Published by the C
International I
Myel
T
oma Founda
ItionNVOLG
UME IV, ISSUE I S
Q1/2007
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 or www.myeloma.org
Susie Novis, President, IMF
VELCADE(bortezomib)Publications
1stQuarter,2007
NBortezomib in relapsed multiple myeloma: response rates and duration of response are independent
of a chromosome 13q-deletion.
Sagaster V, Ludwig H, Kaufmann H, Odelga V, Zojer N, Ackermann J, Kuenburg E, Wieser R, Zielinski C, Drach J.
Leukemia. 2006 Nov 9; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17096015&query_
hl=1&itool=pubmed_DocSum
The authors provide evidence for remarkable activity of bortezomib in multiple myeloma with deletion of chromosome 13q14.
Studies of bortezomib in patients with relapsed multiple myeloma (MM) suggested that bortezomib may be active even in the presence of
adverse prognostic factors. We therefore evaluated 62 patients with relapsed/refractory MM who were treated with single-agent bortezomib,
and addressed the question whether or not the negative prognostic impact of unfavorable cytogenetic abnormalities may be overcome
by bortezomib. By interphase fluorescence in situ hybridization (FISH), a deletion of chromosome 13q14 [del(13q14)] was present in 33
patients (53%). Overall response rates to bortezomib were similar in patients with and without del(13q14) (45 versus 55%; P=0.66), and
rates of complete remission (CR) near CR were also not different between the two patient populations (18 versus 14%). Three patients
had a t(4;14)(p16;q32) in addition to del(13q14), and all of them had a >50% paraprotein reduction. Median duration of response was
12.3 months in patients with del(13q14) compared with 9.3 months in patients with normal 13q-status (P=0.25), and survival was also not
different between the two patient populations. Patients not benefiting from single-agent bortezomib were characterized by the combined
presence of a del(13q14) and low serum albumin (median survival 4.6 months). Our results provide evidence for remarkable activity of
bortezomib in MM with del(13q14). Patients who do not respond to bortezomib and consecutively have short time to treatment failure and
overall survival can be identified by low serum albumin in addition to del(13q14) and should be considered for bortezomib combinations.
www.myeloma.org
(800) 452 - CURE (2873)
Funded by an educational grant from Millennium Pharmaceuticals, Inc.
NProteasome inhibitors: antitumor effects and beyond.
Nencioni A, Grunebach F, Patrone F, Ballestrero A, Brossart P.
Leukemia. 2006 Nov 9; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17096016&query_
hl=1&itool=pubmed_DocSum
This review offers an overview of the biological effects that have been involved in proteasome inihibitors' antitumor activity and
suggests prospective future applications for these drugs, which include bortezomib.
Proteasome inhibitors are emerging as effective drugs for the treatment of multiple myeloma and possibly certain subtypes of non-Hodgkin's
lymphoma. Bortezomib (Velcade) is the first proteasome inhibitor proven to be clinically useful and will soon be followed by a second
generation of small molecule inhibitors with improved pharmacological properties. Although it is now understood that certain types of
malignancies have an exquisite dependence on a functional proteasome for their survival, the underlying reason(s) remain unclear as of
now. In this context, addiction to nuclear factor-kappaB (NF-kappaB)-induced survival signals, activation of the unfolded protein response
as well as a reduced proteasomal activity in differentiated plasma cells have all been proposed to justify proteasome inhibitors' activity in
susceptible tissues. In addition to their anticancer properties, bortezomib and related drugs modulate inflammatory and immune responses
by affecting function and survival of immune cells such as lymphocytes and dendritic cells. The present review offers an overview of the
biological effects that have been involved in proteasome inhibitors' antitumor activity and suggests prospective future applications for these
drugs based on their recently characterized anti-inflammatory and immunomodulatory effects.
NSevere pulmonary complications after bortezomib treatment for multiple myeloma: An unrecognized
pulmonary vasculitis?
Pitini V, Arrigo C, Altavilla G, Naro C.
Leuk Res. 2006 Nov 27; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17134751&query_
hl=1&itool=pubmed_DocSum
The authors alert physicians to bortezomib's potential complication of vasculitis, which they point out has been reported as a
complication in every known class of drugs.
Every known class of drugs has been reported to cause vasculitis as also reported for bortezomib. In clinical practice physicians should
be well informed of this peculiar complication especially in view of the fact that systemic corticosteroid therapy almost always resolve the
pulmonary lesions.
NAggresome induction by proteasome inhibitor bortezomib and alpha-tubulin hyperacetylation
by tubulin deacetylase (TDAC) inhibitor LBH589 are synergistic in myeloma cells.
Catley L, Weisberg E, Kiziltepe T, Tai YT, Hideshima T, Neri P, Tassone P, Atadja P, Chauhan D, Munshi NC, Anderson KC.
Blood. 2006 Nov 15;108(10):3441-9. [Epub 2006 May 25.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16728695&query_
hl=11&itool=pubmed_docsum
This study confirms the potential clinical benefit of combining histone deacetylase inhibitors with proteasome inhibitors, and
provides insight into the mechanisms of synergistic anti-myeloma activity of bortezomib in combination with LBH589, a novel
hydroxamic acid derivative.
Histone deacetylase (HDAC) inhibitors have shown cytotoxicity as single agents in preclinical studies for multiple myeloma (MM) cells.
LBH589 is a novel hydroxamic acid derivative that at low nanomolar concentrations induces apoptosis in MM cells resistant to conventional
therapies via caspase activation and poly-(ADP-ribose) polymerase (PARP) cleavage. Significant synergistic cytotoxicity was observed with
LBH589 in combination with bortezomib against MM cells that were sensitive and resistant to dexamethasone (Dex), as well as primary
patient MM cells. LBH589 at low nanomolar concentrations also induced alpha-tubulin hyperacetylation. Aggresome formation was
observed in the presence of bortezomib, and the combination of LBH589 plus bortezomib induced the formation of abnormal bundles of
hyeracetylated alpha-tubulin but with diminished aggresome size and apoptotic nuclei. These data confirm the potential clinical benefit
of combining HDAC inhibitors with proteasome inhibitors, and provide insight into the mechanisms of synergistic anti-MM activity of
bortezomib in combination with LBH589.
www.myeloma.org
(800) 452 - CURE (2873)
NPhase I clinical trial of bortezomib in combination with gemcitabine in patients with advanced
solid tumors.
Ryan DP, Appleman LJ, Lynch T, Supko JG, Fidias P, Clark JW, Fishman M, Zhu AX, Enzinger PC, Kashala O, Cusack J Jr, Eder JP.
Cancer. 2006 Nov 15;107(10):2482-9.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17036355&query_
hl=1&itool=pubmed_DocSum
The authors establish maximum tolerated dosages and dose-limiting toxicities of bortezomib in combination with gemcitabine in
patients with recurring/refractory advanced solid tumors.
BACKGROUND: Bortezomib is the first proteasome inhibitor to show preliminary evidence of activity against solid tumors. Findings
from preclinical studies prompted a Phase I trial to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of
bortezomib in combination with gemcitabine in patients with recurring/refractory advanced solid tumors. The effect of gemcitabine on
proteasome inhibition by bortezomib in whole blood was also investigated.
METHODS: Bortezomib was administered as an intravenous bolus injection on Days 1, 4, 8, and 11, with gemcitabine (30-minute infusion)
on Days 1 and 8 of a 21-day cycle. Groups of > or =3 patients were evaluated at each dose level. Escalating doses of gemcitabine 500 mg/
m2 to 1000 mg/m2 with bortezomib 1.0 mg/m2 to 1.5 mg/m2 were planned.
RESULTS: There were no DLTs in patients receiving bortezomib 1.0 mg/m2 and gemcitabine 500 mg/m2 to 1000 mg/m2 in the first 3 dose
levels. Dose-limiting nausea, vomiting, gastrointestinal obstruction, and thrombocytopenia occurred in 4 of 5 evaluable patients in dose
level 4 (bortezomib 1.3 mg/m2, gemcitabine 800 mg/m2), establishing bortezomib 1.0 mg/m2 and gemcitabine 1000 mg/m2 as the MTD. Most
common Grade > or =3 toxicities were neutropenia (6 patients), thrombocytopenia (5 patients), gastrointestinal disorders (6 patients),
and general disorders (4 patients) such as fatigue. One patient with nonsmall cell lung carcinoma achieved a partial response and 7
achieved stable disease. Inhibition of 20S proteasome activity by bortezomib was unaffected by gemcitabine coadministration.
CONCLUSION: Dosages of bortezomib and gemcitabine suitable for further evaluation of antitumor activity have been established.
NLate onset of bortezomib-associated cutaneous reaction following herpes zoster.
Varettoni M, Vassallo C, Borroni G, Mangiacavalli S, Zappasodi P, Rosso R, Lazzarino M, Corso A.
Ann Hematol. 2006 Nov 25; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17131123&query_
hl=1&itool=pubmed_DocSum
No abstract.
NActivity and safety of bortezomib in multiple myeloma patients with advanced renal failure:
a multicenter retrospective study.
Chanan-Khan AA, Kaufman JL, Mehta J, Richardson PG, Miller KC, Lonial S, Munshi NC, Schlossman R, Tariman J, Singhal S.
Blood. 2006 Nov 30; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17138816&query_
hl=1&itool=pubmed_DocSum
This retrospective case analysis evaluates the feasibility and activity of bortezomib-based therapy in myeloma patients requiring
dialysis support for advanced renal failure. The results suggest that bortezomib or bortezomib-based regimens can be used in
myeloma patients requiring dialysis, with manageable toxicities.
Patients with multiple myeloma (MM) frequently present with concomitant renal dysfunction, and those requiring dialysis have particularly
poor outcomes. Bortezomib is a reversible proteasome inhibitor with significant activity in MM. This retrospective case analysis evaluated
the feasibility and activity of bortezomib-based therapy in MM patients (N = 24) requiring dialysis support for advanced renal failure. All
but 1 patient were undergoing dialysis at the time of therapy. Patients received bortezomib alone or bortezomib-based combination therapy.
Among 20 patients with available response data, overall response rate (complete response [CR] + partial response) was 75%, with 30% CR
+ near CR. One patient was spared dialysis, and 3 other patients became independent of dialysis following bortezomib-based treatment.
These encouraging results suggest that bortezomib or bortezomib-based regimens can be used in MM patients requiring dialysis, with
manageable toxicities. Further studies will more formally evaluate the impact of bortezomib-based regimens in this patient population.
www.myeloma.org
(800) 452 - CURE (2873)
NCurrent status of new drugs for the treatment of patients with multiple myeloma.
Kenealy M, Prince HM.
Intern Med J. 2006 Dec;36(12):781-9.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17096741&query_
hl=1&itool=pubmed_DocSum
This review focuses on the use of thalidomide, lenalidomide and bortezomib in the treatment of myeloma, presenting current
clinical experience with respect to efficacy and toxicity of these agents.
Multiple myeloma, a malignant disorder of plasma cells, is the second most common haematological malignancy. Although treatable,
multiple myeloma remains incurable in virtually all cases, with a median survival of 3-4 years. Fortunately for patients with this disease,
traditional treatment paradigms have been challenged with the emergence of a number of new therapies entering clinical practice over the
last 6 years. In this review, we focus on the use of thalidomide (Thalidomide Pharmion; Boulder, CO, USA), lenalidomide (Revlimid; Celgene
Corporation, Summit, NJ, USA) and bortezomib (Velcade; Janssen Pharmaceutica N.V., Belgium) in the treatment of myeloma. We present
the current clinical experience with respect to efficacy and toxicity of these promising new agents and how the incorporation of these drugs
with traditional therapies may improve the outcome for patients with multiple myeloma.
NBortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand
concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma.
Terpos E, Heath DJ, Rahemtulla A, Zervas K, Chantry A, Anagnostopoulos A, Pouli A, Katodritou E, Verrou E, Vervessou EC,
Dimopoulos MA, Croucher PI.
Br J Haematol. 2006 Dec;135(5):688-92.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17107351&query_
hl=1&itool=pubmed_DocSum
The authors show bortezomib to reduce DKK-1 and RANKL serum levels, leading to the normilization of bone remodeling in
relapsed myeloma.
The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum
concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), sRANKL/osteoprotegerin ratio,
C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and
osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced
serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin,
irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the
normalisation of bone remodelling in relapsed myeloma.
NQuantitative Sensory Findings in Patients With Bortezomib-Induced Pain.
Cata JP, Weng HR, Burton AW, Villareal H, Giralt S, Dougherty PM.
J Pain. 2006 Dec 14; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17175202&query_
hl=29&itool=pubmed_DocSum
The authors conclude that neuropathic pain caused by bortezomib is accompanied by dysfunction in all fiber types in sensory
nerves, and that impaired Abeta and C sensory function also extends into areas of skin that are not perceived as affected by pain.
Bortezomib (PS-341) is a newly developed proteosome inhibitor that shows extremely promising antineoplastic effects against a variety of
neoplasias. Neuropathic pain is emerging as a major complication of bortezomib. Although clinical reports have appeared in the literature
describing the general symptoms of bortezomib chemoneuropathy, specific quantitative sensory data that detail the sensory deficits that
might yield insight to the primary afferent dysfunction contributing to this pain is lacking. In this report, it is shown that patients with
bortezomib-induced neuropathic pain have significantly elevated touch detection threshold and slotted peg board time, impaired sharpness
detection, and elevated thresholds for the detection of skin warming and heat pain. Patients also had increased reports of cold pain.
These data indicate that bortezomib-induced neuropathy is associated with deficits in Abeta, Adelta, and C caliber primary afferent fibers.
PERSPECTIVE: This work demonstrates that pain induced by the chemotherapy drug bortezomib is accompanied by dysfunction in all fiber
types in sensory nerves. Impaired Abeta and C sensory function also extends into areas of skin that are not perceived as affected by pain.
www.myeloma.org
(800) 452 - CURE (2873)
NA Phase I study of bortezomib plus irinotecan in patients with advanced solid tumors.
Ryan DP, O'neil BH, Supko JG, Lima CM, Dees EC, Appleman LJ, Clark J, Fidias P, Orlowski RZ, Kashala O, Eder JP,
Cusack JC Jr.
Cancer. 2006 Dec 1;107(11):2688-97.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17075878&query_
hl=1&itool=pubmed_DocSum
The authors conduct a Phase I trial to study to investigate optimal dosage for combined bortezomib plus irinotecan in patients
with advanced solid tumors.
BACKGROUND.: The authors conducted a Phase I dose-finding trial to study the use of combined bortezomib plus irinotecan in patients
with advanced solid tumors.
METHODS.: Patients who had received >/=1 prior chemotherapy regimen were eligible. Patients received bortezomib (1.0 mg/m2, 1.3 mg/
m2, or 1.5 mg/m2) on Days 1, 4, 8, and 11 and received irinotecan (from 50 mg/m2 to 125 mg/m2) on Days 1 and 8 of each 21-day cycle for a
maximum of 8 cycles. Bortezomib followed irinotecan on coadministration days in Cycle 1 and Cycles 3 through 8 but preceded irinotecan
in Cycle 2 to assess the effect of administration sequence on bortezomib pharmacodynamics.
RESULTS.: Fifty-one enrolled patients with malignancies, including colorectal cancer (n = 23 patients), lung cancer (n = 6 patients),
gastroesophageal cancer (n = 6 patients), and pancreatic cancer (n = 3 patients), received >/=1 dose of study drug. Nausea, vomiting,
and diarrhea were the principal dose-limiting toxicities and led to the maximum tolerated doses of 1.3 mg/m2 bortezomib and 125 mg/m2
irinotecan. The most common grade >/=3 bortezomib-related nonhematologic adverse events were fatigue (n = 5 episodes), diarrhea (n
= 4 episodes), and nausea (n = 4 episodes). grade >/=3 bortezomib-related hematologic adverse events included neutropenia (n = 6
episodes) and thrombocytopenia (n = 4 episodes) and rarely were dose limiting. Of 34 evaluable patients, no objective responses according
to the Response Evaluation Criteria in Solid Tumors were seen; 10 patients achieved stable disease. The degree of proteasome inhibition in
whole blood indicated that the biologic activity of bortezomib was unaffected by irinotecan coadministration.
CONCLUSIONS.: The results of this Phase I study in patients with solid tumors indicated that bortezomib at a dose of 1.3 mg/m2 on Days 1,
4, 8, and 11 plus irinotecan at a dose of 125 mg/m2 on Days 1 and 8 every 21 days were the recommended Phase II doses.
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.
Blood. 2006 Dec 5; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17148584&query_
hl=1&itool=pubmed_DocSum
This phase I/II trial seeks to determine the dosing, safety, and efficacy of the 4-drug combination of bortezomib ( Velcade),
melphalan, prednisone, and thalidomide ( VMPT). The authors conclude that VMPT is an effective salvage therapy with a very high
proportion of responses and unexpectedly low incidences of neurotoxicity.
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 I/II trial, dosing, safety, and efficacy of the 4-drug combination,
bortezomib (VELCADE(R)), melphalan, prednisone and thalidomide (VMPT) was determined. Bortezomib was administered at three dose
levels (1.0 mg/m2, 1.3 mg/m2 or 1.6 mg/m2) on days 1, 4, 15, 22; melphalan at 6 mg/m2 on days 1-5, prednisone at 60 mg/m2 on days 1-5.
Thalidomide was delivered at 50 mg on days 1-35. 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 partial response. 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.
www.myeloma.org
(800) 452 - CURE (2873)
NGene expression profiling and correlation with outcome in clinical trials of the proteasome inhibitor
bortezomib.
Mulligan G, Mitsiades C, Bryant B, Zhan F, Chng WJ, Roels S, Koenig E, Fergus A, Huang Y, Richardson P, Trepicchio WL,
Broyl A, Sonneveld P, Shaughnessy JD Jr, Bergsagel PL, Schenkein D, Esseltine DL, Boral A, Anderson KC.
Blood. 2006 Dec 21; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17185464&query_
hl=13&itool=pubmed_DocSum
The authors aim to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of
bortezomib in multiple myeloma, and to develop predictive classifiers of response and survival with bortezomib.
The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials
of bortezomib in multiple myeloma, and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed
myeloma enrolled in phase II and phase III clinical trials of bortezomib and consented to genomic analyses of pre-treatment tumor samples.
Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were utilized for gene
expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene
expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response
and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival
classifier improved upon the risk stratification provided by the International Staging System. Predictive models and biological correlates of
response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that
predict clinical outcome can be derived from prospective clinical trials of new anti-cancer agents.
NBortezomib disrupts tumour-dendritic cell interactions in myeloma and lymphoma: therapeutic
implications.
Kukreja A, Hutchinson A, Mazumder A, Vesole D, Angitapalli R, Jagannath S, O'connor OA, Dhodapkar MV.
Br J Haematol. 2007 Jan;136(1):106-10.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17222199&query_
hl=13&itool=pubmed_DocSum
The authors conclude that disruption of tumor-dendritic cell interactions may contribute to the clinical effects of bortezomib.
Recent studies have shown that the interactions between tumour and dendritic cells (DCs) promote clonogenic growth of
lymphoproliferative tumours, particularly myeloma. The present study showed that the proteasome inhibitor, bortezomib, disrupts this
interaction. Targeting the drug to DCs was required for optimal suppression of tumour growth, including primary myeloma tumour
progenitors in clonogenic assays. Bortezomib lead to dose-dependent induction of apoptosis in both myeloid and plasmacytoid DCs, and the
sensitivity of DCs to bortezomib was comparable with that of tumour cells. These data suggest that disruption of tumour-DC interactions may
contribute to the clinical effects of bortezomib.
NProteasome inhibitors in the clinical setting: benefits and strategies to overcome multiple myeloma
resistance to proteasome inhibitors.
Cheriyath V, Jacobs BS, Hussein MA.
Drugs R D. 2007;8(1):1-12.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17249845&query_
hl=1&itool=pubmed_DocSum
The authors address the evidence that myeloma cells respond to the stress caused by proteasome inhibitors (such as bortezomib),
and therefore, in order for this important class of agents to remain vital, the need for further clinical study in order delineate
these molecular pathways and the mechanisms to circumvent them.
The majority of intracellular proteins undergo degradation through the ubiquitin-proteasome pathway. The proteasome pathway has a role
in regulating cell proliferation, differentiation, survival and apoptosis. The naturally occurring proteasome inhibitor lactacystin was the
first proteasome inhibitor noted to induce apoptosis in vitro. Compared with first-generation proteasome inhibitors, bortezomib (PS-341),
a dipeptide boronic acid, has exhibited higher potency and specificity, and has been approved for the treatment of relapsed or refractory
myeloma. However, there are some patients who do not respond to therapy or who respond briefly and then relapse. It is becoming
increasingly clear that myeloma cells respond to the stress caused by proteasome inhibitors (bortezomib) via rapidly up-regulating pathways
that suppress apoptosis, thus attenuating its antitumour activity. The delineation of these molecular pathways and mechanisms to circumvent
them are needed to allow this important class of agents to remain vital in the armamentarium of the management of multiple myeloma and
other malignancies.
www.myeloma.org
(800) 452 - CURE (2873)
NProteasome as an emerging therapeutic target in cancer.
Zavrski I, Kleeberg L, Kaiser M, Fleissner C, Heider U, Sterz J, Jakob C, Sezer O.
Curr Pharm Des. 2007;13(5):471-85.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17348844&query_
hl=1&itool=pubmed_DocSum
The authors discuss proteasome inhibition as a potential treatment option for cancer, and the success of bortezomib in the
treatment of multiple myeloma.
The 26S proteasome is a multicatalytic intracellular protease expressed in eukaryotic cells. It is responsible for selective degradation of
intracellular proteins that are responsible for cell proliferation, growth, regulation of apoptosis and transcription of genes involved in
execution of key cellular functions. Thus proteasome inhibition is a potential treatment option for cancer and diseases due to aberrant
inflammation condition. Treatment with proteasome inhibitors results in stabilization and accumulation proteasome substrates, a
phenomenon that may result in confounding signals in cells, cell cycle arrest and activation of apoptotic programs. The inhibition of the
transcriptional factor nuclear factor kappaB (NF-kappaB) activation was found as one of crucial mechanisms in induction of apoptosis,
overcoming resistance mechanisms and inhibition of immune response and inflammation mechanisms. Bortezomib (PS-341) and PS-519
are the first proteasome inhibitors that have entered clinical trials. In multiple myeloma, both the FDA (United States Food and Drug
Administration) and EMEA (European Medicine Evaluation Agency) granted an approval for the use of bortezomib (Velcade) for the
treatment of relapsed multiple myeloma. At present, several phase II and phase III trials in hematological malignancies and solid tumors
are ongoing. PS-519 that focuses on inflammation, reperfusion injury and ischemia is currently under evaluation for the indication of acute
stroke.
NAn internationally recognized uniform cytogenetic classification system is needed for multiple myeloma.
Dispenzieri A.
Leukemia. 2007 Jan;21(1):9-11.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17167528&query_
hl=1&itool=pubmed_DocSum
No abstract available.
NBortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion
in phase 2 and 3 trials.
Jagannath S, Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Cowan JM,
Anderson KC.
Leukemia. 2007 Jan;21(1):151-7. [Epub 2006 Nov 9.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17096017&query_
hl=13&itool=pubmed_DocSum
In multiple myeloma, deletion of chromosome 13 (del(13)) is associated with poor prognosis regardless of treatment. This
study analyzes the impact of del(13) status on response and survival following treatment with either bortezomib or high-dose
dexamethasone. Their analysis suggests that bortezomib may overcome some of the poor impact of del(13) as an independent
prognostic factor.
In multiple myeloma, deletion of chromosome 13 (del(13)) is associated with poor prognosis regardless of treatment. This study analyzed
the impact of del(13) status on response and survival following treatment with either bortezomib or high-dose dexamethasone in patients
in the SUMMIT and APEX trials. Additionally, matched-pairs subset analyses were conducted of patients with and without del(13), balanced
for age and International Staging System parameters. In both SUMMIT and APEX, prognosis appeared to be poorer in bortezomib-treated
patients with del(13) compared with patients with no del(13) by metaphase cytogenetics. In the SUMMIT and APEX matched-pairs analysis,
response and survival appeared comparable in bortezomib-treated patients with or without del(13) by metaphase cytogenetics. However,
patients with del(13) receiving dexamethasone in APEX appeared to have markedly decreased survival compared with those without del(13)
by metaphase cytogenetics. These matched-pairs analyses suggest that bortezomib may overcome some of the poor impact of del(13) as an
independent prognostic factor. However, sample sizes were very small; these findings require confirmation from further studies.
www.myeloma.org
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NBortezomib in combination with pegylated liposomal doxorubicin for the treatment
of multiple myeloma.
Manochakian R, Miller KC, Chanan-Khan AA.
Clin Lymphoma Myeloma. 2007 Jan;7(4):266-71.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17324333&query_
hl=1&itool=pubmed_DocSum
The authors review the rationale for combining bortezomib with peg ylated liposomal doxorubicin for the treatment of multiple
myeloma (MM) and conclude that to date the results have been sufficiently encouraging to initiate a phase III trial.
Many novel agents and new combinations (including bortezomib, thalidomide, and lenalidomide) have been developed in recent years for
the treatment of multiple myeloma (MM), creating major shifts in therapeutic management. Achieving complete response (CR)/near CR
(nCR) generally serves as a reliable clinical surrogate for overall treatment outcome, ie, prolonged survival. Indeed, some newer induction
regimens are yielding similar median time to disease progression effects compared with transplantation. Thus, it can be a dilemma whether
a patient with CR/nCR needs to be subjected to the potential morbidity associated with transplantation after induction therapy. Combining
new agents with chemotherapy-based regimens appears to offer higher overall response and CR/nCR rates than similar combinations that do
not include chemotherapy. We review the preclinical and clinical rationale for combining bortezomib with pegylated liposomal doxorubicin
for the treatment of MM. The synergistic interaction in sensitizing each other toward myeloma cells in vitro and their complementary in
vivo activities have justified clinical studies. We summarize data for completed and ongoing phase I/II trials of this combination. To date,
results have been sufficiently encouraging to initiate an international, multicenter, randomized, phase III trial comparing bortezomib with
or without pegylated liposomal doxorubicin in patients with relapsed/refractory MM. The results of this trial will confirm whether the
rationale for combining bortezomib with pegylated liposomal doxorubicin is validated by improved clinical outcome, ie, improved time to
progression, for patients with MM.
NBortezomib in relapsed multiple myeloma: response rates and duration of response are independent of a
chromosome 13q-deletion.
Sagaster V, Ludwig H, Kaufmann H, Odelga V, Zojer N, Ackermann J, Kuenburg E, Wieser R, Zielinski C, Drach J.
Leukemia. 2007 Jan;21(1):164-8. [Epub 2006 Nov 9.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17096015&query_
hl=13&itool=pubmed_DocSum
The authors evaluate 62 patients with relapsed/refractory multiple myeloma (MM) treated with single-agent bortezomib, and
address the question whether or not the negative prognostic impact of unfavorable cytogenetic abnormalities may be overcome by
bortezomib. They conclude that their results provide evidence for remarkable activity of bortezomib in MM with del(13q14).
Studies of bortezomib in patients with relapsed multiple myeloma (MM) suggested that bortezomib may be active even in the presence of
adverse prognostic factors. We therefore evaluated 62 patients with relapsed/refractory MM who were treated with single-agent bortezomib,
and addressed the question whether or not the negative prognostic impact of unfavorable cytogenetic abnormalities may be overcome
by bortezomib. By interphase fluorescence in situ hybridization (FISH), a deletion of chromosome 13q14 [del(13q14)] was present in 33
patients (53%). Overall response rates to bortezomib were similar in patients with and without del(13q14) (45 versus 55%; P=0.66), and
rates of complete remission (CR) near CR were also not different between the two patient populations (18 versus 14%). Three patients
had a t(4;14)(p16;q32) in addition to del(13q14), and all of them had a >50% paraprotein reduction. Median duration of response was
12.3 months in patients with del(13q14) compared with 9.3 months in patients with normal 13q-status (P=0.25), and survival was also not
different between the two patient populations. Patients not benefiting from single-agent bortezomib were characterized by the combined
presence of a del(13q14) and low serum albumin (median survival 4.6 months). Our results provide evidence for remarkable activity of
bortezomib in MM with del(13q14). Patients who do not respond to bortezomib and consecutively have short time to treatment failure and
overall survival can be identified by low serum albumin in addition to del(13q14) and should be considered for bortezomib combinations.
www.myeloma.org
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NProteasome inhibitors: antitumor effects and beyond.
Nencioni A, Grunebach F, Patrone F, Ballestrero A, Brossart P.
Leukemia. 2007 Jan;21(1):30-6. [Epub 2006 Nov 9.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17096016&query_
hl=13&itool=pubmed_DocSum
The authors offer an overview of the biological effects that have been involved in proteasome inhibitors' (including bortezomib)
antitumor activity and suggest prospective future applications for these drugs based on their recently characterized anti-
inflammatory and immunomodulatory effects.
Proteasome inhibitors are emerging as effective drugs for the treatment of multiple myeloma and possibly certain subtypes of non-Hodgkin's
lymphoma. Bortezomib (Velcade) is the first proteasome inhibitor proven to be clinically useful and will soon be followed by a second
generation of small molecule inhibitors with improved pharmacological properties. Although it is now understood that certain types of
malignancies have an exquisite dependence on a functional proteasome for their survival, the underlying reason(s) remain unclear as of
now. In this context, addiction to nuclear factor-kappaB (NF-kappaB)-induced survival signals, activation of the unfolded protein response
as well as a reduced proteasomal activity in differentiated plasma cells have all been proposed to justify proteasome inhibitors' activity in
susceptible tissues. In addition to their anticancer properties, bortezomib and related drugs modulate inflammatory and immune responses
by affecting function and survival of immune cells such as lymphocytes and dendritic cells. The present review offers an overview of the
biological effects that have been involved in proteasome inhibitors' antitumor activity and suggests prospective future applications for these
drugs based on their recently characterized anti-inflammatory and immunomodulatory effects.
NBIRB 796 enhances cytotoxicity triggered by bortezomib, heat shock protein (Hsp) 90 inhibitor, and
dexamethasone via inhibition of p38 mitogen-activated protein kinase/Hsp27 pathway in multiple
myeloma cell lines and inhibits paracrine tumour growth.
Yasui H, Hideshima T, Ikeda H, Jin J, Ocio EM, Kiziltepe T, Okawa Y, Vallet S, Podar K, Ishitsuka K, Richardson PG, Pargellis C,
Moss N, Raje N, Anderson KC.
Br J Haematol. 2007 Feb;136(3):414-23. [Epub 2006 Dec 14.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17173546&query_
hl=13&itool=pubmed_DocSum
This study examines anti-myeloma activity of a novel p38 MAPK inhibitor, BIRB 796, alone and in combination with conventional
and novel therapeutic agents, and concludes that BIRB 796 overcomes drug-resistance in the bone marrow microenvironment,
providing the framework for clinical trials of a p38 MAPK inhibitor, alone and in combination with bortezomib, Hsp90 inhibitor,
or Dex, to improve patient outcome in multiple myeloma.
Summary We have previously shown that heat shock protein (Hsp) 27 or its upstream activator p38 mitogen-activated protein kinase (MAPK)
confers resistance to bortezomib and dexamethasone (Dex) in multiple myeloma (MM) cells. This study examined anti-MM activity of a
novel p38 MAPK inhibitor, BIRB 796, alone and in combination with conventional and novel therapeutic agents. BIRB 796 blocked baseline
and bortezomib-triggered upregulation of p38 MAPK and Hsp27 phosphorylation, thereby enhancing cytotoxicity and caspase activation.
The Hsp90 inhibitor 17-allylamino-17-demethoxy-geldanamycin (17-AAG) upregulated protein expression and phosphorylation of Hsp27;
conversely, BIRB 796 inhibited this phosphorylation and enhanced 17-AAG-induced cytotoxicity. Importantly, BIRB 796 inhibited Hsp27
phosphorylation induced by 17-AAG plus bortezomib, thereby enhancing cytotoxicity. In bone marrow stromal cells (BMSC), BIRB 796
inhibited phosphorylation of p38 MAPK and secretion of interleukin-6 (IL-6) and vascular endothelial growth factor triggered by either
tumour necrosis factor-alpha or tumour growth factor-beta1. BIRB 796 also inhibited IL-6 secretion induced in BMSCs by adherence to
MM cells, thereby inhibiting tumour cell proliferation. These studies therefore suggest that BIRB 796 overcomes drug-resistance in the BM
microenvironment, providing the framework for clinical trials of a p38 MAPK inhibitor, alone and in combination with bortezomib, Hsp90
inhibitor, or Dex, to improve patient outcome in MM.
www.myeloma.org
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NThe Emerging Role of Novel Therapies for the Treatment of Relapsed Myeloma.
Richardson PG, Hideshima T, Mitsiades C, Anderson KC.
J Natl Compr Canc Netw. 2007 Feb;5(2):149-162.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17335684&query_
hl=1&itool=pubmed_DocSum
This review focuses on results from key phase II and II trials of bortezomib, thalidomide, and lenalidomide alone or in
combination, and their emerging role in improving outcomes.
Despite advances in the first-line treatment of multiple myeloma, almost all patients eventually relapse, become chemoresistant, and
die of the disease. Improved understanding of potential myeloma targets and molecular mechanisms of drug resistance, along with the
development and clinical investigation of targeted antitumor agents, have led to new strategies for the treatment of relapsed myeloma. The
proteasome inhibitor bortezomib, the immunomodulatory agent thalidomide, and the thalidomide derivative lenalidomide, are all recently
approved treatment options for myeloma. Single-agent bortezomib has been shown to provide significantly greater efficacy than high-dose
dexamethasone, and bortezomib has also been investigated in combination with other agents commonly used to treat myeloma, including
thalidomide and lenalidomide, with high overall and complete response rates. The safety profile of bortezomib has been well characterized,
and side effects have been shown to be generally predictable and manageable, including in high-risk and elderly patients and those with
renal impairment. Thalidomide has been extensively studied alone and in combination in patients with relapsed myeloma, demonstrating
substantial efficacy, and is therefore widely used in this setting. The toxicity profile is dose- and duration-linked, with lower doses appearing
to be better tolerated. Lenalidomide plus dexamethasone has been shown to have significantly greater activity than dexamethasone alone
in the relapsed setting, with impressive duration of disease control. Other combinations are also under investigation, with promising
early results. Some aspects of the toxicity profile appear significantly reduced relative to thalidomide, although myelosuppression is
increased. Other novel therapies at earlier stages of development are being studied and may provide further options in the treatment of
relapsed myeloma. This review focuses on results from key phase II and III trials of bortezomib, thalidomide, and lenalidomide alone or in
combination, and their emerging role in improving outcomes.
NManaging Systemic Light-Chain Amyloidosis.
Comenzo RL.
J Natl Compr Canc Netw. 2007 Feb;5(2):179-187.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17335687&query_
hl=1&itool=pubmed_DocSum
The author discusses the new agents, such as bortezomib, that show promising activity in the treatment of amyloidosis, and the
novel antibody-based approaches for imaging amyloid and accelerating removal of deposits that are being actively investigated.
Amyloidosis is a rare disease in which a specific protein is deposited as aggregated interstitial fibrils that can compromise organ function and
lead to death. Immunoglobulin (Ig) light-chain amyloidosis (AL), caused by the monoclonal gammopathy of a plasma cell dyscrasia, is the
most common type. A hereditary type is also caused by mutant transthyretin and other proteins. Rarely, a patient with amyloid has both a
monoclonal gammopathy and a hereditary protein. In AL, circulating monoclonal Ig light chains can be measured with the free light-chain
(FLC) assay and provide a target for therapy to eliminate the underlying plasma cell dyscrasia while supporting the patient's organ function.
Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor FLC is eliminated. For patients with
limited organ involvement, intravenous melphalan in doses from 100 to 200 mg/m2 with autologous stem cell support (SCT) is an effective
approach and, when followed at 3 months post-SCT with adjuvant thalidomide and dexamethasone for persistent plasma cell disease, has
a 1-year hematologic response rate of 77%. Monthly oral melphalan and dexamethasone for 1 year can also be effective therapy for patients
too sick for SCT (67% response rate). Hematologic complete responses are usually durable and result in long-term survival and a variable
degree of organ recovery. For patients with advanced cardiac involvement, the prognosis remains guarded even with treatment. Drugs
effective in multiple myeloma are usually active in AL, depending on side effects. New agents such as bortezomib and lenalidomide have
shown promising activity, and novel antibody-based approaches for imaging amyloid and accelerating removal of deposits are being actively
investigated.
www.myeloma.org
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NA phase I and pharmacologic study of sequences of the proteasome inhibitor, bortezomib (PS-341,
Velcade), in combination with paclitaxel and carboplatin in patients with advanced malignancies.
Ma C, Mandrekar SJ, Alberts SR, Croghan GA, Jatoi A, Reid JM, Hanson LJ, Bruzek L, Tan AD, Pitot HC, Erlichman C,
Wright JJ, Adjei AA.
Cancer Chemother Pharmacol. 2007 Feb;59(2):207-15. [Epub 2006 Jun 9.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16763792&query_
hl=1&itool=pubmed_DocSum
The authors study two different treatment schedules of bortezomib in combination with paclitaxel and carboplatin to evaluate
the effects of scheduling on toxicities, pharmacodynamics and clinical activity, and conclude that administration of sequential
bortezomib followed by chemotherapy was well tolerated and associated with an encouraging number of objective responses
within their small group of patients.
PURPOSE: Bortezomib, a selective inhibitor of the 20S proteasome with activity in a variety of cancers, exhibits sequence-dependent
synergistic cytotoxicity with taxanes and platinum agents. Two different treatment schedules of bortezomib in combination with paclitaxel
and carboplatin were tested in this phase I study to evaluate the effects of scheduling on toxicities, pharmacodynamics and clinical activity.
METHODS: Patients with advanced malignancies were alternately assigned to receive (schedule A) paclitaxel and carboplatin (IV d1) followed
by bortezomib (IV d2, d5, d8) or (schedule B) bortezomib (IV d1, d4, d8) followed by paclitaxel and carboplatin (IV d2) on a 21-day cycle.
RESULTS: Fifty-three patients (A 25, B 28) were treated with a median of 3 cycles (range 1-8) for schedule A and 3.5 cycles (range 1-10)
for schedule B. Grade 3 or higher treatment related hematologic adverse events in all cycles of treatment included neutropenia (A 52%, B
50%), anemia (A 12%, B 7.1%) and thrombocytopenia (A 16%, B 17.9%). Non-hematologic treatment related adverse events were fairly mild
(primarily grades 1 and 2). The maximum tolerated dose and the recommended doses for future phase II trials are bortezomib 1.2 mg/m2,
paclitaxel 135 mg/m2 and carboplatin AUC = 6 for schedule A and bortezomib 1.2 mg/m2, paclitaxel 175 mg/m2 and carboplatin AUC =
6 for schedule B. Six (21.4%) partial responses (PR) were seen with schedule B. In contrast, only 1 (4%) PR was achieved with schedule A.
Similar proteasome inhibition was achieved at MTD for both schedules.
CONCLUSION: Administration of sequential bortezomib followed by chemotherapy (schedule B) was well tolerated and associated with an
encouraging number of objective responses in this small group of patients. Further studies with this administration schedule are warranted.
NRole of bone marrow transplantation in the disease pathway of myeloma.
Harousseau JL, Moreau P.
J Natl Compr Canc Netw. 2007 Feb;5(2):163-9.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17335685&query_
hl=1&itool=pubmed_DocSum
The authors address the introduction of novel agents, such as bortezomib, as potentially shifting the standard of myeloma patient
care away from autologous stem cell transplantation.
In multiple myeloma, autologous stem cell transplantation (ASCT) has been considered a standard of care in younger patients. The
introduction of novel agents (i.e., thalidomide, lenalidomide, and bortezomib) may change this scenario. These agents can be administered
before or after ASCT with the goal of increasing the complete remission (CR) rate and prolonging remission. For instance, thalidomide
given as maintenance therapy after double ASCT increases CR rate, event-free survival (EFS), and overall survival. Moreover, combinations
of conventional chemotherapy with novel agents such as thalidomide or bortezomib yield CR rates and EFS comparable to those achieved
with standard single ASCT. Prospective randomized studies are needed to evaluate the impact of novel agents versus or in combination
with ASCT. Myeloablative conditioning regimens before allogeneic stem cell transplantation are being replaced with concurrent autologous-
transplantation and reduced-intensity conditioning allogeneic stem cell transplantation. Transplant-related mortality associated with this
procedure is lower, but more follow-up is needed before definite conclusions can be drawn.
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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 Feb 13; [Epub ahead of print.]
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17299090&query_
hl=1&itool=pubmed_DocSum
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 anti-tumor immunity, including against primary tumor cells, without the
need for any additional adjuvants.
Most anti-cancer chemotherapies are immunosuppressive and induce non-immunogenic 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 anti-
tumor 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 anti-tumor immunity.
NCommunity experience with bortezomib in patients with multiple myeloma.
Onitilo AA, Engel J, Olatosi B, Fagbemi S.
Am J Hematol. 2007 Feb 14; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17301970&query_
hl=1&itool=pubmed_DocSum
The authors present their community practice experience with multiple myeloma patients and find bortezomib response rates
comparable to those from clinical trials.
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.
NBortezomib-associated rash: a new recognizable and avoidable side-effect.
Villarrubia B, Betlloch I, Mataix J, Lucas A, Botella C.
Br J Dermatol. 2007 Feb 6; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17286633&query_
hl=1&itool=pubmed_DocSum
No abstract available.
NPulmonary fibrosis in a myeloma patient on bortezomib treatment. A new severe adverse effect
of a new drug.
Duek A, Feldberg E, Haran M, Berrebi A.
Am J Hematol. 2007 Feb 14; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17301973&query_
hl=1&itool=pubmed_DocSum
No abstract available.
www.myeloma.org
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NAssessing response rates in clinical trials of treatment for relapsed or refractory multiple myeloma:
a study of bortezomib and thalidomide.
Prince HM, Schenkel B, Mileshkin L.
Leukemia. 2007 Feb 15; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17301817&query_
hl=1&itool=pubmed_DocSum
No abstract available.
NExtensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition.
Meister S, Schubert U, Neubert K, Herrmann K, Burger R, Gramatzki M, Hahn S, Schreiber S, Wilhelm S, Herrmann M, Jack
HM, Voll RE.
Cancer Res. 2007 Feb 15;67(4):1783-92.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17308121&query_
hl=1&itool=pubmed_DocSum
The authors find that proteasome inhibitors induce apoptosis preferentially in cells with high synthesis rate of immunoglobulin
associated with accumulation of unfolded proteins/defective ribosomal products inducing endoplasmic reticulum stress.
Multiple myeloma is an incurable plasma cell neoplasia characterized by the production of large amounts of monoclonal immunoglobulins.
The proteasome inhibitor bortezomib (PS-341, Velcade) induces apoptosis in various malignant cells and has been approved for treatment of
refractory multiple myeloma. Inhibition of the antiapoptotic transcription factor nuclear factor-kappaB (NF-kappaB) apparently contributes
to the antitumor effects of bortezomib; however, this mechanism cannot fully explain the exceptional sensitivity of myeloma cells. Extensive
protein synthesis as in myeloma cells is inherently accompanied by unfolded proteins, including defective ribosomal products (DRiPs),
which need to be degraded by the ubiquitin-proteasome system. Therefore, we hypothesized that the proapoptotic effect of bortezomib in
multiple myeloma is mainly due to the accumulation of unfolded proteins in cells with high protein biosynthesis. Using the IgG-secreting
human myeloma cell line JK-6L and murine muH-chain-transfected Ag8.H myeloma cells, apoptosis induction upon proteasome inhibition
was clearly correlated with the amount of immunoglobulin production. Preferentially in immunoglobulin-high myeloma cells, bortezomib
triggered activation of caspases and induction of proapoptotic CHOP, a component of the terminal unfolded protein response induced
by endoplasmic reticulum (ER) stress. In immunoglobulin-high cells, bortezomib increased the levels of proapoptotic Bax while reducing
antiapoptotic Bcl-2. Finally, IgG-DRiPs were detected in proteasome inhibitor-treated cells. Hence, proteasome inhibitors induce apoptosis
preferentially in cells with high synthesis rate of immunoglobulin associated with accumulation of unfolded proteins/DRiPs inducing ER
stress. These findings further elucidate the antitumor activities of proteasome inhibitors and have important implications for optimizing
clinical applications.
NAssessing response rates in clinical trials of treatment for relapsed or refractory multiple myeloma:
a study of bortezomib and thalidomide by H Prince, Brad Schenkel and Linda Mileshkin.
Durie BG, Rajkumar SV.
Leukemia. 2007 Feb 15; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17301816&query_
hl=1&itool=pubmed_DocSum
No abstract available.
www.myeloma.org
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NPKC412 demonstrates JNK-dependent activity against human multiple myeloma cells.
Sharkey J, Khong T, Spencer A.
Blood. 2007 Feb 15;109(4):1712-9. [Epub 2006 Oct 10.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17032922&query_
hl=1&itool=pubmed_DocSum
The authors demonstrate that PKC412 induces JNK-dependent apoptosis of HMCLs and primary multiple myeloma cells and
that this effect is enhanced by NFkappaB inhibition. Sequential inhibition of NFkappaB activation with bortezomib or SN50
synergistically enhanced cell killing.
The effect and mode of action of the protein kinase C (PKC) inhibitor PKC412 on human multiple myeloma (MM) cell lines (HMCLs) and
primary MM cells was explored. We found that PKC412 induced apoptosis of HMCLs and primary MM cells with variable efficacy; however,
some activity was seen against all HMCLs and primary MM cells with at least 0.5 microM PKC412. PARP cleavage and decreased PKC
activity was observed in all HMCLs tested. Furthermore, PKC412 inhibited C-FOS transcription and nuclear protein expression, induced
reactive oxygen species (ROS) production, and induced both sustained C-JUN expression and phosphorylation. The latter was inhibited
by cotreatment with the JNK inhibitor SP600125, which similarly abrogated PKC412-induced apoptosis, suggesting that PKC412-induced
apoptosis is a JNK-dependent event. PKC412 treatment secondarily induced prosurvival stress responses as evidenced by activation of
NFkappaB and increased expression of the heat shock proteins HSP70 and HSP90. Consistent with the former, sequential inhibition of
NFkappaB activation with bortezomib or SN50 synergistically enhanced cell killing. Our results demonstrate that PKC412 induces JNK-
dependent apoptosis of HMCLs and primary MM cells and that this effect is enhanced by NFkappaB inhibition. The further evaluation of
PKC412 in the treatment of MM is justified.
NEmerging drugs in multiple myeloma.
Ghobrial IM, Leleu X, Hatjiharissi E, Hideshima T, Mitsiades C, Schlossman R, Anderson KC, Richardson P.
Expert Opin Emerg Drugs. 2007 Mar;12(1):155-63.
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17355220&query_
hl=1&itool=pubmed_DocSum
This review summarizes the role of novel therapeutic agents in multiple myeloma (including bortezomib) and the promising
effect of multiple new agents in development.
The treatment of multiple myeloma has seen significant changes from the time of the initial use of cytotoxic agents such as melphalan, to the
introduction of high-dose chemotherapy and stem cell transplantation, and most recently the era of novel targeted agents. These new drugs
have rapidly become the mainstay of therapy of this disease and transformed the treatment paradigm, leading to improvements in survival
and quality of life. Existing therapeutic options include agents such as thalidomide, bortezomib and lenalidomide, either used alone or in
combination with standard agents, including glucocorticoids, and in conjunction with high-dose chemotherapy supported with stem cell
transplantation. Several other targeted agents have demonstrated exciting preclinical activity, and are presently being tested in early Phase I
and II clinical trials. This review summarizes the role of novel therapeutic agents in multiple myeloma, and the promising effect of multiple
new agents in development.
www.myeloma.org
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NExtended follow-up of outcome measures in multiple myeloma patients treated on a phase I study
with bortezomib and pegylated liposomal doxorubicin.
Biehn SE, Moore DT, Voorhees PM, Garcia RA, Lehman MJ, Dees EC, Orlowski RZ.
Ann Hematol. 2007 Mar;86(3):211-6. [Epub 2006 Dec 5.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17146676&query_
hl=1&itool=pubmed_DocSum
This phase I study of a combination of bortezomib and peg ylated liposomal doxorubicin showed significant anti-tumor activity
against advanced multiple myeloma, findings which compare favorably with results reported for bortezomib alone.
A phase I study of a combination of the proteasome inhibitor bortezomib and pegylated liposomal doxorubicin showed significant anti-
tumor activity against advanced multiple myeloma, with 36% of patients achieving a complete or near-complete response and 73% having a
partial response or better. Given this encouraging efficacy, it was therefore of interest to update the prior experience and define parameters
such as time to progression, time to retreatment, and overall survival. Additional follow-up was collected on all evaluable multiple myeloma
patients and revealed a median time to progression of 9.3 months versus 3.8 months on whatever had been the patient's prior therapy. Time
to retreatment was prolonged from 5.9 months after the patient's prior therapy to 24.2 months after bortezomib with pegylated liposomal
doxorubicin. The median overall survival after therapy with bortezomib and pegylated liposomal doxorubicin was 38.3 months. These
findings compare favorably with results reported for bortezomib alone and support the possibility that the bortezomib/pegylated liposomal
doxorubicin regimen may provide superior efficacy against relapsed/refractory multiple myeloma.
NMaintenance therapy in multiple myeloma.
Mihelic R, Kaufman JL, Lonial S.
Leukemia. 2007 Mar 8; [Epub ahead of print.]
:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17344913&query_
hl=1&itool=pubmed_DocSum
This review summarizes the currently available data in the maintenance setting for multiple myeloma and 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.
www.myeloma.org
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www.myeloma.org
www.myeloma.org
(800) 452 - CURE (2873)