2006 ASH Abstract 797
Bortezomib and Pegylated Liposomal Doxorubicin
as Induction Therapy for Adult Patients with
Symptomatic Multiple Myeloma : Cancer and
Leukemia Group B Study 10301
Robert Z. Orlowski1, Bercedis L. Peterson2, Ben Sanford2, Asher A.
Chanan-Khan3, Lee M. Zehngebot4, Peter R. Watson5, Michael A.
Caligiuri6, Richard A. Larson7, the Cancer and Leukemia Group B
1Department of Medicine, Division of Hematology/Oncology, University of North Carolina at
Chapel Hill, Chapel Hill, NC, USA; 2Biostatistics Bioinformatics CALGB Statistical Center,
Duke University, Durham, NC, USA; 3Department of Medicine, Roswell Park Cancer
Institute, Buffalo, NY, USA; 4Florida Hospital Cancer Institute, Orlando, FL, USA; 5Lenoir
Memorial Cancer Center, Kinston, NC, USA; 6Department of Internal Medicine, Division of
Hematology/Oncology, Ohio State University, Columbus, OH, USA; 7Department of
Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA
Disclosures for Authors
Research Support
None
Employee/Stockholder
None
Consultant
Robert Z. Orlowski: Ortho Biotech Products, L.P.
Asher Chanan-Khan: Millennium Pharmaceuticals,
Speakers Bureau
Inc.
Honoraria
None
Robert Z. Orlowski: Millennium Pharmaceuticals,
Scientific Advisory Board
Inc.; Asher Chanan-Khan: Millennium
Pharmaceuticals, Inc.
· This presentation does discuss off-label use of pegylated
liposomal doxorubicin (PLD) and bortezomib for initial
therapy of multiple myeloma
Pre-clinical Rationale
· Interactions occur through multiple
pathways to enhance anti-tumor efficacy
­ Bortezomib abrogates anthracycline resistance
·NF-B1,2, Bcl-2, P-glycoprotein, DNA damage
repair3
­ Anthracyclines abrogate bortezomib resistance
· Suppression of stress response protein MKP-14
· Additive to synergistic effects are seen in
both in vitro1,2,3 and in vivo4 model systems
1Ma, MH et al. Clin. Cancer Res. 9:1136, 2003. 2Mitsiades, N et al. Blood 101:2377, 2003.
3Hideshima, T et al. Blood 101:1530, 2003. 4Small, GW et al. Mol. Pharmacol. 66:1478,
2004.
Clinical Rationale
· Three-week cycle length
·PLD @ 30 mg/m2
­ Bortezomib (
) days 1, 4, · Bortezomib
8, 11
­ 0.90 to 1.50 mg/m2
­ PLD (
) on day 4
Week 1
Week 2
Week 3
· MTD based on cycle 1
· Activity evaluated q2 cycles
Orlowski, RZ et al. Blood 105: 3058, 2005.
Response Rates
· CR rate (CR + n-CR) 36% (8/22)
· Overall RR (CR+PR) 73% (8/22)
· CRs seen even at first dose level (0.90
mg/m2 bortezomib)
· 38% CR, 62% ORR in patients (n = 13)
with anthracycline non-responsive disease
­ Supports chemosensitization
Orlowski, RZ et al. Blood 105: 3058, 2005.
Time to Progression
TTP on prior therapy vs. TTP on
·TTP was
bortezomib/PLD
9.3 mos. vs.
3.8 mos. on
the prior
therapy
­ (p = 0.02)
·Median OS
37 mos.
Biehn, SE et al. Ann. Hematol. In press and available online, 2006.
Phase II Bortezomib/PLD
· Primary objectives
· Secondary objectives
­ Determine the CR +
­ Determine the overall
near-CR rate
response rate (CR + near-
­ Evaluate the toxicities
CR + PR)
of bortezomib/PLD
­ Evaluate time to
when administered to
progression
this patient population
­ Collect data about stem cell
· Bortezomib 1.3 mg/m2
collection and engraftment
iv days 1, 4, 8, 11 q 21
­ Evaluate the impact of
· PLD 30 mg/m2 iv on
day 4
therapy on serum IL-6 and
MIP-1 levels
Study Schema
Cycles 1, 2
Response evaluation
SD, MR, PR, near-CR, or CR
PD
Cycles 3, 4
Off study
Response evaluation
CR after 1,2 & 3,4
SD, MR, PR, near-CR, or CR
PD
Off study
Cycles 5,6
Off study
Response evaluation
CR after 3,4 & 5,6
MR, PR, near-CR, CR & PBSCT
PD or SD
Off study
Off study
Off study
Significant improvement
Option for cycles 7,8
Off study
Accrual / Data Analysis
· Closed in October of 2005
· Total of 63 patients accrued
· Adverse event (AE) data available for 57
patients at the time of ASH abstract
deadline
· Preliminary response data available on 57
patients (pts)
­ 29 patients had final response data
Hematologic Grade 3/4 Adverse Events
25%
25%
Grade 3
20%
Grade 4
15%
16%
10%
11%
9%
9%
5%
7%
2% 5% 2% 2%
0%
ia
a
ents
penia
pen
l ev
to
nemi
A
Al
eutro
N
bocy
ymphopenia
L
rom
Th
Non-Hematologic AEs
· Grade 3 in 32 pts (58%), grade 4 in 5 (9%)
· Events seen in at least 5% of pts included:
­ Fatigue (seen in 16% of pts)
­ Sensory neuropathy (13%)
­ Hand-foot syndrome (9%)
­ Syncope (9%)
­ Motor neuropathy, dehydration, rash, weight
loss, hypotension, diarrhea, nausea, infection,
and dyspnea (seen in 5% each)
Preliminary Response Data
60%
CR
· At least some
near-CR
58%
50%
response data (2
PR
cycles of therapy)
40%
ORR (CR 42%
available on 57 pts
30%
+ PR)
· CR or near-CR in
20%
9/57 (16%)
10%
16%
· PR or better in 33/57
(58%)
0%
Proportion (%)
Final Response Data
· Final response data
80%
CR
(pts off therapy with a 70%
near-CR
79%
final response
60%
PR
documented) was
50%
ORR (PR
+ CR)
52%
available on 29 pts
40%
· CR + near-CR in 8
30%
(28%)
20%
28%
10%
· PR in 23 (79%)
0%
Proportion (%)
PFS and OS / Stem Cell Collection
· Progression-free and overall survival cannot
yet be estimated because of a paucity of events
at a median of 10 mos. of follow-up
· Stem cell collection data available from 6 pts
­ Median of 13.6 x 106 CD34+ cells/kilogram were
mobilized (range 11.2 - 48.6 x 106)
­ No data yet available on post-transplant recovery
Conclusions
· These preliminary data suggest that
bortezomib and PLD is well-tolerated by
chemotherapy-naïve multiple myeloma
patients in this study
· This steroid-free regimen has promising
activity, and does not seem to compromise
the ability to collect stem cells for later
transplantation
Acknowledgements
· The patients who made this study possible
· Study investigators and staff at the CALGB
institutions involved
· CTEP-NCI
· Pre-clinical studies