/var/www/vhosts/myeloma.org/httpdocs/spider_articles/pdfs/Citings-NovelTherapies-June2011

Published by the IC
nternational M I
yeloma FT
oundation
IN
VOLUME VIG
II, ISSUE V
J S
UNE 2011
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 June 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 JUNE 2011
General Discussions & Reviews
NImmunomodulatory effects of anti-angiogenic drugs.
Heine A, Held SA, Bringmann A, Holderried TA, Brossart P.
Leukemia. 2011 Jun;25(6):899-905. doi: 10.1038/leu.2011.24. [Epub 2011 Feb 25.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21350557
The authors summarize recent reports on the immunomodulatory function of recently introduced clinically applied anti-
angiogenic compounds, including bortezomib.
Much progress and significant therapeutic changes have been made in the field of tumor therapy in the past decades. Besides
chemotherapy and radiotherapy, a special focus was laid on targeted therapies such as small molecule tyrosine kinase inhibitors
(TKIs) and other immunomodulatory drugs, which have become standard therapies and important combination partners in a
variety of malignancies. In contrast to the widely established use of these often anti-angiogenic drugs, many functional molecular
mechanisms are yet not completely understood. Recent analyses focused not only on their direct anti-tumor responses, but
also on their influence on tumor microenvironment, as well as on their effects on malignant and healthy cells. Different anti-
angiogenic compounds targeting the vascular endothelial growth factor (VEGF) or platelet-derived growth factor pathways seem
to be capable of modulating immune responses, in a positive, as well as apparently harmful manner. For an optimal clinical anti-
cancer treatment, a better understanding of these immunomodulatory effects is necessary. Here we summarize recent reports
on the immunomodulatory function of lately introduced clinically applied anti-angiogenic compounds, such as the humanized
monoclonal antibody against VEGF bevacizumab, the small molecule TKIs sunitinib, sorafenib, imatinib, dasatinib, nilotinib
and the proteasome inhibitor bortezomib.
NIs subcutaneous bortezomib ready for prime time?
Lonial S.
Curr Hematol Malig Rep. 2011 Jun;6(2):73-4.
:
http://www.ncbi.nlm.nih.gov/pubmed/21327564
No abstract available.
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Funded by unrestricted educational grants from Celgene Corporation and Onyx Pharmaceuticals.

NNew immunomodulatory drugs in myeloma.
Lacy MQ.
Curr Hematol Malig Rep. 2011 Jun;6(2):120-5.
:
http://www.ncbi.nlm.nih.gov/pubmed/21327565
This review discusses the data regarding the upfront use of lenalidomide with dexamethasone or in multidrug combinations,
as well as its potential role as maintenance therapy in the treatment of myeloma.
Multiple myeloma (MM) is an incurable malignancy of plasma cells. The introduction of thalidomide was a milestone in the
treatment of MM. Thalidomide analogues termed immunomodulatory drugs (IMiDs) have been developed that are more
effective and have less toxicity than thalidomide. The role of lenalidomide in relapsed MM has been well defined. This review
discusses the data regarding the upfront use of lenalidomide with dexamethasone or in multidrug combinations, as well as its
potential role as maintenance therapy. It also reviews our experience with pomalidomide, a new IMid with remarkable activity
in relapsed, refractory MM.
NProteasome inhibitors in cancer therapy.
Crawford LJ, Walker B, Irvine AE.
J Cell Commun Signal. 2011 Jun;5(2):101-10. [Epub 2011 Jan 31.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21484190
This review summarizes the main mechanisms of action of proteasome inhibitors in cancer, the development of proteasome
inhibitors as therapeutic agents and the properties and progress of next generation proteasome inhibitors in the clinic.
The ubiquitin proteasome pathway plays a critical role in regulating many processes in the cell which are important for tumour
cell growth and survival. Inhibition of proteasome function has emerged as a powerful strategy for anti-cancer therapy. Clinical
validation of the proteasome as a therapeutic target was achieved with bortezomib and has prompted the development of a second
generation of proteasome inhibitors with improved pharmacological properties. This review summarises the main mechanisms
of action of proteasome inhibitors in cancer, the development of proteasome inhibitors as therapeutic agents and the properties
and progress of next generation proteasome inhibitors in the clinic.
Mechanisms & pathways
NLenalidomide Enhances Antigen-Specific Activity and Decreases CD45RA Expression of T Cells from
Patients with Multiple Myeloma.
Neuber B, Herth I, Tolliver C, Schoenland S, Hegenbart U, Hose D, Witzens-Harig M, Ho AD, Goldschmidt H, Klein B,
Hundemer M.
J Immunol. 2011 Jun 15. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21677134
The authors investigate whether the specific T cell response against the myeloma Ag HM1.24 is enhanced by the
immunomodulatory drug lenalidomide. They show (for the first time, to their knowledge) that lenalidomide enhances the
Ag-specific activation of T cells and the subsequent downregulation of CD45RA expression of T cells in vitro and in vivo.
The aim of this study was to investigate whether the specific T cell response against the multiple myeloma Ag HM1.24 is enhanced
by the immunomodulatory drug lenalidomide (Revlimid). Ag-specific CD3(+)CD8(+) T cells against the HM1.24 Ag were
expanded in vitro by dendritic cells in 29 healthy donors and 26 patients with plasma cell dyscrasias. Ag-specific activation was
analyzed by IFN-, granzyme B, and perforin secretion using ELISA, ELISPOT assay, and intracellular staining, and generation
of Ag-specific T cells was analyzed by tetramer staining. Expression of T cell maturation markers (CD45RA, CD45R0, CCR7,
and CD28) was investigated by flow cytometry. We found that activation of HM1.24-specific T cells from healthy donors and
patients with plasma cell dyscrasias was enhanced significantly by lenalidomide and furthermore that the impact of lenalidomide
on T cells depends on the duration of the exposure. Notably, lenalidomide supports the downregulation of CD45RA on T cells
upon activation, observed in healthy donors and in patients in vitro and also in patients during lenalidomide therapy in vivo. We
showed for the first time, to our knowledge, that lenalidomide enhances the Ag-specific activation of T cells and the subsequent
downregulation of CD45RA expression of T cells in vitro and in vivo.
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NIntegrin {beta}7-mediated regulation of multiple myeloma cell adhesion, migration, and invasion.
Neri P, Ren L, Azab AK, Brentnall M, Gratton K, Klimowicz AC, Lin C, Duggan P, Tassone P, Mansoor A, Stewart DA, Boise LH,
Ghobrial IM, Bahlis NJ.
Blood. 2011 Jun 9;117(23):6202-13. [Epub 2011 Apr 7.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21474670
This research supports a role for integrin-7 (ITGB7) in myeloma cells adhesion, migration, bone marrow homing and pave the
way for a novel therapeutic approach targeting this molecule, in part because of the finding that, functionally, shRNA-mediated
silencing of ITGB7 reduces myeloma cells adhesion to extracellular matrix elements and reverses cell-adhesion mediated drug
resistance sensitizing them to bortezomib and melphalan.
Integrin-7 (ITGB7) mRNA is detected in multiple myeloma (MM) cells and its presence is correlated with MAF gene activation.
While the involvement of several integrin family members in MM-stoma cells interaction is well documented, the specific biological
functions regulated by integrin-7 in MM are largely unknown. Clinically we have correlated integrin-7 expression in MM with
poor survival outcomes post autologous stem cell transplantation and post salvage therapy with Bortezomib. Functionally, we
have found that shRNA-mediated silencing of ITGB7 reduces MM cells adhesion to extracellular matrix elements (fibronectin,
E-cadherin) and reverses cell-adhesion mediated drug resistance (CAM-DR) sensitizing them to Bortezomib and Melphalan. In
addition, ITGB7 silencing abrogated MM cells transwell migration in response to SDF1 gradients, reduced vessel density in
xenografted tumors and altered MM cells in vivo homing into the bone marrow. Mechanistically, ITGB7 knockdown inhibited
FAK and Src phosphorylation, Rac1 activation and SUMOylation, reduced VEGF production in MM-BMSC co-cultures and
attenuated p65-NF-B activity. Our findings support a role for integrin-7 in MM cells adhesion, migration, bone marrow
homing and pave the way for a novel therapeutic approach targeting this molecule.
NMetabolism of thalidomide by human liver microsome cytochrome CYP2C19 is required for its antimyeloma
and antiangiogenic activities in vitro.
Li Y, Jiang Z, Xiao Y, Li L, Gao Y.
Hematol Oncol. 2011 Jun 3. doi: 10.1002/hon.992. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21638302
The authors use a system of human liver microsomes to investigate the antimyeloma and antiangiogenic activities of thalidomide.
Their findings suggest that CYP2C19 is required for thalidomide to exhibit its antimyeloma and antiangiogenic activities.
In this study, we used a system of human liver microsomes to investigate the antimyeloma and antiangiogenic activities of
thalidomide. Myeloma cells and human umbilical vein endothelial cells (HUVECs) were treated with thalidomide alone or
thalidomide incubated with human liver microsomal protein. We found that thalidomide alone had no direct effect on several
multiple myeloma cell lines (U266, NCI-H929, RPMI 8226, LP-1, CZ-1) or on HUVECs in vitro. However, when incubated
with human liver microsomal protein, thalidomide (100 µg/ml) caused a decrease of 34.9-46.7% in cell viability in myeloma cells
and 12% in HUVECs. Cell cycle analysis and apoptosis detection indicated that the decreases in cell viability were correlated
with the induction of apoptosis. Thalidomide incubated with microsomal protein also influenced HUVEC migration and tube
formation. These effects were partially reversed by omeprazole (10 µmol/l), a potent inhibitor of CYP2C19, suggesting that
CYP2C19 is required for thalidomide to exhibit its antimyeloma and antiangiogenic activities.
NBortezomib attenuates acute graft-vs.-host disease through interfering with host immature dendritic cells.
Tao Y, Zhang W, Fang Y, Yang D, Wang L, Zhou H, Wang J.
Exp Hematol. 2011 Jun;39(6):710-20. [Epub 2011 Mar 8.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21392555
The authors explore the conditions under which proteasome inhibitor bortezomib improves acute graft-vs.-host disease (aGVHD)
and the mechanism underlying the differential effects of bortezomib on aGVHD. They find that manipulating host immature
dendric cells may represent a novel mechanism by which bortezomib improves aGVHD.
OBJECTIVE: To explore the conditions under which proteasome inhibitor bortezomib improves acute graft-vs.-host disease
(aGVHD) and the mechanism underlying the differential effects of bortezomib on aGVHD. MATERIALS AND METHODS:
Murine aGVHD models (C57BL/6BALB/c) of different severities were set up by infusing with decreasing doses of donor
splenocytes (SC). Bortezomib were administered immediately or 6 days after bone marrow transplantation (BMT). Serum levels
of tumor necrosis factor- (TNF-) and lipopolysaccharide along with the number of donor TNF-(+) T cells in recipients
before intervention were determined. Major histocompatibility complex II expression and interleukin-12 production were
analyzed to evaluate the maturation state of host dendritic cells (DCs) before intervention. Phenotypic changes, apoptosis,
allogeneic stimulation, and IB expression levels in bortezomib-treated mature DCs or immature DCs were analyzed in vitro.
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RESULTS: Neither early bortezomib (day 0 BMT) administration in a modest (SC 1 × 107) or severe (SC 2 × 107) aGVHD
model, nor delayed administration (day +6 BMT) could protect mice form aGVHD. Marked inhibition of aGVHD was
observed in a mild aGVHD model (SC 5 × 106) with early intervention. This inhibition correlated with a relatively immature
state of host DCs before intervention. Additional in vitro studies showed that, in comparison to mature DCs, bortezomib
inhibited phenotypic and functional maturation as well as induced more potent apoptosis in immature DCs through suppression
of nuclear factor-B activity. CONCLUSIONS: Manipulating host immature DCs may represent a novel mechanism by which
bortezomib improves aGVHD.
New Combinations
NBendamustine in combination with thalidomide and dexamethasone is an effective therapy for myeloma
patients with end stage renal disease.
Ramasamy K, Hazel B, Mahmood S, Corderoy S, Schey S.
Br J Haematol. 2011 Jun 21. doi: 10.1111/j.1365-2141.2011.08754.x. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21689088
No abstract available.
NCyclophosphamide, thalidomide, and dexamethasone (CTD) as initial therapy for patients with multiple
myeloma unsuitable for autologous transplantation.
Morgan GJ, Davies FE, Gregory WM, Russell NH, Bell SE, Szubert AJ, Navarro Coy N, Cook G, Feyler S, Byrne JL, Roddie H,
Rudin C, Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA.
Blood. 2011 Jun 7. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21652683
As part of the randomized MRC Myeloma IX trial, the authors compare an attenuated regimen of cyclophosphamide,
thalidomide, and dexamethasone (CTDa) with melphalan and prednisolone (MP) in patients with newly diagnosed myeloma
ineligible for autologous stem-cell transplantation. They find that in elderly newly diagnosed myeloma patients, CTDa produces
higher response rates than MP, but is not associated with improved survival outcomes. They also highlight the importance of
cytogenetic profiling at diagnosis and effective management of adverse events.
As part of the randomized MRC Myeloma IX trial, we compared an attenuated regimen of cyclophosphamide, thalidomide, and
dexamethasone (CTDa) (n = 426) with melphalan and prednisolone (MP) (n = 423) in patients with newly diagnosed multiple
myeloma (NDMM) ineligible for autologous stem-cell transplantation. The primary endpoints were overall response rate (ORR),
progression-free survival (PFS), and overall survival (OS). The ORR was significantly higher with CTDa than MP (63.8% vs
32.6%; P < .0001), primarily due to increases in the rate of complete responses (13.1% vs 2.4%) and very good partial responses
(16.9% vs 1.7%). PFS and OS were similar between groups. In this population, OS correlated with the depth of response
(P < .0001) and favorable interphase FISH profile (P < .001). CTDa was associated with higher rates of thromboembolic events,
constipation, infection, and neuropathy than MP. In elderly patients with NDMM (median age, 73 years), CTDa produced
higher response rates than MP, but was not associated with improved survival outcomes. We highlight the importance of
cytogenetic profiling at diagnosis and effective management of adverse events. This trial was registered at www.ISRCTN.org as
# 68454111.
NMolecular Target Characterization and Anti-myeloma Activity of the Novel, Insulin-like Growth Factor 1
Receptor Inhibitor, GTx-134.
Liang SB, Yang XZ, Trieu Y, Li ZH, Zive J, Leung-Hagesteijn C, Wei E, Zozulya S, Coss CC, Dalton JT, Fantus IG, Trudel S.
Clin Cancer Res. 2011 Jun 1. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21632854
The authors describe GTx-134 and characterize its antitumor activity in preclinical models of myeloma. Their studies support
the potential therapeutic efficacy of GTx-134 in myeloma, as well as providing a rationale for clinical application in combination
with established anti-myeloma treatments and novel targeted therapies, including lenalidomide, which shows synergy when
combined with GT-x-134 in vitro.
PURPOSE: Therapeutic strategies that target insulin-like growth factor 1 receptor (IGF-1R) hold promise in a wide variety of
cancers including multiple myeloma (MM). In this study we describe GTx-134, a novel small molecule inhibitor of IGF-1R and
insulin receptor (IR) and characterized its antitumor activity in preclinical models of MM. EXPERIMENTAL DESIGN: The
activity of GTx-134 as a single agent and in combination was tested in MM cell lines and primary patient samples. Downstream
effector proteins and correlation with apoptosis was evaluated. Cytotoxcity in bone marrow stroma co-culture experiments was
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assessed. Lastly, the in vivo efficacy was evaluated in a human myeloma xenograft model. RESULTS: GTx-134 inhibited the
growth of 11 of 14 myeloma cell lines (< 5 µM) and induced apoptosis. Sensitivity to GTx-134 correlated with IGF-1R signal
inhibition. Expression of MDR-1 and CD45 were associated with resistance to GTx-134. Co-culture with insulin-growth
factor-1 (IGF-1) or adherence to bone marrow stroma conferred modest resistance, but did not overcome GTx-134-induced
cytotoxicity. GTx-134 showed in vitro synergies when combined with dexamethasone or lenalidomide. Further, GTx-134
enhanced the activity of PD173074, a fibroblast growth factor receptor 3 (FGFR3) inhibitor, against t(4;14) myeloma cells.
Therapeutic efficacy of GTx-134 was demonstrated against primary cells and xenograft tumors. Although dysregulation of
glucose homeostasis was observed in GTx-134 treated mice, impairment of glucose tolerance was modest. CONCLUSIONS:
These studies support the potential therapeutic efficacy of GTx-134 in MM. Further, they provide a rationale for clinical
application in combination with established anti-myeloma treatments and novel targeted therapies.
NSignal transducer and activator of transcription 3 pathway mediates genipin-induced apoptosis in U266
multiple myeloma cells.
Lee JC, Ahn KS, Jeong SJ, Jung JH, Kwon TR, Rhee YH, Kim SH, Kim SY, Yoon HJ, Zhu S, Chen CY, Kim SH.
J Cell Biochem. 2011 Jun;112(6):1552-62. doi: 10.1002/jcb.23077.
:
http://www.ncbi.nlm.nih.gov/pubmed/21344490
Using several myelogenous cell lines, the authors investigate the effect of genipin (an active compound of Gardenia fruit) on the
STAT3 pathway and apoptosis. Their data suggest that genipin effectively potentiates the cytotoxic effect of chemotherapeutic
agents, such as bortezomib, thalidomide, and paclitaxel in U266 cells, and that through regulation of Src and SHP-1, genipin
antagonizes STAT3 for the induction of apoptosis in myeloma cells.
It has drawn a lot of attention to target signal transducer and activator of transcription 3 (STAT3) as a potential strategy for
cancer therapeutics. Using several myelogenous cell lines, the effect of genipin (an active compound of Gardenia fruit) on the
STAT3 pathway and apoptosis was investigated. Genipin suppressed the constitutive STAT3 activation in U266 and U937 cells
and stimulated Src homology 2 domain-containing phosphatase 1 (SHP-1), which dephosphorylates and inactivates STAT3.
Specifically, genipin blocked STAT3 activation via repressing the activation of c-Src, but not Janus kinase 1 (JAK1). Genipin also
downregulated the expression of STAT3 target genes including Bcl-2, Bcl-x(L) , Survivin, Cyclin D1, and VEGF. Conversely,
protein tyrosine phosphatase inhibitor pervanadate blocked genipin induced STAT3 inactivation. Using DNA fragmentation
or TUNEL assays, we demonstrated the apoptotic effect of genipin on U266, MM.1S, and U937 cells. Furthermore, genipin
effectively potentiated the cytotoxic effect of chemotherapeutic agents, such as bortezomib, thalidomide, and paclitaxel in U266
cells. Our data suggest that through regulation of Src and SHP-1, genipin antagonizes STAT3 for the induction of apoptosis in
myeloma cells.
NTanespimycin and bortezomib combination treatment in patients with relapsed or relapsed and refractory
multiple myeloma: results of a phase 1/2 study.
Richardson PG, Chanan-Khan AA, Lonial S, Krishnan AY, Carroll MP, Alsina M, Albitar M, Berman D, Messina M, Anderson KC.
Br J Haematol. 2011 Jun;153(6):729-40. doi: 10.1111/j.1365-2141.2011.08664.x. [Epub 2011 Apr 28.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21534941
This open-label, dose escalation, multicenter phase 1/2 trial was undertaken to determine the safety and tolerability of the
heat shock protein 90 (HSP90) inhibitor tanespimycin plus bortezomib. Pharmacodynamic analyses indicate that tanespimycin
plus bortezomib effectively inhibit the proteasome, as evidenced by decreased 20S proteasome activity, and inhibited HSP90,
as reflected by increased HSP70 expression; the results of this study support additional studies of this combination approach
in myeloma.
This open-label, dose escalation, multicentre phase 1/2 trial was undertaken to determine the safety and tolerability of the heat
shock protein 90 (HSP90) inhibitor tanespimycin (100-340 mg/m2 ) + bortezomib (0·7-1·3 mg/m2 ) given on days 1, 4, 8 and
11 in each 21-d cycle. Phase 2 expansion occurred at the highest tested dose of tanespimycin at 340 mg/m2 and bortezomib at
1·3 mg/m2 . Seventy-two patients (median age, 60 years) with relapsed or relapsed and refractory multiple myeloma (MM) were
enrolled; 63 patients (89%) completed the study. Tanespimycin in combination with bortezomib was well tolerated; few patients
experienced significant neutropenia, constipation and anorexia (<10%), and no patients developed severe peripheral neuropathy.
Among 67 efficacy-evaluable patients, there were 2 (3%) complete responses and 8 (12%) partial responses, for an objective
response rate (ORR) of 27%, including 8 (12%) minimal responses. Response rates were highest among bortezomib-naive
patients and proved durable in all patient subgroups, including those with bortezomib-refractory disease. Pharmacodynamic
analyses indicated that tanespimycin plus bortezomib effectively inhibited the proteasome, as evidenced by decreased 20S
proteasome activity, and inhibited HSP90, as reflected by increased HSP70 expression. The results of this study support
additional studies of this combination approach in MM.
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Newly Diagnosed
NThalidomide for previously untreated elderly patients with multiple myeloma: meta-analysis of 1685
individual patient data from six randomized clinical trials.
Fayers PM, Palumbo A, Hulin C, Waage A, Wijermans P, Beksaç M, Bringhen S, Mary JY, Gimsing P, Termorshuizen F, Haznedar R,
Caravita T, Moreau P, Turesson I, Musto P, Benboubker L, Schaafsma M, Sonneveld P, Facon T.
Blood. 2011 Jun 13. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21670471
The authors oversee six randomized controlled trials, launched in or after 2000, comparing melphalan and prednisone alone
(MP) and with thalidomide (MPT). They conclude that thalidomide added to MP improves overall survival and progression free
survival in previously untreated elderly myeloma patients, extending the median survival time by on average 20%.
The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized
controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The
effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials.
The primary endpoint was OS, and progression-free survival (PFS) and one-year response rates were secondary endpoints. There
was a highly significant benefit to OS from adding thalidomide to MP (HR 0.83, 95% CI 0.73-0.94, p=0.004), representing
increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also
associated with superior PFS (HR 0.68, 95% CI 0.61-0.76, p<0.0001) and better one-year response rates (partial response
or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and
thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors.
We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple
myeloma, extending the median survival time by on average 20%.
NA randomized trial with melphalan and prednisone versus melphalan and prednisone plus thalidomide
in newly diagnosed multiple myeloma patients not eligible for autologous stem cell transplant.
Sacchi S, Marcheselli R, Lazzaro A, Morabito F, Fragasso A, Renzo ND, Balleari E, Neri S, Quarta G, Ferrara R, Vigliotti ML,
Polimeno G, Musto P, Consoli U, Zoboli A, Buda G, Pastorini A, Masini L.
Leuk Lymphoma. 2011 Jun 12. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21663513
The authors evaluate the efficacy and toxicity of melphalan and prednisone (MP) versus MP plus thalidomide (MPT) in newly
diagnosed myeloma patients who were transplant-ineligible or over age 65. Their results show an improved activity of MPT at a
cost of increased toxicity, and they believe that MPT can be considered one of the new standard of care for elderly or transplant-
ineligible myeloma patients.
Several trials comparing the efficacy of standard melphalan and prednisone (MP) therapy with MP plus thalidomide (MPT) in
elderly patients with multiple myeloma (MM) have been reported, with inconsistent results. The primary goal of our study was
to evaluate the efficacy and toxicity of MP versus MPT in newly diagnosed patients with MM who were transplant-ineligible
or over age 65. A total of 135 patients were enrolled. Either minimal response or better or partial response or better were more
frequent with MPT treatment (p=0.001). After a median follow-up of 30 months, median progression-free survival (PFS) and
overall survival (OS) were 33 and 52 months for MPT versus 22 and 32 months for MP, respectively. The comparison showed
a significant advantage for MPT versus MP in PFS (p=0.02) and only a trend for OS (p=0.07). Severe adverse events were
observed more frequently with MPT. In conclusion, our results show an improved activity of MPT at a cost of increased toxicity.
We believe that MPT can be considered one of the new standard of care for elderly or transplant-ineligible patients with MM.
NTreatment of newly diagnosed multiple myeloma in transplant-eligible patients.
Kumar S.
Curr Hematol Malig Rep. 2011 Jun;6(2):104-12.
:
http://www.ncbi.nlm.nih.gov/pubmed/21394431
This review summarizes the current approach to the treatment of newly diagnosed myeloma in transplant-eligible patients,
including the use of thalidomide, bortezomib and lenaldiomide.
Treatment of myeloma has changed significantly in the past decade as a result of better understanding of disease biology, more
effective treatments, and improved supportive care. Autologous stem cell transplantation (SCT) is an effective treatment for
myeloma and remains a critical component in its management. Given the potential impact of therapy on stem cell collection,
initial treatment decisions in myeloma still depend on the patient's transplant eligibility. The goals of initial therapy remain rapid
disease control allowing for reversal of disease complications, as well as reduction in the risk of early death-all with minimal
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toxicity. The introduction of new drugs such as thalidomide, bortezomib, and lenalidomide has enabled us to achieve this goal,
and combinations of these drugs have also led to unprecedented response depth. In addition, the newer drugs are being explored
as maintenance therapy following SCT. This review summarizes the current approach to the treatment of newly diagnosed
myeloma in transplant-eligible patients.
NTreatment of newly diagnosed myeloma in patients not eligible for transplantation.
Mateos MV, San-Miguel J.
Curr Hematol Malig Rep. 2011 Jun;6(2):113-9.
:
http://www.ncbi.nlm.nih.gov/pubmed/21347656
The authors discuss the standards of care for the treatment of elderly patients with newly diagnosed myeloma, including the
use of novel agents (including bortezomib and lenalidomide) and their treatment-related adverse events.
Melphalan plus prednisone (MP) has long been considered the gold-standard treatment for elderly patients with newly diagnosed
myeloma, and it still forms the backbone for combinations based on novel agents. MP plus thalidomide (MPT), bortezomib
(VMP), or lenalidomide (MPR), as induction plus maintenance, have proved to be superior to MP and are currently the treatment
of choice for this population. Low-dose dexamethasone in combination with thalidomide and cyclophosphamide (CTDa) or
with lenalidomide can be an alternative option for these patients. The benefit of these novel agents in terms of prolonged
survival is accompanied by increases in treatment-related adverse events, however, which may be particularly pronounced in older
individuals. In managing these patients, efficacy and toxicity should be balanced, and thus prophylactic measures to avoid adverse
effects are mandatory. Moreover, reduced-intensity regimens are recommended for fragile or very elderly patients. Finally, the
wide array of new treatment options will facilitate individualized treatment approaches, based on characteristics of the disease,
patient comorbidities, and personal and social circumstances.
Relapsed/Refractory Treatment
NThalidomide, dexamethasone and lovastatin with autologous stem cell transplantation as a salvage
immunomodulatory therapy in patients with relapsed and refractory multiple myeloma.
Hus M, Grzasko N, Szostek M, Pluta A, Helbig G, Woszczyk D, Adamczyk-Cioch M, Jawniak D, Legiec W, Morawska M, Kozinska
J, Waciski P, Dmoszynska A.
Ann Hematol. 2011 Jun 23. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21698395
The results of this study suggest that the addition of lovastatin to a thalidomide-dexamethasone regimen may improve the
response rate in patients with relapsed or refractory myeloma.
The treatment of patients with multiple myeloma usually includes many drugs including thalidomide, lenalidomide and
bortezomib. Lovastatin and other inhibitors of HMG-CoA reductase demonstrated to exhibit antineoplasmatic and proapoptotic
properties in numerous in vitro studies involving myeloma cell lines. We treated 91 patients with relapsed or refractory multiple
myeloma with thalidomide, dexamethasone and lovastatin (TDL group, 49 patients) or thalidomide and dexamethasone (TD
group, 42 patients). A clinical response defined of at least 50% reduction of monoclonal band has been observed in 32% of TD
patients and 44% of TDL patients. Prolongation of overall survival and progression-free survival in the TDL group as compared
with the TD group has been documented. The TDL regimen was safe and well tolerated. The incidence of side effects was
comparable in both groups. Plasma cells have been cultured in vitro with thalidomide and lovastatin to assess the impact of both
drugs on the apoptosis rate of plasma cells. In vitro experiments revealed that the combination of thalidomide and lovastatin
induced higher apoptosis rate than apoptosis induced by each drug alone. Our results suggest that the addition of lovastatin to
the TD regimen may improve the response rate in patients with relapsed or refractory myeloma.
NBortezomib-Cyclophosphamide-Dexamethasone for Relapsing Multiple Myeloma.
Fu W, Delasalle K, Wang J, Song S, Hou J, Alexanian R, Wang M.
Am J Clin Oncol. 2011 Jun 18. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21694573
The authors treat 44 patients with relapsing myeloma with the combination of bortezomib-cyclophosphamide-dexamethasone,
which they find is an effective, well-tolerated combination for the treatment of relapsing myeloma.
OBJECTIVES: In vitro studies have shown synergistic antimyeloma effects with the combination of bortezomib and alkylating
agents. Combinations of bortezomib, cyclophosphamide, and dexamethasone are rational with the prospect of superior antitumor
activity with independent toxicity. METHODS: Between December 2004 and April 2007, we treated 44 patients with relapsing
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multiple myeloma with the combination of bortezomib 1.3 mg/m intravenously on days 1, 4, 8, 11; dexamethasone 20 mg/m
orally daily for 4 days beginning on days 1, 9 and 17; and cyclophosphamide 70 mg/m orally twice daily for 4 days. A second
course was given 1 month later. RESULTS: Clinical response was observed in 32 patients (73%) including 26 with disease in
partial remission (59%), and 6 with disease in complete remission (14%). Side effects were uncommon and mild, except for grade
3 thrombocytopenia in 15%, infection in 5% and constipation in 2% of patients. The median remission time of responding
patients was 10 months that contributed to significantly longer median survival for patients with responsive disease (33 mo) than
for those with unresponsive disease (12 mo) (P < 0.01). CONCLUSION: Bortezomib-cyclophosphamide-dexamethasone was
an effective, well-tolerated combination for the treatment of relapsing multiple myeloma.
NEfficacy of retreatment with immunomodulatory drugs (IMiDs) in patients receiving IMiDs for initial
therapy of newly diagnosed multiple myeloma.
Madan S, Lacy MQ, Dispenzieri A, Gertz MA, Buadi F, Hayman SR, Detweiler-Short K, Dingli D, Zeldenrust S, Lust J, Greipp PR,
Rajkumar SV, Kumar S.
Blood. 2011 Jun 14. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21673347
The authors study 140 patients who received either thalidomide-dexamethasone or lenalidomide-dexamethasone as first line
therapy of myeloma followed by repeat IMiD as one of the salvage regimens. They find that response rates with lenalidomide
retreatment are higher compared with repeat administration of thalidomide.
The efficacy of retreatment with immunomodulatory drugs (IMiDs) among patients with multiple myeloma (MM) who received
this class of drugs for initial therapy is unknown. We studied 140 patients who received either thalidomide-dexamethasone (81;
58%) or lenalidomide-dexamethasone (59; 42%) as first line therapy of MM followed by repeat IMiD [thalidomide (34; 24%) or
lenalidomide (106; 76%)] as one of the salvage regimens. A median of 2 treatments (range, 1-6), including a stem cell transplant
(SCT) in 105 (75%) patients, was administered prior to IMiD based salvage therapy. The median time from diagnosis to repeat
exposure to IMiD was 28 months. Among the 113 evaluable patients, 50 (44%) patients achieved at least a partial response and
63 (56%) patients achieved less than a partial response to repeat IMiD. Response rates with lenalidomide retreatment were higher
compared with repeat administration of thalidomide.
NPredictive factors for successful salvage high-dose therapy in patients with multiple myeloma relapsing
after autologous blood stem cell transplantation.
Fenk R, Liese V, Neubauer F, Bruns I, Kondakci M, Balleisen S, Saure C, Schröder T, Haas R, Kobbe G.
Leuk Lymphoma. 2011 Jun 10. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21657961
This retrospective study reports on 55 patients who were treated with salvage high-dose therapy (HDT) with a conditioning
regimen of melphalan, melphalan and busulfan, or melphalan and bortezomib. The authors find that salvage HDT followed by
autologous peripheral blood stem cell transplantation is an effective treatment option for patients with relapsed or refractory
myeloma, but that patients with an early relapse after their first transplant do not benefit from this treatment modality.
For patients with relapsed or refractory multiple myeloma (MM) treated with a prior high-dose therapy (HDT) followed by
autologous peripheral blood stem cell transplantation (PBSCT), the reapplication of HDT is a widely used salvage strategy.
In this retrospective study, we report on 55 patients who were treated with salvage HDT at our institution. The conditioning
regimen consisted of melphalan 200 mg/m2 (27%), melphalan 140 mg/m2 and busulfan 12 mg/kg body weight (40%), or
melphalan 200 mg/m2 and bortezomib 1.3 mg/m2 (33%). Treatment-related mortality was 5% and response rates were as
follows: 9% complete remission, 9% very good partial remission, 56% partial remission, 11% minimal response + stable disease,
and 4% progressive disease (5% not assessable). Toxicity was moderate and the median event-free (EFS) and overall survival
(OS) were 14 months and 52 months, respectively. The different conditioning regimens did not result in differences in terms of
remission rates, EFS and OS, or toxicity. In multivariate analysis a duration of remission of more than 12 months after the first
transplant was the only predictive factor for both EFS (p < 0.0001) and OS (p = 0.0001). In conclusion, salvage HDT followed
by autologous PBSCT is an effective treatment option for patients with relapsed or refractory MM, while patients with an early
relapse after their first transplant do not benefit from this treatment modality.
NLenalidomide is active for extramedullary disease in refractory multiple myeloma.
Nakazato T, Mihara A, Ito C, Sanada Y, Aisa Y.
Ann Hematol. 2011 Jun 7. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21647581
No abstract available.
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NTreatment of relapsed and refractory multiple myeloma in the era of novel agents.
van de Donk NW, Lokhorst HM, Dimopoulos M, Cavo M, Morgan G, Einsele H, Kropff M, Schey S, Avet-Loiseau H, Ludwig H,
Goldschmidt H, Sonneveld P, Johnsen HE, Bladé J, San-Miguel JF, Palumbo A.
Cancer Treat Rev. 2011 Jun;37(4):266-83. [Epub 2010 Sep 21.]
:
http://www.ncbi.nlm.nih.gov/pubmed/20863623
This review provides an overview of the various salvage regimens and gives recommendations for treatment of patients with
relapsed/refractory myeloma in different clinical settings.
The introduction of the Immunomodulatory drugs (IMiDs) and proteasome inhibitors, used either as a single-agent or combined
with classic anti-myeloma therapies, has improved the outcome for patients with relapsed myeloma. However, there is currently no
generally accepted standard treatment for relapsed/refractory myeloma patients, partly because of the absence of trials comparing
the efficacy of the novel agents in relapsed/refractory myeloma. Choice of a new treatment regimen depends on both patient and
disease-specific characteristics. A lenalidomide-based regimen is the first choice in patients with neuropathy, while bortezomib has
the highest efficacy in patients with renal insufficiency and is not associated with increased risk of thromboembolism. A second
autologous stem cell transplantation (auto-SCT) can be applied in patients with a progression-free period of 18-24months
after the first auto-SCT. In high-risk relapse such as occurring early after auto-SCT consolidation with allogeneic SCT can be
considered. In this review we provide an overview of the various salvage regimens and give recommendations for treatment of
patients with relapsed/refractory myeloma in different clinical settings.
supportive Care
NRenal improvement in myeloma with bortezomib plus plasma exchange.
Burnette BL, Leung N, Rajkumar SV.
N Engl J Med. 2011 Jun 16;364(24):2365-6.
:
http://www.ncbi.nlm.nih.gov/pubmed/21675906
No abstract available.
NActivation of coagulation by a thalidomide-based regimen.
Hoshi A, Matsumoto A, Chung J, Isozumi Y, Koyama T.
Blood Coagul Fibrinolysis. 2011 Jun 10. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21670663
The authors investigate the procoagulant effects of thalidomide when combined with chemotherapeutic agents in vitro, focusing
on tissue factor (TF) and phosphatidylserine. They find that when thalidomide is given in combination with chemotherapies or
dexamethasone, endothelial cell and monocyte procoagulant activity may be induced through phosphatidylserine exposure, or
TF expression. Induction may be protracted by thalidomide, which has an antiangiogenic activity. They therefore conclude that
prophylactic anticoagulant strategies should be considered in thalidomide-based combination regimens.
Combining thalidomide (Thal) with chemotherapeutic agents or steroid preparations led to improved response rates in the
treatment of multiple myeloma. However, deep vein thrombosis (DVT) is one of the most serious side-effects noted with this
regimen, and how a Thal-based regimen causes DVT is unclear. We investigated the procoagulant effects of Thal when combined
with chemotherapeutic agents in vitro, focusing on tissue factor (TF) and phosphatidylserine. We examined the effects of the
chemotherapeutic doxorubicin hydrochloride (Dox) and the steroid dexamethasone (Dex), with or without Thal. Our study
used the human vascular endothelial, monocytic, and myeloma cell lines, EAhy926, THP-1, and RPMI8226, respectively. In
EAhy926 and THP-1, Dex treatment increased expression of TF, which may induce procoagulant activity (PCA). Upregulation
of TF mRNA correlated with activation of the Egr-1 pathway. In Thal and Dex treatments, the increase of PCA induction
from phosphatidylserine exposure was modest. In contrast, Dox and Thal-Dox increased phosphatidylserine exposure in both
cell types. In THP-1 cells, cell surface phosphatidylserine exposure correlated with increased PCA by Dox. Thal alone showed
a modest increase in phosphatidylserine exposure in endothelial cells and monocytes. When Thal is given in combination with
chemotherapies or Dex, endothelial cell and monocyte PCA may be induced through phosphatidylserine exposure, or TF
expression. Induction may be protracted by Thal, which has an antiangiogenic activity. Therefore, prophylactic anticoagulant
strategies should be considered in Thal-based combination regimens.
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NDelayed treatment with vitamin C and N-acetyl-L: -cysteine protects Schwann cells without compromising
the anti-myeloma activity of bortezomib.
Nakano A, Abe M, Oda A, Amou H, Hiasa M, Nakamura S, Miki H, Harada T, Fujii S, Kagawa K, Takeuchi K, Watanabe T,
Ozaki S, Matsumoto T.
Int J Hematol. 2011 Jun;93(6):727-35. [Epub 2011 Apr 28.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21526377
The authors screen for cytoprotective agents to devise a method of rescuing Schwann cells from the cytotoxic effects
of bortezomib without compromising its anti-myeloma effects. They find that delayed addition of vitamin C and/or N-acetyl-L:
-cysteine after the exposure to bortezomib alleviates the cytotoxicity in Schwann cells but not myeloma cells. These results
suggest that delayed treatment with these agents may be instrumental in prophylaxis of bortezomib-induced peripheral
neuropathy.
Bortezomib-induced peripheral neuropathy (BIPN) emerges as a disabling adverse effect. As rat models for BIPN have
demonstrated damage in nerve Schwann cells, we screened for cytoprotective agents to devise a method of rescuing Schwann
cells from the cytotoxic effects of bortezomib without compromising its anti-myeloma effects. Schwann cells underwent
macroautophagy along with cytoplasmic inclusion body and vacuole formation, and appeared much less susceptible to
bortezomib-induced cytotoxicity than did myeloma cells. Vitamin C or N-acetyl-L: -cysteine (NAC) achieved near-complete
rescue of Schwann cells treated with bortezomib at 30 nM or less, and these agents in combination are able to cooperatively
inhibit the morphological changes and the cytotoxicity in Schwann cells with higher doses of bortezomib. The delayed addition
of vitamin C and/or NAC after the exposure to bortezomib alleviated the cytotoxicity in Schwann cells but not myeloma cells.
These results suggest that delayed treatment with these agents may be instrumental in prophylaxis of BIPN.
Toxicities & adverse Effects
NStevens-Johnson syndrome after lenalidomide therapy for multiple myeloma: a case report and a review
of treatment options.
Allegra A, Alonci A, Penna G, Russo S, Gerace D, Greve B, D'Angelo A, Catena S, Musolino C.
Hematol Oncol. 2011 Jun 23. doi: 10.1002/hon.1000. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21702057
The authors describe a patient with Stevens- Johnson syndrome (SJS) while receiving lenalidomide in combination with
prednisolone for treatment-naïve myeloma. They conclude that although SJS has been reported rarely as an adverse reaction
to lenalidomide, it should be considered, and that the increased use of lenalidomide therapy for myeloma should stress the
awareness of its potentially serious side effects.
Stevens- Johnson syndrome (SJS) is a severe and life-threatening condition. Although allopurinol, an antihyperuricemia drug, is
the drug most commonly associated with SJS, more than 100 different causative drugs have been reported. Among hematologic
drugs recently introduced into the market, drugs such as rituximab, imatinib, and bortezomib are reported. Here, we describe
a patient with SJS while receiving lenalidomide in combination with prednisolone for treatment-naïve multiple myeloma.
Although SJS has been reported rarely as an adverse reaction to Lenalidomide, this drug should be considered in the etiology of
SJS, and the increased number of prescriptions of Lenalidomide for the therapy of multiple myeloma has to stress the awareness
of its potentially serious side-effects.
NFollow-Up Psychophysical Studies in Bortezomib-Related Chemoneuropathy Patients.
Boyette-Davis JA, Cata JP, Zhang H, Driver LC, Wendelschafer-Crabb G, Kennedy WR, Dougherty PM.
J Pain. 2011 Jun 22. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21703938
This is the first article to address the persistence, and potential contributing factors, of bortezomib chemoneuropathy, and its
results indicate a persistent, painful peripheral neuropathy in patients treated with bortezomib.
Many frontline chemotherapeutic agents produce robust neuropathy as a dose-limiting side effect; however, the persistence of
chemotherapy-related sensory disturbances and pain are not well documented. We have previously investigated the qualities
of bortezomib-induced pain, and now seek to determine the ongoing nature of this pain. Twenty-six control subjects and 11
patients who had previously been treated with bortezomib and who were experiencing ongoing pain consented to recurring
quantitative sensory testing. A pilot immunohistochemistry study of skin innervation was also performed on patient-obtained
biopsies. Psychophysical testing in patients revealed persistent changes including decreased skin temperature in the area of pain,
diminished touch and sharpness detection, increased pegboard completion times, and decreased sensitivity to skin heating.
Additionally, the intensity of pain, as captured by the use of a visual analog scale and pain descriptors, was reported by patients
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to be unchanged during the retest despite similar morphine equivalent daily doses. The patient skin biopsies displayed a
marked decrease in the density of epidermal nerve fibers and Meissner's corpuscles. These results signify a persistent and severe
impairment of A, A, and C fibers in patients with chronic bortezomib-induced chemoneuropathy. Further, this study reports
a loss of both epidermal nerve fibers and Meissner's corpuscles. PERSPECTIVE: The results of this article indicate a persistent,
painful peripheral neuropathy in patients treated with bortezomib. Pilot data indicates a loss of nerve fibers innervating the area
of pain. This is the first paper to address the persistence, and potential contributing factors, of bortezomib chemoneuropathy.
NBisphosphonate-related osteonecrosis of the jaws - Characteristics, risk factors, clinical features,
localization and impact on oncological treatment.
Otto S, Schreyer C, Hafner S, Mast G, Ehrenfeld M, Stürzenbaum S, Pautke C.
J Craniomaxillofac Surg. 2011 Jun 13. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21676622
This single-center study collated medical records (2003-2009) of all patients that suffered from osteonecrosis of the jaw (ONJ)
within the Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians-University of Munich, Germany. The authors
conclude that the development of ONJ has a multi-factorial aetiology and the clinical presentation can vary markedly; ONJ
cannot only impair the quality of life but also the treatment of the underlying disease.
INTRODUCTION: Osteonecrosis of the jaw (ONJ) is a serious side-effect of intravenous nitrogen-containing bisphosphonate
therapy frequently used in the treatment of malignant diseases. Despite numerous case series published so far studies with detailed
investigations into risk factors, the precise localization of ONJ and impact of ONJ on the oncological treatment remain sparse.
PATIENTS AND METHODS: This single-centre study collated medical records (2003-2009) of all patients that suffered from
ONJ within the Department of Oral and Maxillofacial Surgery, Ludwig-Maximilians-University of Munich, Germany. In total,
126 patients fulfilled the case criteria of ONJ and were examined clinically. The complete medical history including detailed
questionnaires was collected of 66 patients, focussing in particular on the identification of underlying risk factors, clinical
features, ONJ localization as well as the impact on the oncological treatment. RESULTS: The majority of ONJ cases occurred
in patients suffering from malignant diseases (n=117; 92.8%), in particular breast cancer (n=57; 45.2%), multiple myeloma
(n=37; 29.4%) and prostate cancer (n=13; 10.3%), all received nitrogen-containing bisphosphonates intravenously. ONJ was
also diagnosed in 9 patients (7.1%) suffering from osteoporosis or rheumatoid arthritis. The most prevalent clinical feature was
exposed necrotic bone (93.9%) in the oral cavity which was accompanied in 78.8% of cases by pain. A predilection for the
mandible and in particular for molar and premolar regions in both jaws was shown. Although no recommendation concerning
the oncologic treatment was made, the manifestation of ONJ resulted (in a significant proportion of the patients) in a change
of medication and schedule. The most frequent co-medications were steroids and anti-angiogenetic drugs, such as thalidomide.
DISCUSSION: The predilection for mandibular molar and premolar regions, and the infectious conditions that often precede
the onset of ONJ support recent pathogenesis theories stating that local inflammation and associated pH-changes may trigger
the release and activation of nitrogen-containing bisphosphonates ultimately resulting in necrosis. CONCLUSION: The
development of ONJ has a multi-factorial aetiology and the clinical presentation can vary markedly. ONJ cannot only impair
the quality of life but also the treatment of the underlying disease.
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 Jun;93(6):791-4. [Epub 2011 May 7.]
:
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
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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.
NThyroid abnormalities in patients treated with lenalidomide for hematological malignancies:
Results of a retrospective case review.
Figaro MK, Clayton W Jr, Usoh C, Brown K, Kassim A, Lakhani VT, Jagasia S.
Am J Hematol. 2011 Jun;86(6):467-70. doi: 10.1002/ajh.22008. [Epub 2011 May 4.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21544854
The authors review medical records of patients treated with lenalidomide at a single center form 2005 to 2010 and extracted
demographic, clinical, and laboratory data; 148 were treated for myeloma and 6% had thyroid abnormalities attributable
only to lenalidomide. The authors conclude that because symptoms of thyroid dysfunction could be alleviated by appropriate
treatment, thyroid function should be evaluated during the course of lenalidomide to improve patients' quality of life.
Lenalidomide is an antiangiogenic drug associated with hypothyroidism. We describe a case-series of lenalidomide use in
hematological cancers and the prevalence of thyroid abnormalities. We reviewed medical records of patients treated with
lenalidomide at a single center form 2005 to 2010 and extracted demographic, clinical, and laboratory data. Of 170 patients
with confirmed lenalidomide use (age 64.9±15 years), 148 were treated for multiple myeloma and 6% had thyroid abnormalities
attributable only to lenalidomide. In patients with a previous diagnosis of thyroid dysfunction, the addition of lenalidomide
therapy was associated with a higher incidence of subsequent TFTF abnormality (17%) as compared to patients with no
previous diagnosis of thyroid dysfunction (6%) (P=0.0001). Many patients (44%) with pre-existing disease and a change in
thyroid function before or while on lenalidomide had no further follow-up of their thyroid abnormalities, Of 20 patients who
did not undergo any thyroid finction testing either before starting or while on lenalidomide for a median of 9.4 months (±6.5),
35% developed new symptoms compatible with hypothyroidism, including worsened fating, constipation or cold intolerance.
Symptoms of thyroid dysfunction overlap with side effects of lenalidomide. Thyroid hormone levele are not regularly evaluated in
patients on lenalidomide. While on this treatment, thyroid abnormalities can occur in patients with no previous diagnoses and in
patients with pre-existing abnormalities. Because symptoms of thyroid dysfunction could be alleviated by appropriate treatment,
thyroid function should be evaluated during the course of lenalidomide to improve patients' quality of life.
Transplantation & Induction Therapies
NLenalidomide maintenance following non-myeloablative allogeneic stem cell transplantation in multiple
myeloma is not feasible: results of the HOVON 76 trial.
Kneppers E, van der Holt B, Kersten MJ, Zweegman S, Meijer E, Huls G, Cornelissen JJ, Janssen JJ, Huisman C, Cornelisse PB,
Bruijnen CP, Emmelot M, Sonneveld P, Lokhorst HM, Mutis T, Minnema MC.
Blood. 2011 Jun 20. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21690556
To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in myeloma as part of first line treatment, the
authors prospectively investigate the feasibility and efficacy of lenalidomide maintenance. They conclude that lenalidomide
maintenance 10 mg daily after non myeloablative allo-SCT with unmanipulated graft in myeloma patients is not feasible, mainly
due to the rapid induction of acute graft versus host disease.
To improve the outcome of allogeneic stem cell transplantation (allo-SCT) in Multiple Myeloma (MM) as part of first
line treatment we prospectively investigated the feasibility and efficacy of lenalidomide maintenance. Patients started with
maintenance 1-6 months after non myeloablative (NMA) allo-SCT. Lenalidomide was dosed 10 mg on day 1-21 of a 28 day
schedule for a total of 24 cycles. Peripheral blood samples were taken to evaluate immune modulating effects. Thirty five eligible
patients were enrolled and 30 started with lenalidomide. After 2 cycles, 14 patients (47%) had to stop treatment, mainly because
of the development of acute graft versus host disease (GvHD). In total, 13 patients (43%) stopped treatment due to development
of GvHD, 5 patients (17%) due to other adverse events and 5 patients (17%) due to progression. Responses improved in 37%
of patients and the estimated 1 year PFS from start of maintenance was 69% (90% CI, 53-81%). Lenalidomide increased
the frequency of HLA-DR+ T cells and regulatory T cells but this did not correlate with clinical parameters. In conclusion,
lenalidomide maintenance 10 mg daily after NMA allo-SCT with unmanipulated graft in MM patients is not feasible, mainly
due to the rapid induction of acute GvHD. The trial was registered at www.trialregister.nl under ID number NTR1645.
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NInternational Myeloma Working Group consensus approach to the treatment of multiple myeloma patients
who are candidates for autologous stem cell transplantation.
Cavo M, Rajkumar SV, Palumbo A, Moreau P, Orlowski R, Bladé J, Sezer O, Ludwig H, Dimopoulos MA, Attal M, Sonneveld P,
Boccadoro M, Anderson KC, Richardson PG, Bensinger W, Johnsen HE, Kroeger N, Gahrton G, Bergsagel PL, Vesole DH, Einsele
H, Jagannath S, Niesvizky R, Durie BG, San Miguel J, Lonial S; on behalf of the International Myeloma Working Group.
Blood. 2011 Jun 9;117(23):6063-6073. [Epub 2011 Mar 29.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21447828
This manuscript reviews the current literature and provides important perspectives and guidance on the major issues
surrounding the optimal current management of younger, transplant-eligible myeloma patients, including the use of
thalidomide, lenalidomide and bortezomib.
The role of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in the treatment of multiple
myeloma (MM) continues to evolve in the novel agent era. The choice of induction therapy has moved from conventional
chemotherapy to newer regimens incorporating the immunomodulatory derivatives (IMiDs) thalidomide or lenalidomide, and
the proteasome inhibitor bortezomib. These drugs combine well with traditional therapies and with one another to form various
doublet, triplet and quadruplet regimens. Up-front use of these induction treatments, in particular three-drug combinations,
has effected unprecedented rates of complete response that rival those previously seen with conventional chemotherapy and
subsequent ASCT. Autotransplantation applied after novel-agent-based induction regimens provides further improvement in the
depth of responses, a gain which translates into extended progression-free survival and, potentially, overall survival. High activity
shown by IMiDs and bortezomib before ASCT has recently led to their successful use as consolidation and maintenance therapies
after autotransplantation. Novel agents and ASCT are complementary treatment strategies for MM. This manuscript reviews
the current literature and provides important perspectives and guidance on the major issues surrounding the optimal current
management of younger, transplant-eligible MM patients.
NStem cell mobilization in patients with newly diagnosed multiple myeloma after lenalidomide induction
therapy.
Cavallo F, Bringhen S, Milone G, Ben-Yehuda D, Nagler A, Calabrese E, Cascavilla N, Montefusco V, Lupo B, Liberati AM, Crippa
C, Rossini F, Passera R, Patriarca F, Cafro AM, Omedè P, Carella AM, Peccatori J, Catalano L, Caravita T, Musto P, Petrucci MT,
Boccadoro M, Palumbo A.
Leukemia. 2011 Jun 3. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21637283
This prospective study investigates the influence of lenalidomide on stem cell collection in newly diagnosed patients. They
confirm that a short induction with lenalidomide allows sufficient stem cells collection to perform autologous transplantation
in 91% of newly diagnosed patients.
Lenalidomide has raised concerns regarding its potential impact on the ability to collect stem cells for autologous stem cell
transplantation, especially after prolonged exposure. The use of cyclophosphamide plus granulocyte colony-stimulating factor
(G-CSF) to mobilize peripheral blood stem cells may overcome this concern. In newly diagnosed multiple myeloma (MM)
patients, we investigated the influence of lenalidomide on stem cell collection. In a prospective study, 346 patients received four
cycles of lenalidomide-dexamethasone (Rd). Stem cells were mobilized with cyclophosphamide and G-CSF. Patients failing to
collect a minimum of 4 × 106 CD34(+)/kg cells received a second mobilization course. After mobilization, a median yield of 8.7
× 106 CD34(+)/kg was obtained from patients receiving Rd induction. After first mobilization, inadequate yield was observed
in 21% of patients, whereas only 9% of patients failed to collect the target yield after the second mobilization attempt. In
conclusion, we confirm that a short induction with lenalidomide allowed sufficient stem cells collection to perform autologous
transplantation in 91% of newly diagnosed patients.
NRe-transplantation after bortezomib-based therapy.
Morris C, Cook G, Streetly M, Kettle P, Drake M, Quinn M, Cavet J, Tighe J, Kazmi M, Ashcroft J, Cook M, Snowden J,
Olujohungbe A, Marshall S, Conn J, Oakervee H, Popat R, Cavenagh J.
Br J Haematol. 2011 Jun;153(5):666-8. doi: 10.1111/j.1365-2141.2010.08521.x. [Epub 2011 Jan 31.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21275960
No abstract available.
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...and More
NDonor cell leukaemia after allogeneic haematopoietic SCT followed by prolonged thalidomide
maintenance for multiple myeloma.
Chan TS, Au WY, Lam K, Lam YF, So CC, Leung AY, Tse E, Lie AK, Kwong YL.
Bone Marrow Transplant. 2011 Jun 27. doi: 10.1038/bmt.2011.136. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21706063
No abstract available.
NEx vivo graft purging and expansion of autologous blood progenitor cell products from patients
with Multiple Myeloma.
Yang H, Robinson SN, Nieto Y, Jones RJ, Gocke CD, Lu J, Giralt S, Jones RB, Decker WK, Xing D, Steiner D, Champlin RE,
McMannis JD, Ng J, Thomas MW, Shah N, Andersson BS, Parmar S, Shpall EJ.
Cancer Res. 2011 Jun 6. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21646477
The authors report a sequential purging strategy targeting mature and immature clonogenic myeloma cell populations in
the autograft. They find that overall, ex vivo treatment of apheresis products with rituximab, bortezomib and co-culture with
normal donor mesenchymal stem cells deplete mature and immature myeloma cells from clinical aphereses, while expanding
the normal hematopoietic progenitor cell compartment.
Autologous peripheral blood progenitor cell (PBPC) transplantation is the treatment of choice for selected myeloma patients.
However, tumor cells contaminating the apheresis product are a potential source of relapse. Here we report a sequential purging
strategy targeting mature and immature clonogenic myeloma cell populations in the autograft. Thawed PBPC products of
myeloma patients were treated with rituximab to kill CD138(-)20(+) B cells (highly clonogenic immature cells), and bortezomib
to target CD138(+) cells (normal and differentiated myeloma plasma cells), followed by co-culture with allogeneic mesenchymal
stem cells (MSC) from normal donors. After 7 days of co-culture, non-adherent cells were removed and cultured in the absence
of MSC for an additional 7 days. Then, efficacy of purging (removal of CD138(-)20(+) and CD138(+) cells) was assessed by
flow cytometry and PCR. We used our ex vivo purging strategy to treat frozen aphereses from 16 patients. CD138(+) and
CD138(-)20(+)(19(+)) cells present in the initial products were depleted more than 3 and 4 logs, respectively based on 106 flow
acquisition events, and to levels below the limit of detection by PCR. In contrast, TNC, CD34(+) cell and colony-forming cell
numbers were increased by approximately 1220, 8 and 23 fold, respectively. Overall, ex vivo treatment of apheresis products
with rituximab, bortezomib and co-culture with normal donor MSC depleted mature and immature myeloma cells from clinical
aphereses, while expanding the normal hematopoietic progenitor cell compartment.
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