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Published by the C
International I
Myel
T
oma Founda
ItionNSpG
ecial Edition: S
ASCO 2006
VELCADE®(bortezomib)Issue
Welcome to the The International Myeloma Foundation's (IMF) special edition of
CITINGS, our premiere publication featuring the most up-to-date information on myeloma
treatment. This issue focuses on VELCADE (bortezomib), the first of a new class of drugs called
proteasome inhibitors. In this issue, we provide a list of selected bortezomib data being presented
at the annual American Society of Clinical Oncology (ASCO) meeting to be held June 2-6,
2006. As always, readers will also find a comprehensive list of references to the latest published
studies on bortezomib from both national and international medical journals and publications.
We hope that CITINGS provides a detailed and informative update of the VELCADE litera-
ture, as well as assists in navigating the ASCO meeting. Please feel free to contact the IMF at
(800) 452-CURE or www.myeloma.org
Susie Novis, President, IMF
AmericanSocietyofClinicalOncologyPresentations2006
Saturday, June 3, 2006
8:00 AM 12:00 PM
n Extended follow-up of outcome measures and analysis of prognostic factors in multiple myeloma
patients treated on a phase I study with bortezomib and pegylated liposomal doxorubicin.
Presenter: Suzanne E Biehn, BA
Abstract No: 7617 Poster No: Y7
General Poster Session
n In vivo changes in gene expression profiles (GEP) after bortezomib (V) for multiple myeloma
(MM): Differential effects on plasma cells (PC) and micro-environment (ME).
Presenter: John D Shaughnessy
Abstract No: 7603 Poster No: X4
General Poster Session
www.myeloma.org
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Funded by an educational grant from Millennium Pharmaceuticals, Inc.

Saturday, June 3, 2006 · 8:00 AM 12:00 PM, continued
Monday, June 5, 2006
n Lenalidomide and bortezomib induce
10:00
osteoclast cytotoxicity and decrease BAFF
AM 10:15 AM
secretion in osteoclasts in human multiple
n High CR and near-CR rate with bortezomib
myeloma: Clinical implications.
incorporated into up-front therapy of multiple
Presenter: Iris Breitkreutz
myeloma with tandem transplants.
Abstract No: 7606 Poster Number: X8
Presenter: Bart Barlogie
General Poster Session
Abstract No: 7519
Oral Presentation
n Phase I study of bortezomib and
153Sm-lexidronam combination for
2:00 PM 6:00 PM
refractory and relapsed multiple myeloma.
n Impact of prior autologous stem cell
Presenter: Howard S Yeh
transplant (ASCT) in patients receiving
Abstract No: 7614 Poster No: Y3
bortezomib or dexamethasone for relapsed/
General Poster Session
refractory multiple myeloma in the APEX trial.
n A phase I/II study of arsenic trioxide,
Presenter: Dan T. Vogl
bortezomib, and ascorbic acid in relapsed or
Abstract No: 7546 Poster No: 22
refractory multiple myeloma.
Poster Discussion
Presenter: James R Berenson
n A prospective study of the effects of once
Abstract No: 7611 Poster No: X13
weekly bortezomib on markers of bone
General Poster Session
metabolism in patients with multiple myeloma
(MM).
Sunday, June 4, 2006
Presenter: Shachar Peles, MD
10:00 AM 10:15 AM
Abstract No: 7548 Poster No: 24
Poster Discussion
n Single-agent bortezomib in previously
untreated multiple myeloma (MM):
n Weekly bortezomib in the treatment of
Results of a phase II multicenter study.
patients (pts) with previously treated multiple
Presenter: Kenneth Anderson
myeloma: A phase II trial of the Minnie Pearl
Abstract No: 7504
Cancer Research Network.
Clinical Science Symposium
Presenter: Frank A Greco
Abstract No: 7547 Poster Number: 23
2:00 PM 6:00 PM
Poster Discussion
n Phase 1 clinical trial of KOS-953 +
bortezomib (BZ) in relapsed refractory
multiple myeloma (MM).
Presenter: Asher Chanan-Khan
Abstract No: 3066 Poster No: Y8
General Poster Session
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2ndQuarter2006VELCADE®(bortezomib)Publications
NBortezomib (Velcade) for progressive myeloma after autologous stem cell transplantation
and thalidomide.
Musto P, Falcone A, Sanpaolo G, Guglielmelli T, Zambello R, Balleari E, Catalano L, Spriano M,
Cavallo F, La Sala A, Mantuano S, Nobile M, Melillo L, Scalzulli PR, Dell'Olio M, Bodenizza C,
Greco MM, Carella AM Jr, Merla E, Carella AM, Boccadoro M, Cascavilla N, Palumbo A.
Leuk Res. 2006 Mar;30(3):283-5. Epub 2005 Aug 18.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16111749&query_hl=7&itool=pubmed_DocSum
The authors conclude that bortezomib alone may induce high quality responses as third-line
salvage therapy with acceptable toxicity in a significant proportion of homogeneously pre-treated
myeloma patients with progressive disease after autologous transplantation and thalidomide.
NCrystal structure of the boronic acid-based proteasome inhibitor bortezomib in complex
with the yeast 20S proteasome.
Groll M, Berkers CR, Ploegh HL, Ovaa H.
Structure. 2006 Mar;14(3):451-6.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16531229&query_hl=7&itool=pubmed_DocSum
The authors determine the crystal structure of the yeast 20S proteasome in complex with
bortezomib to establish the specificity and binding mode of bortezomib to the proteasome's
different catalytically active sites. This structure should enable the rational design of new boronic
acid derivatives with improved affinities and specificities for individual active subunits.
NCutaneous leucoclastic vasculitis (LV) following bortezomib therapy in a myeloma
patient; association with pro-inflammatory cytokines.
Min CK, Lee S, Kim YJ, Eom KS, Lee JW, Min WS, Kim CC, Cho CS, Park G.
Eur J Haematol. 2006 Mar;76(3):265-8.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16451401&query_hl=7&itool=pubmed_DocSum
The authors report a patient with myeloma who developed a cutaneous leucoclastic vasculitis (LV)
after bortezomib treatment. The patient with LV exhibited a marked increase in serum levels of
IL-6, TNF-alpha, and C-reactive protein. Bortezomib administration may enhance the release of
non NF-kappa ß mediated pro-inflammatory cytokines, which might play a role in bortezomib-
induced cutaneous LV.
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NExtended follow-up of a phase II trial in relapsed, refractory multiple myeloma: final
time-to-event results from the SUMMIT trial.
Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin DH, Rajkumar SV,
Srkalovic G, Alsina M, Anderson KC.
Cancer. 2006 Mar 15;106(6):1316-9.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16470606&query_hl=7&itool=pubmed_DocSum
The results of this study suggest that treatment with bortezomib results in no cumulative toxicity,
and other meaningful long-term benefit for patients with relapsed and refractory myeloma
NExtramedullary relapse of multiple myeloma presenting as hematemesis and melena.
Dawson MA, Polizzotto MN, Gordon A, Roberts SK, Spencer A.
Nat Clin Pract Oncol. 2006 Apr;3(4):223-226.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16596146&query_hl=7&itool=pubmed_DocSum
The authors assess a 60-year-old woman with multiple myeloma relapsed after a good partial
response to high-dose chemotherapy (melphalan 200 mg/m(2)) and autologous stem-cell
transplantation, followed by thalidomide and prednisolone maintenance therapy. She presented with
hematemesis and melena following salvage chemotherapy with dexamethasone, cyclophosphamide,
etoposide, cisplatin, and rescue therapy with single-agent bortezomib. The authors diagnose the
patient with multifocal extramedullary relapse of multiple myeloma involving the stomach and
duodenum and suggest management via high-dose infusion of omeprazole, blood product support,
palliative analgesics, and anxiolytic agents.
NInvestigation of drug-drug interaction potential of bortezomib in vivo in female Sprague-
Dawley rats and in vitro in human liver microsomes.
Lu C, Gallegos R, Li P, Xia CQ, Pusalkar S, Uttamsingh V, Nix D, Miwa GT, Gan LS.
Drug Metab Dispos. 2006 Apr;34(4):702-8. Epub 2006 Jan 27.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16443666&query_hl=7&itool=pubmed_DocSum
The authors address a preclinical toxicology study in which treatment of the rats with bortezomib
resulted in liver enlargement (35%). To address the likelihood of clinical drug-drug interactions,
the P450 inhibition potential of bortezomib and its major deboronated metabolites M1 and M2
and their dealkylated metabolites M3 and M4 was evaluated in human liver microsomes for the
major P450 isoforms 1A2, 2C9, 2C19, 2D6, and 3A4/5. The results of this study suggest that no
major P450-mediated clinical drug-drug interactions are anticipated for bortezomib or its major
metabolites.
www.myeloma.org
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NNew treatment strategy of multiple myeloma for cure [in Japanese].
Murakami H, Handa H.
Gan To Kagaku Ryoho (Cancer & Chemotherapy). 2006 Apr;33(4):417-23.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16612147&query_hl=7&itool=pubmed_DocSum
The authors address the treatment advances made in the field of multiple myeloma, including
the novel drugs (thalidomide, thalidomide/dexamethasone, lenalidomide, bortezomib) that have
been introduced in the treatment of patients with relapsed/refractory multiple myeloma, and the
improved prognosis and life span of these patients.
NOxidative deboronation of the peptide boronic acid proteasome inhibitor bortezomib:
contributions from reactive oxygen species in this novel cytochrome p450 reaction.
Labutti J, Parsons I, Huang R, Miwa G, Gan LS, Daniels JS.
Chem Res Toxicol. 2006 Apr;19(4):539-46.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16608165&query_hl=7&itool=pubmed_DocSum
This study addresses bortezomib as a potent first-in-class dipeptidyl boronic acid proteasome
inhibitor employed in the treatment of patients with relapsed multiple myeloma, where the disease
is refractory to conventional lines of therapy. The potency of bortezomib is owed primarily to the
presence of the boronic acid moiety, one that is suited to establish a tetrahedral intermediate with
the active site N-terminal threonine residue of the proteasome. The authors' findings indicate
that the oxidase activity of P450 enzymes (i.e., formation of reactive oxygen species) represents a
mechanism of deboronation.
NProteasome inhibition: novel therapy for multiple myeloma.
Kaufman JL, Lonial S.
Onkologie. 2006 Apr;29(4):162-8. Epub 2006 Mar 29.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16601373&query_hl=7&itool=pubmed_DocSum
The authors address bortezomib, a novel proteasome inhibitor, as a therapeutic option for patients
with myeloma. The success of proteasome inhibition in the treatment of myeloma is a model for
effective translation of preclinical research into tangible clinical benefits for patients with cancer.
NComplete remission upon bortezomib-dexamethasone therapy in three heavily pretreated
multiple myeloma patients relapsing after allogeneic stem cell transplantation.
Tosi P, Zamagni E, Cangini D, Tacchetti P, Perrone G, Ceccolini M, Baccarani M, Cavo M.
Ann Hematol. 2006 Apr 13; Epub ahead of print.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16614846&query_hl=7&itool=pubmed_DocSum
Letter.
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NInhibition of p38alpha MAPK enhances proteasome inhibitor-induced apoptosis of
myeloma cells by modulating Hsp27, Bcl-X(L), Mcl-1 and p53 levels in vitro and inhibits
tumor growth in vivo.
Navas TA, Nguyen AN, Hideshima T, Reddy M, Ma JY, Haghnazari E, Henson M, Stebbins EG,
Kerr I, O'young G, Kapoun AM, Chakravarty S, Mavunkel B, Perumattam J, Luedtke G, Dugar S,
Medicherla S, Protter AA, Schreiner GF, Anderson KC, Higgins LS.
Leukemia. 2006 Apr 13; Epub ahead of print.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16617327&query_hl=7&itool=pubmed_DocSum
The authors show that continued treatment of multiple myeloma (MM) cells with bortezomib
leads to a SCIO-469-enhanced downregulation of Hsp27 and to increased MM apoptosis, and
that p38 inhibition enhances the bortezomib-induced MM apoptosis by upregulation of p53 and
downregulation of Bcl-X(L) and Mcl-1. They conclude that in addition to its role in suppressing
an activated MM microenvironment, co-treatment with a p38 inhibitor, such as SCIO-469, may
enhance the cytotoxicity of bortezomib by modulating pro-apoptotic and anti-apoptotic factors in
MM cells, suggesting great potential for co-therapy.
NRemarkable activity of novel agents bortezomib and thalidomide in patients not
responding to donor lymphocyte infusions following nonmyeloablative allogeneic stem cell
transplantation in multiple myeloma.
van de Donk NW, Kroger N, Hegenbart U, Corradini P, San Miguel JF, Goldschmidt H,
Perez-Simon JA, Zijlmans M, Raymakers RA, Montefusco V, Ayuk FA, van Oers MH, Nagler A,
Verdonck LF, Lokhorst HM.
Blood. 2006 Apr 15;107(8):3415-6.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16597603&query_hl=7&itool=pubmed_DocSum
Letter.
NBortezomib: an effective agent in extramedullary disease in multiple myeloma.
Laura R, Cibeira MT, Uriburu C, Yantorno S, Salamero O, Blade J, Montserrat E.
Eur J Haematol. 2006 May;76(5):405-8. Epub 2006 Mar 9.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16529604&query_hl=7&itool=pubmed_DocSum
The authors address the lack of information on the effect of bortezomib on extramedullary
myeloma. In their study, 4 of 23 patients treated with bortezomib at their institution had
extramedullary involvement at the time of relapse. In 3 of these patients, large soft-tissue
plasmacytomas disappeared, indicating that bortezomib may be useful in clinical situations
of extramedullary disease in which other agents, such as thalidomide, may not be effective.
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NNovel treatment approaches for patients with relapsed and refractory multiple myeloma.
Sinha R, Lonial S.
Curr Treat Options Oncol. 2006 May;7(3):246-57.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16615880&query_hl=7&itool=pubmed_DocSum
The authors address the newly developing treatment options for patients with relapsed myeloma.
They note that the next generation of novel agents targeting heat shock proteins, the mitogen-
activated protein kinase pathway, and monoclonal antibodies are further expanding the list of
future potential agents and that the rapid clinical development of targeting agents will allow for
more options to treat patients with relapsed or refractory myeloma, thereby improving quality of
life and overall survival.
NSevere pulmonary complications in Japanese patients after bortezomib treatment for
refractory multiple myeloma.
Miyakoshi S, Kami M, Yuji K, Matsumura T, Takatoku M, Sasaki M, Narimatsu H, Fujii T,
Kawabata M, Taniguchi S, Ozawa K, Oshimi K.
Blood. 2006 May 1;107(9):3492-4. Epub 2006 Jan 12.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16410442&query_hl=7&itool=pubmed_DocSum
The authors report that between June 2004 and September 2005, 13 Japanese patients with
multiple myeloma were treated with bortezomib. Four of them developed severe pulmonary
complications, and 2 died of respiratory failure without progression of underlying disease. To
the authors' knowledge, this is the first report on life-threatening pulmonary adverse effects after
bortezomib therapy. Previous clinical studies on bortezomib, mostly in the United States and
Europe, have shown low incidences of pulmonary adverse effects. These incidences suggests that
bortezomib can cause serious lung injury, and that its incidence might vary among different
ethnicities. Clinicians need to be alert to the possibility.
NPerifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro
and in vivo cytotoxicity in human multiple myeloma cells.
Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C, Podar K, Munshi NC,
Chauhan D, Richardson PG, Anderson KC.
Blood. 2006 May 15;107(10):4053-62. Epub 2006 Jan 17.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=16418332&query_hl=7&itool=pubmed_DocSum
The authors address perifosine, a synthetic novel alkylphospholipid and a new class of antitumor
agent which targets cell membranes and inhibits Akt activation, concluding that perifosine
augments dexamethasone, doxorubicin, melphalan, and bortezomib-induced multiple myeloma
cell cytotoxicity and demonstrates significant antitumor activity in a human plasmacytoma mouse
model, associated with down-regulation of Akt phosphorylation in tumor cells.
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