Published by the C
International I
Myel
T
oma Founda
ItionNVOLG
UME IV, ISSUE III S
Q3/2007
VELCADE®(bortezomib)Issue
Welcome to the International Myeloma Foundation's (IMF) special edition of
CITINGS, our premiere publication featuring the most up-to-date information on myeloma
treatment. This issue focuses on VELCADE (bortezomib), the first of a new class of drugs called
proteasome inhibitors. In this issue, we provide a list of references to the latest published studies
on bortezomib from both national and international medical journals and publications.
We hope that CITINGS provides a detailed and informative update of the VELCADE literature.
Please feel free to contact the IMF at (800) 452-CURE (2873)or www.myeloma.org
Susie Novis, President, IMF
VELCADE(bortezomib)Publications
3rdQuarter,2007
NCurrent treatment strategies for multiple myeloma.
Thomas S, Alexanian R.
Clin Lymphoma Myeloma. 2007 Apr;7 Suppl 4:S139-44.
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This article discusses myeloma treatment strategies with novel agents and novel combinations, including bortezomib, and reports
upon their response rates.
In recent years, there have been major advances in the treatment of multiple myeloma. Among previously untreated patients, different
combinations of dexamethasone, lenalidomide, thalidomide, and bortezomib have produced overall response rates of 80%-90% with
complete response rates of 10%-32%, and remissions are often achieved after only 2 cycles of initiating systemic therapy. Subsequent
intensification with high-dose chemotherapy supported by autologous stem cell transplantation has enabled younger patients to achieve
partial and complete responses with evidence of prolonged survival. Tandem autologous stem cell transplantation and reduced-intensity
allogeneic stem cell transplantation are under investigation in attempts to improve outcomes. For patients unable to pursue consolidation
therapy with stem cell transplantation, remissions obtained with induction therapy can often be extended with the use of maintenance
systemic therapy. Despite available therapies, relapse of disease is inevitable for nearly all patients, and treatment strategies with novel agents
and novel combinations of established agents are under study.
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Funded by an educational grant from Millennium Pharmaceuticals, Inc.
NEmerging data on the use of anthracyclines in combination with bortezomib in multiple myeloma.
Voorhees PM, Orlowski RZ.
Clin Lymphoma Myeloma. 2007 Apr;7 Suppl 4:S156-62.
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The authors review the preclinical data supporting the use of bortezomib with anthracyclines and the promising clinical data with
these combinations.
Since the inception of infusional vincristine/doxorubicin/pulsed dexamethasone (VAD) for the treatment of multiple myeloma, anthracyclines
have remained an important class of antimyeloma agents. More recently, the introduction of pegylated liposomal doxorubicin with improved
pharmacokinetic characteristics has led to the development of newer anthracycline-containing regimens with improved toxicity profiles.
Bortezomib, a first in class reversible inhibitor of the proteasome, has also emerged as an important novel agent for the treatment of
multiple myeloma and is currently approved for patients with relapsed/refractory disease progressing after 1 previous therapy. Although
both classes of agents have potent proapoptotic activity, they also induce activation of an antiapoptotic prosurvival program that limits
their own efficacy, a process known as inducible chemotherapy resistance. Importantly, in preclinical studies, each of these drugs has been
shown to attenuate chemotherapy resistance induced by the other, and combinations of the 2 have demonstrated striking synergistic activity.
Furthermore, early phase I/II clinical trials have shown impressive activity of pegylated liposomal doxorubicin and conventional doxorubicin
in combination with bortezomib in patients with newly diagnosed and relapsed/refractory myeloma. Phase II/III clinical trials evaluating these
regimens in patients with newly diagnosed and relapsed/refractory disease have recently completed accrual and will better define the role
of these combinations in myeloma therapy. Herein, we review the preclinical data supporting the use of bortezomib with anthracyclines and
the promising clinical data with these combinations.
NReversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose
dexamethasone-containing regimens and the impact of novel agents.
Kastritis E, Anagnostopoulos A, Roussou M, Gika D, Matsouka C, Barmparousi D, Grapsa I, Psimenou E, Bamias A,
Dimopoulos MA.
Haematologica. 2007 Apr;92(4):546-9.
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The authors conclude that renal failure is reversible in the majority of newly diagnosed myeloma patients treated with high-dose
dexamethasone containing regimens, and that the addition of novel agents, such as bortezomib, induces a more rapid reversal.
The impact of high dose dexamethasone containing regimens with or without the novel agents thalidomide and bortezomib on the reversal
of renal failure (RF) was evaluated in 41 consecutive newly diagnosed patients with multiple myeloma (MM) treated in a single institution.
RF was reversed in 73% of all patients within a median of 1.9 months. In patients treated with dexamethasone and novel agents (thalidomide
and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months. Severe RF and significant Bence Jones proteinuria were
associated with a lower probability of RF reversal. Patients who responded to treatment achieved RF reversal more often than in those who
did not (85% versus 56%, p=0.046). In conclusion, RF is reversible in the majority of newly diagnosed MM patients treated with high-dose
dexamethasone containing regimens. The addition of novel agents induces a more rapid RF reversal.
NBortezomib, melphalan, prednisone, and thalidomide for relapsed multiple myeloma.
Palumbo A, Ambrosini MT, Benevolo G, Pregno P, Pescosta N, Callea V, Cangialosi C, Caravita T, Morabito F, Musto P,
Bringhen S, Falco P, Avonto I, Cavallo F, Boccadoro M; Italian Multiple Myeloma Network; Gruppo Italiano Malattie
Ematologicche dell'Adulto.
Blood. 2007 Apr 1;109(7):2767-72.
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This multi-center phase I/II trial assesses dosing, safety, and efficacy of the 4-drug combination of bortezomib, melphalan,
prednisone, and thalidomide.
In multiple myeloma (MM), the addition of thalidomide or bortezomib to the standard oral melphalan/prednisone combination significantly
increased response rate and event-free survival. In this multicenter phase 1/2 trial, dosing, safety, and efficacy of the 4-drug combination,
bortezomib, melphalan, prednisone, and thalidomide (VMPT) was determined. Bortezomib was administered at 3 dose levels (1.0 mg/m2,
1.3 mg/m2, or 1.6 mg/m2) on days 1, 4, 15, and 22; melphalan was given at a dose of 6 mg/m2 on days 1 through 5 and prednisone at
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60 mg/m2 on days 1 through 5. Thalidomide was delivered at 50 mg on days 1 through 35. Each course was repeated every 35 days. The
maximum tolerated dose of bortezomib was 1.3 mg/m2. Thirty patients with relapsed or refractory MM were enrolled; 20 patients (67%)
achieved a partial response (PR) including 13 patients (43%) who achieved at least a very good PR. Among 14 patients who received VMPT
as second-line treatment, the PR rate was 79% and the immunofixation-negative complete response rate 36%. The 1-year progression-
free survival was 61%, and the 1-year survival from study entry was 84%. Grade 3 nonhematologic adverse events included infections (5
patients), fatigue (1), vasculitis (1), and peripheral neuropathy (2); no grade 4 toxicities were recorded. Initial results showed that VMPT is
an effective salvage therapy with a very high proportion of responses. The incidence of neurotoxicities was unexpectedly low.
NSurvival of genetic subtypes of relapsed myeloma may be modulated by secondary events.
Chng WJ, Mulligan G, Bryant B, Bergsagel L.
Blood. 2007 Apr 15;109(8):3610-1.
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No abstract available.
NMedical management update: multiple myeloma.
Stoopler ET, Vogl DT, Stadtmauer EA.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 May;103(5):599-609. [Epub 2007 Feb 7.]
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This medical management update reviews recent clinical and therapeutic advances in the field of myeloma and highlights issues
that are important to the oral health care provider.
Multiple myeloma (MM) is a hematologic malignancy characterized by abnormal proliferation of immunoglobulin-secreting plasma
cells. Manifestations of MM may include anemia, osteolytic lesions, and renal dysfunction. Treatment for this disease chiefly consists of
corticosteroids, bisphosphonates, chemotherapy, and hematopoietic stem-cell transplantation. This medical management update will review
recent clinical and therapeutic advances in the field of MM and highlight issues that are important to the oral health care provider.
NInhibition of chronic graft-vs-host disease with retention of anti-myeloma effects by the proteasome
inhibitor bortezomib.
Todisco E, Sarina B, Castagna L, Mazza R, Rahal D, Nozza A, Santoro A.
Leuk Lymphoma. 2007 May;48(5):1015-8.
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No abstract available.
NSevere Epidermal Necrolysis after Bortezomib Treatment for Multiple Myeloma.
Fang B, Song Y, Ma J, Zhao RC.
Acta Haematol. 2007 May 15;118(2):65-67 [Epub ahead of print.]
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No abstract available.
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NNew treatment of multiple myeloma [Article in French].
Hulin C.
Rev Med Interne. 2007 May 24; [Epub ahead of print.]
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The author reviews bortezomib in the treatment of myeloma.
PURPOSE: After decades of minimal progress, two new classes of drugs with novels mechanisms of action: immunomodulatory drugs
(thalidomide and lenalidomide) and proteasome inhibitors (bortezomib) have shown great activity for the treatment of multiple myeloma.
CURRENT KNOWLEDGE AND KEY POINTS: Thalidomide acts by a variety of mechanisms; its efficacy is well known in disease relapse
especially associated with dexamethasone. Recent results prove that combination of thalidomide with melphalan and prednisone should be
considered as the first line standard of care in elderly patient. The main side effects are peripheral neuropathy and deep-vein thrombosis.
Bortezomib is the first proteasome inhibitor. It is approved for the treatment in first disease relapse. The combination with glucocorticoids
is synergistic. This combination in induction treatment before autologous stem cell transplantation is promising, as well as the combination
with melphalan and prednisone in elderly patient. The main toxicities are fatigue and peripheral neuropathy. Lenalidomide is a structural
analogue of thalidomide. Its efficacy in combination with dexamethasone has been proved in relapsing patients. The main toxicity is
hematologic. Utilisation as first line treatment is also promising.
FUTURE PROSPECTS AND PROJECTS: These three drugs have toxicities predictable and manageable and can be used successively or in
combination for greater effectiveness. They have an impact on the multiple myeloma treatment strategies and on the disease course itself.
NBortezomib in combination with thalidomide-dexamethasone for previously untreated multiple
myeloma.
Wang M, Giralt S, Delasalle K, Handy B, Alexanian R.
Hematology. 2007 Jun;12(3):235-9.
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The authors find the addition of bortezomib to a thalidomide-dexamethasone regimen to be a highly effective primary treatment
for newly diagnosed myeloma patients.
In a previous trial among 137 previously untreated patients with multiple myeloma, the combination of thalidomide-dexamethasone induced
remission in 66% of patients, including complete remission in 13%. In an attempt to induce more frequent remissions, we added bortezomib
to this program. Between 7/03 and 3/06, 38 newly diagnosed patients with multiple myeloma received at least one, but no more than 3,
courses of bortezomib in a dose of 1.3 mg/m(2) IV x 4; dexamethasone 20 mg/m(2) PO for 4 days beginning on days 1, 9, 17; thalidomide
100 mg PO daily increasing to a maximum of 200 mg. There was rapid onset of remission in 33 patients (87%) including 6 patients with
complete remission (16%). Most side effects were preventable, but otherwise were usually mild and reversible. After a median of 4 months,
25 eligible patients received intensive therapy with high-dose melphalan supported by autologous blood stem cells, so that the myeloma was
in complete remission in 14 patients (37% of all patients). The combination of bortezomib-thalidomide-dexamethasone was a highly effective
primary treatment for newly diagnosed patients with multiple myeloma.
NBortezomib therapy response is independent of cytogenetic abnormalities in relapsed/refractory multiple
myeloma.
Chang H, Trieu Y, Qi X, Xu W, Stewart KA, Reece D.
Leuk Res. 2007 Jun;31(6):779-82. [Epub 2006 Sep 22.]
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To investigate whether bortezomib is active in relapsed/refractory myeloma patients with genetic risk factors, the authors evaluate
the outcome of 65 patients and correlate the clinical response with 13q deletion, translocations t(11;14) and t(4;14) and CKS1B
amplification. They conclude that in this pilot study, bortezomib is an effective salvage therapy for refractory/relapsed myeloma,
irrespective of genetic risk factors.
Myeloma patients with unfavorable molecular cytogenetics have a poor prognosis irrespective of treatment with conventional chemotherapy
or autologous stem cell transplant. To investigate whether bortezomib, a new proteasome inhibitor, is active in relapsed/refractory
myeloma patients with genetic risk factors, we evaluated the outcome of 65 patients and correlated the clinical response with 13q deletion,
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translocations t(11;14) and t(4;14) and CKS1B amplification as detected by interphase cytoplasmic fluorescence in situ hybridization (cIg-
FISH). Thirty-seven of 61 (61%) evaluable patients had an objective response to bortezomib with median progression free (PFS) and overall
survivals (OS) of 9.5 and 15.1 months, respectively. Of 43 cases with evaluable bone marrows, cIg-FISH determination of del(13q), t(4;14),
t(11;14) and CKS1B amplification was done on 40, 41, 41 and 37 cases and the frequency of their detection was 35%, 15%, 15%, and 32%,
respectively. There was no statistically significant difference in response to bortezomib for patients with or without 13q deletion (77%
versus 50%), t(4;14) (67% versus 56%), t(11;4) (33% versus 62%), or CKS1B amplification (67% versus 57%). Furthermore, there was no
statistically significant difference in PFS or OS following bortezomib therapy between patients with or without these molecular cytogenetic
abnormalities. Our data suggest that, in this pilot study, bortezomib is an effective salvage therapy for refractory/relapsed myeloma,
irrespective of genetic risk factors.
NMaintenance therapy in multiple myeloma.
Mihelic R, Kaufman JL, Lonial S.
Leukemia. 2007 Jun;21(6):1150-7. [Epub 2007 Mar 8.]
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This review summarizes the currently available data in the maintenance setting for multiple myeloma (including novel agent
bortezomib), as well as potential future trials to further address this important issue.
Therapeutic advances in the treatment of multiple myeloma have significantly improved remission duration and overall survival (OS). These
strategies have included the use of immunotherapy (interferon), novel agents (bortezomib, thalidomide, and lenalidomide), corticosteroids,
and chemotherapy. While novel agents have had a major impact on response rates with initial therapy, most patients with multiple myeloma
will eventually relapse. In the setting of minimal residual disease following standard dose or high-dose therapy, a number of different
`maintenance' strategies have emerged to prolong the duration of initial or subsequent remissions. The impact of these strategies on OS and
event-free survival (EFS) is critically important, as the use of ineffective maintenance therapy adds the burden of additional cost, morbidity,
and may reduce quality of life. Truly successful maintenance therapy will be effective in the setting of minimal residual disease, and will
improve not only EFS, but also OS. This review summarizes the currently available data in the maintenance setting for multiple myeloma,
and will discuss potential future trials to further address this important issue.
NNew drugs for myeloma.
Richardson PG, Mitsiades C, Schlossman R, Munshi N, Anderson K.
Oncologist. 2007 Jun;12(6):664-89.
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This review focuses on the extensive clinical data available from studies of bortezomib in the treatment of newly diagnosed and
advanced multiple myeloma.
Although multiple myeloma remains incurable with conventional treatments, management of the disease has recently been transformed
with the introduction of three novel agents, bortezomib, thalidomide, and lenalidomide. The proteasome inhibitor bortezomib is approved
for the treatment of patients who have received one prior therapy; there is a growing body of clinical evidence showing its effectiveness
alone and in combination in the frontline setting, with high response rates and consistently high rates of complete response. Thalidomide
plus dexamethasone is approved as frontline treatment of multiple myeloma. Other combination regimens including thalidomide have
demonstrated substantial activity in both relapsed and frontline settings. Recently, the thalidomide analogue lenalidomide has been
approved, in combination with dexamethasone, for the treatment of patients who have received one prior therapy; this regimen has
shown promising results in the frontline setting. These agents represent a new generation of treatments for multiple myeloma that affect
both specific intracellular signaling pathways and the tumor microenvironment. Other novel, targeted therapies are also being evaluated
in preclinical and clinical studies. Regimens incorporating bortezomib, thalidomide, lenalidomide, and other novel agents, together with
commonly used conventional drugs, represent a promising future direction in myeloma treatment. At present, further investigation is
required to assess the safety and activity of combinations integrating these other novel agents. However, bortezomib, thalidomide, and
lenalidomide are now in widespread clinical use. This review therefore focuses on the extensive clinical data available from studies of these
drugs in the treatment of newly diagnosed and advanced multiple myeloma. Disclosure of potential conflicts of interest is found at the end
of this article.
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NBortezomib enhances dendritic cell (DC)-mediated induction of immunity to human myeloma via
exposure of cell surface heat shock protein 90 on dying tumor cells: therapeutic implications.
Spisek R, Charalambous A, Mazumder A, Vesole DH, Jagannath S, Dhodapkar MV.
Blood. 2007 Jun 1;109(11):4839-45. [Epub 2007 Feb 13.]
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The authors show that the uptake of human myeloma cells by dendritic cells after tumor cell death by bortezomib, but not
gamma irradiation or steroids, leads to the induction of antitumor immunity, including against primary tumor cells, without the
need for any additional adjuvants.
Most anticancer chemotherapies are immunosuppressive and induce nonimmunogenic tumor cell death. Bortezomib, a specific inhibitor
of 26S proteasome, has shown clinical activity in several human tumors, including myeloma. Here we show that the uptake of human
myeloma cells by dendritic cells (DCs) after tumor cell death by bortezomib, but not gamma irradiation or steroids, leads to the induction of
antitumor immunity, including against primary tumor cells, without the need for any additional adjuvants. The delivery of activating signal
from bortezomib-killed tumor cells to DCs depends on cell-cell contact between DCs and dying tumor cells and is mediated by bortezomib-
induced exposure of heat shock protein 90 (hsp90) on the surface of dying cells. The combination of bortezomib and geldanamycin (an
hsp90 inhibitor) leads to greater apoptosis of tumor cells but abrogates their immunogenicity. These data identify drug-induced exposure of
endogenous heat shock proteins on the surface of dying cells as a mechanism of immunogenic death of human tumors. Specific targeting of
bortezomib to tumors may enhance their immunogenicity and the induction of antitumor immunity.
NNoxa up-regulation and Mcl-1 cleavage are associated to apoptosis induction by bortezomib in multiple
myeloma.
Gomez-Bougie P, Wuillčme-Toumi S, Ménoret E, Trichet V, Robillard N, Philippe M, Bataille R, Amiot M.
Cancer Res. 2007 Jun 1;67(11):5418-24.
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The authors conclude that, in myeloma cells, the mechanistic basis for bortezomib sensitivity can be explained mainly by the
model in which the sensitizer Noxa can displace Bim, a BH3-only activator, from Mcl-1, thus leading to Bax/Bak activation.
Targeting the ubiquitin-proteasome pathway has emerged as a potent anticancer strategy. Bortezomib, a specific proteasome inhibitor, has
been approved for the treatment of relapsed or refractory multiple myeloma. Multiple myeloma cell survival is highly dependent on Mcl-1
antiapoptotic molecules. In a recent study, proteasome inhibitors induced Mcl-1 accumulation that slowed down their proapoptotic effects.
Consequently, we investigated the role of Bcl-2 family members in bortezomib-induced apoptosis. We found that bortezomib induced
apoptosis in five of seven human myeloma cell lines (HMCL). Bortezomib-induced apoptosis was associated with Mcl-1 cleavage regardless of
Mcl-1L accumulation. Furthermore, RNA interference mediated Mcl-1 decrease and sensitized RPMI-8226 HMCL to bortezomib, highlighting
the contribution of Mcl-1 in bortezomib-induced apoptosis. Interestingly, an important induction of Noxa was found in all sensitive HMCL
both at protein and mRNA level. Concomitant to Mcl-1 cleavage and Noxa induction, we also found caspase-3, caspase-8, and caspase-9
activation. Under bortezomib treatment, Mcl-1L/Noxa complexes were highly increased, Mcl-1/Bak complexes were disrupted, and there
was an accumulation of free Noxa. Finally, we observed a dissociation of Mcl-1/Bim complexes that may be due to a displacement of Bim
induced by Noxa. Thus, in myeloma cells, the mechanistic basis for bortezomib sensitivity can be explained mainly by the model in which the
sensitizer Noxa can displace Bim, a BH3-only activator, from Mcl-1, thus leading to Bax/Bak activation.
NPredictive value of alkaline phosphatase for response and time to progression in bortezomib-treated
multiple myeloma patients.
Zangari M, Esseltine D, Cavallo F, Neuwirth R, Elice F, Burns MJ, Yaccoby S, Richardson P, Sonneveld P, Tricot G.
Am J Hematol. 2007 Jun 1; [Epub ahead of print.]
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The authors assess the relationship of changes in alkaline phosphatase levels during bortezomib therapy with response and time
to progression on this therapy and conclude that markers of osteoblastic activation may predict quality and duration of response
in multiple myeloma. In addition, this study's data suggests that bone anabolism could inhibit myeloma growth.
Myeloma bone disease is characterized by osteolytic destruction associated with suppressed osteoblastic activity. Using data from the APEX
(Richardson et al., N Engl J Med 2005;352:2487-2498) study, we have assessed the relationship of changes in alkaline phosphatase (ALP)
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levels during bortezomib therapy with response and time to progression on this therapy. The percentage of ALP increments in responders
(complete and partial response) and nonresponders was analyzed at different thresholds and time points. For all bortezomib-treated patients
enrolled in the trial (N = 333), at least a 25% increase in ALP from the baseline at 6 week was the most powerful predictor of treatment
response (P < 0.0001) and time to progression (206 vs. 169 days) relative to patients with less than a 25% increase in ALP (P = 0.01).
Markers of osteoblastic activation may predict quality and duration of response in multiple myeloma. In addition, our data suggest that bone
anabolism could inhibit myeloma growth.
NPreclinical studies of the pan-Bcl inhibitor obatoclax (GX015-070) in multiple myeloma.
Trudel S, Li ZH, Rauw J, Tiedemann RE, Wen XY, Stewart AK.
Blood. 2007 Jun 15;109(12):5430-8. [Epub 2007 Mar 1.]
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The authors find that GX015-070 enhanced the antimyeloma activity induced by melphalan, dexamethasone, or bortezomib.
Bcl family members Bcl-2, Bcl-x(L), and Mcl-1, are frequently expressed and implicated in the survival of myeloma cells. Obatoclax (GX015-
070) is a novel, small-molecule antagonist of the BH3-binding groove of the Bcl family of proteins. We show that GX015-070 inhibits the
binding of Bak to Mcl-1, up-regulates Bim, induces cytochrome c release, and activates capase-3 in human myeloma cell lines (HMCLs),
confirming the predicted mechanism of action. Consequently, GX015-070 potently inhibited the viability of 15 of 16 HMCLs (mean IC(50) of
246 nM), including those resistant to melphalan and dexamethasone. In combination studies, GX015-070 enhanced the antimyeloma activity
induced by melphalan, dexamethasone, or bortezomib. Sensitivity to GX015-070 correlated with the absence or near absence of Bcl-x(L).
Coculture with interleukin-6 or adherence to bone marrow stroma conferred modest resistance; however, it did not overcome GX015-070-
induced cytotoxicity. Of importance, GX015-070 as a single agent induced potent cytotoxic responses against patient-derived tumor cells.
GX015-070 inhibited normal bone marrow-derived colony formation; however, cytotoxicity to human blood lymphocytes was not observed.
Taken together, these studies describe a novel BH3 mimic with selectivity for Mcl-1, and support the therapeutic application of GX015-070
for diverse neoplasias including multiple myeloma.
NMultiple myeloma [Article in Spanish].
García-Sanz R, Mateos MV, San Miguel JF.
Med Clin (Barc). 2007 Jun 16;129(3):104-15.
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The authors review myeloma's current standards of care, including the emergence of thalidomide and lenalidomide.
Multiple myeloma is the second most common hematological malignancy. It is defined by the presence of monoclonal plasma cells capable
to produce a monoclonal paraprotein causing clinical abnormalities such as anemia, renal insufficiency, hypercalcemia, or bone lesions. New
chromosomal or molecular abnormalities have been identified allowing a better management. Multiple myeloma is treatable and, although it
remains incurable, the patient prognosis and quality of life has notably improved, so it is not rare to see series with a median survival longer
than 5 years. Even more, it is possible by now to expect improvements respect to the standard autologous stem cell transplantation. This
must be attributed to the emergence of a number of new therapies entering clinical practice over the last 6 years: thalidomide (Thalomid®
Pharmion, Boulder, CO, USA), lenalidomide (Revlimid®, Celgene Corporation, Summit, NJ, USA) and bortezomib (Velcade®, Janssen
Pharmaceutica N.V., Belgium). Finally, we also will review the current clinical experience in supportive therapy, which has also contributed
to the patient outcome improvement with approaches such as: new indications for dialysis, use of erythropoietin receptor stimulating agents
and bisphosphonates, and new surgical therapies such as vertebroplasty and balloon kyphoplasty.
NAllografting or autografting for myeloma.
van Rhee F, Crowley J, Barlogie B.
N Engl J Med. 2007 Jun 21;356(25):2646-8; author reply 2646-8.
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Comment on: N Engl J Med. 2007 Mar 15;356(11):1110-20.
www.myeloma.org
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NCommunity experience with bortezomib in patients with multiple myeloma.
Onitilo AA, Engel J, Olatosi B, Fagbemi S.
Am J Hematol. 2007 Jul;82(7):637-9.
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The authors find that bortezomib is well tolerated in their population of multiple myeloma patients, with the exception of
infection adverse events that are generally mild grade 1-2.
Community practice experience allows a nonselective care of patient using information derived from a more controlled clinical trial
environment. We present our community experience with multiple myeloma patients with advanced age, long disease duration since
diagnosis, advanced stage, multiple prior therapies including stem cell transplantation, co-morbidities, and other poor prognostic features,
such as low albumin, high B-2 microglobulin, renal failure, and the presence of poor risk chromosomal abnormalities. Our response rates
are comparable to those from clinical trials. Bortezomib is well tolerated in this population of multiple myeloma patients with the exception
of infection adverse events that are generally mild grade 1-2.
NIncorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3.
Barlogie B, Anaissie E, van Rhee F, Haessler J, Hollmig K, Pineda-Roman M, Cottler-Fox M, Mohiuddin A, Alsayed Y, Tricot G,
Bolejack V, Zangari M, Epstein J, Petty N, Steward D, Jenkins B, Gurley J, Sullivan E, Crowley J, Shaughnessy JD.
Br J Haematol. 2007 Jul;138(2):176-85.
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The authors incorporate bortezomib into a melphalan-based tandem transplant regimen for 303 newly diagnosed patients with
myeloma. Results of this phase II study demonstrate that bortezomib can be safely combined with multi-agent chemotherapy,
effecting near-complete remission status and 2-year survival rates in more than 80% of patients.
Total therapy 3 incorporated bortezomib into a melphalan-based tandem transplant regimen for 303 newly diagnosed patients with myeloma.
Induction chemotherapy prior to and consolidation chemotherapy after transplants each consisted of two cycles of VTD-PACE (bortezomib,
thalidomide, dexamethasone and 4-d continuous infusions of cis-platin, doxorubicin, cyclophosphamide, etoposide); 3-year maintenance
comprised monthly cycles of VTD in the first and TD in the remaining years. The median age was 59 years (age >64 years, 28%). A
minimum of 20 x 10(6) CD34 cells/kg was collected in 87% of patients; 83% completed both transplants, and only 5% suffered a treatment-
related death. At 24 months, 83% had achieved near-complete remission, which was sustained in 88% at 2 years from its onset. With a
median follow-up of 20 months, 2-year estimates of event-free and overall survival were 84% and 86% respectively. The 44 patients who
experienced an event more often had a high-risk gene array profile, cytogenetic abnormalities and indicators of high lactate dehydrogenase,
beta-2-microglobulin, creatinine and International Staging System stage. Toxicities of grade > 2 included thrombo-embolic events in 27%
and peripheral neuropathy in 12%. Results of this phase-2 study demonstrated that bortezomib could be safely combined with multi-agent
chemotherapy, effecting near-complete remission status and 2-year survival rates in more than 80% of patients.
NMelphalan and its role in the management of patients with multiple myeloma.
Falco P, Bringhen S, Avonto I, Gay F, Morabito F, Boccadoro M, Palumbo A.
Expert Rev Anticancer Ther. 2007 Jul;7(7):945-57.
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The authors discuss thalidomide, lenalidomide and bortezomib, in combination with oral melphalan in the elderly and with
intravenous melphalan in younger patients, as changing the traditional treatment paradigm of multiple myeloma.
Melphalan is an alkylating agent approved for the treatment of multiple myeloma and ovarian cancer. The combination of oral melphalan
and prednisone was first introduced in the 1960s and remains the standard therapy for elderly multiple myeloma patients. High-dose
melphalan followed by autologous stem cell support became the standard treatment for younger patients since the 1990s. The occurrence
of drug resistance is the major limiting factor for the long-term success of this therapy, and relapse always occurs. In recent years, advances
in the understanding of the pathogenesis of myeloma and the mechanism of drug resistance have led to the development of novel targeted
therapies that are able to overcome resistance and show additive or synergistic effects with melphalan. Thalidomide, its immunomodulatory
derivative lenalidomide, and the proteasome inhibitor bortezomib, in combination with oral melphalan in the elderly and with intravenous
melphalan in younger patients, are changing the traditional treatment paradigm of multiple myeloma.
www.myeloma.org
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NPatient-reported outcomes helped predict survival in multiple myeloma using partial least squares
analysis.
Viala M, Bhakar AL, de la Loge C, van de Velde H, Esseltine D, Chang M, Dhawan R, Dubois D.
J Clin Epidemiol. 2007 Jul;60(7):670-679. [Epub 2007 Jan 24.]
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The authors use four Patient-Reported Outcomes (PRO) measures to evaluate the efficacy and safety of bortezomib in myeloma
patients.
OBJECTIVE: The prognostic value of Patient-Reported Outcomes (PRO) in predicting mortality during treatment of multiple myeloma (MM)
patients was assessed using partial least square (PLS) regression, a statistical method that is well-adapted for highly correlated data.
STUDY DESIGN AND SETTING: Four PRO measures, The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30,
the EORTC QLQ-MY24, the FACIT-Fatigue scale, and the FACT/GOG-Ntx scale, were administered during a trial designed to evaluate the
efficacy and safety of bortezomib (VELCADE 1.3mg/m(2)) in MM patients (N=202). Clinical and PRO data were analyzed for predictive value
by univariate and multivariate logistic regression methods and then by PLS regression.
RESULTS: Fifteen baseline PRO parameters were significant in predicting mortality during treatment when univariate logistic regression was
used. In contrast, only two variables were retained in the multivariate analysis, as correlated variables were excluded from the model. Using
PLS regression, 14 of the 21 PRO predictors were significant in predicting mortality. Clinical and PRO data used together increased the
predictive power of all models compared to clinical data alone.
CONCLUSION: The prognostic value of PRO was established and was more informative using PLS regression. PLS regression may therefore
be a valuable method for analyzing PRO data.
NSevere pulmonary complications after bortezomib treatment for multiple myeloma: An unrecognized
pulmonary vasculitis?
Pitini V, Arrigo C, Altavilla G, Naro C.
Leuk Res. 2007 Jul;31(7):1027-8. [Epub 2006 Nov 28.]
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No abstract available.
NMultiple myeloma: A prototypic disease model for the characterization and therapeutic targeting of
interactions between tumor cells and their local microenvironment.
Mitsiades CS, Mitsiades NS, Richardson PG, Munshi NC, Anderson KC.
J Cell Biochem. 2007 Jul 1;101(4):950-68.
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The authors highlight the recent advances in the understanding of cellular and molecular mechanisms of interactions between
myeloma cells and their milieu, and on the development the series of new classes of therapeutic agents, including thalidomide
and lenalidomide.
The interaction between tumor cells and the local milieu where are homing has recently become the focus of extensive research in a broad
range of malignancies. Among them, multiple myeloma (MM) is now recognized as a prototypical tumor model for the characterization
of these interactions. This is due not only to the propensity of MM cells to target the skeleton and form lytic bone lesions, but because
interactions of MM cells with normal cells of the bone milieu can attenuate the anti-tumor activity of conventional therapies, such as
glucocorticoids and standard cytotoxic agents, including alkylators. Herein, we highlight the recent advances in our understanding of cellular
and molecular mechanisms of interactions between MM cells and their milieu. Particular emphasis is placed on the interface between MM
cells and normal cell compartments of the BM, especially bone marrow stromal cells (BMSCs), and on the development of a series of new
classes of therapeutic agents, including the proteasome inhibitor bortezomib, thalidomide and lenalidomide, which counteract specific
aspects of those MM-BM interactions. The significant clinical activity of these novel therapies has not only led to a new era in the therapeutic
management of this disease, but also underscored the importance of comprehensively characterizing the role of the local microenvironment
in the pathophysiology of human neoplasias.
www.myeloma.org
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NThe proteasome inhibitor bortezomib affects osteoblast differentiation in vitro and in vivo in multiple
myeloma patients.
Giuliani N, Morandi F, Tagliaferri S, Lazzaretti M, Bonomini S, Crugnola M, Mancini C, Martella E, Ferrari L, Tabilio A, Rizzoli
Blood. 2007 Jul 1;110(1):334-8. [Epub 2007 Mar 19.]
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This study shows that bortezomib significantly induced a stimulatory effect on osteoblast markers in human mesenchymal
cells without affecting the number of osteoblast progenitors in bone marrow cultures or the viability of mature osteoblasts, and
supports the hypothesis that a direct stimulatory effect on bone formation process could occur during bortezomib treatment.
The proteasome inhibitor bortezomib may increase osteoblast-related markers in multiple myeloma (MM) patients; however, its potential
osteoblastic stimulatory effect is not known. In this study, we show that bortezomib significantly induced a stimulatory effect on osteoblast
markers in human mesenchymal cells without affecting the number of osteoblast progenitors in bone marrow cultures or the viability of
mature osteoblasts. Consistently we found that bortezomib significantly increased the transcription factor Runx2/Cbfa1 activity in human
osteoblast progenitors and osteoblasts without affecting nuclear and cytoplasmatic active beta-catenin levels. Consequently a stimulatory
effect of bortezomib on bone nodule formation was also demonstrated in osteoblast progenitors. These in vitro observations were confirmed
in vivo by the finding of a significant increase in the number of osteoblastic cells x mm(2) of bone tissue and in the number of Runx2/Cbfa1-
positive osteoblastic cells that was observed in MM patients who responded to bortezomib. Our in vitro and in vivo observations support the
hypothesis that a direct stimulatory effect on bone formation process could occur during bortezomib treatment.
NA pivotal role for Mcl-1 in Bortezomib-induced apoptosis.
Podar K, Gouill SL, Zhang J, Opferman JT, Zorn E, Tai YT, Hideshima T, Amiot M, Chauhan D, Harousseau JL, Anderson KC.
Oncogene. 2007 Jul 23; [Epub ahead of print.]
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This study examines the role of Mcl-1 in bortezomib-induced apoptosis. The results support an important role of Mcl-1 and a Mcl-
1 fragment in bortezomib-induced cell death in general, and in myeloma in particular. To prevent relapse of myeloma in patients
treated with bortezomib, the authors recommend the combination of bortezomib with agents that induce myeloma cell death
independent of Mcl-1.
Bortezomib is a proteasome inhibitor for the treatment of relapsed/refractory multiple myeloma (MM). Mechanisms of resistance to
Bortezomib are undefined. Myeloid cell leukemia-1 (Mcl-1) is an antiapoptotic protein, which protects tumor cells against spontaneous
and chemotherapy-induced apoptosis. In MM, specific downregulation of Mcl-1 induces apoptosis. Here, we examined the role of Mcl-1
in Bortezomib- and doxorubicin-induced apoptosis. We demonstrate that Bortezomib, but not doxorubicin, triggers caspase-dependent
generation of a 28 kDa Mcl-1-fragment, in several MM cell lines, including MM.1S cells. Conversely, transient transfection of MM.1S cells
with a previously reported 28 kDa Mcl-1(128-350) fragment, but not with the Mcl-1(1-127) fragment, induces apoptosis. Therefore, both
downregulation of full-length antiapoptotic Mcl-1, as well as Bortezomib-induced generation of Mcl-1(128-350) cleaved protein, contribute
to MM cell apoptosis. To verify further these findings, we next compared effects triggered by Bortezomib, doxorubicin and melphalan in Mcl-
1(wt/wt) and Mcl-1(Delta/null) murine embryonic fibroblasts (MEFs). Our results show that Bortezomib, but not doxorubicin or melphalan,
triggers Mcl-1 cleavage in Mcl-1(wt/wt), but not Mcl-1(Delta/null) MEFs and induces sub-G(1) phase cells; caspase-3 and -9, and PARP
cleavage as well as morphological signs of apoptosis. Taken together, these results support an important role of Mcl-1 and a Mcl-1 fragment
in Bortezomib-induced cell death in general, and in MM in particular. To prevent relapse of MM in patients treated with Bortezomib, we
therefore recommend the combination of Bortezomib with agents that induce MM cell death independent of Mcl-1.
www.myeloma.org
(800) 452 - CURE (2873)
NNeurotoxicity of bortezomib therapy in multiple myeloma: A single-center experience and review of the
literature.
Badros A, Goloubeva O, Dalal JS, Can I, Thompson J, Rapoport AP, Heyman M, Akpek G, Fenton RG.
Cancer. 2007 Jul 25; [Epub ahead of print.]
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The authors retrospectively review the incidence, severity, and risk factors for peripheral neuropathy (PN) in 78 patients who
received bortezomib, and conclude that the risk of bortezomib-related PN was greater in patients who have PN and diabetes
mellitus at baseline.
BACKGROUND.: Bortezomib is active in heavily pretreated multiple myeloma patients; the dose-limiting toxicity is peripheral neuropathy
(PN).
METHODS.: The authors retrospectively reviewed the incidence, severity, and risk factors for PN in 78 patients who received bortezomib.
The median age was 57 years (range, 33-80 years), 62% of patients were men, and 37% of patients were African Americans. Seventeen
patients (22%) had diabetes mellitus (DM), and 66 patients (85%) had received thalidomide. Before bortezomib treatment, 37% of the
patients reported subjective, grade 1 or 2 PN. Patients received bortezomib alone (n = 10 patients) plus dexamethasone (n = 36 patients)
and thalidomide (n = 20 patients) or chemotherapy (n = 12 patients). PN affected 52% of patients, including grade 3 and 4 PN in 15% and
7%, respectively.
RESULTS.: Twelve patients stopped bortezomib because of side effects that included PN (n = 9 patients), diarrhea (n = 2 patients) and
cytomegalovirus pneumonia (n = 1 patient); 11 patients had dose reductions because of PN. Grade 4 PN affected 6 patients (sensory, n
= 4 patients; motor/sensory, n = 2 patients). The onset of grade 4 PN was sudden rather than cumulative. Factors that were predictive of
PN grade were baseline PN (P = .002), prior thalidomide use (P = .03), and the presence of DM (P = .03). Multiple myeloma responses
included complete, near complete, and partial responses in 5% of patients, 10% of patients, and 27% of patients, respectively. Responses
were independent of PN and of whether bortezomib was combined with chemotherapy or thalidomide. Patients remained on therapy longer
for a median of 5 cycles (range, 2-36 cycles) when they received bortezomib plus thalidomide versus 3 cycles (range, 1-19 cycles) for the
other combinations. PN therapy was mostly supportive. It was noteworthy that 6 of 9 patients with PN who received lenalidomide as salvage
therapy after bortezomib had significant improvement in their symptoms.
CONCLUSIONS.: The risk of bortezomib-related PN was greater in patients who had PN and DM at baseline. The authors concluded that an
unexpected, symptomatic improvement of PN on lenalidomide is worth further investigation.
NAntimyeloma effects of arsenic trioxide are enhanced by melphalan, bortezomib and ascorbic acid.
Campbell RA, Sanchez E, Steinberg JA, Baritaki S, Gordon M, Wang C, Shalitin D, Chen H, Pang S, Bonavida B, Said J,
Berenson JR.
Br J Haematol. 2007 Aug;138(4):467-78. [Epub 2007 Jun 22.]
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The authors examine the antimyeloma effects of arsenic trioxide ATO alone and in combination with bortezomib, melphalan
and ascorbic acid both in vitro and in vivo using a severe combined immunodeficient (SCID)-hu murine myeloma model. Their
results suggest that addition of ATO to other antimyeloma agents may result in improved outcomes for patients with relapsed or
refractory myeloma.
Arsenic trioxide (ATO) induces apoptosis of malignant plasma cells through multiple mechanisms, including inhibition of DNA binding by
nuclear factor kappa-B, a key player in the development of chemoresistance in multiple myeloma (MM). This activity suggests that ATO may
be synergistic when combined with other active antimyeloma drugs. To evaluate this, we examined the antimyeloma effects of ATO alone
and in combination with bortezomib, melphalan and ascorbic acid (AA) both in vitro and in vivo using a severe combined immunodeficient
(SCID)-hu murine myeloma model. Marked synergistic antimyeloma effects were demonstrated when human MM Los Angeles xenograft
IgG lambda light chain (LAGlambda-1) cells were treated in vitro with ATO and any one of these agents. SCID mice bearing human MM
LAGlambda-1 tumours were treated with single-agent ATO, bortezomib, melphalan, or AA, or combinations of ATO with either bortezomib
or melphalan and AA. Animals treated with any of these drugs alone showed tumour growth and increases in paraprotein levels similar to
control mice, whereas animals treated with ATO-containing combinations showed markedly suppressed tumour growth and significantly
reduced serum paraprotein levels. These in vitro and in vivo results suggest that addition of ATO to other antimyeloma agents may result in
improved outcomes for patients with relapsed or refractory MM.
www.myeloma.org
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NBortezomib and extramedullary disease in multiple myeloma: The shine and dark side of the moon.
Ali R, Ozkalemkas F, Ozkan A, Ozkocaman V, Ozcelik T, Ozan U, Kurt M, Tunali A.
Leuk Res. 2007 Aug;31(8):1161-3. [Epub 2006 Sep 1.]
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No abstract available.
NBortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral
cyclophosphamide for relapsed multiple myeloma.
Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kröger N, Salwender H, Metzner B, Sezer O,
Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J; Deutsche Studiengruppe Multiples Myelom.
Br J Haematol. 2007 Aug;138(3):330-7.
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The authors conduct a phase 2 trial to study the combination of bortezomib with intermediate-dose dexamethasone (DEX),
and continuous low-dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma. They find that bortezomib
combined with DEX and CY is a highly effective treatment for relapsed myeloma.
A phase 2 trial was performed to study the combination of bortezomib (VELCADE) with intermediate-dose dexamethasone (DEX), and
continuous low-dose oral cyclophosphamide (CY ) in patients with relapsed multiple myeloma (MM). Fifty-four patients with advanced MM
were enroled to receive eight 3-week treatment cycles with bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11, followed by three 5-week cycles
with bortezomib 1.3 mg/m(2) on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection
and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients
completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and
8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event-free survival was 12 months, with a median overall
survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes
zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at
an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory.
NThe combination of cyclophosphamide, velcade and dexamethasone induces high response rates with
comparable toxicity to velcade alone and velcade plus dexamethasone.
Davies FE, Wu P, Jenner M, Srikanth M, Saso R, Morgan GJ.
Haematologica. 2007 Aug;92(8):1149-50.
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The authors find that the combination of bortezomib, pulsed dexamethasone and weekly cyclophosphamide (DVD) in relapsed/
refractory myeloma patients induces high overall and complete response rates compared to bortezomib/dexamethasone and
bortezomib alone.
The combination of bortezomib (velcade), pulsed dexamethasone and weekly cyclophosphamide (CVD) in relapsed/refractory myeloma
patients induces high overall (75%) and complete (31%) response rates compared to velcade/dexamethasone (overall 47%, CR 5%) and
velcade alone (overall 27%, CR 0%). The toxicity profiles including thrombocytopenia, neutropenia, and neuropathy were comparable
between the groups.
www.myeloma.org
(800) 452 - CURE (2873)
NEffects of proteasome inhibitors on leukemias-review [Article in Chinese].
Lü SQ, Yang JM, Wang JM.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2007 Aug;15(4):896-900.
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The authors review studies on the effects of proteasome inhibitors, such as bortezomib, on multiple myeloma and leukemia.
The proteasome is primarily responsible for intracellular protein degradation. The abnormality of its activity is sign of tumorigenesis. It
was confirmed that proteasome inhibitors have activities against a variety of malignancies. Bortezomib, the first proteasome inhibitor,
obtained permission of clinical trial and on sale. Multiple myeloma patients treated with bortezomib have gained a high overall response
rate and complete remission rate. A lot of studies on effects of proteasome inhibitors on leukemias, including plasma cell leukemia; chronic
lymphocytic leukemia, adult T cell lymphoma/leukemia, chronic myeloid leukemia and acute myeloid leukemia, were reviewed in this article.
NEfficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed or refractory
multiple myeloma: a systematic comparison.
Prince HM, Adena M, Smith DK, Hertel J.
Eur J Haematol. 2007 Aug;79(2):93-9. [Epub 2007 Jun 28.]
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The authors conduct a review of the efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed/
refractory myeloma and find that bortezomib is associated with significantly higher response rate and complete remission rate
using both M-protein and EBMT criteria.
OBJECTIVE: To conduct a systematic review of the efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed/
refractory multiple. METHODS: Publications in English from 1966 to June 2005 (MEDLINE, EMBASE, Cochrane library), publication
reference lists, Janssen-Cilag data-on-file and abstracts from recent multiple myeloma conferences were reviewed. Prospective studies
containing at least a single arm of either treatment group with n> or =30 were included. Studies adding dexamethasone for non-
responders were excluded. Statistical pooling was performed for response rate and overallsurvival. RESULTS: One bortezomib study (n =
333, NEJM 2005, 352; 2487-98) and 15 thalidomide (n = 1007) studies met these criteria and were included. Patient baseline characteristics
including age, gender, IgG : IgA, disease duration and beta-2 microglobulin were well matched except that 48% of bortezomib patients had
received prior thalidomide. Response rate, defined as serum M-protein reduction > or =50%, was 53% for patients receiving bortezomib
vs. 32% for thalidomide (P < 0.001, n = 10 studies). Response rate determined by European Group for Blood and Marrow Transplantation
(EBMT) criteria was 41% for patients receiving bortezomib vs. 22% for thalidomide (P < 0.001, n = 4 studies). CONCLUSION: Bortezomib
was associated with a significantly higher response rate and complete remission rate using both M-protein and EBMT criteria.
NUnexpected cardiotoxicity in haematological bortezomib treated patients.
Enrico O, Gabriele B, Nadia C, Sara G, Daniele V, Giulia C, Antonio S, Mario P.
Br J Haematol. 2007 Aug;138(3):396-7. [Epub 2007 Jun 11.]
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No abstract available.
NRapid response to high-dose steroids of severe bortezomib-related pulmonary complication in multiple
myeloma.
Zappasodi P, Dore R, Castagnola C, Astori C, Varettoni M, Mangiacavalli S, Lazzarino M, Corso A.
J Clin Oncol. 2007 Aug 1;25(22):3380-1.
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No abstract available.
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NAutologous stem cell transplantation in the elderly including pre- and post-treatment options.
Kumar SK, Hayman SR, Kyle RA.
Bone Marrow Transplant. 2007 Aug 6; [Epub ahead of print.]
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The authors discuss the role of high-dose chemotherapy and autologous stem cell transplantation in the treatment of myeloma
patients over 65 years of age.
Multiple myeloma (MM) is a disease of the elderly with a median age at diagnosis of 67 years in a referral population. High-dose
chemotherapy (HDT) and autologous stem cell transplantation has been shown to improve survival in patients with MM in randomized trials
and remains the preferred option for eligible patients. However, the randomized clinical trials demonstrating an advantage for HDT included
only patients younger than 65 years and evidence supporting its role for the elderly patients has been based on retrospective reviews. The
introduction of thalidomide, lenalidomide and bortezomib has changed the paradigm for treatment of myeloma and improved the outcome
for these patients. Several ongoing clinical trials are evaluating the role of these novel agents in this population, specifically comparing these
to HDT-based approaches. Other trials are examining the role of maintenance therapy post-HDT with these novel drugs with or without
steroids. The role of HDT will be further redefined in the coming years with improvements in other therapies.
NHigh-dose chemotherapy and autologous hematopoietic stem cell transplantation in myeloma patients
under the age of 65 years.
Mehta J, Singhal S.
Bone Marrow Transplant. 2007 Aug 6; [Epub ahead of print.]
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The authors discuss the uses of novel agents, such as bortezomib, with respect to high-dose chemotherapy and stem cell
transplantation for myeloma patients under 65 years of age.
One or two cycles of high-dose chemotherapy with autologous hematopoietic stem cell transplantation have been shown to improve
response rates and survival in myeloma. While this observation has largely been made in patients under the age of 65 years, there is evidence
to suggest that the conclusions can be extrapolated to older individuals as well. In contrast to other hematologic malignancies treated with
high-dose therapy, autografted myeloma patients continue to relapse several years after transplantation, and few patients are cured with this
modality. However, up to a third of patients may be alive beyond a decade; some with excellent quality of life giving rise to the concept of
`operational cure'. Relapsing disease can be treated with novel agents or repeat high-dose chemotherapy and transplantation. The pressing
questions to which answers are not obvious at the moment are whether tandem transplantation should be offered to all patients, and
whether novel agents should be used before transplantation or reserved for relapse. Despite their excellent activity, there is no evidence so
far that novel agents such as thalidomide, bortezomib and lenalidomide can replace high-dose chemotherapy and stem cell transplantation.
NExtended follow-up of a phase 3 trial in relapsed multiple myeloma: final time-to-event results of the
APEX trial.
Richardson PG, Sonneveld P, Schuster M, Irwin D, Stadtmauer E, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt
H, Reece D, San Miguel J, Blade J, Boccadoro M, Cavenagh J, Alsina M, Rajkumar SV, Lacy M, Jakubowiak A, Dalton W, Boral A,
Esseltine DL, Schenkein D, Anderson KC.
Blood. 2007 Aug 9; [Epub ahead of print.]
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This updated analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial confirms the activity of
bortezomib and supports extended treatment in relapsed myeloma patients tolerating therapy.
Initial analysis of the Assessment of Proteasome Inhibition for Extending Remissions (APEX) trial of relapsed multiple myeloma patients
showed significantly longer time to progression, higher response rate, and improved survival with single-agent bortezomib vs high-dose
dexamethasone. In this updated analysis (median follow-up: 22 months) survival was assessed in both arms, and efficacy updated for the
bortezomib arm. Median survival was 29.8 months for bortezomib vs 23.7 months for dexamethasone, a 6-month benefit, despite substantial
crossover from dexamethasone to bortezomib. Overall/complete response rates with bortezomib were 43% and 9%, respectively; among
responding patients, 56% improved response with longer therapy beyond initial response, leading to continued improvement in overall
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quality of response. Higher response quality (100% M-protein reduction) was associated with longer response duration; response duration
was not associated with time to response. These data confirm the activity of bortezomib and support extended treatment in relapsed
multiple myeloma patients tolerating therapy. This study is registered at http://clinicaltrials.gov (Study ID NCT00048230).
NMyeloma bone disease and proteasome inhibition therapies.
Terpos E, Sezer O, Croucher P, Dimopoulos MA.
Blood. 2007 Aug 15;110(4):1098-104. [Epub 2007 May 9.]
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This article discusses the value of bortezomib in the treatment of bone disease, as well as the need for additional prospective
studies.
Bone disease is one of the most debilitating manifestations of multiple myeloma. A complex interdependence exists between myeloma bone
disease and tumor growth, creating a vicious circle of extensive bone destruction and myeloma progression. Proteasome inhibitors have
recently been shown to promote bone formation in vitro and in vivo. Preclinical studies have demonstrated that proteasome inhibitors,
including bortezomib, which is the first-in-class such agent, stimulate osteoblast differentiation while inhibiting osteoclast formation and
bone resorption. Clinical studies are confirming these observations. Bortezomib counteracts the abnormal balance of osteoclast regulators
(receptor activator of nuclear factor-kappaB ligand and osteoprotegerin), leading to osteoclast inhibition and decreased bone destruction,
as measured by a reduction in markers of bone resorption. In addition, bortezomib stimulates osteoblast function, possibly through the
reduction of dickkopf-1, leading to increased bone formation, as indicated by the elevation in bone-specific alkaline phosphatase and
osteocalcin. The effect of bortezomib on bone disease is thought to be direct and not only a consequence of the agent's antimyeloma
properties, making it an attractive agent for further investigation, as it may combine potent antimyeloma activity with beneficial effects on
bone. However, the clinical implication of these effects requires prospective studies with specific clinical end points.
NInitial Therapy of Multiple Myeloma in Patients who are Candidates for Stem Cell Transplantation.
Bensinger W.
Curr Treat Options Oncol. 2007 Aug 25; [Epub ahead of print.]
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This article discusses the use of novel agents, including bortezomib, in myeloma induction therapy.
OPINION STATEMENT: Multiple myeloma (MM), a B cell hematologic malignancy involving plasma cells, responds to a variety of drugs
including alkylators, steroids, anthracyclines, immunomodulators and proteosome inhibitors. The disease, however, remains largely incurable
for the majority of patients. For patients who are suitable candidates, high dose chemotherapy with autologous stem cell support (ASCT)
after induction therapy has been shown to improve response rates, progression free survival and overall survival compared to conventional
chemotherapy. The availability of new drugs including thalidomide, lenalidomide and bortezomib has rapidly changed induction strategies.
These drugs have been combined with corticosteroids, alkylators and anthracyclines to treat front-line patients with MM. Preliminary,
phase 1-2 studies have indicated very high response rates and complete response rates formerly only seen with ASCT. Emerging data from
randomized trials suggest that older regimens such as vincristine, adriamycin and dexamethasone (VAD) are not as effective for induction as
newer combinations. Thus new regimens incorporating novel agents should improve overall response rates, increase complete responders
which should translate into improved progression free and overall survival.
NManagement of multiple myeloma: The changing landscape.
Reece DE.
Blood Rev. 2007 Aug 28; [Epub ahead of print.]
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This report highlights some of the key recent findings in multiple myeloma, including the introduction of novel agents such as
thalidomide and lenalidomide, and describes areas for future research.
Many changes have been incorporated into the approach to multiple myeloma over the last few years, due to improvements in our
understanding of the disease biology. New diagnostic and prognostic criteria from the International Myeloma Working Group have clarified
the initial clinical approach to this disease. The prognostic impact of chromosomal abnormalities is now recognized, and the detection of
specific abnormal cytogenetics is beginning to influence therapeutic decisions. The introduction of the novel agents thalidomide, bortezomib
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and lenalidomide has expanded treatment options at different points in the disease course; these agents are being evaluated in conjunction
with conventional chemotherapy and stem cell transplantation. This report highlights some of the key recent findings in multiple myeloma,
and describes areas for future research.
NBortezomib inhibits human osteoclastogenesis.
von Metzler I, Krebbel H, Hecht M, Manz RA, Fleissner C, Mieth M, Kaiser M, Jakob C, Sterz J, Kleeberg L, Heider U, Sezer O.
Leukemia. 2007 Sep;21(9):2025-34. [Epub 2007 Jun 21.]
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The authors find that both bortezomib and PS-1145 inhibit osteoclast differentiation in a dose- and time-dependent manner and
furthermore, the bone resorption activity of osteoclasts. They conclude that proteasomal inhibition should be considered as a
novel therapeutic option of cancer-induced lytic bone disease.
In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) leads to the induction
of NF-kappaB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to
examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to
compare the outcome of proteasome versus selective NF-kappaB inhibition using bortezomib (PS-341) and I-kappaB kinase inhibitor PS-
1145. Primary human osteoclasts were derived from CD14+ precursors in presence of RANKL and macrophage colony-stimulating factor
(M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose- and time-dependent manner and furthermore, the
bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to
the inhibition of p38 mitogen-activated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to
inhibition of p38, AP-1 and NF-kappaB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial
growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic
option of cancer-induced lytic bone disease.
NThe effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma.
Terpos E, Dimopoulos MA, Sezer O.
Leukemia. 2007 Sep;21(9):1875-84. [Epub 2007 Jul 5.]
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http://www.ncbi.nlm.nih.gov/sites/entrez?Db=pubmed&Cmd=ShowDetailView&TermToSearch=17611556&ordinalpos=13&itool=EntrezSy
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This review summarizes all available data for immunomodulatory drugs and bortezomib that combine potent anti-myeloma
activity with beneficial effects on bone that may alter the management of myeloma-related bone disease.
Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and
relapsed/refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma
cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical
studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide
reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no
effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the
inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces
biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation
markers reducing levels of dickkopf-1 protein. Whether these effects are direct and not only a consequence of the agents' antimyeloma
activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with
beneficial effects on bone and may alter the way of management of myeloma-related bone disease.
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NInhibition of Akt induces significant downregulation of survivin and cytotoxicity in human multiple
myeloma cells.
Hideshima T, Catley L, Raje N, Chauhan D, Podar K, Mitsiades C, Tai YT, Vallet S, Kiziltepe T, Ocio E, Ikeda H, Okawa Y,
Hideshima H, Munshi NC, Yasui H, Richardson PG, Anderson KC.
Br J Haematol. 2007 Sep;138(6):783-91.
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The authors' preclinical studies provide the framework for clinical trials of bortezomib with Perifosine to improve patient
outcome in myeloma.
Akt mediates growth and drug resistance in multiple myeloma (MM) cells in the bone marrow (BM) microenvironment. We have shown
that a novel Akt inhibitor Perifosine induces significant cytotoxicity in MM cells in the BM milieu. This study further delineated molecular
mechanisms whereby Perifosine triggered cytotoxicity in MM cells. Neither the intensity of Jun NH(2)-terminal kinase phosphorylation nor
caspase/poly (ADP-ribose) polymerase cleavage correlated with Perifosine-induced cytotoxicity in MM.1S, INA6, OPM1 and OPM2 MM cells.
However, survivin, which regulates caspase-3 activity, was markedly downregulated by Perifosine treatment, without changes in other anti-
apoptotic proteins. Downregulation of survivin by siRNA significantly inhibited OPM1 MM cell growth, confirming that survivin mediates
MM cell survival. Perifosine significantly downregulated both function and protein expression of beta-catenin. Co-culture with BM stromal
cells (BMSCs) upregulated both beta-catenin and survivin expression in MM cells, which was blocked by Perifosine. Importantly, Perifosine
treatment also downregulated survivin expression in human MM cells grown in vivo in a severe combined immunodeficient mouse xenograft
model. Finally, Perifosine inhibited bortezomib-induced upregulation of survivin, associated with enhanced cytotoxicity of combined
bortezomib and Perifosine treatment. These preclinical studies provide the framework for clinical trials of bortezomib with Perifosine to
improve patient outcome in MM.
NMini-Midi-Maxi? How to harness the graft-versus-myeloma effect and target molecular remission after
allogeneic stem cell transplantation.
Kröger N.
Leukemia. 2007 Sep;21(9):1851-8. [Epub 2007 Jun 14.]
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This review focuses on potential strategies of how treatment-related morbidity and mortality might be kept low without an
increased risk of relapse and how remission status after transplantation can be enhanced by using the newly established donor
immunosystems after allografting as a platform for post-transplant treatment strategies with new drugs (including thalidomide
and lenalidomide) or immunotherapy, in order to achieve remission on a molecular level.
Allogeneic stem cell transplantation in multiple myeloma after standard myeloablative conditioning induces a high rate of complete
remissions, but long-term freedom from disease is achieved in 30-40% of the cases only. The therapeutic effect of allogeneic stem cell
transplantation is due to cytotoxicity of high-dose chemotherapy and immune-mediated graft-versus-myeloma effect by donor T cells.
Retrospective studies clearly suggest that both (a) reducing the intensity of high-dose chemotherapy by using reduced-intensity or non-
myeloablative conditioning regimen or (b) reducing the immunotherapy of donor T cells by using T-cell depletion result in lower treatment-
related morbidity and mortality, but also in higher rate of relapse. Therefore, this review will focus on potential strategies of how treatment-
related morbidity and mortality might be kept low without an increased risk of relapse and how remission status after transplantation can be
enhanced by using the newly established donor immunosystems after allografting as a platform for post-transplant treatment strategies with
new drugs (thalidomide, lenalidomide, bortezomib) or immunotherapy (donor lymphocyte infusion, vaccination, tumor-specific T cells) in
order to achieve remission on a molecular level, which seems to be a `conditio sine qua non' to cure myeloma patients.
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NPredictive value of alkaline phosphatase for response and time to progression in bortezomib-treated
multiple myeloma patients.
Zangari M, Esseltine D, Cavallo F, Neuwirth R, Elice F, Burns MJ, Yaccoby S, Richardson P, Sonneveld P, Tricot G.
Am J Hematol. 2007 Sep;82(9):831-3.
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Using data from the APEX study, the authors assess the relationship of changes in alkaline phosphatase levels during bortezomib
therapy with response and time to progression on this therapy.
Myeloma bone disease is characterized by osteolytic destruction associated with suppressed osteoblastic activity. Using data from the APEX
(Richardson et al., N Engl J Med 2005;352:2487-2498) study, we have assessed the relationship of changes in alkaline phosphatase (ALP)
levels during bortezomib therapy with response and time to progression on this therapy. The percentage of ALP increments in responders
(complete and partial response) and nonresponders was analyzed at different thresholds and time points. For all bortezomib-treated patients
enrolled in the trial (N = 333), at least a 25% increase in ALP from the baseline at 6 week was the most powerful predictor of treatment
response (P < 0.0001) and time to progression (206 vs. 169 days) relative to patients with less than a 25% increase in ALP (P = 0.01).
Markers of osteoblastic activation may predict quality and duration of response in multiple myeloma. In addition, our data suggest that bone
anabolism could inhibit myeloma growth.
NRandomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with
bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to
progression.
Orlowski RZ, Nagler A, Sonneveld P, Bladé J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I,
Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL.
J Clin Oncol. 2007 Sep 1;25(25):3892-901. [Epub 2007 Aug 6.]
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This phase III international study compares the efficacy and safety of a combination of peg ylated liposomal doxorubicin (PLD)
plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma and finds that PLD with
bortezomib is the superior treatment, though also associated with a higher incidence of side effects.
PURPOSE: This phase III international study compared the efficacy and safety of a combination of pegylated liposomal doxorubicin (PLD)
plus bortezomib with bortezomib monotherapy in patients with relapsed or refractory multiple myeloma. PATIENTS AND METHODS: Six
hundred forty-six patients were randomly assigned to receive either intravenous bortezomib 1.3 mg/m(2) on days 1, 4, 8, and 11 of an
every 21-days cycle, or the same bortezomib regimen with PLD 30 mg/m(2) on day 4. RESULTS: Median time to progression was increased
from 6.5 months for bortezomib to 9.3 months with the PLD + bortezomib combination (P = .000004; hazard ratio, 1.82 [monotherapy v
combination therapy]; 95% CI, 1.41 to 2.35). The 15-month survival rate for PLD + bortezomib was 76% compared with 65% for bortezomib
alone (P = .03). The complete plus partial response rate was 41% for bortezomib and 44% for PLD + bortezomib, a difference that was not
statistically significant. Median duration of response was increased from 7.0 to 10.2 months (P = .0008) with PLD + bortezomib. Grade
3/4 adverse events were more frequent in the combination group (80% v 64%), with safety profiles consistent with the known toxicities of
the two agents. An increased incidence in the combination group was seen of grade 3/4 neutropenia, thrombocytopenia, asthenia, fatigue,
diarrhea, and hand-foot syndrome. CONCLUSION: PLD with bortezomib is superior to bortezomib monotherapy for the treatment of patients
with relapsed or refractory multiple myeloma. The combination therapy is associated with a higher incidence of grade 3/4 myelosuppression,
constitutional symptoms, and GI and dermatologic toxicities.
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