citings_velcadeasco_newsletter.qxp

CITINGS
Published by the International Myeloma Foundation
Special Edition : ASCO 2005
Velcade® (bortezomib) Issue
The International Myeloma Foundation (IMF) is pleased to present our first
VELCADE® (bortezomib)-focused edition of CITINGS for 2005, a relatively recent publication
featuring the most up-to-date information on new therapies for multiple myeloma. VELCADE is
the first of a new class of drugs called proteasome inhibitors. Because it is a new type of drug,
VELCADE represents a new treatment option for patients who have relapsed on other standard
therapies. This issue of CITINGS has been prepared by the IMF to correspond with the annual
meeting of the American Society of Clinical Oncology (ASCO) in Orlando, Florida. In this issue,
readers will find three key resources related to VELCADE:
1) a list of selected bortezomib data being presented at the ASCO meeting, along with dates
and times of each presentation,
2) a list of selected bortezomib-related studies presented at the 10th International Myeloma
Workshop in Sydney, Australia from April 10th- 14th 2005, and
3) references to the latest published studies on bortezomib.
We hope this issue will provide readers with a detailed update on the VELCADE literature and
will be a useful tool for navigating the ASCO meeting. Please feel free to contact the IMF at
(800) 452-CURE or by clicking on www.myeloma.org.
--Susie Novis, President, IMF
American Society of Clinical Oncology Presentations 2005
Oral Presentation:
[6501] Bortezomib Appears to Overcome Poor Prognosis Conferred by Chromosome 13 Deletion in Phase 2
and 3 Trials
Date/Time: Sunday May 14, 9:30 am-10:45am
Authors: Sundar Jagannath, Paul G. Richardson, Pieter Sonneveld, Michael W. Schuster, David Irwin, Edward
A. Stadtmauer, Thierry Facon, Jean-Luc Harousseau, Janet M. Cowan, Kenneth C. Anderson
Session Info: Integrated Educational Session Level 2, 230A: Leukemia, Lymphoma, Myeloma, and
Transplantation (Adult) (8:00am-12:00pm)
Poster Discussions:
[6535] Health-Related Quality of Life Associated With Bortezomib Compared With High-Dose
Dexamethasone in Relapsed Multiple Myeloma: Results From The APEX Study
Date/Time: Monday May 16, 4:30pm-5:30pm
www.myeloma.org
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Funded by an educational grant from Millennium Pharmaceuticals, Inc.

Authors: Stephanie J. Lee, Paul G. Richardson, Pieter Sonneveld, Michael Schuster, David Irwin, J. Massaro,
Bruce Crawford, R. Dhawan, S. Gupta, Kenneth C. Anderson
Session Info: Poster Discussion Level 2, Hall F1: Leukemia, Lymphoma, Myeloma, and Transplantation (Adult)
1:30pm-5:30pm
[6533] Safety and Efficacy of Bortezomib in High-Risk and Elderly Patients With Relapsed Myeloma
Date/Time: Monday, May 16, 4:30pm-5:30pm
Authors: Paul G. Richardson, Pieter Sonneveld, Michael W. Schuster, David Irwin,
Edward A. Stadtmauer, Thierry Facon, Jean-Luc Harousseau, Dina Ben-Yehuda,
Sagar Lonial, Kenneth C. Anderson
Poster Info: Poster Discussion Level 2, Hall F1: Leukemia, Lymphoma, Myeloma, and Transplantation (Adult)
1:30pm-5:30pm
[6536] Response to Bortezomib (BOR) and Bone Metabolism in Multiple Myeloma Patients
Date/Time: Monday, May 16
Authors: Zangari Maurizio, Esseltine Dixie-Lee, Najarian Kevin, Elice Francesca, Lee Choon-Kee, Yaccoby
Shmuel, Barlogie Bart, Tricot Guido
Poster Info: Poster Discussion: Level 2, Hall F1: Leukemia, Lymphoma, Myeloma, and Transplantation (Adult)
4:30pm-5:30pm
General Poster Sessions:
[6653] Bortezomib (VELCADE®) Plus Dexamethasone as Induction Treatment Prior to Autologous Stem
Cell Transplantation in Patients With Newly Diagnosed Multiple Myeloma: Results of an IFM Phase II
Study
Date/Time: Tuesday May 17
Authors: Jean-Luc Harousseau, Michel Attal, Xavier Leleu, Jacques Troncy, Rémy Gressin, Anne-Marie Stoppa,
Cyrille Hulin, Lofti Benboubker, Jean-Gabriel Fuzibet, François Guilhot, on behalf of the IFM
Poster Info: General Poster Session Level 2, Hall C: Leukemia, Lymphoma, Myeloma, and Transplantation
(Adult) 8:00am-12:00pm
[6610] Bortezomib-Associated Transient and Cyclical Thrombocytopenia:
Evidence for Lack of Marrow Cytotoxicity
Date/Time: Tuesday May 17
Authors: Sagar Lonial, Edmund K. Waller, Paul G. Richardson, Sundar Jagannath, Robert Z. Orlowski,
Cynthia R. Giver, David L. Jaye, Bart Barlogie, Leonard T. Heffner, and Kenneth C. Anderson, for the SUM-
MIT/CREST Investigators
Poster Info: General Poster Session Level 2, Hall C: Leukemia, Lymphoma, Myeloma, and Transplantation
(Adult) 8:00am-12:00pm
Pre-Clinical Poster Session
[2081] Bortezomib's Effect on NFkB Nuclear Localization Is Not Sufficient Information for Predicting its
Modulation of Chemotheraphy-Induced Cytotoxicity.
Date/Time: Sunday May 15
Authors: R.L. Dubowy, N. Schiff, B. Toms
Poster Info: General Poster Session Level 2, Hall C: Development Therapeutics: Cytotoxic Chemotherapy
8:00am 12:00pm
www.myeloma.org
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10th International Myeloma Workshop Presentations
A complete summary of the all plenary sessions that took place in Sydney can be found at www.myeloma.org.
A printed guide to the workshop with a companion DVD containing key sessions and interviews will be pub-
lished shortly by the IMF. Abstracts of the posters and presentations were published in a special supplement of
the journal Haematologica as part of the April 20, 2005 issue.
Oral Presentations:
Phase I Study of the safety and efficacy of bortexomib (Velcade) in combination with lenalidomide
(Revlimid) in relapsed and refractory multiple myeloma.
Richardson PG, Schlossman R, Munshi N, et al.
Plenary Session 5: New Therapeutic Agents
Because both agents are antiangiogenic and have immunomodulatory effects, the expectation was that the com-
bination would overcome resistance to therapy and enhance overall efficacy. The objective of this study was to
identify the maximum tollerated dose (MTD) and recommended dose for a phase II trial. At this stage the
researchers presented results from 10 of 11 patients enrolled and showed an overall response of 91%. The MTD
has not yet been reached and the last available cohort received 1.3mg/m2 bortezomib and 10mg of lenalidomide.
Dr. Richardson indicated that the future trials will include a phase II study in relapsed/refractory patients and a
phase II study in newly-diagnosed patients.
Total therapy for newly diagnosed multiple myeloma: the Arkansas experience
Barlogie B
Plenary Session 4: Autologous Transplantation
The presentation was an update on total therapy 2 (TT 2) versus total therapy 1 (TT 1). Dr. Barlogie reviewed
data supporting the superiority of TT 2 over TT 1 with improved CR duration and doubled EFS. TT 3, a suc-
cessor protocol including Velcade with DT PACE, shortens the induction phase to 2 cycles to allow for comple-
tion of tandem transplants. Dr. Barlogie cautioned that the study is ongoing and that results will be discussed at
future meetings in 2005
In vitro activity of a novel small molecule cyclin dependent kinase inhibitor, CYC202 (seliciclib or
RRoscovitine), in multiple myeloma
Raje N
Focus Session 11: Experimental Agents
CYC202 (selicicib or R-Roscovitine) is a purine analog that has shown activity in 19 human cancer cell lines and
is currently being evaluated in ongoing phase I trials. Within 24 hours, CYC202 induces cytotoxicity in
myeloma cells sensitive or resistant to conventional chemotherapy or steroids. Dr. Raje has also shown that
CYC202 is synergistic with Velcade and doxorubicin; a situation which should be explored in future trials.
Combined farnesyl transferase inhibition and proteasome inhibition synergistically induce apoptosis via
downregulation of p-AKT
Lonial S
Focus Session 11: Experimental Agents
The farnesyl transferase inbitor, tipifamib, blocks the RAS pathway and induces apoptosis in myeloma cells while
Velcade has proven efficacacy in myeloma in several clinical settings. The author of this study shows that the com-
bination of these two agents results in greater response than with either given individually. In combination rapid
caspase dependant and independent apoptosis is induced.
www.myeloma.org
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Lack of Mcl-1 confers resistance to bortezomib and melphalan but not doxorubicin
Le Gouill S
Focus Session 12: Drug resistance, mechanisms and treatment strategies
Mcl-1 is an antiapoptotic protein that protects myeloma cells against spontaneous and dexamethasone-induced
apoptosis. This particular study investigated the role of Mcl-1 in bortezomib-induced apoptosis in comparison
to conventional therapies doxorubicin and melphalan. Dr. Le Gouill's analysis s suggest that bortezomib and
melphalan, but not doxorubicin, triggers Mcl-1-dependent-induced apoptosis pathways.
Tumor immune interactions in myeloma
Dhodapkar M
Plenary Session 11: Immune Biology
Dr. Dhodapkar discussed some of his current research including phase I trial data exploring whether natural killer
(NKT) cells could be reliably and specifically manipulated in patients. He showed that it is possible to expand the
number of NKT cells in patients but these cells mediate activation of T cell immunity by a third party dendritic
cell (DC) in vivo. The question of how to maintain the expansion of NKT cells in patients by vaccines is being
explored. Dr. Dhodapkar postulated that effective suppression of myeloma requires that myeloma cells and DC
be targeted by a proteasome inhibitor such as Velcade.
The role of Wnt signaling in myeloma and its interaction with marrow stromal cells
Tian E
Focus Session 8: Bone and Tumour Microenvironment
Dr. Tian examined the role of over expressed DKK1 in patients with myeloma bone disease. In a mouse model,
a monoclonal antibody used against DKK1 showed increased numbers of osteoblasts, reduced number of osteo-
clasts, reduced bone loss, and reduced tumor burden. Additionally, data shows that DKK1 can be activated by
genotoxic and non-genotoxic agents in other tumor cells, activated by tumor and non-tumor cells, activated by
thalidomide and other drugs, but not activated by Velcade or other proteasome inhibitors.
Poster Sessions:
[PO.720] Bortexomib demonstrates superior efficacy compared with high-dose dexamethasone, with pre-
dictable toxicity.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, et al.
This is the final report from the multi-center, international APEX trial; the largest study to date in relapsed myelo-
ma. Patients who had previously received 1-3 prior therapies were randomized to receive either bortezomib 1.3
mg/m2 or dex 40 mg (669 patients total). The results showed bortezomib to be superior to dex, demonstrating
a highly significant 78% improvement in median time to progression (hazard ratio 0.55, p<0.0001), higher
response rates using EBMT criteria (complete + partial response, 38% vs 18%; p<0.0001), and an improvement
in 1-year survival (80% vs 66%, p= 0.0025). The safety profile of bortezomib was predictable and manageable.
[PO.721] Bortezomib at first relapse is superior to high-dose dexamethasone and more effective than when
given later in relapsed multiple myeloma
Sonneveld P, Richardson PG, Schuster MW, Irwin D, et al.
This paper is further analysis of the APEX trial data. The key observation made in this paper was that Velcade
appeared to result in a longer time to progression (TTP) and higher response rate (RR) when used earlier as sec-
ond line compared with its use as later salvage therapy. It is also important to note that it was unaffected by type
of prior therapy, except when that prior therapy included thalidomide.
www.myeloma.org
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[PO.722] Bortezomib induces remissions in patients with relapsed/refractory myeloma independent of their
cytogenetic risk profile and addition of dexamethasone or dexamethasone plus chemotherapy can restore
responsiveness.
Ludwig H, Zojer N, Ackermann J, Kaufmann H, et al.
This study involved 30 pre-treated patients and looked at the efficacy of Velcade in relation to the cytogenetics of
particular patients. Interestingly the paper showed that: (a) Velcade was effective regardless of cytogentics present
[including one with del(13q) plus translocation t(4;14)(p16;q32)] with an overall response of 42% for Velcade
alone and (b) the addition of dex can induce a further response after the initial response to Velcade has faded.
[PO.724] Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplanta-
tion in patients with newly diagnosed multiple myeloma. Prelinary results of an IFM Phase II study
Harousseau JL, Attal M, Leleu X, Gressin R, et al.
The preliminary data reported here includes 48 patients recruited to the trial as of August 2004. So far the over-
all response rate was 75% and the CR rate was 21%. The side effects observed were usually mild (grade 1/2) only
and in all cases stem cells could be adequately collected. Complete results will be reported later in 2005.
[PO.725] Bortezomib therapy alone and in combination with dexamethasone for patients with previously
untreated multiple myeloma
S Jagannath S, Durie BMG, Wolf J, Camacho E, et al.
In this study Velcade (1.3 mg/m2 ) was administered on days 1, 4, 8, and 11 of a 3-week cycle for a maximum
of 6 cycles. Oral dex 40 mg was given to patients who achieved < partial response (PR) after 2 cycles or < com-
plete response (CR) after 4 cycles. Initial data includes results from 40 patients. Bortezomib alone or in combi-
nation with dex was highly active in the first-line treatment of patients with myeloma overall response rate (ORR)
85%, CR/nCR 20%. The combination of bortezomib + dex demonstrated additional benefit. Toxicities were
manageable and reversible. Although experience has been limited to date, stem cell transplantation was success-
ful in all attempts.
[PO.726] A Phase I/II national, multiple-center, open-label study of Velcade plus melphalan and prednisone
(V-MP) in elderly untreated multiple myeloma patients
Mateos MV, Blade J, Diaz Mediavilla J, Lahuerta JJ, et al.
This study includes 47 patients - 12 in the phase I and 35 in the phase II. The results of the phase I section of
the trial recommended a phase II dose of 1.3 mg/m2 of Velcade in combination with melphalan and prednisone.
So far, no patient has developed dose limiting toxicity (DLT.) The combination of V-MP is well tolerated with a
manageable toxicity. Significant M-protein responses have been observed. Initial results of the phase II trial show
a 92% overall response. Complete results will be presented later in the year.
[PO.727] Bortezomib in combination with dexamethasone for relapsed multiple myeloma
Kropff M, Bisping G, Schuck E, Berde W, et al.
Fifteen consecutive patients with relapsed multiple myeloma were enrolled in this study and scheduled to receive
bortezomib 1.3 mg/m2 for up to 8 cycles, in combination with dexamethasone 20mg PO once daily on the day
of bortezomib injection and the day thereafter. Results are not complete but preliminary analysis suggests that
bortezomib may be safe even in patients with poor bone marrow reserve, who would not have been candidates
for the SUMMIT trial. Though the remission rate was high, remissions often were not durable. This fact under-
lines the need for consolidating treatment and evaluation of bortezomib combinations with other anti-myeloma
agents.
www.myeloma.org
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[PO.728] Bortezomib in combination with melphalan in the treatment of relapsed or refractory multiple
myeloma: A phase I/II study
Berenson JR, Yang HH, Swift R, et al.
Twenty-two heavily pretreated patients have been accrued to the study. Responses were observed in 70% (21/30)
of patients [CR/PR 50%, median time to progession (TTP) and overall survival not reached]. The complete
response (CR) and near CR occurred in patients receiving bortezomib 1.0 mg/m2 in combination with
melphalan .025 mg/kg however the maximum tollerated dose (MTD) was 1.0 mg/m2 bortezomib, 0.10 mg/kg
melphalan. Partial response (PR) or better was independent of prior type of therapy, and was also observed among
patients who had previously received melphalan or bortezomib.
[PO.730] Bortezomib and pegylated liposomal doxorubicin as initial therapy for adult patients with sympto-
matic multiple myeloma: CALGB Study 10301
Orlowski RZ, Peterson BL, Caligiuri MA, Kelly M, et al.
Previous studies have shown combinations of anthracycline and proteasome inhibitors to have enhanced, possi-
bly synergistic anti-tumor activity in both in vitro and in vivo model systems. This particular research builds on
a previous phase I study [ 36% CR, 73 % OR] and enrolled patients will receive Velcade at 1.3 mg/m2 on days
1, 4, 8, and 11 of every 21-day cycle, while pegLD is being given at 30 mg/m2 on day 4. Accrual is now com-
plete; preliminary shows 80 % RR in 15 evaluable patients. Complete data will be presented later in the year.
[PO.731] Velcade, doxil and low-dose thalidomide as salvage regimen for patients with relapsed or refractory
multiple myeloma and Waldenstroms Macroglobulinemia: Peliminary results of a phase II study
Chanan-Khan A, Millar KC, DiMiceli LA, McCarthy P, et al.
The idea behind this study is to target the bone marrow micro environment (ME) at the same time as the malig-
nant myeloma cells in order to overcome resistance in patients with refractory myeloma. Velcade targets the ME
by down regulation of IL-6 through inhibitory effect on NFkB, while thalidomide, exerts its anti-myeloma effect
through perturbation of the myeloma ME via down regulation of IL-6, VEGF and TNF-a. The authors of this
study combined VT (to target the ME) with doxil (D) (to target myeloma cell). Initial results are promising and
show that of 16 patients enrolled, 63% showed a clinical response 28% CR IF-, 38% PR.
[PO.732] Combination therapy of PS-341 (bortezomib), adriamycin and dexamethasone (PAD) for untreat-
ed patients with multiple myeloma.
Popat R, Oakervee H, Curry N, Morris C, et al.
This is a very exciting study that has shown at least a partial response (PR) in 95% of 21 patients in the first
cohort. Preliminary data suggests that PAD chemotherapy is not only well tolerated, but highly efficacious in the
front line therapy of multiple myeloma. Stem cell collection is not affected. The early results for cohort 2 imply
that the toxicity profile is improved with the lower dose of bortezomib (1.0 mg/m2 vs. 1.3 mg/m2) although suf-
ficient response data is not yet available to make conclusions. Initial data shows a response rate (RR) of 83% at
the lower dose; complete results will be reported later in the year.
www.myeloma.org
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[PO.813] Combination of receptor tyrosine kinase inhibition, proteasome inhibition and dexamethasone
enhances apoptosis in cytogenetically defined multiple myeloma subgroups
Bisping G, Wenning, D, Dreyer B, Kropff M, et al.
This study explored whether combinations of highly selective targeted strategies, such as RTK inhibition, block-
ing VEGF and FGF signaling, and more unspecific antimyeloma agents, including Velcade and dexamethasone,
are capable of enhancing apoptosis in cytogenetically defined myeloma subgroups. The results displayed signifi-
cant induction of apoptosis in t(4;14) and t(14;16) positive myeloma by incubation with the receptor tyrosine
kinase inhibitor BIBF1000. Co-incubation with the Velcade, or dexamethasone or a combination of these drugs
revealed an increase of apoptosis. In parallel, a markedly higher proportion of cleaved caspase-3, caspase-8 and
PARP was found, while caspase-9 was not activated when combining BIBF1000, Velcade, or dexamethasone. This
study provides the rational for clinical trials of these combinations
[PO.901] Bortezomib targets multiple myeloma endothelial cells
Roccaro AM, Hideshima T, Raje N, Kumar S, et al.
In investigators in this study evaluated whether anti-angiogenesis may contribute to the anti-myeloma activity of
Velcade; endothelial cells (ECs) were isolated from the bone marrow of patients with myeloma. Velcade
inhibited in vitro multiple myeloma endothelial cells (MMEC) and HUVEC functions related to angiogenesis,
including proliferation, chemotaxis, spreading on FN, and capillary formation. A significant concentration-
dependent reduction of VEGF and IL-6 production was observed. Importantly, binding of MM.1S cells to
MMECs triggers tumor cell proliferation; which was also inhibited.
www.myeloma.org
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2005 Velcade (bortezomib) Publications
Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with
impaired renal function.
Jagannath S, Barlogie B, Berenson JR, Singhal S, et al.
Cancer. 2005 Mar 15;103(6):1195-200.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5690325
This is the first study to look specifically at the activity of Velcade in patients with impaired kidney function.
Efficacy of Velcade was assessed in relation to baseline creatinine clearance (CrCl); 256 relapse patients were
involved and received a 21-day cycle at 2 doses, 1.0 mg/m2 (n = 28 patients) and 1.3 mg/m2 (n = 228
patients). Results suggest that bortezomib provides clinical benefit with manageable toxicities in this high-risk
population.
Phase I trial of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin in patients
with advanced hematologic malignancies.
Orlowski RZ, Voorhees PM, Garcia RA, et al.
Blood. 2005 Apr 15;105(8):3058-65. [Epub 2004 Dec 30].
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5626743
It has been shown previously that proteasome inhibitors enhance the antitumor efficacy of anthracyclines.
This study looks at the maximum tollerated dose (MTD) and dose limiting toxcitiy (DLT) of Velcade and
pegylated liposomal doxorubicin (PegLD). The combination showed complete response (CR) or partial
response (PR) in 16 of the 22 myeloma patients involved (including several with anthracycline-refractory
disease).
Efficacy of bortezomib therapy for extramedullary relapse of myeloma after autologous and non-mye-
loablative allogeneic transplantation.
Patriarca F, Prosdocimo S, Tomadini V, et al.
Haematologica. 2005 Feb; 90(2):278-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5710593
This paper described the successful treatment of extramedullary disease in relapse with Velcade.
A Phase I and pharmacologic trial of two schedules of the proteasome inhibitor, PS-341 (Bortezomib,
Velcade), in patients with advanced cancer.
Dy GK, Thomas JP, Wilding G, Bruzek L, et al.
Clin Cancer Res. 2005 May 1;11(9):3410-6.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5867242
This study looked at the relative toxicities of two schedules for the administration of Velcade (44 patients
total). The researchers concluded that Velcade was better tolerated if given 1.5 mg/m2 twice weekly for 2 of
every 3 weeks rather than twice weekly for 4 of 6 week
www.myeloma.org
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Activity probe for in vivo profiling of the specificity of proteasome inhibitor bortezomib.
Berkers CR, Verdoes M, Lichtman E, et al.
Nat Methods. 2005 Apr 21; 2(5):357-362 [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5846363
This report describes the synthesis and use of a cell-permeant active site-directed probe, which allows profil-
ing of proteasomal activities in living cells. When compared proteasome activity patterns in cultured cells and
crude cell extracts with this probe, substantial differences were observed, stressing the importance for bioas-
says compatible with live cells to ensure accuracy of such measurements.
High serum bone-specific alkaline phosphatase level after bortezomib-combined therapy in refractory
multiple myeloma: possible role of bortezomib on osteoblast differentiation.
Shimazaki C, Uchida R, Nakano S, Namura K, et al.
Leukemia. 2005 Apr 14; [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5830008
Mitochondrial-mediated disregulation of Ca2+ is a critical determinant of Velcade (PS-341/Bortezomib)
cytotoxicity in myeloma cell lines.
Landowski TH, Megli CJ, Nullmeyer KD, et al.
Cancer Res. 2005 May 1;65(9):3828-36.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5867381
Although Velcade has been shown to be very active in myeloma, the actual mechanism of action is not well
understood. In this study oligonucleotide microarray analysis of the 8226 multiple myeloma cell line support
the hypothesis that intracellular Ca(2+) disregulation is a critical determinant of bortezomib cytotoxicity.
Combining proteasome inhibition with TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) for
cancer therapy.
Sayers TJ, Murphy WJ.
Cancer Immunol Immunother. 2005 Apr 28; [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5864587
Recent studies have shown that apoptosis in myeloma cell can be induced with exposure to members of the
tumor necrosis factor (TNF) superfamily. This study expands upon that work and explores the possibility of
combining the Apo2L/TRAIL (TNF-related apoptosis-inducing ligand) with Velcade.
Bik/NBK accumulation correlates with apoptosis-induction by bortezomib (PS-341, Velcade) and other
proteasome inhibitors.
Zhu H, Zhang L, Dong F, Guo W, et al.
Oncogene. 2005 Apr 11; [Epub ahead of print].
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5824729
www.myeloma.org
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The proteasome inhibitor bortezomib sensitizes cells to killing by death receptor ligand TRAIL via BH3-
only proteins Bik and Bim.
Nikrad M, Johnson T, Puthalalath H, et al.
Mol Cancer Ther. 2005 Mar; 4(3):443-9.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5767553
p38 MAPK inhibition enhances PS-341 (bortezomib)-induced cytotoxicity against multiple myeloma
cells.
Hideshima T, Podar K, Chauhan D, et al.
Oncogene. 2004 Nov 18;23(54):8766-76.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=1
5480425
It has been shown previously that heat shock protein (Hsp)27 is upregulated after PS-341 treatment, that
over expression of Hsp27 confers PS-341 resistance, and that inhibition of Hsp27 overcomes PS-341 resist-
ance. In this study, although p38 MAPK inhibitor SCIO-469 alone did not induce significant growth inhi-
bition, it blocked baseline and PS-341-triggered phosphorylation of p38 MAPK as well as upregulation of
Hsp27, associated with enhanced cytotoxicity in MM.1S cells. Importantly, SCIO-469 enhanced phospho-
rylation of c-Jun NH2-terminal kinase (JNK) and augmented cleavage of caspase-8 and poly(ADP)-ribose
polymerase.
Licensing Update:
Velcade receives approval from both the Food and Drug Administration (FDA) and European Medicines
Evaluation Agency (EMEA) as a second line treatment for myeloma This approval expands the label to
include the treatment of multiple myeloma patients who have received at least one prior therapy. The
approval was based on data from the randomized phase III APEX study that compared single-agent Velcade
to high-dose dexamethasone (669 patients with relapsed or refractory myeloma at 93 centers in North
America, Europe and Israel). The study demonstrated a statistically significant survival advantage in the
Velcade arm of the study.
www.myeloma.org
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Clinical Trials Update
Phase III Vista Trial (VELCADE as Initial Standard Therapy in multiple myeloma:
Assessment with melphalan and prednisone)
This is a large, multicenter, international phase III clinical trial of Velcade in combination with mel-
phalan and prednisone versus melphalan and prednisone in newly diagnosed patients who are not
planning a stem cell transplants. It will assess efficacy, overall safety and tolerability of the combina-
tion versus melphalan and prednisone alone.
Phase IV Everest Trial (Evaluation of VELCADE Employed as Retreatment for
Efficacy, Safety and Tolerability)
The Everest Trial is a multicenter phase IV clinical trial of Velcade designed to evaluate the efficacy
of retreatment in patients who have previously responded to Velcade and relapsed following a treat-
ment-free remission. It will involve 80 sites in the United States.
Other current trials include:
- UCLA-0409110-01, JJPRD-26866138-MMY-3002 - Phase III Randomized Study of Melphalan
and Prednisone With Versus Without Bortezomib in Older Patients With Newly Diagnosed
Multiple Myeloma
- DOXIL MMY 3001 (NCT00103506) - Phase III of Doxil/Caelyx and Velcade or Velcade
Monotherapy for the Treatment of Relapsed Multiple Myeloma
- UCLA-0306106, MILLENNIUM-MM2003 (NCT00084747) - Phase I/II Study of Adjuvant
Bortezomib as Maintenance Therapy After Autologous Peripheral Blood Stem Cell Transplantation
in Patients With Intermediate or Advanced Multiple Myeloma
- UARK 2001-37, ( NCT00083460) - Study of Combination Velcade and Thalidomide in
Multiple Myeloma
- UARK 2003-33 (NCT00081939 - Total Therapy III
- Phase I Study of Velcade with Revlimid in Relapsed and Refractory MM: The RevVel Study
www.myeloma.org
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