Table of Contents
1
UI - 11843823
AU - Sonneveld P; Suciu S; Weijermans P; Beksac M; Neuwirtova R; Solbu G;
TI -
Lokhorst H; van der Lelie J; Dohner H; Gerhartz H; Segeren CM; Willemze
R; Lowenberg B; European Organization for Research and Treatment of
Cancer (EORTC); Leukaemia Cooperative Group (LCG); Dutch
Haemato-Oncology Cooperative Study Group (HOVON)
Cyclosporin A combined with vincristine, doxorubicin and dexamethasone
(VAD) compared with VAD alone in patients with advanced refractory
multiple myeloma: an EORTC-HOVON randomized phase III study (06914).
SO - Br J Haematol 2001 Dec;115(4):895-902
AD - Department of Haematology, University Hospital Rotterdam Dijkzigt, Room
L407, 3000 CA Rotterdam, TheNetherlands. sonneveld@hema.fgg.eur.nl
Patients with multiple myeloma (MM) refractory to alkylating agents
frequently express P-glycoprotein (Pgp), which is associated with the
multidrug resistance (MDR) phenotype. We have conducted a randomized
phase II/III study of the MDR reversal agent cyclosporin A combined with
VAD (vincristine, doxorubicin, dexamethasone) compared with standard VAD
in patients with MM stage IIA/IIIA who were refractory to or progressive
after treatment with alkylating agents. Out of 81 patients who were
randomized, 75 were eligible and evaluable: 34 in the VAD + cyclosporin
A arm versus 41 in the VAD arm. Toxicities of grade 2-3 were observed
more often with VAD + cyclosporin A than with VAD only: nausea (30%
versus 8%, P = 0.015), mucositis (18% versus 5%, P = 0.13), infection
(45% versus 35%, P = 0.50). The treatment results were similar in the
two arms: 53% versus 49% responded [95% CI (-18.5%, 26.9%)]. The median
progression-free survival (PFS) was 8.6 months (VAD + cyclosporin A)
versus 5.8 months (VAD): [log rank P = 0.16, hazard ratio = 0.71, 95% CI
(0.44, 1.15)], and median overall survival was 13 months versus 14.6
months [log rank P = 0.89, hazard ratio = 0.96, 95% CI (0.62, 1.72)].
The cause of death was progressive disease (85%), toxicity (10%) or
other (5%). Bone marrow analysis performed in 23 patients showed that
the response rate was 67% in Pgp-positive versus 55% in Pgp-negative
patients. Cyclosporin A combined with VAD is relatively well tolerated.
There is no effect of cyclosporin A on the overall response rate, PFS
and overall survival with VAD.
2
UI - 11806971
AU - Moreau P; Facon T; Attal M; Hulin C; Michallet M; Maloisel F; Sotto JJ;
TI -
Guilhot F; Marit G; Doyen C; Jaubert J; Fuzibet JG; Francois S;
Benboubker L; Monconduit M; Voillat L; Macro M; Berthou C; Dorvaux V;
Pignon B; Rio B; Matthes T; Casassus P; Caillot D; Najman N; Grosbois B;
Bataille R; Harousseau JL; Intergroupe Francophone du Myelome
Comparison of 200 mg/m(2) melphalan and 8 Gy total body irradiation plus
140 mg/m(2) melphalan as conditioning regimens for peripheral blood stem
cell transplantation in patients with newly diagnosed multiple myeloma:
final analysis of the Intergroupe Francophone du Myelome 9502 randomized
trial.
SO - Blood 2002 Feb 1;99(3):731-5
AD - Service d'Hematologie, University Hospital Hotel-Dieu, Place Alexis
Recordeau, 44093 Nantes cedex 01, France.
High-dose therapy has become a common treatment for myeloma. The
objective of this study (Intergroupe Francophone du Myelome [IFM] 9502
trial) was to compare in a prospective and randomized trial the 2 most
widely used conditioning regimens before autologous stem cell
transplantation in newly diagnosed symptomatic patients younger than 65
years old: 8 Gy total body irradiation plus 140 mg/m(2) melphalan (arm
A) versus 200 mg/m(2) melphalan (arm B). A total of 282 evaluable
patients were compared--140 in arm A and 142 in arm B. Baseline
characteristics and disease response to 4 cycles of the VAD regimen
performed before randomization and autologous stem cell transplantation
were identical in the 2 treatment arms. In arm B, hematologic recovery
was significantly faster for both the duration of neutropenia and
thrombocytopenia, transfusion requirements were also significantly
lower, and the median duration of hospitalization was significantly
shorter. In arm A, the incidence of severe mucositis was significantly
increased. The median duration of event-free survival was similar in
both arms (21 vs 20.5 months, P =.6), but the 45-month survival was
65.8% in arm B versus 45.5% in arm A (P =.05). This difference might be
attributed in part to better salvage regimens after relapse in arm B
compared with arm A. We conclude that 200 mg/m(2) melphalan is a less
toxic and at least as effective conditioning regimen when compared with
8 Gy total body irradiation with 140 mg/m(2) melphalan. This regimen
should be considered as the standard of care before autologous stem cell
transplantation in multiple myeloma.
3
UI - 11807659
AU - Sucker C; Stockschlader M
TI -
[Extramedullary plasmacytoma]
SO - Dtsch Med Wochenschr 2002 Jan 25;127(4):153-5
AD - Medizinische Klinik und Poliklinik C, Ernst-Moritz-Arndt Universitat
Greifswald, Germany. sucker@uni-griefswald.de
4
UI - 11830525
AU - Fonseca R; Harrington D; Oken MM; Dewald GW; Bailey RJ; Van Wier SA;
TI -
Henderson KJ; Blood EA; Rajkumar SV; Kay NE; Van Ness B; Greipp PR
Biological and prognostic significance of interphase fluorescence in
situ hybridization detection of chromosome 13 abnormalities (delta13) in
multiple myeloma: an eastern cooperative oncology group study.
SO - Cancer Res 2002 Feb 1;62(3):715-20
AD - Department of Hematology and Internal Medicine, Mayo Clinic, Rochester,
Minnesota 55905, USA.
Chromosome 13 abnormalities (Delta13) have been associated with an
unfavorable prognosis in patients with multiple myeloma (MM). The
significance of this has been unresolved because of diverse methods of
detection and heterogeneous groups of patients. We conducted a study of
Delta13 in patients entered into the Eastern Cooperative Oncology Group
trial E9486/E9487. Patients with newly diagnosed MM (median follow-up of
survivors >100 months) were studied for Delta13, using bone marrow
samples obtained at study enrollment. We used interphase fluorescence in
situ hybridization with the probes LSI13 (Rb)/D13S319 with simultaneous
immunofluorescence detection of bone marrow plasma cells (PCs). We
detected Delta13 in 176 of 325 (54%) evaluable patients. Patients with
Delta13 were more likely to have a serum monoclonal protein at a
concentration < or =1 g/dl (22 versus 13%; P = 0.04), light-chain-only
MM (19.3 versus 10.8%; P = 0.04), gamma light chain (42 versus 28%; P =
0.027), stage III (56 versus 42%; P = 0.014), and be female (60 versus
50%; P = 0.087). The PC labeling index and Delta13 correlated (P =
0.03). Patients with Delta13 were less likely to respond to treatment
(74 versus 63%; P = 0.041) and had a significantly shorter median
overall survival (34.9 versus 51 months; P = 0.021). The association of
Delta13 and survival remained an independent prognostic variable in a
regression model. Among patients with Delta13, those receiving IFN had a
worse overall survival that those not receiving the medication (P =
0.03). The presence of Delta13 is an important and independent adverse
prognostic factor in newly diagnosed MM and is associated with specific
biological features.
5
UI - 11841418
AU - Barbui AM; Galli M; Dotti G; Belli N; Borleri G; Gritti G; Bellavita P;
TI -
Viero P; Comotti B; Barbui T; Rambaldi A
Negative selection of peripheral blood stem cells to support a tandem
autologous transplantation programme in multiple myeloma.
SO - Br J Haematol 2002 Jan;116(1):202-10
AD - Divisione di Ematologia, Radioterapia and Centro Trasfusionale, Ospedali
Riuniti, Bergamo, Italy.
We recently described a two-step negative selection procedure whereby
peripheral blood stem cells (PBSCs) were efficiently purged of
contaminating neoplastic cells by a combination of monoclonal
antibodies. Here, we report 60 newly diagnosed multiple myeloma (MM)
patients treated with a double transplant programme and randomized to
receive either unmanipulated or in vitro purged PBSCs. We demonstrated
that this technique is feasible and safe without significant loss of
either CD34+ or CD3+ cells. Haematological engraftment and immunological
reconstitution were rapid without treatment-related mortality. Using
polymerase chain reaction (PCR), we compared the level of minimal
residual disease (MRD) in PBSC before and after in vitro purging and in
vivo after transplant. A median of one tumour cell per 10(2) normal
cells (range 10(1)-10(5)) was seen in the unmanipulated aphereses with a
3-4 log reduction after manipulation in vitro. However, despite this
tumour debulking, all patients remained PCR positive in vivo. At 3
years, the estimated event-free survival was 40% in the control arm and
72% in the experimental arm (P = 0.05), whereas the estimated overall
survival was 83% in both arms. This suggests that autologous
transplantation using efficiently purged PBSCs can be performed safely,
but confirms the need for innovative protocols for MRD eradication in
vivo.
6
UI - 11841419
AU - Tricot G; Spencer T; Sawyer J; Spoon D; Desikan R; Fassas A; Badros A;
TI -
Zangari M; Munshi N; Anaissie E; Toor A; Barlogie B
Predicting long-term (> or = 5 years) event-free survival in multiple
myeloma patients following planned tandem autotransplants.
SO - Br J Haematol 2002 Jan;116(1):211-7
AD - The Myeloma and Transplantation Research Center and the Division of
Biometry, University of Arkansas for Medical Sciences, Little Rock, AR
72205, USA. TricotGuidoJ@uams.edu
Although outcome in multiple myeloma (MM) patients has improved
significantly with the introduction of autotransplants (AT), the
curability of this approach remained to be demonstrated. Therefore, we
analysed outcome and prognostic factors using a logistic regression
model in 515 consecutive newly diagnosed and previously treated patients
intended to receive melphalan-based tandem transplants with follow up of
> or = 5 years. One quarter of patients had event-free survivals (EFS) >
or = 5 years with no further relapses seen after 7 years (46 patients on
plateau). On multivariate analysis, factors associated with EFS > or = 5
years were absence of chromosome 11 and 13 abnormalities (odds ratio:
6.1), < or = 12 months of preceding standard-dose therapy (SDT) (OR:
2.6) and beta-2 microglobulin (B2M) level < or = 2.5 mg/l at time of
first AT (OR: 1.7). Patients with only favourable variables (25%) had a
7-year EFS in excess of 35%, compared with 15% and 10%, respectively,
with one (43%) or two unfavourable variables (27%), and 0% for 5% of
patients with three unfavourable variables (P < 0.0001). Using a 1-year
landmark analysis to allow for guaranteed time and thereby excluding
early treatment failures, attaining a complete remission (CR) had no
significant effect on long-term survival. Our data are consistent with
cure in MM patients with a CR duration . or = 7 years and
re-establishment of a monoclonal gammopathy of undetermined significance
(MGUS) phase in those with persistent evidence of disease post
transplantation, but without disease progression > or = 7 years.
7
UI - 11856800
AU - Weinstein R; Mahmood M
TI -
Case records of Massachusetts General Hospital. Weekly
clinicopathological exercises. Case 6-2002. A 54-year-old woman with
left, then right, central-retinal-vein occlusion.
SO - N Engl J Med 2002 Feb 21;346(8):603-10
AD - Hematology and Transfusion Medicine, St. Elizabeth's Medical Center of
Boston, MA, USA.
8
UI - 11481908
AU - Miseta A; Kellermayer M; Liszt F; Ludany A; Magyarlaki T; Sipos K; Berko
TI -
G; Tokes-Fuzesi M
[Plasma electrolytes in multiple myeloma]
SO - Orv Hetil 2001 Jul 8;142(27):1449-53
AD - Pecsi Tudomanyegyetem, Altalanos Orvostudomanyi Kar, Klinikai Kemiai
Intezet.
The plasma cell myeloma (multiple myeloma, myelomatosis) is a
progressive disease, characterized by bone marrow plasmacytomas and the
presence of monoclonal antibodies (IgG, IgA, IgD, IgE), or free kappa or
lambda immunoglobulin side chains. The monoclonal antibodies or
Bence-Jones protein may precipitate in the tubuli and impair kidney
function. In addition, the plasma protein concentration may increase at
the expense of plasma water level causing unrealistically low
electrolyte levels. Since the isoelectric points of immunoglobulins are
higher than those of most other plasma proteins, the net charge of
plasma proteins may change causing new electrolyte balance. In addition,
some monoclonal antibodies are more hydrated than others, and their high
concentration may cause not only increased plasma viscosity but further
electrolyte imbalance. In the present work the relationship between
plasma protein and electrolyte levels is studied in samples of 100
multiple myeloma patients.
9
UI - 11803357
AU - Biagi JJ; Mileshkin L; Grigg AP; Westerman DW; Prince HM
TI -
Efficacy of thalidomide therapy for extramedullary relapse of myeloma
following allogeneic transplantation.
SO - Bone Marrow Transplant 2001 Dec;28(12):1145-50
AD - Department of Haematology, Peter MacCallum Cancer Institute, A'Beckett
Street, Melbourne, Victoria 8006, Australia.
Treatment options for patients with myeloma who relapse after allogeneic
stem cell transplantation are limited. Thalidomide, an antineoplastic
agent, has been shown to be effective in multiple myeloma through
proposed mechanisms that may include angiogenesis inhibition. Herein we
report successful thalidomide treatment of four patients who relapsed
following allogeneic transplantation, three of whom had predominantly
extramedullary relapse. Thalidomide was well tolerated in all patients;
in two patients interferon-alpha was subsequently added to thalidomide
as maintenance therapy without worsening graft-versus-host disease. We
suggest that extramedullary myeloma is particularly sensitive to
thalidomide, speculating that growth biology may in part be dependent on
angiogenesis.
10
UI - 11857078
AU - Chauhan D; Auclair D; Robinson EK; Hideshima T; Li G; Podar K; Gupta D;
TI -
Richardson P; Schlossman RL; Krett N; Chen LB; Munshi NC; Anderson KC
Identification of genes regulated by dexamethasone in multiple myeloma
cells using oligonucleotide arrays.
SO - Oncogene 2002 Feb 21;21(9):1346-58
AD - The Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology,
Dana Farber Cancer Institute, Harvard Medical School, Boston,
Massachusetts, MA 02115, USA.
Our previous studies have characterized Dexamethasone (Dex)-induced
apoptotic signaling pathways in multiple myeloma (MM) cells; however,
related transcriptional events are not fully defined. In the present
study, gene expression profiles of Dex-treated MM cells were determined
using oligonucleotide arrays. Dex triggers early transient induction of
many genes involved in cell defense/repair-machinery. This is followed
by induction of genes known to mediate cell death and repression of
growth/survival-related genes. The molecular and genetic alterations
associated with Dex resistance in MM cells are also unknown. We compared
the gene expression profiles of Dex-sensitive and Dex-resistant MM cells
and identified a number of genes which may confer Dex-resistance.
Finally, gene profiling of freshly isolated MM patient cells validates
our in vitro MM cell line data, confirming an in vivo relevance of these
studies. Collectively, these findings provide insights into the basic
mechanisms of Dex activity against MM, as well as mechanisms of
Dex-resistance in MM cells. These studies may therefore allow improved
therapeutic uses of Dex, based upon targeting genes that regulate MM
cell growth and survival.
11
UI - 11857082
AU - Hsu JH; Shi Y; Hu L; Fisher M; Franke TF; Lichtenstein A
TI -
Role of the AKT kinase in expansion of multiple myeloma clones: effects
on cytokine-dependent proliferative and survival responses.
SO - Oncogene 2002 Feb 21;21(9):1391-400
AD - Department of Medicine and Pathology, West LA VA-UCLA Medical Center and
Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California, CA
90073, USA.
IL-6 is an established growth factor for multiple myeloma tumor cells,
stimulating proliferative and survival responses. Recent work indicates
that IL-6 can activate the AKT kinase in myeloma cells. Thus, to test a
potential role for AKT in IL-6-induced cellular responses, we
transfected myeloma cell lines with an active 'E40K' or dominant
negative'PH AKT construct using an adenoviral vector. Transfection of
the E40K into myeloma cells resulted in enhanced tumor cell growth and
expression of the PH dominant negative AKT resulted in both inhibition
of the IL-6-dependent proliferative response and a decrease in S phase
distribution. While transfection of E40K protected myeloma cells from
dexamethasone-induced apoptosis, the dominant negative PH had no effect
on the ability of IL-6 to protect these cells from dexamethasone. These
results clearly demonstrate that AKT activation is critical for the IL-6
proliferative response. In addition, although the level of AKT
activation can regulate sensitivity to dexamethasone-induced apoptosis,
additional cytokine-induced AKT-independent pathways can mediate IL-6
protection against dexamethasone. DOI: 10.1038/sj/onc/1205194
12
UI - 11512598
AU - Diamond T; Levy S; Smith A; Day P; Manoharan A
TI -
Non-invasive markers of bone turnover and plasma cytokines differ in
osteoporotic patients with multiple myeloma and monoclonal gammopathies
of undetermined significance.
SO - Intern Med J 2001 Jul;31(5):272-8
AD - Department of Endocrinology, St George Hospital, University of New South
Wales, Sydney, Australia. terrydiamond@optushome.com.au
AIMS: To determine whether various markers of bone turnover and/or
plasma cytokines differ in patients with multiple myeloma (MM) compared
with patients with monoclonal gammopathies of undetermined significance
(MGUS). METHODS: We studied 22 MM patients and 18 MGUS patients
presenting over an 18-month period and compared their data with those
from 20 age- and sex-matched patients presenting with primary
osteoporosis. According to the Salmon and Durie classification, there
were eight patients with stage I, nine with stage II and five with stage
III disease. All patients had densitometric evidence of osteoporosis and
were classified according to bone marrow evidence of plasma cell
dyscrasia. Measured variables included markers of bone formation and
bone resorption, and plasma cytokines. RESULTS: Patients with MM and
MGUS did not differ with respect to their mean age, male : female sex
ratio, height, weight, serum calcium, 25-hydroxyvitamin D and
parathyroid hormone concentrations. Patients with MM had significantly
lower concentrations of haemoglobin (109 vs 135 g/L) and serum
transforming growth factor (TGF)-beta (261 vs 348 pg/mL) than patients
with MGUS, and higher concentrations of serum paraproteins (31.1 vs 7.4
g/L), beta2-microglobulin (3.5 vs 2.2 g/L), % plasma cell numbers (35.3
vs 2.1%) and urinary deoxypyridinoline excretion rates (u-DPYD; 7.7 vs
5.9 nmol/mmol creatinine; P < 0.05 for all comparisons). In multivariate
analysis, the serum paraprotein (beta coefficient = -0.067; 95%
confidence intervals (CI), -0.019 to -0.005; P = 0.0012), u-DPYD
excretion rates (beta coefficient = -0.012; 95% CI, -0.113 to -0.02; P=
0.0058) and serum TGF-beta concentrations (beta coefficient = -0.002;
95% CI, -0.0002 to -0.02; P= 0.02) were the most important variables
differentiating between MM and MGUS, after excluding lytic bone lesions,
% plasma cell numbers and haemoglobin concentrations. CONCLUSIONS: The
well-established criteria for diagnosing MM include the presence of
lytic bone lesions, plasmacytosis, haemoglobin and paraprotein
concentrations. The u-DPYD excretion rate, a sensitive non-invasive
marker of bone resorption, may help in differentiating between MM and
MGUS, as well as serving as a marker of underlying bone disease activity
in these patients.
13
UI - 11721392
AU - Zhao M; Shao Z
TI -
[Advances in the study of hematopoietic cell apoptosis in multiple
myeloma]
SO - Zhonghua Xue Ye Xue Za Zhi 1999 Jun;20(6):334-6
14
UI - 11783679
AU - Glendenning P; Vasikaran SD
TI -
Bone markers in patients with multiple myeloma and monoclonal gammopathy
of undetermined significance.
SO - Intern Med J 2002 Jan-Feb;32(1-2):56-8
15
UI - 11877746
AU - Supiot S; Faivre-Chauvet A; Couturier O; Heymann MF; Robillard N;
TI -
Kraeber-Bodere F; Morandeau L; Mahe MA; Cherel M
Comparison of the biologic effects of MA5 and B-B4 monoclonal antibody
labeled with iodine-131 and bismuth-213 on multiple myeloma.
SO - Cancer 2002 Feb 15;94(4 Suppl):1202-9
AD - INSERM U463, Institut de Biologie, Nantes, France.
BACKGROUND: Using a specific monoclonal antibody (MAb), B-B4, coupled to
bismuth-213 ((213)Bi) by a chelating agent (CITC-DTPA), the feasibility
of alpha-radioimmunotherapy (RIT) for multiple myeloma (MM) has been
demonstrated previously. METHODS: In this study, the two MAbs tested,
MA5 and B-B4, target the epithelial antigens Muc-1 and syndecan-1,
respectively, which are both expressed by MM cell lines. Antibody
characterization was evaluated by flow cytometric analysis of normal and
tumoral hematopoeitic cells of MM patients as well as
immunohistochemical tests of normal, nonhematopoetic tissues.
Radiobiologic effects were evaluated for (213)Bi- and iodine-131
((131)I)--labeled antibodies. We assessed in vitro mortality (thymidine
incorporation, MTT, and clonogenic assays) and cell cycle modifications
with propidium iodide staining. These tests were performed on MM cell
lines until 120 hours postirradiation at several time points, using
radiolabeled antibody concentrations ranging from 0.5 to 20 nM and
specific activities ranging from 240 to 1200 MBq/mg of MAb. RESULTS: MA5
stained all MM cells in only 50% of patients, whereas B-B4 recognized
all MM cells in all patients. B-B4 principally showed hepatic,
pulmonary, and duodenal staining, whereas MA5 marked renal and pulmonary
tissues. RIT with (213)Bi-B-B4 induced specific mortality and G(2)/M
phase cell cycle arrest, which depended on the concentrations and
specific activity. For (213)Bi-MA5, this arrest appeared at
concentrations above 10 nM, an amount fivefold higher than that required
with B-B4. This difference was also found in thymidine incorporation
assays. Furthermore, with (213)Bi-B-B4, the arrest at the G(2)/M phase
appeared quickly, within 24 hours after irradiation, and affected up to
60% of the cells (for 20 nM of (213)Bi-B-B4 at 1,200 MBq/mg). Conversly,
(131)I-B-B4 had a very limited effect on cell mortality and did not
induce any cell cycle arrest. CONCLUSIONS: The results of this study
show that B-B4 might be the more effective therapeutic antibody and
suggest that alpha-RIT might be more suitable than beta-RIT for treating
single-cell tumor models. Thus, these findings set the stage for the
beginning of clinical trials using alpha-emitter--radiolabeled B-B4,
with special attention paid to hepatic, pulmonary, and intestinal side
effects. Copyright 2002 American Cancer Society.
16
UI - 11872076
AU - Knudsen LM; Rasmussen T; Nikolaisen K; Johnsen HE
TI -
Mobilisation of tumour cells along with CD34+ cells to peripheral blood
in multiple myeloma.
SO - Eur J Haematol 2001 Nov-Dec;67(5-6):289-95
AD - Department of Haematology L, Herlev Hospital, University of Copenhagen,
Herlev, Denmark. l.meldgaard@dadlnet.dk
BACKGROUND: Cells belonging to the malignant clone are found in the
peripheral blood in myeloma patients. In order to minimise the content
of tumour cells in the stem cell product it is crucial to perform stem
cell harvest at a time when tumour cells in the peripheral blood are at
a minimum. OBJECTIVE: The aim of the study was to compare the
mobilisation kinetics of normal CD34+ cells and myeloma plasma cells
during mobilisation with either G-CSF alone or high-dose
cyclophosphamide (HDCy) plus G-CSF. DESIGN AND METHODS: Morning blood
samples were drawn each day during mobilisation from start of G-CSF or
HDCy and to the end of leukapheresis, and were analysed by flow
cytometry for content of CD34+ cells and myeloma plasma cells (CD38+ +
CD45-). Tumour cells were also estimated by a patient-specific real-time
polymerase chain reaction (PCR) method based on the 5' nuclease TaqMan
technology. RESULTS: Flow cytometry data from 16 patients showed
concomitant mobilisation of CD34+ cells and myeloma plasma cells. Seven
patients were mobilised twice; first with G-CSF alone and then with HDCy
plus G-CSF. There was no difference between the two mobilisation
regimens regarding tumour cell mobilisation kinetics. Real-time PCR was
performed in one patient and confirmed the mobilisation of tumour cells
at the time when CD34+ blood cells were at a maximum. CONCLUSIONS:
Tumour cells are mobilised to the peripheral blood at the same time as
CD34+ cells in multiple myeloma patients after priming with both G-CSF
alone and HDCy in combination with G-CSF.
17
UI - 11872077
AU - Rasmussen T; Knudsen LM; Johnsen HE
TI -
Frequency and prognostic relevance of cyclin D1 dysregulation in
multiple myeloma.
SO - Eur J Haematol 2001 Nov-Dec;67(5-6):296-301
AD - Department of Hematology L, Herlev Hospital, University of Copenhagen,
Herlev, Denmark. thra@herlevhosp.kbhamt.dk
OBJECTIVE: Cyclin D1 dysregulation has been found with varying
frequencies in multiple myeloma (MM) and has been suggested to be
associated with a poor prognosis. The aim of this study was to
investigate the frequency of cyclin D1 dysregulation in patients being
treated for MM and to test whether cyclin D1 dysregulation is a
prognostic factor for MM patients. METHODS: To achieve the above aims we
designed a highly sensitive and reproducible real-time
reverse-transcription polymerase chain reaction (RT-PCR) assay for
quantitation of cyclin D1 mRNA. Using this assay, 110 diagnostic bone
marrow (BM) samples from patients with MM were screened for cyclin D1
dysfunction. RESULTS: The real-time assay was able to detect the
presence of 0.01% cyclin D1 positive cells allowing a safe detection in
MM BM samples. In 42% (46/110) of MM BM samples a greater-than-or-equals
3-fold increase in cyclin D1 mRNA was observed compared to the cyclin D1
level in normal BM. In the remaining group of MM patients the cyclin D1
mRNA levels were comparable to normal donors. Follow-up of 76 MM
patients showed no significant (P = 0.35) difference in survival between
cyclin D1 positive and negative MM patients. In addition, cyclin D1
dysregulation did not correlate with known prognostic factors.
CONCLUSION: The developed real-time RT-PCR assay for detection of cyclin
D1 mRNA levels offers a fast and safe screening for cyclin D1
dysfunction. When a large cohort of MM patients was screened, the cyclin
D1 gene was found to be frequently dysregulated, but there was no
significant correlation to survival or known prognostic parameters.
18
UI - 11872084
AU - Lim SH; Bumm K; Chiriva-Intemati M; Xue Y; Wang Z
TI -
MAGE-C1 (CT7) gene expression in multiple myeloma: relationship to sperm
protein 17.
SO - Eur J Haematol 2001 Nov-Dec;67(5-6):332-4
19
UI - 11741345
AU - Lauta VM
TI -
Interleukin-6 and the network of several cytokines in multiple myeloma:
an overview of clinical and experimental data.
SO - Cytokine 2001 Nov 7;16(3):79-86
AD - Department of Biomedical Sciences and Human Oncology, Section of
Internal Medicine and Clinical Oncology, University of Bari Medical
School, Policlinico-Piazza Giulio Cesare 11, 70124 Bari, Italy.
dimoclin@cimedoc.uniba.it
Study of the network of cytokines has helped identify cell growth
factors in multiple myeloma. Plasma cells themselves may produce
autocrine interleukin 6 (IL-6) while IL-6 production by bone marrow
stromal cells may operate a paracrine mechanism. Involvement of IL-6 in
multiple myeloma is indicated by its ability to induce the
differentiation of myeloma plasmablasts into mature malignant plasma
cells. Differential diagnosis between multiple myeloma and monoclonal
gammopathies of undetermined significance (MGUS) is generally based on
clinical and laboratory parameters. Nevertheless, evaluation of the
serum level of IL-6, C reactive protein, soluble IL-6 receptor, soluble
IL-2 receptor together with the activity exerted by IL-3 and IL-4 on
some cellular subsets constitutes an additional element in the
differential diagnosis of border-line cases. Serum levels of IL-6,
soluble IL-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R)
and the expression of membrane-bound IL-2 receptors, both on bone marrow
plasma cells and on peripheral blood mononuclear cells are correlated
with disease activity and disease stage. In addition, IL-6 and sIL-6R
serum levels correlate with the duration of survival, as high values at
the time of diagnosis correlate with short duration of survival.
Copyright 2001 Academic Press.
20
UI - 11313244
AU - Badros A; Barlogie B; Morris C; Desikan R; Martin SR; Munshi N; Zangari
TI -
M; Mehta J; Toor A; Cottler-Fox M; Fassas A; Anaissie E; Schichman S;
Tricot G; Aniassie E
High response rate in refractory and poor-risk multiple myeloma after
allotransplantation using a nonmyeloablative conditioning regimen and
donor lymphocyte infusions.
SO - Blood 2001 May 1;97(9):2574-9
AD - Myeloma and Transplantation Research Center and Department of Pathology,
University of Arkansas for Medical Sciences and Veterans Health System,
Little Rock, USA. badrosashrafz@exchange.uams.edu
Standard allogeneic stem cell transplant (allo-SCT) regimens have been
associated with a high transplant-related mortality (TRM) in multiple
myeloma (MM). Nonmyeloablative therapy can establish stable engraftment
after allo-SCT and maintain the antitumor effect with less toxicity,
which is important in heavily pretreated and elderly patients. We report
on 16 poor-risk MM patients receiving allo-SCT from an HLA-matched (n =
14) or mismatched (n = 2) sibling following conditioning with melphalan
100 mg/m(2) (MEL-100). Ten patients had refractory relapse, 4 responsive
relapse, and 2 patients were in near complete remission (nCR) with
poor-prognosis disease. Patients had received 1 (n = 9) or 2 (n = 7)
prior autotransplants. Donor lymphocyte infusions (DLIs) were given to
14 patients with no clinical evidence of graft versus host disease
(GVHD) either to attain full donor chimerism (n = 4) or to eradicate
residual disease (n = 10). Fifteen patients showed myeloid engraftment,
and 12 patients were full donor chimeras at day +21. No TRM was observed
during the first 100 days. Acute GVHD developed in 10 patients; 1 had
fatal grade IV GVHD. Seven progressed to chronic GVHD, limited in 3 and
extensive in 4 patients. At a median follow-up of 1 year, 5 patients
achieved and sustained CR, 3 nCR, and 4 partial remission. Of 4 patients
progressing after transplantation, 3 achieved a remission following
further chemotherapy and DLI. Remarkable graft versus myeloma responses
were seen in chemotherapy-refractory patients. Two patients died of
progressive disease, and 3 died of GVHD complications without active
disease. GVHD remains a major problem with this procedure.
21
UI - 11840272
AU - Kulkarni MS; Daggett JL; Bender TP; Kuehl WM; Bergsagel PL; Williams ME
TI -
Frequent inactivation of the cyclin-dependent kinase inhibitor p18 by
homozygous deletion in multiple myeloma cell lines: ectopic p18
expression inhibits growth and induces apoptosis.
SO - Leukemia 2002 Jan;16(1):127-34
AD - Department of Internal Medicine, University of Virginia School of
Medicine, Charlottesville, VA, USA.
Multiple myeloma (MM) is a clonal neoplasm of plasma cells which offers
an excellent model to study multistep molecular oncogenesis. In 20-25%
of primary tumors and cell lines examined, cyclin D1 is overexpressed
due to the translocation t(11;14)(q13;q32). We have characterized
cyclin-dependent kinase inhibitor p15 (CDKN2B), p16 (CDKN2A) and p18
(CDKN2C) deletions in cyclin D1-expressing and non-expressing MM cell
lines. p18 was found to be frequently deleted (38%); in some cases p18
deletions coexisted with hemizygous p16 deletion. To examine the
function of p18 as a putative tumor suppressor in myeloma cells, a
zinc-inducible p18 construct was stably transfected into KMS12, a MM
cell line with biallelic p18 and monoallelic p16 deletions as well as
cyclin D1 overexpression. Ectopic expression of p18 caused 40-45% growth
suppression as determined by trypan blue exclusion and MTS assays. p18
induction also resulted in apoptosis, suggesting that inhibition of the
cyclin D1/CDK/pRb pathway in these tumor cells could be a crucial step
toward the induction of tumor regression via apoptotic cell death. This
cell cycle pathway is thus frequently mutated and provides a potentially
novel target for gene therapeutic or pharmacologic approaches to human
myeloma.
22
UI - 11840273
AU - Van Driel M; Gunthert U; van Kessel AC; Joling P; Stauder R; Lokhorst
TI -
HM; Bloem AC
CD44 variant isoforms are involved in plasma cell adhesion to bone
marrow stromal cells.
SO - Leukemia 2002 Jan;16(1):135-43
AD - Department of Immunology, University Hospital Utrecht, Utrecht, The
Netherlands.
Expression of CD44v9-containing isoforms (CD44v9) on myeloma plasma
cells correlates with unfavorable prognosis, suggesting that CD44
variant molecules are involved in the disease process. In this study,
the presence of CD44v on B cell lines from different stages of
development was analyzed by flow cytometry and a role in adhesion to
stromal cells from different tissues was evaluated in in vitro binding
assays. CD44v3, v6 and v9 isoforms were exclusively expressed on plasma
cell lines and CD44v9 expression correlated with IL-6-dependent plasma
cell growth. Binding studies using CD44 isoform- specific reagents
showed that CD44v6 and CD44v9 were involved in binding to bone marrow
stromal cells, but not to in vitro synthesized ECM or hyaluronic acid.
CD44v9-mediated plasma cell binding resulted in a significant induction
of IL-6 secretion by bone marrow stromal cells. Large differences in
quantitative plasma cell binding to stromal cells from different tissues
were observed. These, however, could not be related to a differential
use of CD44v in these binding processes. The role of CD44v9 in adhesion
induced IL-6 secretion and its preferential expression on IL-6-dependent
plasma cell lines may explain the previously observed correlation
between CD44v9 expression and adverse prognosis in multiple myeloma.
23
UI - 11573449
AU - Mikala G; Jako J; Valyi-Nagy I
TI -
[Role of thalidomide in the treatment of multiple myeloma]
SO - Orv Hetil 2001 Aug 19;142(33):1789-98
AD - Egeszsegtudomanyi Kar, Belgyogyaszati es Geriatriai Klinika, Semmelweis
Egyetem, Budapest.
Multiple myeloma is a relatively common hematologic malignancy with no
definitive treatment available. Although, therapy may include allogenic
bone marrow transplantation, high-dose ablative chemotherapy followed by
bone marrow or peripheral stem cell transplantation,
melphalan/corticosteroid therapy, alpha-interferon treatment, and
combined cytostatic chemotherapy, currently none of these alternatives
offers cure for the disease. Thalidomide is an infamous molecule for its
teratogenicity, yet it possesses potent immunomodulatory,
anti-angiogeneic and, in higher concentrations, direct anti-myeloma-cell
properties. At present, the drug is only approved for the treatment of
erythema nodosum of leprosy, however, there are several preliminary
results that show clinical efficacy in multiple myeloma. This drug has
especially potent anti-myeloma effects in combinations with
dexamethasone and certain cytostatic chemotherapeutic agents. The
effects are evident both in polyresistant, and relapsing myeloma, a form
with no accepted effective treatment options. In this paper, the
fundamental molecular and cellular effects of thalidomide are summarized
then the most important clinical studies with thalidomide are reviewed.
It is the authors' hope that thalidomide will soon be a full member of
the medical arsenal in the fight against multiple myeloma.
24
UI - 11692875
AU - Brown RD; Ho PJ
TI -
Detection of malignant plasma cells in the bone marrow and peripheral
blood of patients with multiple myeloma.
SO - Methods Mol Biol 2002;179():85-91
AD - Institute of Hematology, Royal Prince Alfred Hospital, Camperdown,
Australia.
25
UI - 11852769
AU - Facon T
TI -
[Multiple myeloma of the bone]
SO - Rev Prat 2002 Jan 1;52(1):63-70
AD - Service des maladies du sang, hopital Huriez, CHRU, 59037 Lille.
26
UI - 11882742
AU - Finkel HE; Raje N
TI -
Case 27-2001: Waldenstrom's macroglobulinemia.
SO - N Engl J Med 2002 Mar 7;346(10):784
27
UI - 11868870
AU - Neki N S; Sharma R K; Sharma N; Multani L S
TI -
Multiple myeloma presenting as proptosis and sixth nerve palsy.
SO - J Assoc Physicians India 2001 Nov;49():1116-7
AD - Department of Medicine, Government Medical College/GND Hospital,
Amritsar.
Cranial and intracranial locations are rare in multiple myeloma (MM).
But their occurrence has a particular significance. Proptosis and 6th
nerve palsy is very uncommon presentation. We report a case of MM with
presenting features as proptosis and 6th nerve palsy.
28
UI - 11550657
AU - van de Kerkhof JJ; Peters WG; Visser J; Creemers GJ
TI -
Acute tumor lysis syndrome in a patient with multiple myeloma treated
with dexamethasone monotherapy.
SO - Neth J Med 2001 Aug;59(2):83-5
29
UI - 11706879
AU - Samson D; Singer C
TI -
Multiple myeloma.
SO - Clin Med 2001 Sep-Oct;1(5):365-70
AD - Imperial College, London.
30
UI - 11868471
AU - Windfuhr JP; Ott G
TI -
Extramedullary plasmacytoma manifesting as a palpable mass in the nasal
cavity.
SO - Ear Nose Throat J 2002 Feb;81(2):110-4
AD - Department of Otorhinolaryngology-Plastic Head and Neck Surgery, St.
Anna Hospital, Albertus Magnus Str. 33, 47259 Duisburg, Germany.
jwindfuhr@aol.com
We report a rare case of plasmacytoma of the nasal cavity in a
60-year-old man. The patient had a history of a steadily growing and
palpable mass in the opening of the left nostril. The tumor was found to
be localized, and it was identified as an extramedullary plasmacytoma.
The patient underwent therapy with 55 Gy of radiation. Six months
following the cessation of radiotherapy, the size of the tumor had not
changed. The mass was then completely excised under microscopic vision.
Histopathologic examination identified the growth as a plasmacytoma with
monotypic light-chain expression. To optimize the management of patients
with an extramedullary plasmacytoma of the head and neck,
interdisciplinary management is mandatory.
31
UI - 11108301
AU - Meloni G; Capria S; Trasarti S; Ferrazza G; Micozzi A; Petrucci MT;
TI -
Simone F; Trisolini SM; Mandelli F
High-dose idarubicine, busulphan and melphalan as conditioning for
autologous blood stem cell transplantation in multiple myeloma. A
feasibility study.
SO - Bone Marrow Transplant 2000 Nov;26(10):1045-9
AD - Department of Biotecnologie Cellulari ed Ematologia, University La
Sapienza, Roma, Italy.
Extensive studies have tested the clinical impact of double and triple
sequential transplants as front-line therapy in MM, following the
suggestion that dose escalation can overcome the marked drug resistance
characteristic of this disease, but the superiority of such approaches
vs one single transplant has still to be demonstrated. The aim of our
study was to evaluate the feasibility and efficacy of high-dose
idarubicine intensification of a standard busulphan-melphalan
conditioning regimen in MM. Twenty-eight patients (median age 55 years)
with sensitive disease received PBSCT after high-dose idarubicine
combined with busulphan and melphalan and followed by s.c. rhG-CSF until
PMN recovery. The most severe toxicity was represented by oral mucositis
which resolved with hemopoietic reconstitution. Overall response and CR
rate were 52% and 40%, respectively. Currently, 36 patients are alive
and 19 are progression-free a median of 20 months (12-36) from
transplant. The 3-year projected probability of progression-free
survival for patients transplanted after first-line treatment is 60%.
The combination of Ida/Bu/Melph appears a promising alternative regimen
for PBSCT in myeloma, with low transplant-related toxicity and fast
hematological recovery. Long-term follow-up and a prospective randomized
study, now ongoing, will probably clarify whether an
idarubicine-intensified regimen will result in superior outcomes to
conventional conditioning and even be comparable to a double consecutive
transplant program.
32
UI - 11855144
AU - Fu W; Hou J; Wang D
TI -
[Study on structure change and hypermethylation of p16 gene in multiple
myeloma]
SO - Zhonghua Xue Ye Xue Za Zhi 2001 Nov;22(11):573-6
AD - Department of Hematology, Changzheng Hospital, Second Military Medical
University, Shanghai 200003, China.
OBJECTIVE: To illustrate the role of structure and hypermethylation of
p16 gene in the pathogenesis of multiple myeloma(MM). METHODS: By using
PCR-single strand conformation polymorphisms(PCR-SSCP) and
methylation-specific PCR(MSP) techniques, the structure and
hypermethylation status of p16 gene in MM cell lines and patients were
analysed. RESULTS: Homozygous deletion of p16 exon 2 was found in KM3
cells. The completely methylated p16 gene and hypermethylation of CPG
island were observed in U266, LP1 cell lines and 55.56% of MM patients.
CONCLUSION: Methylation of p16 gene is important in the pathogenesis of
MM and may provide a new drug target for the treatment of MM.
33
UI - 11855145
AU - Zhu P; Liu J; Lin N
TI -
[The clonal origin of the myeloma cells secreting three kinds of
immunoglobulin from a multiple myeloma patient]
SO - Zhonghua Xue Ye Xue Za Zhi 2001 Nov;22(11):577-80
AD - Peking University First Hospital, Beijing 100034, China.
OBJECTIVE: To explore the clonal origin of myeloma cells from a multiple
myeloma (MM) patient with 3 kinds of immunoglobulin (Ig). METHODS: Six
primers for IgH variable region gene families VH1-VH6 and one primer of
common join region (J) were used to perform reverse transcriptase
polymerase chain reaction(RT-PCR). Five oligonucleotides of constant
region gene (C mu, C delta, C gamma, C alpha and C epsilon) were also
used as reverse primers. Different combination of primers were used to
perform PCR. PCR products of IgH gene rearrangement were cloned and
sequenced. RESULTS: A sharp and dense gene band appeared by using Ig VH3
gene family primer and J primer. The specific IgH gene bands also
appeared by using primers of VH3 with C mu and C gamma and C alpha but
not by primers of VH1, VH2, VH4, VH5 with J as well as VH3 with C delta
and C epsilon. It indicated that there were IgM, IgG and IgA gene
rearrangement. These gene products were cloned and sequenced. All 3 IgM,
IgG and IgA gene sequences are identical. CONCLUSION: Despite the
oligoclonality of MM cell, the sequencing results of 3 IgH genes showed
that all the malignant cells were monoclonal origin.
34
UI - 10848780
AU - Zheng C; Huang DR; Bergenbrant S; Sundblad A; Osterborg A; Bjorkholm M;
TI -
Holm G; Yi Q
Interleukin 6, tumour necrosis factor alpha, interleukin 1beta and
interleukin 1 receptor antagonist promoter or coding gene polymorphisms
in multiple myeloma.
SO - Br J Haematol 2000 Apr;109(1):39-45
AD - Division of Haematology, and Immunological Research Laboratory, Centre
for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden.
chengyun.zheng@cmm.ki.se
Proinflammatory cytokines such as interleukin 6 (IL-6), tumour necrosis
factor alpha (TNF-alpha) and IL-1beta are considered to be involved in
the pathogenesis of multiple myeloma (MM). In the present study, we
examined a G/C polymorphism at position -174 in the promoter region of
IL-6, a biallelic polymorphism at position -308 in the promoter region
of TNF-alpha, the TaqI restriction fragment length polymorphism in exon
5 of IL-1beta and a variable number of identical tandem repeat
polymorphisms in intron 2 of IL-1 receptor antagonist (IL-1Ra) genes.
The alleles of these loci are known to influence the level of production
of the cytokines and the IL-1Ra. Seventy-three patients with MM, 27 with
monoclonal gammopathy of undetermined significance (MGUS) and 129
healthy individuals were included. No difference was found between
patients and healthy controls or between MM and MGUS patients in the
distributions of genotypes and frequencies of alleles of the IL-6
(-174), TNF-alpha (-308), IL-1beta TaqI and IL-1Ra gene polymorphisms.
No associations between the polymorphisms at the loci under study and
clinical factors such as age, sex, clinical stage at onset and M-protein
type were observed. Ou
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