median (range)
151 (42.9)
155 (56.8)
69.3 (13.2)
63.7 (10.6)
5
(2–30)
120
(30–1440)
1383 (767)
1714 (617)
Pharmacodynamics
Emax (%),
mean (SD)
Temax (min),
median (range)
AUE72 (%xh),
mean (SD)
Moreau et al. Lancet Oncol 2011;12:431
• Bortezomib systemic
exposure equivalent
between groups
• AUE72 similar in both
groups
Peripheral neuropathy (PN) with
bortezomib IV vs SC
Bortezomib IV
(n=74)
Bortezomib SC
(n=147)
p-value*
Any PN event, %
53
38
0.044
Grade 2, %
41
24
0.012
Grade 3, %
16
6
0.026
Time to onset of PN, months
4.4
NE
Cumulative dose at first
onset of PN, mg/m2
25.1
41.0
Significantly fewer all-grade, grade 2 and grade 3 PN events with SC
administration compared to IV administration
*P-values based on 2-sided Fisher’s exact test
Moreau et al. Lancet Oncol 2011;12:431
Carfilzomib: background information
Carfilzomib: phase II data in
relapsed/refractory MM
PX-171-003-A1
PX-171-004
Nr of patients
N = 266
N = 126
Type of patients
Bortezomib-refractory (80%)
Bortezomib-naïve
Carfilzomib dosing
20 mg/m2 escalated to 27
mg/m2
20 mg/m2 escalated to 27
mg/m2 from cycle 2
Median nr of prior
treatment lines
5
2
Response
- ORR
- CR
- VGPR
- PR
24%
0.4%
5%
18%
47%
2.4%
20.6%
24.6%
Median DOR
7.8 mo
12 mo
Median OS
15.6 mo
Not reached after 23 mo
Siegel et al. Blood 2012;120:2817
Vij et al. Blood 2012;119:5661
Carfilzomib:
adverse events
Siegel et al. Blood 2012;120:2817
Carfilzomib: clinical development
CRD vs Rd in relapsed MM: ASPIRE
Carfilzomib and kidney function
• 50 patients
• Including all degrees of renal impairment and patients
on dialysis
• Carfilzomib at escalating doses: 15 to 27 mg/m2
• No influence of renal function on:
– pharmacokinetics of carfilzomib
– efficacy
– side effects
Badros et al. Leukemia 201;27: 1707
Carfilzomib in relapsed/refractory MM
data from ASH 2013
•
•
•
•
•
A phase I/II dose expansion of a multi-center trial of carfilzomib and
pomalidomide with dexamethasone in patients with relapsed/refractory
MM (Shah J et al. abstract n° 690)
Dose-escalation study (CHAMPION-1) investigating weekly carfilzomib
in combination with dexamethasone for patients with relapsed or
reractory multiple myeloma (Berenson J et al. abstract n° 1934)
A single-arm, open-label, multi-center phase I/II study of the
combination of panobinostat and carfilzomib in patients with relapsed
or relapsed/refractory multiple myeloma. (Berdeja J et al. abstract n°
1937)
Study of the novel kinesin spindle protein inhibitor ARRY-520 plus
carfilzomib in patients with relapsed and/or refractory multiple
myeloma (Shah J et al. abstract n° 1982)
Phase I trial of carfilzomib plus high dose melphalan conditioning
regimen prior to autologous hematopoietic stem cell transplantation
for relapsed multiple myeloma (Costa L et al. abstract n° 3329)
Other new proteasome inhibitors
Ixazomib
(MLN- 9708)
Marizomib
(NPI-052)
N
60
34
Prior lines of treatment
6 (2-18)
6
MTD
2.97 mg/m2
0.4 mg/m2 in 1h inf. & 0.5
mg/m2 in 2h inf.
Schedule
1,8,15/28d
1,4,8,11/21d
ORR (≥ PR)
15%
14%
≥ MR
17%
14%
reference
Kumar, ASCO 2013
Richardson, ASH 2011
Ocio et al. Leukemia 2014;28:525
Conclusions
• Since 10 years, bortezomib has changed the treatment approach
for patients with relapsed multiple myeloma
• During these past 10 years we have learned that:
– earlier use results in better and more durable responses
– combinations work better than single agent treatment:
• combination with dexamethasone is standard
• other drugs to be added are: cytostatics (e.g. doxorubicin), IMiDs, newer
agents (e.g. HDAC inhibitors)
– retreatment with bortezomib is feasible and safe
– SC and weekly dosing can significantly reduce (neuro-)toxicity
• Future perspective: second-generation proteasome inhibitors
are entering the clinical field:
– to replace bortezomib or to be given for bortezomibrelapsed/refractory patients ?
– in combination with other highly active anti-myeloma compounds

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