/var/www/vhosts/myeloma.org/httpdocs/spider_articles/pdfs/Citings-NovelTherapies-Aug2011

Published by the IC
nternational M I
yeloma FT
oundation
IVN
OLUME VIII, IS G
SUE VII
AU S
GUST 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 August 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 aUGUsT 2011
General Discussions & Reviews
NTargeting the Ubiquitin-Proteasome Pathway: An Emerging Concept in Cancer Therapy.
Frezza M, Schmitt S, Dou QP.
Curr Top Med Chem. 2011 Aug 9. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21824109
The clinical efficacy of the proteasome inhibitor bortezomib toward myeloma and other hematologic malignancies provides the
"proof of concept" that targeting the proteasome is a promising strategy for cancer treatment; the authors discuss the clinical
significance of targeting the tumor survival-associated proteasome pathway for cancer treatment, intervention and prevention.
Selective degradation of proteins by the ubiquitin-proteasome pathway is a critical determinant for maintaining cellular
homeostasis. Most intracellular proteins are degraded by the proteasome, a multicatalytic enzyme complex containing a 20S
catalytic core and two 19S regulatory complexes. Many proteasome target proteins are involved in the regulation of important
processes of carcinogenesis and cancer cell survival, such as cell cycle progression, cell proliferation, differentiation and apoptosis.
Indeed, the ubiquitin-proteasome-dependent degradation pathway plays an essential role in both the up-regulation of cell
proliferation and down-regulation of cell death in human cancer cells. Both in vitro and in vivo experimental and clinical
results have demonstrated the potential use of proteasome inhibitors as novel anticancer drugs. Proteasome inhibition in
cancer cells leads to accumulation of pro-apoptotic target proteins followed by induction of cell death. The clinical efficacy
of the proteasome inhibitor bortezomib toward multiple myeloma and other hematologic malignancies provides the "proof
of concept" that targeting the proteasome is a promising strategy for cancer treatment. Several other proteasome inhibitors
have also been identified from natural resources, such as marine microbial metabolites, green tea polyphenols, flavonoids, and
medicinal compounds. Additionally, the use of metal complexes as proteasome inhibitors has also been investigated as a potential
anticancer strategy. The clinical significance of targeting the tumor survival-associated proteasome pathway for cancer treatment,
intervention and prevention will be discussed.
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Funded by unrestricted educational grants from Celgene Corporation and Onyx Pharmaceuticals.

NIMiDs in hematology.
Wémeau M, Gauthier J, Leleu X, Yakoub-Agha I.
Bull Cancer. 2011 Aug 1;98(8):879-887.
:
http://www.ncbi.nlm.nih.gov/pubmed/21827980
The authors present an overview of IMiDs (such as thalidomide and lenalidomide) in hematology, including mechanisms of
action and known significant side effects.
IMiDs belong to a new pharmalogical class, whose principal therapeutic agents are the thalidomide and the lenalidomide. They
have immunomodulatory and antiangiogenic properties, as well as a direct effect on tumor cells. Thalidomide and lenalidomide
were first approved for multiple myeloma, and in 5q-myelodysplastic syndrome for lenalidomide. Several studies have shown the
efficacy of these drugs in others hematologic malignancies. A third component has been developed, the pomalidomide, which
may be more effective in certain indications. Here we present an overview of IMiDs in hematology, including mechanisms of
action and known significant side effects.
NBortezomib for previously untreated multiple myeloma.
de la Rubia J, Roig M.
Expert Rev Hematol. 2011 Aug;4(4):381-98.
:
http://www.ncbi.nlm.nih.gov/pubmed/21801129
The authors present an overview of the results of bortezomib treatment when administered as a standard component of
front-line therapy for myeloma patients.
The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new
effective drugs with novel mechanisms of action, such as bortezomib, in the last decade have resulted in a new scenario expected
to impact favorably on the outcome of MM patients. In the transplant and nontransplant setting, several randomized trials
have shown that front-line treatment with bortezomib-based combinations are superior to conventional treatment and have
allowed for a significant increase of complete response rate, with a positive impact on progression-free survival. Furthermore,
this drug appears to be active in patients with high-risk disease and comorbidities. Thus, bortezomib-containing regimens are
now considered as a new standard of care for newly diagnosed myeloma patients. In this article, we will attempt to overview the
results of bortezomib when administered as a standard component of front-line therapy for MM patients.
NTargeting the extrinsic apoptosis signaling pathway for cancer therapy.
Sayers TJ.
Cancer Immunol Immunother. 2011 Aug;60(8):1173-80. [Epub 2011 Apr 6.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21626033
The author provides a brief overview of apoptosis signaling by TRAIL and discussion of apoptosis-sensitizing agents, then
primarily focuses on bortezomib and other novel sensitizers recently identified.
The extrinsic apoptosis pathway is triggered by the binding of death ligands of the tumor necrosis factor (TNF) family to their
appropriate death receptors (DRs) on the cell surface. One TNF family member, TNF-related apoptosis-inducing ligand (TRAIL
or Apo2L), seems to preferentially cause apoptosis of transformed cells and can be systemically administered in the absence of
severe toxicity. Therefore, there has been enthusiasm for the use of TRAIL or agonist antibodies to the TRAIL DR4 and DR5 in
cancer therapy. Nonetheless, many cancer cells are very resistant to TRAIL apoptosis in vitro. Therefore, there is much interest
in identifying compounds that can be combined with TRAIL to amplify its apoptotic effects. In this review, I will provide a brief
overview of apoptosis signaling by TRAIL and discuss apoptosis-sensitizing agents, focusing mainly on the proteasome inhibitor
bortezomib (VELCADE) and some novel sensitizers that we have recently identified. Alternative ways to administer TRAIL or
DR agonist antibodies as therapeutic agents will also be described. Finally, I will discuss some of the gaps in our understanding
of TRAIL apoptosis signaling and suggest some research directions that may provide additional information for optimizing the
targeting of the extrinsic apoptosis pathway for future cancer therapy.
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Genetics
NGenetic variations in multiple myeloma II: Association with effect of treatment.
Vangsted A, Klausen TW, Vogel U.
Eur J Haematol. 2011 Aug 28. doi: 10.1111/j.1600-0609.2011.01696.x. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21883476
The authors discuss association studies on genetic variation to treatment effect, which may serve as a predictive marker for
effect of treatment and can also uncover biological pathways behind drug effect. They address the study of single nucleotide
polymorphisms (SNPs) in relation to thalidomide and bortezomib based therapy and conclude that further analysis of SNPs in
clinical trials is needed, with collaboration between scientific groups.
Association studies on genetic variation to treatment effect may serve as a predictive marker for effect of treatment but can also
uncover biological pathways behind drug effect. Single nucleotide polymorphisms (SNPs) have been studied in relation to high-
dose treatment (HDT), thalidomide and bortezomib based therapy, maintenance treatment with interferon- and in relation
to therapy related adverse effects caused by treatment. Candidate genes for prediction of effect of HDT include DNA repair
genes, CYP genes and genes involved in inflammation and apoptosis such as IL1B and RAI. In thalidomide and bortezomib-
based therapy candidate genes include TNFA and genes involved in the NF-B pathway (NFKB2 and TRAF3), respectively. In
maintenance treatment with interferon-, a polymorphism in gene NFKB1 is a candidate gene for prediction for effect. Adverse
effect includes infection, osteonecrosis of the jaw (ONJ), venous thrombotic events (VTE) and peripheral neuropathy (PN). A
SNP in MBL2 and MPO gene was associated with septicaemia and a SNP in the gene CYP2C8 was strongly associated to ONJ.
Several SNPs in genes encoding DNA repair, apoptosis, inflammation and genes involved in function of the nervous system has
been associated to VTE induced by thalidomide and to PN induced by bortezomib. SNP analysis is simple and can be performed
e.g. on blood and buccal cells. Further analysis of SNPs in clinical trials is needed and collaboration between scientific groups
will be an advantage since SNP analysis required large number of patients.
NImpact of gene expression profiling-based risk stratification in patients with myeloma receiving initial
therapy with lenalidomide and dexamethasone.
Kumar SK, Uno H, Jacobus SJ, Van Wier SA, Ahmann GJ, Henderson KJ, Callander NS, Haug JL, Siegel DS, Greipp PR, Fonseca R,
Rajkumar SV.
Blood. 2011 Aug 22. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21860025
The authors examine the utility of two gene expression profiling (GEP)-based risk stratification systems among patients
undergoing initial therapy with lenalidomide in the context of a phase 3 trial, demonstrating the prognostic value for GEP risk
stratification in a group of patients primarily treated with novel agents.
Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple
myeloma (MM); however, gene expression profiling (GEP) based signatures may enable more specific risk categorization. We
examined the utility of two GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide
in the context of a phase 3 trial. Among 45 patients studied at baseline, 7 (16%) and 10 (22%) respectively were high-risk using
the GEP70 and GEP15 signatures. The median overall survival for the GEP70 high-risk group was 19 months vs. not reached
for the rest (HR=14.1). While the medians were not reached, the GEP15 also predicted a poor outcome among the high-risk
patients. The C-statistic for the GEP70, GEP15 and FISH based risk stratification systems was 0.74, 0.7, and 0.7, respectively.
Here we demonstrate the prognostic value for GEP risk stratification in a group of patients primarily treated with novel agents.
NGenomic stratification of multiple myeloma treated with novel agents.
Jiang A, Reece D, Chang H.
Leuk Lymphoma. 2011 Aug 8. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21823830
The authors review recent studies that analyze the impact of specific genomic aberrations on the outcome of myeloma treated
with bortezomib and/or lenalidomide.
ABSTRACT Cytogenetic testing is now routinely performed for the prognostic workup of multiple myeloma (MM). The
abnormalities del(17p), t(4;14), and del(13q) have been established as predictors of poor outcome in MM patients treated
with conventional chemotherapy or stem cell transplant; chromosome 1q gains and 1p losses have also been identified as novel
prognostic factors. In recent years, bortezomib and lenalidomide have emerged as effective treatments for both relapsed/refractory
and newly diagnosed MM. However, the effect of cytogenetic abnormalities is unclear among MM patients treated with these
novel agents. Here we review recent studies that analyze the impact of specific genomic aberrations on the outcome of MM
treated with bortezomib and/or lenalidomide.
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New Combinations
NTargeting heat shock protein 90 induces apoptosis and inhibits critical survival and
proliferation pathways in multiple myeloma.
Khong T, Spencer A.
Mol Cancer Ther. 2011 Aug 22. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21859842
The authors study NVP-HSP990 and find that it synergizes with azacytidine and bortezomib in cell lines and primary myeloma
samples; the mechanism of HSP90 inhibition in myeloma warrants further evaluation.
The second most commonly diagnosed haematologic malignancy, multiple myeloma (MM), affects predominantly older patients
(>60s) and is characterised by paraprotein in the serum or urine. Clinical manifestations include anaemia, hypercalcaemia,
progressive renal impairment and osteolytic bone destruction. Despite promising new therapies, MM eventually relapses in
almost all patients. Heat shock proteins (HSP) are ubiquitous and highly conserved in prokaryotes and eukaryote organisms.
Exposure to a broad range of stimuli results in increased HSP protein expression. These chaperone proteins are involved in protein
transportation, prevent protein aggregation and ensure correct folding of nascent and stress-accumulated misfolded proteins. In
cancer, HSP expression is dysregulated resulting in elevated expression which promotes cancer by preventing programmed cell
death and supporting autonomous cells growth, ultimately leading to resistance to heat, chemotherapy and other stresses. Client
proteins of HSP90 such as AKT, p53, MEK, STAT3 and Bcr-Abl are vital in tumour progression, including MM, and their
maturation and stability is dependent on HSP90. Therefore inhibition of HSP90 via a HSP90 inhibitor (such as NVP-HSP990)
should interrupt multiple signaling pathways essential for oncogenesis and growth in MM. Our study demonstrated that NVP-
HSP990 triggered apoptosis in a panel of human MM cells, induced cell cycle arrest, PARP cleavage, down regulation of client
proteins, inability to reactivate phospho-STAT3 following exogenous IL-6 stimulation and synergises with azacytidine and
bortezomib in cell lines and primary MM samples. The mechanism of HSP90 inhibition in MM warrants further evaluation.
NMonoclonal antibody-based therapy as a new treatment strategy in multiple myeloma.
van de Donk NW, Kamps S, Mutis T, Lokhorst HM.
Leukemia. 2011 Aug 19. doi: 10.1038/leu.2011.214. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21852787
The authors provide an overview of various monoclonal antibodies (mAbs) targeting myeloma tumor cells directly or indirectly
via effects on the bone marrow microenvironment. They give special focus to the combination of these mAbs with IMiDs and
bortezomib.
The introduction of autologous stem cell transplantation combined with the introduction of immunomodulatory drugs (IMiDs)
and proteasome inhibitors has significantly improved survival of multiple myeloma patients. However, ultimately the majority
of patients will develop refractory disease, indicating the need for new treatment modalities. In preclinical and clinical studies,
promising results have been obtained with several monoclonal antibodies (mAbs) targeting the myeloma tumor cell or the bone
marrow microenvironment. The mechanisms underlying the therapeutic efficacy of these mAbs include direct induction of tumor
cell apoptosis via inhibition or activation of target molecules, complement-dependent cytotoxicity and antibody-dependent cell-
mediated cytotoxicity (ADCC). The capability of IMiDs to enhance ADCC and the modulation of various important signaling
cascades in myeloma cells by both bortezomib and IMiDs forms the rationale to combine these novel agents with mAbs as new
treatment strategies for myeloma patients. In this review, we will give an overview of various mAbs directly targeting myeloma
tumor cells or indirectly via effects on the bone marrow microenvironment. Special focus will be on the combination of these
mAbs with IMiDs or bortezomib.
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NIn Vitro and In Vivo Selective Antitumor Activity of a Novel Orally Bioavailable Proteasome Inhibitor
MLN9708 against Multiple Myeloma Cells.
Chauhan D, Tian Z, Zhou B, Kuhn D, Orlowski R, Raje N, Richardson P, Anderson KC.
Clin Cancer Res. 2011 Aug 15;17(16):5311-21. [Epub 2011 Jun 30.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21724551
The authors evaluate the efficacy of the novel orally bioactive proteasome inhibitor MLN9708/MLN2238 in myeloma using well-
established in vitro and in vivo models. They find that combining MLN2238 with lenalidomide triggers synergistic anti-myeloma
activity.
PURPOSE: The success of bortezomib therapy for treatment of multiple myeloma (MM) led to the development of structurally
and pharmacologically distinct novel proteasome inhibitors. In the present study, we evaluated the efficacy of one such novel
orally bioactive proteasome inhibitor MLN9708/MLN2238 in MM using well-established in vitro and in vivo models.
EXPERIMENTAL DESIGN: MM cell lines, primary patient cells, and the human MM xenograft animal model were used
to study the antitumor activity of MN2238. RESULTS: Treatment of MM cells with MLN2238 predominantly inhibits
chymotrypsin-like activity of the proteasome and induces accumulation of ubiquitinated proteins. MLN2238 inhibits growth
and induces apoptosis in MM cells resistant to conventional and bortezomib therapies without affecting the viability of normal
cells. In animal tumor model studies, MLN2238 is well tolerated and inhibits tumor growth with significantly reduced tumor
recurrence. A head-to-head analysis of MLN2238 versus bortezomib showed a significantly longer survival time in mice treated
with MLN2238 than mice receiving bortezomib. Immununostaining of MM tumors from MLN2238-treated mice showed
growth inhibition, apoptosis, and a decrease in associated angiogenesis. Mechanistic studies showed that MLN2238-triggered
apoptosis is associated with activation of caspase-3, caspase-8, and caspase-9; increase in p53, p21, NOXA, PUMA, and E2F;
induction of endoplasmic reticulum (ER) stress response proteins Bip, phospho-eIF2-, and CHOP; and inhibition of nuclear
factor kappa B. Finally, combining MLN2238 with lenalidomide, histone deacetylase inhibitor suberoylanilide hydroxamic acid,
or dexamethasone triggers synergistic anti-MM activity. CONCLUSION: Our preclinical study supports clinical evaluation of
MLN9708, alone or in combination, as a potential MM therapy.
NDihydroxypentamethoxyflavone Downregulates Constitutive and Inducible Signal Transducers and
Activators of Transcription (STAT)-3 Through the Induction of Tyrosine Phosphatase SHP-1.
Phromnoi K, Prasad S, Gupta SC, Kannappan R, Reuter S, Limtrakul P, Aggarwal BB.
Mol Pharmacol. 2011 Aug 4. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21816954
The authors identify a flavone from the leaves of a Thai plant, Gardenia obtusifolia, 5,3'-dihydroxy-3,6,7,8,4'-pentamethoxyflavone
(PMF) that has ability to inhibit STAT3 activation. They find that PMF significantly potentiates the apoptotic effects of bortezomib
and thalidomide in myeloma cells with overall results suggesting that PMF is a novel blocker of STAT3 activation and thus may
have potential in suppression of tumor cell proliferation and reversal of chemoresistance in myeloma cells.
Because constitutive activation of STAT3 has been linked with cellular transformation, survival, proliferation, chemoresistance,
and angiogenesis of various tumor cells, agents that can suppress STAT3 activation have potential as cancer therapeutics. In
the present report, we identified a flavone from the leaves of a Thai plant, Gardenia obtusifolia, 5,3'-dihydroxy-3,6,7,8,4'-
pentamethoxyflavone (PMF) that has ability to inhibit STAT3 activation. PMF inhibited both constitutive and interleukin-6-
inducible STAT3 activation in multiple myeloma (MM) cells, as indicated by suppression of STAT3 phosphorylation, nuclear
translocation, DNA binding, and STAT3-regulated gene expression. The inhibition of STAT3 by PMF was reversible. We
found that the activation of various kinases including Janus-activated kinase (JAK)-1, JAK-2, c-Src, ERK1/2, AKT and EGFR,
implicated in STAT3 activation, were inhibited by the flavone. Interestingly, pervanadate suppressed the ability of PMF to inhibit
the phosphorylation of STAT3, suggesting protein tyrosine phosphatase was involved. PMF induced the expression of SHP-1 and
was linked to the dephosphorylation of STAT3, as its deletion by small interfering RNA abolished the PMF-induced constitutive
as well as inducible STAT3 inhibition. STAT3 inhibition led to the suppression of proteins involved in proliferation (cyclin D1
and c-myc), survival (survivin, Mcl-1, Bcl-xL, Bcl-2 and cIAP-2), and angiogenesis (VEGF). Finally, PMF inhibited proliferation
and induced apoptosis of MM cells. PMF also significantly potentiated the apoptotic effects of velcade and thalidomide in MM
cells. Overall, these results suggest that PMF is a novel blocker of STAT3 activation and thus may have potential in suppression
of tumor cell proliferation and reversal of chemoresistance in MM cells.
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Newly Diagnosed
NAspirin or enoxaparin thromboprophylaxis for newly-diagnosed multiple myeloma patients treated
with lenalidomide.
Larocca A, Cavallo F, Bringhen S, Di Raimondo F, Falanga A, Evangelista A, Cavalli M, Stanevsky A, Corradini P, Pezzati S,
Patriarca F, Cavo M, Peccatori J, Catalano L, Carella AM, Cafro AM, Siniscalchi A, Crippa C, Petrucci MT, Ben Yehuda D,
Beggiato E, Caravita Di Toritto T, Boccadoro M, Nagler A, Palumbo A.
Blood. 2011 Aug 11. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21835953
This prospective, open-label, randomized substudy of a phase 3 trial compares the efficacy and safety of thromboprophylaxis
with low-dose aspirin (ASA) or low-molecular-weight heparin (LMWH) in newly-diagnosed myeloma patients treated with
lenalidomide and low-dose dexamethasone induction and melphalan-prednisone-lenalidomide consolidation. The authors
conclude that in previously untreated myeloma patients receiving lenalidomide with a low thromboembolic risk, ASA could be
an effective and less-expensive alternative to LMWH thromboprophylaxis.
Lenalidomide plus dexamethasone is effective in the treatment of multiple myeloma (MM) but is associated with an increased risk
of venous thromboembolism (VTE). This prospective, open-label, randomized substudy of a phase 3 trial compared the efficacy
and safety of thromboprophylaxis with low-dose aspirin (ASA) or low-molecular-weight heparin (LMWH) in newly-diagnosed
MM patients, treated with lenalidomide and low-dose dexamethasone (Rd) induction and melphalan-prednisone-lenalidomide
consolidation. Overall, 342 patients who did not have clinical indications or contraindications to antiplatelet or anticoagulant
therapy, were randomized to receive ASA 100 mg/day (n=176) or LMWH enoxaparin 40 mg/day (n=166). The incidence of
VTE was 2.27% in the ASA group and 1.20% in the LMWH group. Compared with LMWH, the absolute difference in the
proportion of VTE was +1.07% (95% CI, -1.69 to 3.83; P = 0.452) in the ASA group. Pulmonary embolism was observed
in 1.70% of patients in the ASA group and none in the LMWH group. No arterial thrombosis, acute cardiovascular events,
or sudden deaths were reported. No major hemorrhagic complications were reported. In previously untreated MM patients
receiving lenalidomide with a low thromboembolic risk, ASA could be an effective and less-expensive alternative to LMWH
thromboprophylaxis. This study is registered at http://www.clinicaltrials.gov as NCT00551928.
NBortezomib, Liposomal Doxorubicin and Dexamethasone (BDD) Followed by Thalidomide and
Dexamethasone (TD) Is an Effective Treatment for Newly Diagnosed Multiple Myeloma Patients
with ISS stage II or III, or Extramedullary Disease.
Landau H, Pandit-Taskar N, Hassoun H, Cohen A, Lesokhin A, Lendvai N, Drullinsky P, Schulman P, Jhanwar S, Hoover E, Bello C,
Riedel E, Nimer SD, Comenzo RL.
Leuk Lymphoma. 2011 Aug 9. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21824051
The authors evaluate sequential bortezomib, liposomal doxorubicin and dexamethasone (BDD) followed by thalidomide and
dexamethasone (TD) or bortezomib and TD (BTD) in untreated myeloma patients with ISS stage II/III or extramedullary disease.
They conclude that BDD followed by TD or BTD is effective initial therapy for this higher risk myeloma population and results
in rapid disease control and a high response rate.
ABSTRACT We evaluated sequential bortezomib, liposomal doxorubicin and dexamethasone (BDD) followed by thalidomide
and dexamethasone (TD) (if partial response (PR)) or bortezomib and TD (BTD) if < PR in untreated multiple myeloma
patients with ISS stage II/III or extramedullary disease. Of the 42 patients enrolled, two thirds had cytogenetic abnormalities
including high risk findings (del(13q) by karyotype, t(4;14), loss of p53 or gain 1q) in one third. After the planned 3 cycles of
BDD, the overall response rate (ORR) was 81% with 40% very good partial response (VGPR), including 26% near complete
and complete responses (nCR/CR). After the additional 2 cycles of TD or BTD, ORR was 83% with 60% VGPR including
43% nCR/CR, indicating deeper responses following sequential therapy (P = 0.008). Two-thirds of patients who presented with
significant renal impairment had improved renal function. All patients undergoing stem cell harvest had a successful collection.
BDD followed by TD or BTD is effective initial therapy for this higher risk myeloma population and results in rapid disease
control and a high response rate.
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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, Coy NN, Cook G, Feyler S, Byrne JL, Roddie H, Rudin C,
Drayson MT, Owen RG, Ross FM, Jackson GH, Child JA; for the NCRI Haematological Oncology Study Group.
Blood. 2011 Aug 4;118(5):1231-1238. [Epub 2011 Jun 7.]
:
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.
NThalidomide for previously untreated elderly patients with multiple myeloma:
meta-analysis of 1685 individual patient data from 6 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;
on behalf of the Nordic Myeloma Study Group, Italian Multiple Myeloma Network, Turkish Myeloma Study Group,
Hemato-Oncologie voor Volwassenen Nederland, Intergroupe Francophone du Myélome, and European Myeloma Network.
Blood. 2011 Aug 4;118(5):1239-1247. [Epub 2011 Jun 13.]
:
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%.
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NLenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma:
results from a phase 2 trial.
Kumar SK, Lacy MQ, Hayman SR, Stewart K, Buadi FK, Allred J, Laumann K, Greipp PR, Lust JA, Gertz MA, Zeldenrust SR,
Bergsagel PL, Reeder CB, Witzig TE, Fonseca R, Russell SJ, Mikhael JR, Dingli D, Rajkumar SV, Dispenzieri A.
Am J Hematol. 2011 Aug;86(8):640-5. doi: 10.1002/ajh.22053. [Epub 2011 May 31.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21630308
This trial studies the combination of cyclophosphamide, lenalidomide, and dexamethasone (CRd) as initial therapy for myeloma.
The authors find that CRd is an effective and well-tolerated regimen for upfront therapy of myeloma with high response rates
and excellent two-year overall survival, and is suitable for long-term therapy.
The combination of lenalidomide and low-dose dexamethasone is an effective treatment for multiple myeloma (MM). Addition
of alkylating agents to lenalidomide or thalidomide results in increased response rates and deeper responses. We designed this
trial to study the combination of cyclophosphamide, lenalidomide, and dexamethasone (CRd) as initial therapy for MM.
Fifty-three patients with previously untreated symptomatic MM was enrolled. Patients received 4-week treatment cycles consisting
of lenalidomide (25 mg daily for 3 weeks), dexamethasone (40 mg weekly), and cyclophosphamide (300 mg/m2 weekly for
3 weeks). A partial response or better was seen in 85% of patients including 47% with a very good partial response or better.
The toxicities were manageable with over 80% of planned doses delivered; six patients went off study for toxicity. The median
progression free survival (PFS) for the entire group was 28 months (95% CI: 22.7-32.6) and the overall survival (OS) at 2 years
was 87% (95% CI: 78-96). Importantly, 14 patients with high-risk MM had similar PFS and OS as the standard-risk patients
(n = 39). CRd is an effective and well-tolerated regimen for upfront therapy of MM with high response rates and excellent 2-year
OS, and is suitable for long-term therapy.
Relapsed/Refractory Treatment
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 Aug 18;118(7):1763-5. [Epub 2011 Jun 14.]
:
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.
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NRapid early monoclonal protein reduction after therapy with bortezomib or bortezomib and pegylated
liposomal doxorubicin in relapsed/refractory myeloma is associated with a longer time to progression.
Shah J, Bladé J, Sonneveld P, Harousseau JL, Lantz K, Londhe A, Lowery C, Orlowski RZ.
Cancer. 2011 Aug 15;117(16):3758-62. doi: 10.1002/cncr.25937. [Epub 2011 Feb 15.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21328327
These analyses support the possibility that a robust early M protein response is a good prognostic factor for long-term outcome
of myeloma patients with relapsed and/or refractory disease receiving bortezomib or pegylated liposomal doxorubicin +
bortezomib.
BACKGROUND: A rapid and early monoclonal (M) protein response during initial therapy in patients with multiple myeloma
had been identified as a predictor of superior long-term outcome in some-but not all-studies. METHODS: To determine if
the parameter of M protein reduction was of value in the relapsed and/or refractory setting, retrospective landmark analyses
were performed at the end of cycles 2 and 4 of a phase 3 study, which randomized such patients to receive bortezomib alone or
pegylated liposomal doxorubicin (PLD) with bortezomib. RESULTS: Compared with a <25% reduction in M protein at the
landmark time point, patients with a 50% to <75% reduction after cycle 2 had a significantly lower hazard ratio (HR) for time
to progression (HR = 0.41; 95% confidence interval [CI], 0.26-0.64; P <.001), as did those with a 75% reduction (HR = 0.26;
95% CI, 0.15-0.45; P < .001). In all of these groups, PLD + bortezomib provided superior outcomes to bortezomib alone, and
did so without an increase in the risk of adverse events overall and with a predictable toxicity profile. CONCLUSIONS: These
analyses supported the possibility that a robust early M protein response is a good prognostic factor for long-term outcome of
myeloma patients with relapsed and/or refractory disease receiving bortezomib or PLD + bortezomib.
NPhase II randomized trial of bevacizumab versus bevacizumab and thalidomide for relapsed/refractory
multiple myeloma: a California Cancer Consortium trial.
Somlo G, Lashkari A, Bellamy W, Zimmerman TM, Tuscano JM, O'Donnell MR, Mohrbacher AF, Forman SJ, Frankel P, Chen HX,
Doroshow JH, Gandara DR.
Br J Haematol. 2011 Aug;154(4):533-535. doi: 10.1111/j.1365-2141.2011.08623.x. [Epub 2011 Apr 26.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21517811
No abstract available.
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 Aug;52(8):1455-62. [Epub 2011 Jun 10.]
:
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.
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Transplantation & Induction Therapy
NBortezomib and high dose melphalan conditioning for stem cell transplantation for AL amyloidosis:
a pilot study.
Sanchorawala V, Quillen K, Sloan JM, Andrea NT, Seldin DC.
Haematologica. 2011 Aug 22. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21859734
No abstract available.
NBortezomib plus dexamethasone versus reduced-dose bortezomib, thalidomide plus dexamethasone as
induction treatment prior to autologous stem cell transplantation in newly diagnosed multiple myeloma.
Moreau P, Avet-Loiseau H, Facon T, Attal M, Tiab M, Hulin C, Doyen C, Garderet L, Randriamalala E, Araujo C, Lepeu G,
Marit G, Caillot D, Escoffre M, Lioure B, Benboubker L, Pégourié B, Kolb B, Stoppa AM, Fuzibet JG, Decaux O, Dib M,
Berthou C, Chaleteix C, Sebban C, Traullé C, Fontan J, Wetterwald M, Lenain P, Mathiot C, Harousseau JL.
Blood. 2011 Aug 17. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21849487
This randomized trial compares bortezomib-dexamethasone (VD) as induction prior to high-dose therapy (HDT) and
autologous stem cell transplantation (ASCT) to a combination consisting of reduced doses of bortezomib and thalidomide
plus dexamethasone (vtD) in patients with myeloma. The authors find that vtD, including reduced doses of bortezomib and
thalidomide, yields higher very good partial response rates as compared with VD and can be considered as a new effective
triplet combination prior to HDT/ASCT.
The IFM conducted a randomized trial to compare bortezomib-dexamethasone (VD) as induction prior to high-dose therapy
(HDT) and autologous stem cell transplantation (ASCT) to a combination consisting of reduced doses of bortezomib and
thalidomide plus dexamethasone (vtD) in patients with multiple myeloma. Overall, a total of 199 patients were centrally
randomly assigned to receive VD (99 patients) or vtD (100 patients). After four cycles, the complete response (CR) rate was
the same in both groups (13% in the vtD arm, 12% in the VD arm, p = 0.74). However, the CR + very good partial response
(VGPR) rate was significantly higher in the vtD arm (49% versus 36%, p = 0.05). After ASCT, the CR + VGPR rate was
significantly higher in the vtD arm (74% versus 58%, p = 0.02). The reduced doses of bortezomib and thalidomide in the vtD
arm translated into a reduced incidence of peripheral neuropathy (PN): grade 2 PN were reported in 34% in the VD arm
versus 14% in the vtD arm (p=0.001). vtD including reduced doses of bortezomib and thalidomide yields higher VGPR rates as
compared with VD and can be considered as a new effective triplet combination prior to HDT/ASCT. This study is registered
with www.ClinicalTrials.gov (NCT00910897) and EudraCT (no. 2007-005204-40).
NAllogeneic Stem Cell Transplantation in Multiple Myeloma Relapsed After Autograft:
A Multicenter Retrospective Study Based on Donor Availability.
Patriarca F, Einsele H, Spina F, Bruno B, Isola M, Nozzoli C, Nozza A, Sperotto A, Morabito F, Stuhler G, Festuccia M, Bosi A,
Fanin R, Corradini P.
Biol Blood Marrow Transplant. 2011 Aug 3. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21820394
The authors investigate the role of reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (allo-SCT) in
patients with myeloma who relapsed after autologous stem cell transplantation and were then treated with a salvage therapy
based on novel agents. This study provides evidence for a significant progression-free survival benefit of salvage treatment with
novel drugs (including bortezomib, thalidomide and lenalidomide) followed by RIC allo-SCT in patients with relapsed myeloma
who have a suitable donor.
Allogeneic stem cell transplantation (allo-SCT) using reduced-intensity conditioning (RIC) is a feasible procedure in selected
patients with relapsed multiple myeloma (MM), but its efficacy remains a matter of debate. The mortality and morbidity related
to the procedure and the rather high relapse risk make the use of allo-SCT controversial. In addition, the availability of novel
antimyeloma treatments, such as bortezomib and immunomodulatory agents, have made allo-SCT less appealing to clinicians.
We investigated the role of RIC allo-SCT in patients with MM who relapsed after autologous stem cell transplantation and were
then treated with a salvage therapy based on novel agents. This study was structured similarly to an intention-to-treat analysis
and included only those patients who underwent HLA typing immediately after the relapse. Patients with a donor (donor
group) and those without a suitable donor (no-donor group) were compared. A total of 169 consecutive patients were evaluated
retrospectively in a multicenter study. Of these, 75 patients found a donor and 68 (91%) underwent RIC allo-SCT, including
24 from an HLA-identical sibling (35%) and 44 from an unrelated donor (65%). Seven patients with a donor did not undergo
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allo-SCT for progressive disease or concomitant severe comorbidities. The 2-year cumulative incidence of nonrelapse mortality
was 22% in the donor group and 1% in the no-donor group (P < .0001). The 2-year progression-free survival (PFS) was 42%
in the donor group and 18% in the no-donor group (P < .0001). The 2-year overall survival (OS) was 54% in the donor group
and 53% in the no-donor group (P = .329). In multivariate analysis, lack of a donor was a significant unfavorable factor for PFS,
but not for OS. Lack of chemosensitivity after salvage treatment and high-risk karyotype at diagnosis significantly shortened OS.
In patients who underwent allo-SCT, the development of chronic graft-versus-host disease had a significant protective effect on
OS. This study provides evidence for a significant PFS benefit of salvage treatment with novel drugs followed by RIC allo-SCT
in patients with relapsed MM who have a suitable donor.
NNovel agents-based regimens as induction treatment prior to autologous stem-cell transplantation
in newly diagnosed multiple myeloma: a meta-analysis of randomized controlled trials.
Wang L, Ran X, Wang B, Sheng Z, Liu L.
Hematol Oncol. 2011 Aug 2. doi: 10.1002/hon.1007. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21809367
In order to investigate the effect of novel agents like bortezomib, lenalidomide and thalidomide as part of induction treatment
prior to autologous stem-cell transplantation (ASCT) for previously untreated patients with myeloma, the authors perform a
meta-analysis of randomized controlled trials. Their analysis shows that novel agents as induction treatment prior to ASCT
improve complete response and progression-free survival, but not overall survival.
To investigate the effect of novel agents like bortezomib, lenalidomide and thalidomide as part of induction treatment prior
to autologous stem-cell transplantation (ASCT) for previously untreated patients with multiple myeloma, we performed a
meta-analysis of randomized controlled trials (RCTs). Medline, Embase, the Cochrane controlled trials register and the Science
Citation Index were searched for RCTs of novel agents as part of induction therapy before ASCT. Three RCTs of bortezomib,
two RCTs of thalidomide and no RCT of lenalidomide were identified, covering a total of 2,316 subjects. Due to different
mechanisms of action, we performed a subgroup analysis by type of agent (thalidomide or bortezomib). The weighted risk ratios
of a complete response (CR) were 4.25 [95% CI: 2.44-7.41] (p < 0.001) for bortezomib and 1.66 [95% CI: 1.15-2.38] (p=0.007)
for thalidomide, respectively. The summary hazard ratios for progression-free survival (PFS) were 0.73 [95% CI: 0.59-0.89]
(p=0.002) for bortezomib and 0.68 [95% CI: 0.59-0.79] (p<0.001) for thalidomide, respectively. The corresponding ratios for
overall survival (OS) were 0.87 [95% CI: 0.64-1.18] (p=0.37) and 0.88 [95% CI: 0.73-1.05] (p=0.14), respectively. Additionally,
there was a statistically significant heterogeneity between subgroups (thalidomide and bortezomib) for CR (p=0.005) but non-
significant for PFS (p=0.64) and OS (p=0.97). In conclusion, our analysis showed novel agents as induction treatment prior to
ASCT improved CR and PFS but not OS.
and More
NSuccessful bone reconstruction after bortezomib therapy in a myeloma patient.
Tanaka T, Yamasaki R, Omura H, Hino N.
Int J Hematol. 2011 Aug 23. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21861100
No abstract available.
NCereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide.
Zhu YX, Braggio E, Shi CX, Bruins LA, Schmidt JE, Van Wier S, Chang XB, Bjorklund CC, Fonseca R, Bergsagel PL, Orlowski RZ,
Stewart AK.
Blood. 2011 Aug 22. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21860026
The authors investigate the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of
IMiDs. They find that CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment
of anti-myeloma efficacy.
The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs
(IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic
target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells
but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to
the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary
genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide.
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Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further
demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory
factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide
had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD
activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy.
NPersonalized therapy in multiple myeloma according to patient age and vulnerability:
a report of the European Myeloma Network (EMN).
Palumbo A, Bringhen S, Ludwig H, Dimopoulos MA, Bladé J, Mateos MV, Rosiñol L, Boccadoro M, Cavo M, Lokhorst H,
Zweegman S, Terpos E, Davies F, Driessen C, Gimsing P, Gramatzki M, Hàjek R, Johnsen HE, Leal Da Costa F, Sezer O, Spencer A,
Beksac M, Morgan G, Einsele H, San Miguel JF, Sonneveld P.
Blood. 2011 Aug 12. [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/pubmed/21841166
This article discusses improved outcomes due to the introduction of novel agents, such as thalidomide, bortezomib and
lenalidomide; however, elderly myeloma patients are more susceptible to side effects and are often unable to tolerate full drug
doses. The authors conclude that for these patients, lower-dose-intensity regimens improve the safety profile and thus optimize
treatment outcome; further research into the best treatment strategies for vulnerable elderly patients is urgently needed.
The majority of patients with newly diagnosed multiple myeloma (MM) are aged >65 years with 30% aged >75 years. Many
elderly patients are also vulnerable due to comorbidities that complicate the management of MM. The prevalence of MM is
expected to rise over time due to an aging population. Most elderly MM patients are ineligible for autologous transplantation
and the standard treatment has, until recently, been melphalan plus prednisone. The introduction of novel agents, such as
thalidomide, bortezomib and lenalidomide, has improved outcomes; however, elderly MM patients are more susceptible to
side effects and are often unable to tolerate full drug doses. For these patients, lower-dose-intensity regimens improve the safety
profile and thus optimize treatment outcome. Further research into the best treatment strategies for vulnerable elderly patients is
urgently needed. Appropriate screening for vulnerability and an assessment of cardiac, pulmonary, renal, hepatic and neurological
function, as well as age >75 years, at the start of therapy allows treatment strategies to be individualized and drug doses to be
tailored to improve tolerability and optimize efficacy. Similarly, occurrence of serious non-hematologic adverse events during
treatment should be carefully taken into account to adjust doses and optimize outcomes.
NIdentification and evaluation of a panel of serum biomarkers for predicting response to thalidomide
in multiple myeloma patients.
Xiong Q, Ge F.
Expert Rev Proteomics. 2011 Aug;8(4):439-42.
:
http://www.ncbi.nlm.nih.gov/pubmed/21819299
The authors evaluate a study by Rajpal R, Dowling P, Meiller J et al, which developed a novel panel of protein biomarkers for
predicting response to thalidomide-based therapy in newly diagnosed myeloma patients; this panel of biomarkers may not only
guide initial therapy, but can also provide direct implications for personalized medicine in myeloma patients.
Evaluation of: Rajpal R, Dowling P, Meiller J et al. A novel panel of protein biomarkers for predicting response to thalidomide-
based therapy in newly diagnosed multiple myeloma patients. Proteomics 11(8), 1391-1402 (2011). Predicting response to
thalidomide-based therapy remains a challenging task faced by clinicians in the treatment of multiple myeloma. The pioneering
work reported by Rajpal et al. moves one step further towards solving this challenge. They developed a proteomics-based
approach that combines immunodepletion, 2D-difference gel electrophoresis analysis and mass spectrometry to search for serum
proteins with expressions that show significant correlations to thalidomide treatment. This integrated approach allowed them to
identify a panel of protein biomarkers. By using ELISA-based validation and strict statistical analysis, the authors have achieved
an overall 84.0% predictive accuracy, with associated sensitivity and specificity values of 81.8 and 86.2%, respectively. Their
methods and significant findings are reviewed within this article. This panel of biomarkers may not only guide initial therapy,
but can also provide direct implications for personalized medicine in multiple myeloma patients.
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