Published by the C
International I
Myel
T
oma Founda
ItionN
Special
G
Edition: ASCO 2007 S
Q2/2007
VELCADE®(bortezomib)Issue
The International Myeloma Foundation (IMF) presents this special edition of CITINGS, our
premiere publication featuring the most up-to-date information on myeloma treatment, focused on VELCADE
(bortezomib). This special edition corresponds with the 43rd annual meeting of American Society of Clinical
Oncology (ASCO). In this CITINGS, we have highlighted selected VELCADE data presentations from the
ASCO meeting. We also provide references to the latest published journal articles on VELCADE from the
second quarter of this year.
It is our hope that CITINGS will help keep you abreast of the latest developments in myeloma treatment.
As always, we welcome your feedback; you may contact the IMF at (800) 452-CURE (2873) or at our website
www.myeloma.org.
Susie Novis, President, IMF
AmericanSocietyofClinicalOncology
Presentations2007
Saturday, June 2, 2007
Tanespimycin (T) + bortezomib (BZ) in multiple myeloma (MM): Pharmacology, safety and activity in
relapsed/refractory (rel/ref) patients (Pts).
Presenter: Paul G Richardson, MD
Time: 2:00 PM6:00 PM
Location: S102a
Time: 5:00 PM6:00 PM
Location: S100a
Abstract No: 3532
Poster Number: 3
Poster Discussion Sessions: Developmental Therapeutics: Molecular Therapeutics
Sunday, June 3, 2007
Phase II study of total therapy 3 (TT3) with added bortezomib (V) for multiple myeloma (MM).
Presenter: Bart Barlogie, MD, PhD
Time: 2:00 PM2:15 PM
Location: E354b
Abstract No: 8020
Oral Abstract Presentation Sessions: Myeloma
www.myeloma.org
(800) 452 - CURE (2873)
Funded by an educational grant from Millennium Pharmaceuticals, Inc.
Impact of prior thalidomide (T) therapy on the efficacy of pegylated liposomal doxorubicin (PLD) and
bortezomib (B) in relapsed/refractory multiple myeloma (RRMM).
Presenter: Pieter Sonneveld, MD
Time: 3:00 PM3:15 PM
Location: 354b
Abstract No: 8023
Oral Abstract Presentation Sessions: Myeloma
Final results of a phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction
regimen prior autologous stem cell transplantation (ASCT) in younger patients with multiple myeloma
(MM): Efficacy and clinical implications of tumor response.
Presenter: Laura Rositol
Time: 3:15 PM3:30 PM
Location: E354b
Abstract No: 8024
Oral Abstract Presentation Sessions: Myeloma
Monday, June 4, 2007
Effect of the combination of pegylated liposomal doxorubicin and bortezomib on time to progression
(TTP) and overall survival of patients with relapsed/refractory multiple myeloma compared with
bortezomib alone.
Presenter: Jean L Harousseau, MD
Time: 8:00 AM8:15 AM
Location: E Arie Crown Theater
Abstract No: 8002
Clinical Science Symposium: How New Agents Work in Multiple Myeloma
Bortezomib (BTZ) prior to and as maintenance therapy after autologous stem cell transplant (ASCT)
in multiple myeloma (MM): Long-term follow-up of a phase II study.
Presenter: Sagun D Goyal, MD
Time: 2:00 PM6:00 PM
Location: E451a
Time: 5:00 PM6:00 PM
Location: E354b
Abstract No: 8044
Poster Number: 19
Poster Discussion Sessions: Lymphoma and Plasma Cell Disorders
Factors predictive of outcome in relapsed, refractory multiple myeloma patients treated with
bortezomib, melphalan, prednisone, and thalidomide (VMPT).
Presenter: Antonio Palumbo, MD
Time: 2:00 PM6:00 PM
Location: E451a
Time: 5:00 PM6:00 PM
Location: E354b
Abstract No: 8048
Poster Number: 23
Poster Discussion Sessions: Lymphoma and Plasma Cell Disorders
www.myeloma.org
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Phase I/II study of bortezomib (B) in patients with systemic AL-amyloidosis (AL).
Presenter: Donna E Reece, MD
Time: 2:00 PM6:00 PM
Location: E451a
Time: 5:00 PM6:00 PM
Location: E354b
Abstract No: 8050
Poster Number: 25
Poster Discussion Sessions: Lymphoma and Plasma Cell Disorders
Prospective comparison of subcutaneous to intravenous administration of bortezomib in patients with
multiple myeloma: Pharmacokinetics, efficacy and toxicity.
Presenter: Philippe Moreau
Time: 2:00 PM6:00 PM
Location: E451a
Time: 5:00 PM6:00 PM
Location: E354b
Abstract No: 8046
Poster Number: 21
Poster Discussion Sessions: Lymphoma and Plasma Cell Disorders
Tuesday, June 5, 2007
Prediction of response to bortezomib and dexamethasone resistance in myeloma (MM) by novel
mutations in the NFKB pathway.
Presenter: Wee J Chng, MD
Time: 11:15 AM11:30 AM
Location: 354b
Abstract No: 8007
Special Sessions: Translational Oral Session II: Development and Validation of Predictive Biomarkers
www.myeloma.org
(800) 452 - CURE (2873)
VELCADE®Publications2ndQuarter,2007
NAntibody targeting of the insulin-like growth factor I receptor enhances the anti-tumor response of
multiple myeloma to chemotherapy through inhibition of tumor proliferation and angiogenesis.
Wu KD, Zhou L, Burtrum D, Ludwig DL, Moore MA.
Cancer Immunol Immunother. 2007 Mar;56(3):343-57. [Epub 2006 Jul 11.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16832681&query_
hl=15&itool=pubmed_DocSum
The authors test a fully human anti-IFG-IR antibody (A12) against multiple myeloma as monotherapy and in combination with
bortezomib and melphalan, and find the tumor burden is most sharply decrease and overall survival most significantly prolonged
when the therapies are in combination.
Although many multiple myeloma (MM) patients initially respond to cytotoxic therapy, most eventually relapse. Novel
therapeutic strategies employing a combination of chemotherapy with targeted biologics may significantly enhance the response
of tumor cells to treatment. We tested a fully human anti-IGF-IR antibody (A12) against MM, and showed specific inhibition
of IGF-I or serum-induced IGF-IR signaling in MM cells in vitro. The A12 as a single agent was demonstrated to exert modest
to significant inhibition of tumor growth in vivo in various subcutaneous xenograft MM models. The A12 was also evaluated
in a disseminated xenograft MM.1S NOD/SCID model as monotherapy or in combination with other drugs (bortezomib,
melphalan) currently in clinical use. The tumor burden, as determined by luciferase bioimaging, was sharply decreased, and
overall survival significantly prolonged when the therapies were combined. Immunohistochemical analysis demonstrated that
the A12 treated tumors had significantly decreased vascularization compared to control tumors. Furthermore, most MM lines
constitutively secreted significant quantities of VEGF, and this was enhanced following IGF-I treatment. Inhibition of IGF-IR by
the A12 in vitro suppressed both constitutive and IGF-I-induced secretion of VEGF, indicating that a putative anti-angiogenic
mechanism associated with the A12 treatment may contribute to its anti-tumor effect.
NBortezomib-induced peripheral neurotoxicity: A neurophysiological and pathological study in the rat.
Cavaletti G, Gilardini A, Canta A, Rigamonti L, Rodriguez-Menendez V, Ceresa C, Marmiroli P, Bossi M, Oggioni N,
D'Incalci M, De Coster R.
Exp Neurol. 2007 Mar;204(1):317-25. [Epub 2007 Jan 9.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17214983&query_
hl=15&itool=pubmed_DocSum
The authors address the mechanisms underlying bortezomib neurotoxicity by establishing a preclinical model and characterizing
the changes induced on the peripheral nerves, dorsal root ganglia (DRG) and spinal cord when bortezomib is administered to
Wistar rats.
Bortezomib is a new proteasome inhibitor with a high antitumor activity, but also with a potentially severe peripheral
neurotoxicity. To establish a preclinical model and to characterize the changes induced on the peripheral nerves, dorsal root
ganglia (DRG) and spinal cord, bortezomib was administered to Wistar rats (0.08, 0.15, 0.20, 0.30 mg/kg/day twice [2q7d] or
three times [3q7d] weekly for a total of 4 weeks). At baseline, on days 14, 21 and 28 after the beginning the treatment period
and during a 4-week follow-up period sensory nerve conduction velocity (SNCV) was determined in the tail of each animal.
Sciatic nerve, DRG and spinal cord specimens were processed for light and electron microscope observations and morphometry.
At the maximum tolerated dose bortezomib induced a significant reduction in SNCV, with a complete recovery at the end of
the follow-up period. Sciatic nerve examination and morphometric determinations demonstrated mild to moderate pathological
changes, involving predominantly the Schwann cells and myelin, although axonal degeneration was also observed. Bortezomib-
induced changes were also observed in DRG and they were represented by satellite cell intracytoplasmatic vacuolization due
to mitochondrial and endoplasmic reticulum damage, closely resembling the changes observed in sciatic nerve Schwann cells.
Only rarely did the cytoplasm of DRG neurons has a dark appearance and clear vacuoles occurring in the cytoplasm. Spinal
cord was morphologically normal. This model is relevant to the neuropathy induced by bortezomib in the treatment of human
malignancies and it could be useful in increasing our knowledge regarding the mechanisms underlying bortezomib neurotoxicity.
www.myeloma.org
(800) 452 - CURE (2873)
NMultiple myeloma therapies.
Strobeck M.
Nat Rev Drug Discov. 2007 Mar;6(3):181-2.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17396289&query_
hl=5&itool=pubmed_DocSum
No abstract available.
NTargeted therapeutics for multiple myeloma: The arrival of a risk-stratified approach.
Fonseca R, Stewart AK.
Mol Cancer Ther. 2007 Mar;6(3):802-10.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17363477&query_
hl=15&itool=pubmed_DocSum
The authors discuss the use of novel drugs, including bortezomib, in combination, as myeloma treatment becomes increasingly
personalized and guided by genetic testing and prognostic factors.
Multiple myeloma (MM) remains an incurable hematologic malignancy characterized by frequent early responses, inevitably
followed by treatment relapse. Until recently, few effective therapies existed. Indeed, the use of alkylating agents and
corticosteroids had remained the treatment of choice for almost four decades. Several novel agents for MM have now become
available, including the immunomodulatory drugs thalidomide and lenalidomide, as well as the proteasome inhibitor bortezomib.
Each of these agents is undergoing extensive clinical evaluation in combination with other therapies to produce unprecedented
response rates in newly diagnosed and relapsed MM. Nevertheless, relapse remains universal and further therapeutics with broad
activity are required. Importantly, it has become clear that pivotal genetic events are the primary harbingers of clinical outcome
and novel targeted therapy approaches using existing approved drugs or novel agents, which address that disrupted signaling
pathways are now in various stages of clinical testing. It seems increasingly likely that novel drug combinations, which together
turn off these critical Achilles heels, will become the standard of care and that treatment will become increasingly personalized
and guided by genetic testing and prognostic factors.
NActivity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a
multicenter retrospective study.
Chanan-Khan AA, Kaufman JL, Mehta J, Richardson PG, Miller KC, Lonial S, Munshi NC, Schlossman R, Tariman J, Singhal S.
Blood. 2007 Mar 15;109(6):2604-6. [Epub 2006 Nov 30.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17138816&query_
hl=15&itool=pubmed_DocSum
This retrospective case analysis evaluates the feasibility and activity of bortezomib-based therapy in myeloma patients requiring
dialysis support for advanced renal failure and find that bortezomib or bortezomib-based regimens can be used in myeloma
patients requiring dialysis, with manageable toxicities.
Patients with multiple myeloma (MM) frequently present with concomitant renal dysfunction, and those requiring dialysis have
particularly poor outcomes. Bortezomib is a reversible proteasome inhibitor with significant activity in MM. This retrospective
case analysis evaluated the feasibility and activity of bortezomib-based therapy in MM patients (n = 24) requiring dialysis support
for advanced renal failure. All but 1 patient were undergoing dialysis at the time of therapy. Patients received bortezomib alone or
bortezomib-based combination therapy. Among 20 patients with available response data, overall response rate (complete response
[CR] + partial response) was 75%, with 30% CR + near CR. One patient was spared dialysis, and 3 other patients became
independent of dialysis following bortezomib-based treatment. These encouraging results suggest that bortezomib or bortezomib-
based regimens can be used in MM patients requiring dialysis, with manageable toxicities. Further studies will more formally
evaluate the impact of bortezomib-based regimens in this patient population.
www.myeloma.org
(800) 452 - CURE (2873)
NA phase I/II study of arsenic trioxide/bortezomib/ascorbic acid combination therapy for the treatment of
relapsed or refractory multiple myeloma.
Berenson JR, Matous J, Swift RA, Mapes R, Morrison B, Yeh HS.
Clin Cancer Res. 2007 Mar 15;13(6):1762-8.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17363530&query_
hl=15&itool=pubmed_DocSum
This phase I/II dose escalation study assessed the safety/tolerability and initial efficacy of arsenic trioxide/bortezomib/ascorbic
acid (ABC) combination therapy in patients with relapsed/refractory multiple myeloma. The authors find that the ABC regimen
produced preliminary signs of efficacy, findings warranting further clinical evaluation.
PURPOSE: This multicenter, open-label, phase I/II dose escalation study assessed the safety/tolerability and initial efficacy of
arsenic trioxide/bortezomib/ascorbic acid (ABC) combination therapy in patients with relapsed/refractory multiple myeloma.
EXPERIMENTAL DESIGN: Enrolled in six cohorts, patients were given arsenic trioxide (0.125 or 0.250 mg/kg), bortezomib
(0.7, 1.0, or 1.3 mg/m(2)), and a fixed dose of ascorbic acid (1 g) i.v. on days 1, 4, 8, and 11 of a 21-day cycle for a maximum
of eight cycles. The primary end point was safety/tolerability of the ABC regimen. RESULTS: Twenty-two patients (median age,
63 years) were enrolled, having failed a median of 4 (range, 3-9) prior therapies. One occurrence of grade 4 thrombocytopenia
was observed. One patient had asymptomatic arrhythmia and withdrew from the study. Objective responses were observed in 6
(27%) patients, including two partial responses and four minor responses. Median progression-free survival was 5 months (95%
confidence interval, 2-9 months), and median overall survival had not been reached. The 12-month progression-free survival
and overall survival rates were 34% and 74%, respectively. One (minor response) of six patients receiving the lowest dose of
bortezomib (0.7 mg/m(2)) and 5 (2 partial responses and 3 minor responses) of 16 patients receiving the higher doses (1.0 or
1.3 mg/m(2)) responded. CONCLUSIONS: The ABC regimen was well tolerated by most patients, and it produced preliminary
signs of efficacy with an objective response rate of 27% in this heavily pretreated study population. These findings warrant
further clinical evaluation of the ABC combination for treatment of relapsed/refractory multiple myeloma.
NResveratrol inhibits proliferation, induces apoptosis, and overcomes chemoresistance through down-
regulation of STAT3 and nuclear factor-kappaB-regulated antiapoptotic and cell survival gene products
in human multiple myeloma cells.
Bhardwaj A, Sethi G, Vadhan-Raj S, Bueso-Ramos C, Takada Y, Gaur U, Nair AS, Shishodia S, Aggarwal BB.
Blood. 2007 Mar 15;109(6):2293-302. [Epub 2006 Dec 12.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17164350&query_
hl=15&itool=pubmed_DocSum
The authors investigate whether resveratrol could suppress the proliferation of multiple myeloma cells and conclude that their
findings suggest that resveratrol may have potential in its treatment, including potentiating the apoptotic effects of bortezomib.
Whether resveratrol, a component of red grapes, berries, and peanuts, could suppress the proliferation of multiple myeloma
(MM) cells by interfering with NF-kappaB and STAT3 pathways, was investigated. Resveratrol inhibited the proliferation of
human multiple myeloma cell lines regardless of whether they were sensitive or resistant to the conventional chemotherapy
agents. This stilbene also potentiated the apoptotic effects of bortezomib and thalidomide. Resveratrol induced apoptosis as
indicated by accumulation of sub-G(1) population, increase in Bax release, and activation of caspase-3. This correlated with
down-regulation of various proliferative and antiapoptotic gene products, including cyclin D1, cIAP-2, XIAP, survivin, Bcl-
2, Bcl-xL, Bfl-1/A1, and TRAF2. In addition, resveratrol down-regulated the constitutive activation of AKT. These effects of
resveratrol are mediated through suppression of constitutively active NF-kappaB through inhibition of IkappaBalpha kinase
and the phosphorylation of IkappaBalpha and of p65. Resveratrol inhibited both the constitutive and the interleukin 6-induced
activation of STAT3. When we examined CD138(+) plasma cells from patients with MM, resveratrol inhibited constitutive
activation of both NF-kappaB and STAT3, leading to down-regulation of cell proliferation and potentiation of apoptosis induced
by bortezomib and thalidomide. These mechanistic findings suggest that resveratrol may have a potential in the treatment of
multiple myeloma.
www.myeloma.org
(800) 452 - CURE (2873)
NThe proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple
myeloma patients.
Giuliani N, Morandi F, Tagliaferri S, Lazzaretti M, Bonomini S, Crugnola M, Mancini C, Martella E, Ferrari L, Tabilio A, Rizzoli V.
Blood. 2007 Mar 19; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17371942&query_
hl=15&itool=pubmed_DocSum
The authors' in vitro and in vivo observations support the hypothesis that a direct stimulatory effect on bone formation process
could occur during bortezomib treatment.
The proteasome inhibitor Bortezomib may increase osteoblast related markers in multiple myeloma (MM) patients, however its
potential osteoblastic stimulatory effect is not known. In this study, we show that Bortezomib significantly induced a stimulatory
effect on osteoblast markers in human mesenchymal cells without affecting the number of osteoblast progenitors in bone marrow
cultures or the viability of mature osteoblasts. Consistently we found that Bortezomib significantly increased the transcription
factor Runx2/Cbfa1 activity in human osteoblast progenitors and osteoblasts without affecting nuclear and cytoplasmatic active
beta-catenin levels. Consequently a stimulatory effect of Bortezomib on bone nodule formation was also demonstrated in
osteoblast progenitors. These in vitro observations were confirmed in vivo by the finding of a significant increase in the number
of osteoblastic cells X mm(2) of bone tissue and in the number of Runx2/Cbfa1 positive osteoblastic cells that was observed in
MM patients responder to Bortezomib. Our in vitro and in vivo observations support the hypothesis that a direct stimulatory
effect on bone formation process could occur during Bortezomib treatment.
NJS-K, a GST-activated nitric oxide generator, induces DNA double strand breaks, activates DNA damage
response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells.
Kiziltepe T, Hideshima T, Ishitsuka K, Ocio EM, Raje N, Catley L, Li CQ, Trudel LJ, Yasui H, Vallet S, Kutok JL, Chauhan D,
Mitsiades CS, Saavedra JE, Wogan GN, Keefer LK, Shami PJ, Anderson KC.
Blood. 2007 Mar 23; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17384201&query_
hl=15&itool=pubmed_DocSum
This article investigates the cytotoxicity of JS-K, a prodrug designed to release nitric oxide following reaction with glutathione
S-transferases in multiple myeloma (MM). The authors find that JS-K showed significant cytotoxicity and that bortezomib
significantly enhanced JS-K-induced cytotoxicity.
Here we investigated the cytotoxicity of JS-K, a prodrug designed to release nitric oxide (NO(*)) following reaction with
glutathione S-transferases, in multiple myeloma (MM). JS-K showed significant cytotoxicity in both conventional therapy-
sensitive and -resistant MM cell lines, as well as patient derived MM cells. JS-K induced apoptosis in MM cells which was
associated with PARP, caspase 8, and caspase 9 cleavage; increased Fas/CD95 expression; Mcl-1 cleavage; Bcl-2 phosphorylation;
as well as cyt c, AIF and EndoG release. Moreover, JS-K overcame the survival advantages conferred by IL-6 and IGF-1, or by
adherence of MM cells to bone marrow stromal cells. Mechanistic studies revealed that JS-K induced cytotoxicity was mediated
via NO(*) in MM cells. Furthermore, JS-K induced DNA double strand breaks and activated DNA damage responses, as
evidenced by neutral comet assay, as well as H2AX, Chk2 and p53 phosphorylation. JS-K also activated JNK in MM cells;
conversely inhibition of JNK markedly decreased JS-K-induced cytotoxicity. Importantly, bortezomib significantly enhanced
JS-K-induced cytotoxicity. Finally, JS-K is well tolerated, inhibits tumor growth, and prolongs survival in human MM xenograft
mouse model. Taken together, these data provide the preclinical rationale for the clinical evaluation of JS-K to improve patient
outcome in MM.
NCurrent therapies for multiple myeloma.
Tariman JD.
J Infus Nurs. 2007 Mar-Apr;30(2):113-8; quiz 121.
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17413496&query_
hl=5&itool=pubmed_DocSum
This article overviews multiple myeloma and its current therapies, with emphasis on bortezomib and lenalidomide.
Multiple myeloma is an incurable B-cell malignancy of plasma cells but also a highly treatable disease. This article is an overview
of multiple myeloma and its current therapies, with emphasis on bortezomib and lenalidomide. Important nursing considerations
related to the management of common adverse events are also described.
www.myeloma.org
(800) 452 - CURE (2873)
NAssessing response rates in clinical trials of treatment for relapsed or refractory multiple myeloma:
a study of bortezomib and thalidomide.
Prince HM, Schenkel B, Mileshkin L.
Leukemia. 2007 Apr;21(4):818-20. [Epub 2007 Feb 15.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17301817&query_
hl=15&itool=pubmed_DocSum
No abstract available.
NAssessing response rates in clinical trials of treatment for relapsed or refractory multiple myeloma:
a study of bortezomib and thalidomide by H Prince, Brad Schenkel and Linda Mileshkin.
Durie BG, Rajkumar SV.
Leukemia. 2007 Apr;21(4):821. [Epub 2007 Feb 15.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17301816&query_
hl=15&itool=pubmed_DocSum
No abstract available.
NBortezomib after Allografting in Multiple Myeloma: Association between Neurotoxicity and Cyclosporine
Treatment.
Giaccone L, Sorasio R, Patriarca F, Mattei D, Montefusco V, Peccatori J, Carnevale-Schianca F, Petrucci MT, Milone G, Guidi S,
Rotta M, Fanin R, Corradini P, Boccadoro M, Bruno B; Gruppo Italiano Trapianti di Midollo (GITMO).
Biol Blood Marrow Transplant. 2007 Apr;13(4):497-9.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17382258&query_
hl=15&itool=pubmed_DocSum
No abstract available.
NTargeted therapy of multiple myeloma based upon tumor-microenvironmental interactions.
Anderson KC.
Exp Hematol. 2007 Apr;35(4 Suppl 1):155-62.
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17379101&query_
hl=15&itool=pubmed_DocSum
The author discusses the recent advances in genomics and proteomics that has allowed for the establishment of a new myeloma
treatment paradigm, including bortezomib's ability to overcome conventional drug resistance.
Multiple myeloma (MM) remains incurable, but recent advances in genomics and proteomics have allowed for advances in our
understanding of disease pathogenesis, identified novel therapeutic targets, allowed for molecular classification, and provided the
scientific rationale for combining targeted therapies to increase tumor cell cytotoxicity and abrogate drug resistance. Besides these
advances, recognition of the role of the bone marrow (BM) milieu in conferring growth, survival, and drug resistance in MM
cells, both in laboratory and animal models, has allowed for the establishment of a new treatment paradigm targeting the tumor
cell and its microenvironment to overcome drug resistance and improve patient outcomes in MM. In particular, thalidomide,
bortezomib, and lenalidamide all overcome conventional drug resistance, not only by directly inducing tumor cell cytotoxicity,
but by inhibiting adhesion of MM cells to BM. This abrogates constitutive and MM-binding-induced transcription and secretion
of cytokines, inhibits angiogenesis, and augments host anti-MM immunity. These three drugs have rapidly translated from
bench to bedside and in treatment protocols of MM, first in patients with relapsed refractory disease, and then alone and in
combination in newly diagnosed patients. Promising novel targeted agents include the novel proteasome inhibitor NPI-0052 and
the heat shock protein inhibitor KOS-953. Importantly, gene-array, proteomic, and cell-signaling studies have not only helped to
identify in vivo mechanisms of action and drug resistance to novel agents, but also aided in the design of promising combination-
therapy protocols.
www.myeloma.org
(800) 452 - CURE (2873)
NMolecular dissection of hyperdiploid multiple myeloma by gene expression profiling.
Chang WJ, Kumar S, Vanwier S, Ahmann G, Price-Troska T, Henderson K, Chung TH, Kim S, Mulligan G, Bryant B, Carpten J,
Gertz M, Rajkumar SV, Lacy M, Dispenzieri A, Kyle R, Greipp P, Bergsagel PL, Fonseca R.
Cancer Res. 2007 Apr 1;67(7):2982-9.
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17409404&query_
hl=5&itool=pubmed_DocSum
The authors identify four hyperdiploid multiple myeloma patient clusters. They find that patients in one particular cluster,
characterized by genes involved in tumor necrosis factor/nuclear factor-kappaB signaling and antiapoptosis, have better response
to bortezomib as compared with patients within other clusters.
Hyperdiploid multiple myeloma (H-MM) is the most common form of myeloma. In this gene expression profiling study, we
show that H-MM is defined by a protein biosynthesis signature that is primarily driven by a gene dosage mechanism as a result
of trisomic chromosomes. Within H-MM, four independently validated patient clusters overexpressing nonoverlapping sets
of genes that form cognate pathways/networks that have potential biological importance in multiple myeloma were identified.
One prominent cluster, cluster 1, is characterized by high expression of cancer testis antigen and proliferation-associated genes.
Tumors from these patients were more proliferative than tumors in other clusters (median plasma cell labeling index, 3.8; P <
0.05). Another cluster, cluster 3, is characterized by genes involved in tumor necrosis factor/nuclear factor-kappaB signaling and
antiapoptosis. These patients have better response to bortezomib as compared with patients within other clusters (70% versus
29%; P = 0.02). Furthermore, for a group of patients generally thought to have better prognosis, a cluster of patients with short
survival (cluster 1; median survival, 27 months) could be identified. This analysis illustrates the heterogeneity within H-MM and
the importance of defining specific cytogenetic prognostic factors. Furthermore, the signatures that defined these clusters may
provide a basis for tailoring treatment to individual patients.
NInefficacy of bortezomib therapy for CNS involvement of refractory multiple myeloma.
Mele G, Pinna S, Alloro E, Brocca MC, Coppi MR, Quarta G.
Leuk Res. 2007 May;31(5):721-3. [Epub 2006 Aug 4.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16890285&query_
hl=5&itool=pubmed_DocSum
No abstract available.
NA novel Bcl-2/Bcl-X(L)/Bcl-w inhibitor ABT-737 as therapy in multiple myeloma.
Chauhan D, Velankar M, Brahmandam M, Hideshima T, Podar K, Richardson P, Schlossman R, Ghobrial I, Raje N, Munshi N,
Anderson KC.
Oncogene. 2007 Apr 5;26(16):2374-80. [Epub 2006 Oct 2.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17016430&query_
hl=5&itool=pubmed_DocSum
This study provides a rationale for clinical protocols evaluating ABT-737, alone and together with botezomib, mephalan or
dexamethasone, to enhance MM cell killing, overcome drug resistance conferred by Bcl-2 and improve patient outcome in MM.
Bcl-2 or Bcl-X(L) confers resistance to chemotherapy in multiple myeloma (MM). Here we characterized the effects of ABT-
737, a potent small-molecule inhibitor of antiapoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w with markedly higher affinity than
previously reported compounds, on human MM cells. ABT-737 induces apoptosis in MM cells, including those resistant to
conventional therapy. Examination of purified patient MM cells demonstrated similar results, without significant toxicity against
normal peripheral blood mononuclear cells and MM bone marrow stromal cells. Importantly, ABT-737 decreases the viability
of bortezomib-, dexamethasone-(Dex) and thalidomide-refractory patient MM cells. Additionally, ABT-737 abrogates MM cell
growth triggered by interleukin-6 or insulin-like growth factor-1. Mechanistic studies show that ABT-737-induced apoptosis is
associated with activation of caspase-8, caspase-9 and caspase-3, followed by poly(ADP-ribose) polymerase cleavage. Combining
ABT-737 with proteasome inhibitor bortezomib, melphalan or dexamethasone induces additive anti-MM activity. Taken together,
our study provides the rationale for clinical protocols evaluating ABT-737, alone and together with botezomib, mephalan or
dexamethasone, to enhance MM cell killing, overcome drug resistance conferred by Bcl-2 and improve patient outcome in MM.
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NGene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor
bortezomib.
Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng WJ, Roels S, Koenig E, Fergus A, Huang Y, Richardson P, Trepicchio WL,
Broyl A, Sonneveld P, Shaughnessy JD Jr,
Leif Bergsagel P, Schenkein D, Esseltine DL, Boral A, Anderson KC.
Blood. 2007 Apr 15;109(8):3177-88. [Epub 2006 Dec 21.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17185464&query_
hl=5&itool=pubmed_DocSum
The authors aim to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of
bortezomib in multiple myeloma, and to develop predictive classifiers of response and survival with bortezomib.
The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical
trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients
with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of
pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and
these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes
were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study
of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated
with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the
International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather
than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from
prospective clinical trials of new anticancer agents.
NSafety and efficacy of bortezomib in high-risk and elderly patients with relapsed multiple myeloma.
Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S,
San Miguel JF, Cavenagh JD, Anderson KC.
Br J Haematol. 2007 Apr 19; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17451408&query_
hl=7&itool=pubmed_DocSum
The authors find that bortezomib demonstrates substantial clinical activity and should be considered an appropriate treatment in
high-risk and elderly patients.
Adverse prognostic factors in multiple myeloma include advanced age, number of prior therapies, and higher International
Staging System (ISS) disease stage. In the international, randomised, phase-3 Assessment of Proteasome Inhibition for Extending
Remissions (APEX) study, bortezomib demonstrated significantly longer time to progression (TTP), higher response rates and
improved survival compared with high-dose dexamethasone in patients with relapsed multiple myeloma following one to three
prior therapies. In this APEX subgroup analysis, efficacy of bortezomib and dexamethasone was compared in elderly (age >/=65
years) and high-risk (>1 prior line of therapy; ISS stage II/III; refractory to prior therapy) patients. Bortezomib demonstrated
substantial clinical activity in these patients. Response rate (34-40% vs. 13-19%), including complete response rate (5-8%
vs. 0-1%), was significantly higher with bortezomib versus dexamethasone in all four subgroups. Similarly, median TTP was
significantly longer with bortezomib versus dexamethasone, and 1-year survival probability was significantly higher in all
subgroups. As in the total APEX population, rates of grade 3/4 adverse events were higher in bortezomib- versus dexamethasone-
treated patients aged >/=65 years and with >1 prior line, while rates of serious adverse events were similar; toxicities generally
proved manageable. Bortezomib should be considered an appropriate treatment for elderly and high-risk patients with relapsed
multiple myeloma.
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NThe proteasome: A worthwhile target for the treatment of solid tumours?
Milano A, Iaffaioli RV, Caponigro F.
Eur J Cancer. 2007 May;43(7):1125-1133. Epub 2007 Mar 26.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17379504&query_
hl=6&itool=pubmed_DocSum
The authors detail studies of bortezomib and a single-agent and in combination for the treatment of solid tumors.
Proteasomes have a fundamental function since they degrade numerous different proteins, including those involved in the
regulation of the cell cycle. Proteasome inhibition is a novel approach to the treatment of solid tumours. PS-341 (bortezomib)
is a small, cell-permeable molecule that selectively inhibits the proteasome binding it in a reversible manner. The proteasome
has been established as an important target in haematologic malignancies and has been approved for the treatment of
multiple myeloma. Bortezomib induces apoptosis of malignant cells through the inhibition of NF-kappaB and stabilisation of
proapoptotic proteins. In preclinical studies, bortezomib also promoted chemo and radiosensitisation of malignant cells in vitro
and inhibited tumour growth in murine xenografts models. The single-agent and combination studies of bortezomib in solid
tumours are detailed.
NImexon-based combination chemotherapy in A375 human melanoma and RPMI 8226 human myeloma
cell lines.
Scott J, Dorr RT, Samulitis B, Landowski TH.
Cancer Chemother Pharmacol. 2007 Jun;59(6):749-57. [Epub 2007 Feb 28.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17333195&query_
hl=5&itool=pubmed_DocSum
This study evaluates the cytotoxic effects of imexon in tumor cells when combined with a broad panel of chemotherapeutic drugs
and finds that imexon shows synerg y with bortezomib in myeloma cells, perhaps related to an increase in reactive oxygen species
from both drugs.
PURPOSE: This study evaluated the cytotoxic effects of imexon (NSC-714597) in tumor cells when combined with a broad
panel of chemotherapeutic drugs.
METHODS: The sulforhodamine B (SRB) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)
cytotoxicity assays were used to analyze the degree of growth inhibition for the combination studies in the A375 human
malignant melanoma and RPMI 8226 human multiple myeloma cell lines, respectively. Cells were continuously exposed to both
drugs at a constant molar ratio for 4-5 days. Combination effects were analyzed using the Median Effect method. Statistical
significance was inferred if the 95% confidence interval for the combination interaction (C.I.) values for a particular two-drug
combination did not include 1.0 (additivity). Synergy was inferred for C.I. values < 1.0 and antagonism for CI values > 1.0.
RESULTS: Imexon was synergistic when combined with DNA-binding agents (cisplatin, dacarbazine, melphalan) and
pyrimidine-based antimetabolites (cytarabine, fluorouracil, gemcitabine) in both cell lines. Antagonistic combinations with
imexon included methotrexate and the topoisomerase I (TOPO I) and II (TOPO II) inhibitors irinotecan, doxorubicin,
mitoxantrone and etoposide. Docetaxel was synergistic with imexon in both cell lines whereas paclitaxel and fludarabine showed
a mixed result. Dexamethasone and the proteasome inhibitor bortezomib showed synergy in myeloma cells and additivity in the
melanoma cells. The vinca alkaloid, vinorelbine, and the multi-targeted antifol, pemetrexed, were additive with imexon in both
cell lines.
DISCUSSION: The consistent synergy seen for imexon and alkylating agents may relate to the sulfhydryl-lowering effect
of imexon, which would render cells more sensitive to electrophilic species from the alkylators. The marked synergy noted
with pyrimidine-based antimetabolites was unexpected and may relate to the induction of cell cycle arrest in S-phase. The
strong antagonism noted for imexon with topoisomerase I and II inhibitors may be due to the effect of imexon at increasing
oxidant levels which are known to antagonize the cytotoxic effects of topoisomerase poisons. In contrast, the synergy seen with
bortezomib in myeloma cells may be related to an increase in reactive oxygen species (ROS) from both drugs. These results
suggest that combinations of imexon with alkylating agents and pyrimidine-based antimetabolites are rational to pursue in
therapeutic studies in vivo.
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