/var/www/vhosts/myeloma.org/httpdocs/spider_articles/pdfs/Citings-NovelTherapiesQ2-May2011

Published by the IC
nternational M I
yeloma FT
oundation
IN
VOLUME VIG
II, ISSUE IV
SMAY2011
Novel Therapies Issue
The International Myeloma Foundation (IMF) presents this edition of Citings, our premiere publication featuring the most
up-to-date information on myeloma treatment, focused on the novel therapies currently under study and in use. This edition
corresponds with articles published in May 2011.
As part of our ongoing efforts to make information about myeloma more accessible, we have implemented a new format for
CITINGS, providing these citations on a monthly basis and organizing them by topic. We welcome your comments.
It is our hope that CITINGS will be a valuable tool in keeping you informed on the latest developments in myeloma treatment.
Please feel free to contact us at (800) 452-CURE (2873) or visit us on the web at myeloma.org.
Susie Novis, President, IMF
NovEl ThERapIEs pUblICaTIoNs May 2011
General Discussions & Reviews
NNovel Proteasome Inhibitors to Overcome Bortezomib Resistance.
Ruschak AM, Slassi M, Kay LE, Schimmer AD.
J Natl Cancer Inst. 2011 May 23. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21606441
This review discusses the structure and function of the proteasome, as well as the molecular biology, chemistry, and the
preclinical and clinical efficacy of novel proteasome inhibitors as strategies to inhibit this target and overcome some forms of
bortezomib resistance.
The proteasome is an intracellular enzyme complex that degrades ubiquitin-tagged proteins and thereby regulates protein levels
within the cell. Given this important role in maintaining cellular homeostasis, it is perhaps somewhat surprising that proteasome
inhibitors have a therapeutic window. Proteasome inhibitors have demonstrated clinical efficacy in the treatment of multiple
myeloma and mantle cell lymphoma and are under evaluation for the treatment of other malignancies. Bortezomib is the first and
only Food and Drug Administration-approved proteasome inhibitor that inhibits this enzyme complex in a reversible fashion.
Although bortezomib improves clinical outcomes when used as a single agent, most patients do not respond to this drug and
those who do respond almost uniformly relapse. As such, efforts are underway to develop proteasome inhibitors that act through
mechanisms distinct from that of bortezomib. Specifically, inhibitors that bind the active site of the proteasome and inhibit the
complex irreversibly have been developed and are in advanced clinical trials. Inhibitors that act on sites of the proteasome outside
of the catalytic center have also been identified and are in preclinical development. In this review, we discuss the structure and
function of the proteasome. We then focus on the molecular biology, chemistry, and the preclinical and clinical efficacy of novel
proteasome inhibitors as strategies to inhibit this target and overcome some forms of bortezomib resistance.
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Funded by unrestricted educational grants from Celgene Corporation and Onyx Pharmaceuticals.

NAdvances in imaging and the management of myeloma bone disease.
Terpos E, Moulopoulos LA, Dimopoulos MA.
J Clin Oncol. 2011 May 10;29(14):1907-15. [Epub 2011 Apr 11.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21483016
The authors discuss myeloma bone disease, including how combination approaches with novel antimyeloma agents, such as
bortezomib with bisphosphonates or with drugs that enhance osteoblast function, such as antidickkopf-1 agents, antisclerostin
drugs, or sotatercept, may favorably alter the management of myeloma bone disease in the near future.
Osteolytic disease is a major complication of multiple myeloma that may lead to devastating skeletal-related events (SREs).
Conventional radiography remains the gold standard for the evaluation of bone disease in patients with myeloma. However,
whole-body magnetic resonance imaging (MRI) is recommended in patients with normal conventional radiography and should
be performed as part of staging in all patients with a solitary plasmacytoma of bone. Urgent MRI is also the diagnostic procedure
of choice to assess suspected cord compression, whereas computed tomography can guide tissue biopsy. Positron emission
tomography with computed tomography can provide complementary information to MRI, but its use in multiple myeloma must
be better defined by further studies. The incorporation of abnormal MRI findings into the definition of symptomatic myeloma
also needs to be clarified. Bisphosphonates remain the cornerstone for the management of myeloma bone disease. Intravenous
pamidronate and zoledronic acid are equally effective in reducing SREs, whereas zoledronic acid seems to offer survival benefits
in symptomatic patients. Caution is needed to avoid adverse events, such as renal impairment and osteonecrosis of the jaw. Novel
antiresorptive agents, such as denosumab, have given encouraging results, but further studies are needed before their approval
for managing myeloma bone disease. Combination approaches with novel antimyeloma agents, such as bortezomib (which has
anabolic effects on bone) with bisphosphonates or with drugs that enhance osteoblast function, such as antidickkopf-1 agents,
antisclerostin drugs, or sotatercept, may favorably alter our way of managing myeloma bone disease in the near future.
NCurrent trends in autologous stem-cell transplantation for myeloma in the era of novel therapies.
Moreau P, Avet-Loiseau H, Harousseau JL, Attal M.
J Clin Oncol. 2011 May 10;29(14):1898-906. [Epub 2011 Apr 11.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21482979
This review presents current trends in autologous stem-cell transplantation for myeloma in the era of novel therapies, including
thalidomide, bortezomib and lenalidomide.
Since the mid 1990s, high-dose therapy followed by autologous stem-cell transplantation (ASCT) has been considered the
standard of care for frontline therapy in younger patients with multiple myeloma (MM). During the past 10 years, thalidomide,
bortezomib, and lenalidomide have been widely incorporated to the therapeutic armamentarium for the treatment of this disease.
These agents show promise for improving the rate of complete remission both before and after ASCT without increasing toxicity.
However, it is not clear whether such therapies are superior if they are used as an alternative to transplantation or whether they
may reduce the need for and use of transplantation in patients in whom treatment is indicated. Therefore, the role of ASCT itself
is a matter of debate: Should it be used upfront or as salvage treatment at the time of progression in patients initially treated with
novel agents? This review presents current trends in ASCT for MM in the era of novel therapies.
NTeratogenic effects of thalidomide: molecular mechanisms.
Ito T, Ando H, Handa H.
Cell Mol Life Sci. 2011 May;68(9):1569-79. [Epub 2011 Jan 5.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21207098
This review summarizes the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects, as well as
a discussion of the questions still to be addressed.
Fifty years ago, prescription of the sedative thalidomide caused a worldwide epidemic of multiple birth defects. The drug is
now used in the treatment of leprosy and multiple myeloma. However, its use is limited due to its potent teratogenic activity.
The mechanism by which thalidomide causes limb malformations and other developmental defects is a long-standing question.
Multiple hypotheses exist to explain the molecular mechanism of thalidomide action. Among them, theories involving oxidative
stress and anti-angiogenesis have been widely supported. Nevertheless, until recently, the direct target of thalidomide remained
elusive. We identified a thalidomide-binding protein, cereblon (CRBN), as a primary target for thalidomide teratogenicity. Our
data suggest that thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting its ubiquitin ligase activity.
In this review, we summarize the biology of thalidomide, focusing on the molecular mechanisms of its teratogenic effects. In
addition, we discuss the questions still to be addressed.
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Induction Therapy
NBortezomib added to high-dose melphalan as pre-transplant conditioning is safe in patients with heavily
pre-treated multiple myeloma.
Thompson PA, Prince HM, Seymour JF, Ritchie D, Stokes K, Burbury K, Wolf M, Peinert S, Joyce T, Harrison SJ.
Bone Marrow Transplant. 2011 May;46(5):764-5. [Epub 2010 Aug 2.]
No abstract available.
:
http://www.ncbi.nlm.nih.gov/pubmed/20676149
Mechanisms & pathways
NNovel insights into the synergistic interaction of Bortezomib and TRAIL: tBid provides the link.
Fulda S.
Oncotarget. 2011 May 16. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21586804
The author discusses a recent study identifiying a new mechanism of action for the synergism of TRAIL and bortezomib.
The proteasome inhibitor Bortezomib has been identified as a potent enhancer of TRAIL-induced apoptosis in several human
cancers. However, the identification of the underlying molecular mechanisms of this synergistic cell death induction has been
ongoing over the last years. A recent study identifies a new mechanism of action for the synergism of TRAIL and Bortezomib.
NBortezomib Primes Neuroblastoma Cells for TRAIL-Induced Apoptosis by Linking the Death Receptor
to the Mitochondrial Pathway.
Naumann I, Kappler R, von Schweinitz D, Debatin KM, Fulda S.
Clin Cancer Res. 2011 May 15;17(10):3204-18. [Epub 2011 Apr 1.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21459798
The authors analyze the effect of bortezomib on TRAIL-induced apoptosis signaling pathways in neuroblastoma cell lines,
primary neuroblastoma cultures and in an in vivo model. They find that bortezomib represents a promising new approach to
prime neuroblastoma cells towards TRAIL, and warrants further investigation.
PURPOSE: Searching for novel strategies to modulate apoptosis in neuroblastoma we investigated the potential of the
proteasome inhibitor Bortezomib. EXPERIMENTAL DESIGN: The effect of Bortezomib on TRAIL-induced apoptosis
signaling pathways was analyzed in neuroblastoma cell lines, primary neuroblastoma cultures and in an in vivo model. RESULTS:
Bortezomib synergistically cooperates with TRAIL to induce apoptosis and to reduce colony formation of neuroblastoma cells
(combination index 0.5). Mechanistic studies reveal that Bortezomib profoundly enhances TRAIL-induced cleavage of Bid into
tBid, accumulation of tBid in the cytosol and its insertion into mitochondrial membranes, pointing to a concerted effect on
Bid cleavage (TRAIL) and stabilization of tBid (Bortezomib), which links the death receptor to the mitochondrial pathway.
Additionally, Bortezomib increases expression of p53 and Noxa. All these changes lead to increased activation of Bax and Bak,
loss of the mitochondrial membrane potential, cytochrome c release, caspase activation and caspase-dependent apoptosis upon
treatment with Bortezomib and TRAIL. Knockdown of either Bid, Noxa or p53 significantly delays the kinetic of Bortezomib-
and TRAIL-induced apoptosis, whereas it does not confer longterm protection. By comparison, overexpression of Bcl-2, which
simultaneously antagonizes tBid and p53, significantly inhibits Bortezomib- and TRAIL-induced apoptosis and even rescues
clonogenic survival. Importantly, Bortezomib and TRAIL act in concert to trigger apoptosis and to suppress tumor growth
in patients' derived primary neuroblastoma cells and in an in vivo model of neuroblastoma. CONCLUSIONS: Bortezomib
represents a promising new approach to prime neuroblastoma cells towards TRAIL, which warrants further investigation.
NIMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation
resulting in inhibition of MM.
Li S, Pal R, Monaghan SA, Schafer P, Ouyang H, Mapara M, Galson DL, Lentzsch S.
Blood. 2011 May 12;117(19):5157-65. [Epub 2011 Mar 9.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21389327
The authors show that IMiD compounds (such as lenalidomide) downregulate CCAAT/enhancer-binding protein beta (C/EBP)
resulting in abrogation of cell proliferation.
Immunomodulatory derivatives of thalidomide (IMiD compounds) such as pomalidomide and lenalidomide are highly active in
multiple myeloma (MM) treatment. However, the precise mechanisms of IMiDs and resistance resistance in MM are unresolved.
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Here we show that IMiD compounds downregulate CCAAT/enhancer-binding protein beta (C/EBP) resulting in abrogation of
cell proliferation. Overexpression of C/EBP rescued MM cells from IMiD-induced inhibition of proliferation, indicating that
C/EBP is critical in mediating antiproliferative effects. IMiD-induced decrease of C/EBP protein led to impaired transcription
of interferon regulatory factor 4 (IRF4). Downregulation of IRF4 by lenalidomide was confirmed by longitudinal studies of
bone marrow samples from 23 patients obtained prior to and during lenalidomide treatment using CD138(+)/IRF4(+) double
labeling. In contrast to downregulation of C/EBP protein, IMiD compounds did not alter C/EBP mRNA levels or protein
stability, suggesting translational regulation of C/EBP. We could demonstrate that C/EBP protein expression is under eIF4E-
translational control in MM. Furthermore, inhibition of the eIF4E-C/EBP axis by IMiD compounds was not observed in
IMiD-resistant MM cells. However, targeting translation at a different level by inhibiting eukaryotic translation initiation factor
4E-binding protein 1 (4EBP1) phosphorylation overcame resistance, suggesting that this pathway is critical and might be a target
to overcome drug resistance.
NMolecular heterogeneity of multiple myeloma: pathogenesis, prognosis, and therapeutic implications.
Avet-Loiseau H, Magrangeas F, Moreau P, Attal M, Facon T, Anderson K, Harousseau J-L, Munshi N, Nikhil M, Minvielle S.
J Clin Oncol. 2011 May 10;29(14):1893-7. [Epub 2011 Apr 11.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21482986
The authors discuss myeloma at the chromosomal level. They conclude that, because of the complex and heterogeneous picture
of the molecular profiles, it is unexpected that targeted therapies might play a role in myeloma. The only recognized indication
is to propose bortezomib-based approaches for the treatment of patients displaying the translocation t(4;14).
Multiple myeloma (MM) is characterized by a significant heterogeneity at the molecular level. The first level is the chromosomal
one. Although cytogenetics is difficult to assess in MM, patients can be divided into two categories: hyperdiploidy and non-
hyperdiploidy (about half in each group). Using molecular cytogenetic techniques, several subgroups of patients are identified,
particularly on the basis of 14q32 translocations. This chromosomal heterogeneity is confirmed by genomic techniques (gene
expression profiling or single nucleotide polymorphism/comparative genomic hybridization arrays). Unsupervised analyses of
gene expression profiles identified several subgroups of patients, essentially on the basis of chromosomal abnormalities such as
hyperdiploidy or 14q32 translocations. However, these analyses failed to separate MM into subentities, which could lead to
specific therapeutic approaches, as is the case for non-Hodgkin's lymphomas. Nevertheless, these chromosomal/genomic data
can be used for prognostication of patients. Specific chromosomal changes, such as loss of the short arm of chromosome 17,
or specific gene expression profiles clearly identify patients with short survival. No molecular change so far has been associated
with long survival or even cure, probably because of the short follow-up observed in all studies. So far, it is unclear how to use
this massive amount of data to treat patients. Because of the complex and heterogeneous picture of the molecular profiles, it is
unexpected that targeted therapies might play a role in MM. The only recognized indication is to propose bortezomib-based
approaches for the treatment of patients displaying the translocation t(4;14).
NPolymorphisms of nuclear factor-{kappa}B family genes are associated with development of multiple
myeloma and treatment outcome in patients receiving bortezomib-based regimens.
Du J, Huo J, Shi J, Yuan Z, Zhang C, Fu W, Jiang H, Yi Q, Hou J.
Haematologica. 2011 May;96(5):729-37. [Epub 2011 Jan 12.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21228035
The authors find that NF-B family member gene polymorphisms play a role in myeloma development and in response to
bortezomib therapy.
Background. The NF-B pathway is an important signaling pathway activated in multiple myeloma cells. Bortezomib inhibits
NF-B activation and is an important antimyeloma agent. However, patients eventually relapse. We hypothesized that the
NF-B pathway may be associated with multiple myeloma and patient responses to bortezomib. Design and Methods. In
this study we analyzed 26 polymorphism sites of NF-B family member genes, IKB, NFB2, and TRAF3, in 527 unrelated
Chinese Han subjects (252 multiple myeloma patients and 275 controls) using Sequenom MassARRAY genotyping assay, and
examined the outcome of 83 patients treated with a bortezomib-based regimen. Results. Single nucleotide polymorphisms
in the TRAF3 rs12147254 A allele and a specific haplotype 1 of TRAF3 [GAACAG] are associated with a decreased risk of
multiple myeloma (odds ratio 0.709, P < 0.001, and odds ratio 0.543, P < 0.0001), while TRAF3 haplotype 4 [GGACAG] was
associated with an increased risk of multiple myeloma development (odds ratio 2.099, P = 0.001). Moreover, patients carrying
the TRAF3 rs11160707 GA+AA genotype was significantly associated with a superior progression-free survival (P = 0.018). The
NFB2 rs12769316 GA+AA genotype had a superior overall survival (P = 0.020), while rs1056890 CT+TT genotype had an
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inferior overall survival (P = 0.037). In exploration analysis, patients having the GA+AA/CC/GG genotype at the rs12769316,
rs1056890, and rs11160707 sites had a significantly superior overall survival compared with patients with wild-type genotype
(P = 0.007). From multivariable analysis, TRAF3 rs11160707 showed to be an independent favorable factor in progression-free
survival (hazard ratio 0.428, P = 0.028). Conclusions. NF-B family member gene polymorphisms play a role in myeloma
development and in response to bortezomib therapy.
New Combinations
NIncreased In vivo Efficacy of Lenalidomide and Thalidomide by Addition of Ethacrynic Acid.
Schmidt M, Kim Y, Gast SM, Endo T, Lu D, Carson D, Schmidt-Wolf IG.
In Vivo. 2011 May-Jun;25(3):325-33.
:
http://www.ncbi.nlm.nih.gov/pubmed/21576405
This study investigates the antitumor effect of ethacrynic acid in vitro and in vivo in a murine myeloma model and finds,
in vitro, a significant additive effect with the combination of lenalidomide as compared to single applications.
BACKGROUND: It was recently confirmed that ethacrynic acid (EA) inhibits Wnt/beta catenin signalling in myeloma.
MATERIALS AND METHODS: This study investigated the antitumor effect of EA in vitro and in vivo in a murine myeloma
model. RESULTS: EA demonstrated major apoptotic activity in different human and murine myeloma and lymphoma cell lines,
as well as in human primary cells. In addition -catenin expression was down-regulated when EA was added to lymphoma cells.
In vivo, tumor growth, as well as overall survival, was significantly reduced in mice treated with EA as compared to untreated
mice. Interestingly, in vitro, a significant additive effect was seen with the combination of lenalidomide plus EA as compared
to single applications. CONCLUSION: These results reveal a significant selective induction of apoptosis by EA and suggest a
significant in vivo effect against myeloma.
NAntimyeloma Activity of a Multitargeted Kinase Inhibitor, AT9283, via Potent Aurora Kinase and STAT3
Inhibition Either Alone or in Combination with Lenalidomide.
Santo L, Hideshima T, Cirstea D, Bandi M, Nelson EA, Gorgun G, Rodig S, Vallet S, Pozzi S, Patel K, Unitt C, Squires M, Hu Y,
Chauhan D, Mahindra A, Munshi NC, Anderson KC, Raje N.
Clin Cancer Res. 2011 May 15;17(10):3259-71. [Epub 2011 Mar 23.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21430070
The authors investigate the preclinical activity of a small-molecule multitargeted kinase inhibitor, AT9283, with potent activity
against Aurora kinase A, Aurora kinase B, and Janus kinase 2/3. They conclude that their findings of in vitro and in vivo anti-
myeloma activity of AT9283 provide the rationale for the clinical evaluation of AT9283 as monotherapy and in combination
therapy with lenalidomide for treating patients with myeloma.
PURPOSE: Aurora kinases, whose expression is linked to genetic instability and cellular proliferation, are being investigated as
novel therapeutic targets in multiple myeloma (MM). In this study, we investigated the preclinical activity of a small-molecule
multitargeted kinase inhibitor, AT9283, with potent activity against Aurora kinase A, Aurora kinase B, and Janus kinase 2/3.
EXPERIMENTAL DESIGN: We evaluated the in vitro antimyeloma activity of AT9283 alone and in combination with
lenalidomide and the in vivo efficacy by using a xenograft mouse model of human MM. RESULTS: Our data showed that
AT9283 induced cell-growth inhibition and apoptosis in MM. Studying the apoptosis mechanism of AT9283 in MM, we
observed features consistent with both Aurora kinase A and Aurora kinase B inhibition, such as increase of cells with polyploid
DNA content, decrease in phospho-histone H3, and decrease in phospho-Aurora A. Importantly, AT9283 also inhibited STAT3
tyrosine phosphorylation in MM cells. Genetic depletion of STAT3, Aurora kinase A, or Aurora kinase B showed growth
inhibition of MM cells, suggesting a role of AT9283-induced inhibition of these molecules in the underlying mechanism of
MM cell death. In vivo studies showed decreased MM cell growth and prolonged survival in AT9283-treated mice compared
with controls. Importantly, combination studies of AT9283 with lenalidomide showed significant synergistic cytotoxicity in
MM cells, even in the presence of bone marrow stromal cells. Enhanced cytotoxicity was associated with increased inhibition of
phosphorylated STAT3 and phosphorylated extracellular signal-regulated kinase. CONCLUSIONS: Demonstration of in vitro
and in vivo anti-MM activity of AT9283 provides the rationale for the clinical evaluation of AT9283 as monotherapy and in
combination therapy for treating patients with MM. ©2011 AACR.
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NPhase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients
with Recurrent or Refractory B-Cell Neoplasms.
Holkova B, Perkins EB, Ramakrishnan V, Tombes MB, Shrader E, Talreja N, Wellons MD, Hogan KT, Roodman GD, Coppola D,
Kang L, Dawson J, Stuart RK, Peer C, Figg WD Sr, Kolla S, Doyle A, Wright J, Sullivan DM, Roberts JD, Grant S.
Clin Cancer Res. 2011 May 15;17(10):3388-3397. [Epub 2011 Mar 29.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21447728
This phase I study seeks to determine the dose-limiting toxicities and maximum tolerated dose (MTD) for the combination
of bortezomib and alvocidib in patients with B-cell malignancies. The authors find that the combination of bortezomib and
alvocidib is tolerable, determine an MTD for the tested schedule, and conclude that the regimen appears active in patients with
relapsed and/or refractory myeloma or non-Hodgkin's lymphoma, justifying phase II studies to determine the activity of this
regimen more definitively.
PURPOSE: A phase I study was conducted to determine the dose-limiting toxicities (DLT) and maximum tolerated dose (MTD)
for the combination of bortezomib and alvocidib in patients with B-cell malignancies (multiple myeloma, indolent lymphoma,
and mantle cell lymphoma). EXPERIMENTAL DESIGN: Patients received bortezomib by intravenous push on days 1, 4, 8,
and 11. Patients also received alvocidib on days 1 and 8 by 30-minute bolus infusion followed by a 4-hour continuous infusion.
Treatment was on a 21-day cycle, with indefinite continuation for patients experiencing responses or stable disease. Dose
escalation employed a standard 3 + 3 design until the MTD was identified on the basis of DLTs. Pharmacokinetic studies and
pharmacodynamic studies were conducted. RESULTS: Sixteen patients were treated. The MTD was established as 1.3 mg/m2
for bortezomib and 30 mg/m2 for alvocidib (both the 30-minute bolus and 4-hour infusions). Common hematologic toxicities
included leukopenia, lymphopenia, neutropenia, and thrombocytopenia. Common nonhematologic toxicities included fatigue
and febrile neutropenia. DLTs included fatigue, febrile neutropenia, and elevated aspartate aminotransferase (AST) levels. Two
complete responses (CR; 12%) and five partial responses (PR; 31%) were observed at the MTD (overall response rate = 44%).
Pharmacokinetic results were typical for alvocidib and pharmacodynamic studies yielded variable results. CONCLUSIONS: The
combination of bortezomib and alvocidib is tolerable and an MTD has been established for the tested schedule. The regimen
appears active in patients with relapsed and/or refractory multiple myeloma or non-Hodgkin's lymphoma, justifying phase II
studies to determine the activity of this regimen more definitively. ©2011 AACR.
NPhase I study of the anti insulin-like growth factor 1 receptor (IGF-1R) monoclonal antibody, AVE1642,
as single agent and in combination with bortezomib in patients with relapsed multiple myeloma.
Moreau P, Cavallo F, Leleu X, Hulin C, Amiot M, Descamps G, Facon T, Boccadoro M, Mignard D, Harousseau JL.
Leukemia. 2011 May;25(5):872-4. [Epub 2011 Feb 15.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21321571
No abstract available.
Newly Diagnosed
NLenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone in newly diagnosed
multiple myeloma: a phase 1/2 Multiple Myeloma Research Consortium trial.
Jakubowiak AJ, Griffith KA, Reece DE, Hofmeister CC, Lonial S, Zimmerman TM, Campagnaro EL, Schlossman RL,
Laubach JP, Raje NS, Anderson T, Mietzel MA, Harvey CK, Wear SM, Barrickman JC, Tendler CL, Esseltine DL, Kelley SL,
Kaminski MS, Anderson KC, Richardson PG.
Blood. 2011 May 23. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21596852
This phase I/II trial evaluates the combination of lenalidomide, bortezomib, pegylated liposomal doxorubicin, and
dexamethasone (RVDD) in newly diagnosed myeloma patients. The authors find that RVDD is generally well tolerated and
highly active, warranting further study in newly diagnosed myeloma patients.
This phase 1/2 trial evaluated combination lenalidomide, bortezomib, pegylated liposomal doxorubicin, and dexamethasone
(RVDD) in newly diagnosed multiple myeloma (MM) patients. Patients received RVDD at 4 dose levels including the maximum
tolerated dose (MTD). Patients with a very good partial response or better ( VGPR) after cycle 4 proceeded to autologous
stem-cell transplantation or continued treatment. The primary objectives were MTD evaluation and response to RVDD after 4
and 8 cycles. Seventy-two patients received a median of 4.5 cycles. The MTDs were lenalidomide 25 mg, bortezomib 1.3 mg/
m2, pegylated liposomal doxorubicin 30 mg/m2, and dexamethasone 20/10 mg, as established with 3-week cycles. The most
common adverse events were fatigue, constipation, sensory neuropathy, and infection; there was no treatment-related mortality.
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Response rates after 4 and 8 cycles were 96% and 95% partial response or better, 57% and 65% VGPR, and 29% and 35%
complete or near complete response, respectively. After a median follow-up of 15.5 months, median progression-free survival
(PFS) and overall survival (OS) were not reached. Estimated 18-month PFS and OS are 80.8% and 98.6%, respectively. RVDD
was generally well tolerated and highly active, warranting further study in newly diagnosed MM patients. This trial was registered
at www.clinicaltrials.gov as #NCT00724568.
NA steroid-independent regimen of bortezomib, liposomal doxorubicin and thalidomide demonstrate
high response rates in newly diagnosed multiple myeloma patients.
Sher T, Ailawadhi S, Miller KC, Manfredi D, Wood M, Tan W, Wilding G, Czuczman MS, Hernandez-Ilizaliturri FJ, Hong F,
Sood R, Soniwala S, Lawrence W, Jamshed S, Masood A, Iancu D, Lee K, Chanan-Khan A.
Br J Haematol. 2011 May 9. doi: 10.1111/j.1365-2141.2011.08703.x. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21554260
A phase II single institute, non-randomized clinical trial is conducted to investigate a novel steroid-free three-drug combination
of bortezomib, pegylated liposomal doxorubicin, and thalidomide--the VDT regimen. The authors conclude that VDT is a
tolerable and an effective regimen capable of inducing high response rates, and can be employed in patients considered to be
poor candidates for steroid-based treatment regimens.
Novel agents have provided a new foundation for multiple myeloma therapies. When combined with other anti-myeloma agents,
these compounds significantly enhance clinical efficacy. High-dose steroids are frequently used in anti-myeloma combination
regimens; however, the doses employed are often poorly tolerated, especially in patients with concurrent comorbid conditions. We
hypothesized that a steroid-independent combination regimen could be developed without significant compromise of efficacy.
The availability of such a regimen will be important for patients whose concurrent ailments make them poor candidates for
steroid containing anti-myeloma regimens. A phase II single institute, non-randomized clinical trial was conducted to investigate
a novel steroid-free three-drug combination of bortezomib (V), pegylated liposomal doxorubicin (D), and thalidomide (T), the
VDT regimen. Forty-three newly diagnosed multiple myeloma patients requiring treatment were enrolled on this study. The
overall response rate and complete response (CR)+near complete response (nCR) rate was 78% and 35%, respectively. Median
time to progression was 29.5 months. Fatigue, rash, neuropathy, constipation and infections were the most common side effects.
We concluded that VDT is a tolerable and an effective regimen capable of inducing high response rates and can be employed in
patients considered to be poor candidates for steroid-based treatment regimens.
phase III Trials
NResults of the first bortezomib-based induction therapy in the treatment of multiple myeloma.
Kortüm M, Einsele H.
Expert Opin Pharmacother. 2011 May 10. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21554151
Commenting on a phase III trial comparing the efficacy and the safety of a bortezomib-containing induction regimen with
conventional chemotherapy before autologous stem-cell transplantation in myeloma patients, the authors find that the
difference in progression-free survival (PFS) is not statistically significant but a trend to longer PFS is seen to favor to the
bortezomib-containing regimen. They therefore support the study's conclusion proposing bortezomib and dexamethasone to
be the standard of care.
This is a comment on the IFM 2005 - 01 Phase III trial that compared, for the first time, the efficacy and the safety of a
bortezomib-containing induction regimen with conventional chemotherapy before autologous stem-cell transplantation
in multiple myeloma (MM) patients. Between 2005 and 2008, 482 patients were randomized to vincristin/doxorubicin/
dexamethasone (VAD), VAD + dexamethasone, cyclophosphamide, etoposide and cisplatin (DCEP) consolidation, bortezomib
+ dexamethasone and bortezomib + dexamethasone + DCEP consolidation followed by autologous stem-cell transplantation.
The trial was conducted in 89 sites in France, Belgium and Switzerland. The novel agent-based induction therapy (bortezomib/
dexamethasone) achieved higher complete remission (CR)/nearCR rates, as well as less treatment-related mortality, but higher
rates of polyneuropathy than the conventional chemotherapy-based induction therapy (VAD/VAD + DCEP). The difference
in progression-free survival (PFS) difference was not statistically significant but a trend to longer PFS was seen to favor to the
bortezomib-containing regimen; bortezomib and dexamethason (BD) was, therefore, proposed to be a standard of care by the
authors of the study.
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NFewer bone disease events, improvement in bone remodeling, and evidence of bone healing
with bortezomib plus melphalan-prednisone vs. melphalan-prednisone in the phase III VISTA trial
in multiple myeloma.
Delforge M, Terpos E, Richardson PG, Shpilberg O, Khuageva NK, Schlag R, Dimopoulos MA, Kropff M, Spicka I, Petrucci MT,
Samoilova OS, Mateos MV, Magen-Nativ H, Goldschmidt H, Esseltine DL, Ricci DS, Liu K, Deraedt W, Cakana A, van de Velde H,
San Miguel JF.
Eur J Haematol. 2011 May;86(5):372-84. doi: 10.1111/j.1600-0609.2011.01599.x. [Epub 2011 Mar 30.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21366694
This post-hoc analysis of the phase III VISTA trial of bortezomib plus melphalan-prednisone (VMP) versus MP in previously
untreated myeloma patients assesses clinical bone disease events and changes in alkaline phosphatase, a marker for osteoblast
activation, and serum Dickkopf-1, an inhibitor of osteoblast differentiation, during treatment. The results suggest a positive
effect of bortezomib on bone metabolism and potentially bone healing in myeloma.
OBJECTIVES: Bone disease is a key presenting feature of myeloma. This post-hoc analysis of the phase III VISTA trial of
bortezomib plus melphalan-prednisone (VMP) versus MP in previously untreated myeloma patients assessed clinical bone
disease events and changes in alkaline phosphatase (ALP), a marker for osteoblast activation, and serum Dickkopf-1 (DKK-1), an
inhibitor of osteoblast differentiation, during treatment. METHODS: Patients received nine 6-week cycles of VMP (bortezomib
1.3 mg/m2, days 1, 4, 8, 11, 22, 25, 29, 32, cycles 1-4, days 1, 8, 22, 29, cycles 5-9, plus melphalan 9 mg/m2 and prednisone 60
mg/m2, days 1-4, cycles 1-9; N=344) or MP alone (N=338). RESULTS: Rates of bisphosphonates use during treatment (73% vs.
82%), progression due to worsening bone disease (3% vs. 11%), and requirement for subsequent radiotherapy (3% vs. 8%) were
lower with VMP vs. MP. Median maximum ALP increase was significantly higher with VMP vs. MP overall (49.7% vs. 30.3%,
P=0.029), and higher by response group (complete response [CR]: 68.7% vs. 43.9%; partial response [PR]: 41.5% vs. 31.2%).
Greater maximum ALP increase was strongly associated with achievement of CR (P0.0001) and CR/PR (P0.01). Median
DKK-1 decreased with VMP by 694.4 pg/mL and increased with MP by 1273.3 pg/mL from baseline to day 4 (P=0.0069).
Available radiologic data revealed evidence of bone healing in 6/11 VMP-treated patients, who achieved best responses of 3 CR,
1 PR, and 2 stable disease. CONCLUSIONS: These results suggest a positive effect of bortezomib on bone metabolism and
potentially bone healing in myeloma.
NSubcutaneous bortezomib: a step towards optimised drug use.
Mateos MV.
Lancet Oncol. 2011 May;12(5):410-1. [Epub 2011 Apr 18.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21507716
No abstract available.
Relapsed/Refractory Disease
NEfficacy and safety of once-weekly and twice-weekly bortezomib in patients with relapsed systemic
AL amyloidosis: results of a phase 1/2 study.
Reece DE, Hegenbart U, Sanchorawala V, Merlini G, Palladini G, Bladé J, Fermand JP, Hassoun H, Heffner L, Vescio RA, Liu K,
Enny C, Esseltine DL, van de Velde H, Cakana A, Comenzo RL.
Blood. 2011 May 11. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21562045
This first prospective phase II study of single-agent bortezomib in relapsed primary systemic AL amyloidosis evaluates the
recommended (maximum planned) doses identified in phase I testing once weekly and twice weekly. The authors find that both
of these bortezomib dose schedules represent active, well-tolerated regimens in relapsed AL.
This first prospective phase 2 study of single-agent bortezomib in relapsed primary systemic AL amyloidosis (AL) evaluated
the recommended (maximum planned) doses identified in phase 1 testing (1.6 mg/m2 once weekly [days 1, 8, 15, 22; 35-day
cycles] and 1.3 mg/m2 twice weekly [days 1, 4, 8, 11; 21-day cycles]). Among all 70 patients enrolled to the study, 44% had 3
organs involved, including 73% and 56% with renal and cardiac involvement. In the 1.6 mg/m2 once-weekly and 1.3 mg/m2
twice-weekly groups the hematologic response rate was 68.8% and 66.7% (37.5% and 24.2% complete responses), respectively;
median time to first/best response was 2.1/3.2 and 0.7/1.2 months, while 78.8% and 75.5% had response durations of 1 year,
respectively. One-year hematologic progression-free rates were 72.2% and 74.6%, and 1-year survival rates were 93.8% and
84.0%, respectively. Outcomes appeared similar in patients with cardiac involvement. Among all 70 patients, organ responses
included 29% renal and 13% cardiac responses. Rates of grade 3 toxicities (79% vs 50%) and discontinuations/dose reductions
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(38/53% vs 28/22%) due to toxicities appeared higher with 1.3 mg/m2 twice-weekly versus 1.6 mg/m2 once-weekly dosing.
Both these bortezomib dose schedules represent active, well-tolerated regimens in relapsed AL. (Study registered with http://
ClinicalTrials.gov: NCT00298766).
NLenalidomide is Effective for Extramedullary Disease in Relapsed or Refractory Multiple Myeloma
Calvo-Villas JM, Alegre A, Calle C, Hernández MT, García-Sánchez R, Ramírez G.
Eur J Haematol. 2011 May 9. doi: 10.1111/j.1600-0609.2011.01644.x. [Epub ahead of print]
:
http://www.ncbi.nlm.nih.gov/pubmed/21557775
No abstract available.
NOptimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement.
Dimopoulos MA, Palumbo A, Attal M, Beksaç M, Davies FE, Delforge M, Einsele H, Hajek R, Harousseau JL, da Costa FL,
Ludwig H, Mellqvist UH, Morgan GJ, San-Miguel JF, Zweegman S, Sonneveld P.
Leukemia. 2011 May;25(5):749-60. [Epub 2011 Feb 4.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21293488
The authors report on an expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination
with dexamethasone in patients with relapsed or refractory multiple myeloma.
An expert panel convened to reach a consensus regarding the optimal use of lenalidomide in combination with dexamethasone
(Len/Dex) in patients with relapsed or refractory multiple myeloma (RRMM). On the basis of the available evidence, the panel
agreed that Len/Dex is a valid and effective treatment option for most patients with RRMM. As with other therapies, using
Len/Dex at first relapse is more effective regarding response rate and durability than using it after multiple salvage therapies.
Len/Dex may be beneficial regardless of patient age, disease stage and renal function, although the starting dose of lenalidomide
should be adjusted for renal impairment and cytopenias. Long-term treatment until there is evidence of disease progression
may be recommended at the best-tolerated doses of both lenalidomide and dexamethasone. Recommendations regarding the
prevention and management of adverse events, particularly venous thromboembolism and myelosuppression, were provided on
the basis of the available evidence and practical experience of panel members. Ongoing trials will provide more insight into the
effects of continuous lenalidomide-based therapy in myeloma.
NSubcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple
myeloma: a randomised, phase 3, non-inferiority study.
Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B,
Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL.
Lancet Oncol. 2011 May;12(5):431-40. [Epub 2011 Apr 18.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21507715
The authors compare the efficacy and safety of subcutaneous versus intravenous bortezomib at the approved 1.3 mg/m2 dose
and twice per week schedule in patients with relapsed myeloma. They find that subcutaneous bortezomib offers non-inferior
efficacy to standard intravenous administration, with an improved safety profile.
BACKGROUND: Intravenous injection is the standard administration route of bortezomib; however, subcutaneous
administration is an important alternative. We compared the efficacy and safety of subcutaneous versus intravenous bortezomib
at the approved 1.3 mg/m2 dose and twice per week schedule in patients with relapsed multiple myeloma. METHODS: This
randomised, phase 3 study was undertaken at 53 centres in ten countries in Europe, Asia, and South America. Patients aged 18
years and older with relapsed multiple myeloma after one to three previous lines of therapy were randomly assigned to receive
up to eight 21-day cycles of bortezomib 1.3 mg/m2, on days 1, 4, 8, and 11, by subcutaneous injection or intravenous infusion.
Randomisation was by an interactive voice response system based on a computer-generated randomisation schedule, stratified
by number of previous lines and disease stage. Patients and treating physicians were not masked to treatment allocation. The
primary objective was to show non-inferiority of subcutaneous versus intravenous bortezomib in terms of overall response rate
(ORR) after four cycles in all patients with a diagnosis of measurable, secretory multiple myeloma who received one or more
dose of drug (response-evaluable population). Non-inferiority was defined as retaining 60% of the intravenous treatment effect.
This study is registered with ClinicalTrials.gov, number NCT00722566, and is ongoing for long-term follow-up. FINDINGS:
222 patients were randomly assigned to receive subcutaneous (n=148) or intravenous (n=74) bortezomib. The response-evaluable
population consisted of 145 patients in the subcutaneous group and 73 in the intravenous group. Patients received a median
of eight cycles (range one to ten) in both groups. ORR after four cycles was 42% in both groups (61 patients in subcutaneous
group and 31 in intravenous group; ORR difference -0.4%, 95% CI -14.3 to 13.5), showing non-inferiority (p=0.002). After
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a median follow-up of 11.8 months (IQR 7.9-16.8) in the subcutaneous group and 12.0 months (8.1-15.6) in the intravenous
group, there were no significant differences in time to progression (median 10.4 months, 95% CI 8.5-11.7, vs 9.4 months,
7.6-10.6; p=0.387) and 1-year overall survival (72.6%, 95% CI 63.1-80.0, vs 76.7%, 64.1-85.4; p=0.504) with subcutaneous
versus intravenous bortezomib. Grade 3 or worse adverse events were reported in 84 (57%) patients in the subcutaneous group
versus 52 (70%) in the intravenous group; the most common were thrombocytopenia (19 [13%] vs 14 [19%]), neutropenia (26
[18%] vs 13 [18%]), and anaemia (18 [12%] vs six [8%]). Peripheral neuropathy of any grade (56 [38%] vs 39 [53%]; p=0.044),
grade 2 or worse (35 [24%] vs 30 [41%]; p=0.012), and grade 3 or worse (nine [6%] vs 12 [16%]; p=0.026) was significantly
less common with subcutaneous than with intravenous administration. Subcutaneous administration was locally well tolerated.
INTERPRETATION: Subcutaneous bortezomib offers non-inferior efficacy to standard intravenous administration, with
an improved safety profile. FUNDING: Johnson & Johnson Pharmaceutical Research and Development, and Millennium
Pharmaceuticals.
NSuccessful treatment with a modified bortezomib schedule of weekly and longer intervals for patients
with refractory/resistance multiple myeloma.
Tokuhira M, Watanabe R, Nemoto T, Hanzawa K, Sagawa M, Tomikawa T, Mori S, Kizaki M.
Leuk Res. 2011 May;35(5):591-7. [Epub 2010 Dec 16.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21167601
The authors present the cases of nine patients with refractory myeloma whose bortezomib administration schedule was
modified from twice weekly to an interval of once weekly or longer the first report of this kind.
Bortezomib is a potent agent for multiple myeloma (MM); however, severe treatment-related toxicities such as peripheral
neuropathy have been observed in conjunction with its use. In this study, we present the cases of 9 patients with refractory MM
whose administration schedule was modified from twice weekly to an interval of once weekly or longer mainly due to adverse
events. The average duration from diagnosis to the time of bortezomib induction was 56 months. The schedule was changed to
the modified administration according to the physician's discretion. The average duration of modified treatment was 16 months.
Six patients with IgG or IgA subtype showed more than a minor response. One patient with BJP had stable disease for 3 years,
and the other BJP-type patient with extramedullary plasmacytomas showed remarkable tumor regression. The treatment-related
toxicities of this strategy were mild and tolerable. To our knowledge, this is the first report of the administration of bortezomib
at intervals longer than once weekly.
supportive Care
NEfficacy of Continuous, Daily, Oral, Ultra-low-dose 200 mg Acyclovir to Prevent Herpes Zoster Events
Among Bortezomib-treated Patients: A Report From Retrospective Study.
Aoki T, Nishiyama T, Imahashi N, Kitamura K.
Jpn J Clin Oncol. 2011 May 25. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21616919
The authors address herpes zoster, the most common infection in myeloma patients treated with bortezomib-containing
regimens, and find that continuous prophylaxis by oral 200 mg/day acyclovir in myeloma patients receiving bortezomib
treatment is effective and sufficient in preventing the infection.
OBJECTIVE: Herpes zoster is the most common infection in patients treated with bortezomib-containing regimens for multiple
myeloma. Some clinical trials have reported on the use of acyclovir prophylaxis to decrease the incidence of herpes zoster.
However, the appropriate acyclovir dose and duration of prophylaxis remain unclear. The primary objective of this study was to
evaluate the efficacy of continuous oral 200 mg/day acyclovir prophylaxis and the secondary objective was to determine the risk
factors for developing herpes zoster. METHODS: We collected medical information from consecutive patients who received
bortezomib with or without acyclovir prophylaxis for relapsed or refractory multiple myeloma at our hospital and retrospectively
analyzed the efficacy of acyclovir prophylaxis and the parameters for predicting the risk factors for developing herpes zoster. The
definition of acyclovir prophylaxis was oral continuous administration of 200 mg of once daily, without cessation, during the
entire period of bortezomib treatment. RESULTS: Six of the 33 patients in the study developed herpes zoster during bortezomib
treatment. No varicella-zoster virus reactivation was observed in the 19 patients in the acyclovir prophylaxis group. The incidence
of herpes zoster was significantly higher in the group that did not receive acyclovir prophylaxis (43%, 6 of 14 patients) than
in the group that did (0%, 0 of 19; P = 0.003). The predictive factors for varicella-zoster virus reactivation were male sex
(P = 0.035) and the use of acyclovir (P = 0.003). CONCLUSIONS: Continuous prophylaxis by oral 200 mg/day acyclovir in
multiple myeloma patients receiving bortezomib treatment is effective and sufficient in preventing herpes zoster.
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Toxicities & adverse Effects
NInflammatory autoimmune neuropathy, presumably induced by bortezomib, in a patient suffering
from multiple myeloma.
Schmitt S, Goldschmidt H, Storch-Hagenlocher B, Pham M, Fingerle-Rowson G, Ho AD, Neben K.
Int J Hematol. 2011 May 7. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21553020
The authors report here the case of a 65-year-old female myeloma patient who was initially treated with bortezomib,
doxorubicin, and dexamethasone (PAD). They conclude that the identification of an inflammatory autoimmune neuropathy,
presumably associated with bortezomib, is a rare but important complication. An extensive neurological examination should
be performed in patients who develop severe or unusual sensory or motor deficits under therapy with bortezomib, so as to
differentiate autoimmune from toxic neuropathies, as therapeutic strategies differ for each.
Bortezomib is a proteasome inhibitor demonstrating substantial activity in multiple myeloma. One of its key toxicities is peripheral
neuropathy, which is reversible in most patients. The possibility that bortezomib might in rare cases induce severe neuropathies
by auto-inflammatory mechanisms remains controversial. We report here the case of a 65-year-old female myeloma patient who
was initially treated with bortezomib, doxorubicin, and dexamethasone (PAD). At the end of the second cycle of PAD, the
patient presented with a rapid and severe onset of paresis of the left arm, accompanied by progressive sensory neuropathy and
increasing neuropathic pain. After an extensive neurological work-up, including electrophysiological and laboratory evaluations
as well as magnet resonance tomography imaging, we diagnosed an inflammatory autoimmune neuropathy, presumably induced
by bortezomib, with accentuation of the left arm nerve plexus. We subsequently initiated regular treatment with polyvalent
immunoglobulins, which gradually improved the neurological symptoms. In conclusion, the identification of an inflammatory
autoimmune neuropathy, presumably associated with bortezomib, is a rare but important complication. An extensive neurological
examination should be performed in patients who develop severe or unusual sensory or motor deficits under therapy with
bortezomib, so as to differentiate autoimmune from toxic neuropathies, as therapeutic strategies differ for each.
NNonproteasomal targets of the proteasome inhibitors bortezomib and carfilzomib:
a link to clinical adverse events.
Arastu-Kapur S, Anderl JL, Kraus M, Parlati F, Shenk KD, Lee SJ, Muchamuel T, Bennett MK, Driessen C, Ball AJ, Kirk CJ.
Clin Cancer Res. 2011 May 1;17(9):2734-43. [Epub 2011 Mar 1.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21364033
The authors seek to determine whether peripheral neuropathy represents a target-mediated adverse drug reaction (ADR). Their
data show that bortezomib-induced neurodegeneration in vitro occurs via a proteasome-independent mechanism and that
bortezomib inhibits several nonproteasomal targets in vitro and in vivo, which may play a role in its clinical ADR profile.
PURPOSE: Bortezomib (Velcade), a dipeptide boronate 20S proteasome inhibitor and an approved treatment option for
multiple myeloma, is associated with a treatment-emergent, painful peripheral neuropathy (PN) in more than 30% of patients.
Carfilzomib, a tetrapeptide epoxyketone proteasome inhibitor, currently in clinical investigation in myeloma, is associated
with low rates of PN. We sought to determine whether PN represents a target-mediated adverse drug reaction (ADR).
EXPERIMENTAL DESIGN: Neurodegenerative effects of proteasome inhibitors were assessed in an in vitro model utilizing
a differentiated neuronal cell line. Secondary targets of both inhibitors were identified by a multifaceted approach involving
candidate screening, profiling with an activity-based probe, and database mining. Secondary target activity was measured in
rats and patients receiving both inhibitors. RESULTS: Despite equivalent levels of proteasome inhibition, only bortezomib
reduced neurite length, suggesting a nonproteasomal mechanism. In cell lysates, bortezomib, but not carfilzomib, significantly
inhibited the serine proteases cathepsin G (CatG), cathepsin A, chymase, dipeptidyl peptidase II, and HtrA2/Omi at potencies
near or equivalent to that for the proteasome. Inhibition of CatG was detected in splenocytes of rats receiving bortezomib and
in peripheral blood mononuclear cells derived from bortezomib-treated patients. Levels of HtrA2/Omi, which is known to be
involved in neuronal survival, were upregulated in neuronal cells exposed to both proteasome inhibitors but was inhibited only
by bortezomib exposure. CONCLUSION: These data show that bortezomib-induced neurodegeneration in vitro occurs via a
proteasome-independent mechanism and that bortezomib inhibits several nonproteasomal targets in vitro and in vivo, which
may play a role in its clinical ADR profile. ©2011 AACR.
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and More
NSpecific Cell-Permeable Inhibitor of Proteasome Trypsin-like Sites Selectively Sensitizes Myeloma Cells
to Bortezomib and Carfilzomib.
Mirabella AC, Pletnev AA, Downey SL, Florea BI, Shabaneh TB, Britton M, Verdoes M, Filippov DV, Overkleeft HS, Kisselev AF.
Chem Biol. 2011 May 27;18(5):608-18.
:
http://www.ncbi.nlm.nih.gov/pubmed/21609842
The authors describe the development of specific cell-permeable inhibitors and an activity-based probe of trypsin-like sites.
These compounds selectively sensitize myeloma cells to inhibitors of the chymotrypsin-like sites, including antimyeloma agents
bortezomib and carfilzomib.
Proteasomes degrade the majority of proteins in mammalian cells, are involved in the regulation of multiple physiological
functions, and are established targets of anticancer drugs. The proteasome has three types of active sites. Chymotrypsin-like
sites are the most important for protein breakdown and have long been considered the only suitable targets for antineoplastic
drugs; however, our recent work demonstrated that inhibitors of caspase-like sites sensitize malignant cells to inhibitors of the
chymotrypsin-like sites. Here, we describe the development of specific cell-permeable inhibitors and an activity-based probe of
the trypsin-like sites. These compounds selectively sensitize multiple myeloma cells to inhibitors of the chymotrypsin-like sites,
including antimyeloma agents bortezomib and carfilzomib. Thus, trypsin-like sites are cotargets for anticancers drugs. Together
with inhibitors of chymotrypsin- and caspase-like sites developed earlier, we provide the scientific community with a complete
set of tools to separately modulate proteasome active sites in living cells.
NInternational Staging System predicts prognosis of Chinese patients with multiple myeloma
across different calendar periods with application of novel agents.
Yang SH, Teng HW, Hong YC, Liu CY, Yu YB, Yang CF, Gau JP, Liu JH, Chang TJ, Yen JJ, Chen PM, Chiou TJ, Tzeng CH,
Hsiao LT.
Ann Hematol. 2011 May 17. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21584671
This is the first study to show the applicability of the International Staging System for Chinese patients with myeloma, especially
for those who have received thalidomide.
The applicability of the International Staging System (ISS) for Chinese patients with multiple myeloma (MM) has not been
demonstrated, especially with respect to treatments with novel agents. Newly diagnosed MM patients at Taipei Veterans General
Hospital were enrolled between 1996 and 2007. Data regarding clinical features, laboratory tests, and outcome at last follow-up
were collected. A total of 389 MM patients (71% male) were enrolled, with median age of 71 years. At diagnosis, 72.7% had
Durie-Salmon (DS) stage III disease, 56.2% had ISS stage III disease, and 34% had serum creatinine 2.0 mg/dL. Compared
with patients diagnosed in the first calendar period 1996-2001, the patients of the second calendar period 2002-2007 were
older and more of these patients had received novel agents, especially thalidomide. The median overall survival period was 20.5
months, with a significant increase of patients in the second calendar period (15.3 and 28.2 months, respectively; P = 0.002),
especially for those with ISS stages I and II. In the Cox proportion model, elevated serum 2 microglobulin at diagnosis (3.5
mg/L), old age (65 years), and impaired renal function were found to be independently associated with poor survival. Over the
entire period, the ISS was found to be effective in providing an accurate prognosis with respect to different ages and calendar
periods. This is the first study to show the applicability of ISS for Chinese patients with MM, especially for those who had
received thalidomide.
NChromosomal aberrations +1q21 and del(17p13) predict survival in patients with recurrent multiple
myeloma treated with lenalidomide and dexamethasone.
Klein U, Jauch A, Hielscher T, Hillengass J, Raab MS, Seckinger A, Hose D, Ho AD, Goldschmidt H, Neben K.
Cancer. 2011 May 15;117(10):2136-44. doi: 10.1002/cncr.25775. [Epub 2010 Dec 4.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21523726
This study suggests that the prognostic significance of t(4;14) may be ameliorated or eliminated in patients treated with
lenalidomide/dexamethasone, whereas the presence of del(17p13) or +1q21 is still associated with a dismal overall survival. The
presence of t(11;14) and del(13q14) as exclusive chromosomal aberrations indicates no impact on outcome. Because of its rarity
in myeloma, a confirmation of the prognostic role of the t(14;16) aberration is still pending.
BACKGROUND: In the era of novel agents such as lenalidomide and bortezomib, risk stratification by chromosomal
abnormalities may enable a more rational selection of therapeutic approaches in patients with multiple myeloma (MM).
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METHODS: The authors analyzed the prognostic value of deletion del(13q14), del(17p13), +1q21, translocation t(4;14),
t(11;14), and t(14;16) by fluorescence in situ hybridization (FISH) in a series of 92 patients with recurrent MM who were treated
with lenalidomide and dexamethasone (len/dex) at the study center. RESULTS: Patients carrying del(13q14) or t(14;16) were
found to have a shorter median time to disease progression (TTP) of 5.1 months (vs 14.4 months; P = .009) and 2.0 months (vs
10.5 months; P <.001), respectively. However, no effect on TTP was observed in patients harboring del(13q14) as an exclusive
chromosomal aberration without the concomitant presence of t(4;14) or del(17p13). The median overall survival (OS) for
patients with del(17p13) or +1q21 was 6.7 months (P = .002) and 8.3 months (P < .001), respectively, whereas the median OS
for patients carrying none of these abnormalities was not reached. Multivariate analysis revealed that the effects of del(17p13)
and +1q21 on OS were independent of patient age as well as the type and number of regimens administered before len/dex.
CONCLUSIONS: The results of the current study suggest that the prognostic significance of t(4;14) may be ameliorated or
eliminated in patients treated with len/dex, whereas the presence of del(17p13) or +1q21 is still associated with a dismal OS.
The presence of t(11;14) and del(13q14) as exclusive chromosomal aberrations indicates no impact on outcome. Because of its
rarity in MM, a confirmation of the prognostic role of the t(14;16) aberration is still pending.
NBone marrow stromal cells protect myeloma cells from bortezomib induced apoptosis by suppressing
microRNA-15a expression.
Hao M, Zhang L, An G, Meng H, Han Y, Xie Z, Xu Y, Li C, Yu Z, Chang H, Qiu L.
Leuk Lymphoma. 2011 May 3. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21534877
This study aims to determine whether bone marrow stromal cells (BMSCs) have a role in the development of chemoresistance
in myeloma. The authors' data suggest that via suppressing miRNA-15a expression, BMSCs provide survival support and protect
myeloma cells from bortezomib induced apoptosis.
Despite unsurpassed anti-tumor activity of bortezomib for multiple myeloma (MM), drug resistance has emerged as a challenge,
especially when MM cells adhere to the stroma. This study aimed to determine whether bone marrow stromal cells (BMSCs)
have a role in the development of chemoresistance in MM. Our data demonstrate that the secretion of interleukin-6 (IL-6),
vascular endothelial growth factor (VEGF), and cell-to-cell contact with microenvironment-derived stromal cells from patients
with multiple myeloma (MM-BMSCs) significantly decreased the sensitivity of myeloma cells to bortezomib treatment.
Mechanistically, we found that microRNA (miRNA)- 15a expression was up-regulated in U266 and NCI-H929 cells treated
by bortezomib, which was inhibited by MM-BMSCs. miRNA-15a transfected myeloma cells were arrested in G1/S checkpoint
and secreted less VEGF compared to control transfected cells, although no significant difference was found in VEGF mRNA
levels. In conclusion, our data suggest that via suppressing miRNA-15a expression, BMSCs provide survival support and protect
myeloma cells from bortezomib induced apoptosis.
NLenalidomide can induce long-term responses in patients with multiple myeloma relapsing after multiple
chemotherapy lines, in particular after allogeneic transplant.
Spina F, Montefusco V, Crippa C, Citro A, Sammassimo S, Olivero B, Gentili S, Galli M, Guglielmelli T, Rossi D, Pia Falcone A,
Grasso M, Patriarca F, De Muro M, Corradini P.
Leuk Lymphoma. 2011 May 3. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21534872
Evidence of long-term response to lenalidomide in heavily pretreated patients with myeloma is lacking. This study seeks to
assess whether long-term responders exist, long-term responders' characteristics, and predictive factors of a long-term response.
The authors find that patients treated with lenalidomide can become long-term responders; allogeneic transplant and response
quality predict long-term response.
Evidence of long-term response to lenalidomide in heavily pretreated patients with multiple myeloma is lacking. This study
sought to assess whether long-term responders exist, long-term responders' characteristics, and predictive factors of a long-term
response. One hundred and four patients with multiple myeloma treated with lenalidomide and dexamethasone after 2 therapy
lines (median, 3) were analyzed. Long-term response was defined as at least a partial response (PR) lasting 12 months. The
overall response rate was 73%, and 80.3% of the responses were achieved within 5 months. The median response was 14.3
months. Patients evaluable for long-term response numbered 87, and a total of 47% were long-term responders. Compared
to non-long-term responders, long-term responders had better overall survival, less light-chain multiple myeloma, and higher
incidence of t(11;14). Previous allogeneic transplant (alloSCT) and the response quality predicted a long-term response. In
conclusion, patients treated with lenalidomide can become long-term responders; alloSCT and response quality predict long-
term response.
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NThe efficacy and safety of bortezomib and dexamethasone as a maintenance therapy in patients
with advanced multiple myeloma who are responsive to salvage bortezomib-containing regimens.
Benevolo G, Larocca A, Gentile M, Pregno P, Gay F, Botto B, Frairia C, Evangelista A, Morabito F, Boccadoro M, Vitolo U,
Palumbo A.
Cancer. 2011 May 1;117(9):1884-90. doi: 10.1002/cncr.25743. [Epub 2010 Nov 18.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21509765
The authors evaluate the use of bortezomib and dexamethasone as maintenance therapy (MT) in patients with advanced
myeloma who responded to salvage therapy that used a bortezomib-containing regimen. They find the regimen to be effective
and well-tolerated; the twice-monthly bortezomib infusion appears to reduce the incidence of grade 3 and 4 neuropathies in
comparison to similar experiences in other settings.
BACKGROUND: Although treatment for multiple myeloma (MM) has considerably improved in the past decade, MM
continues to be an incurable hematological malignancy that causes most patients to eventually relapse and die from their illness.
Thus, the identification of effective salvage strategies remains a priority. METHODS: In this trial, the authors evaluated the
safety and efficacy of bortezomib and dexamethasone [V: on days 1 and 15 (1.3 mg/m2); D: on days 1-2 and 15-16, every 28-day
cycle until progression (20 mg/d)] as maintenance therapy (MT) in patients with advanced MM who responded to salvage
therapy that used a bortezomib-containing regimen. RESULTS: Forty-nine MM patients were enrolled in this study between
October of 2004 and April of 2008. All patients who were included in this study were responsive to a prior salvage therapy
with bortezomib and had a measurable disease. The bortezomib and dexamethasone MT improved the quality of responses to
complete remission in 4 patients and very good partial response in 3 patients. In addition, 10 patients experienced at least a
50% improvement in their symptoms. The median time to progression (TTP) was 16 months with a progression-free survival of
61% after 1 year. The overall response after 1 year was 76%, and the cumulative incidence of death due to disease progression,
which was adjusted for competitive risk events, was 14%. Non-dose-limiting toxicities included neuropathy (predominantly
grade 1), herpes zoster reactivation, pneumonia, and gastrointestinal affections (constipation and diarrhea). Three patients
developed grade 2 neuropathy, which required a bortezomib dose reduction to 1.0 mg/m2. No grade 3 or 4 toxicities were
recorded. CONCLUSIONS: The use of bortezomib and dexamethasone as MT in advanced MM was effective and well
tolerated. The twice-monthly bortezomib infusion appeared to reduce the incidence of grade 3 and 4 neuropathies in comparison
to similar experiences in other settings.
NDurable hematological response and improvement of nephrotic syndrome on thalidomide therapy
in a patient with refractory light chain deposition disease.
Fujita H, Hishizawa M, Sakamoto S, Kondo T, Kadowaki N, Ishikawa T, Itoh J, Fukatsu A, Uchiyama T, Takaori-Kondo A.
Int J Hematol. 2011 May;93(5):673-6. [Epub 2011 Apr 9.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21479586
The authors report the clinical course of a 32-year-old woman with light chain deposition disease who was successfully treated
with thalidomide.
Light chain deposition disease (LCDD) is a rare disease for which an optimal treatment is not yet available. Here, we report the
clinical course of a 32-year-old woman with LCDD who was successfully treated with thalidomide. She presented with nephrotic
syndrome. Based on the renal biopsy findings and the presence of monoclonal immunoglobulin light chains in her serum and
urine, LCDD was diagnosed. Prednisolone and cytotoxic chemotherapy used for multiple myeloma proved ineffective. We
initiated administration of thalidomide (100 mg daily) and dexamethasone (20 mg for 4 days per month). After 8 months of
treatment, she achieved complete hematological remission, defined as the disappearance of monoclonal protein and a normalized
free light chain ratio, which led to improvement of her renal insufficiency. She has shown sustained hematological and organ
response for 31 months with thalidomide therapy. Thus, thalidomide therapy seems to be a promising approach to the treatment
of LCDD.
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