OncoLink - Abramson Cancer Center of the University of Pennsylvania

NCI CANCERLIT^® Search: Plasma Cell Neoplasm - July 2002

National Cancer Institute^®

Bone marrow transplantation for multiple myeloma: where we are today.
Optimizing dendritic cell-based immunotherapy in multiple myeloma.
Interleukin 6 and tumour necrosis factor alpha serum levels in monoclonal gammopathy of undetermined significance.
Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications.
Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk.
Thromboembolic events during treatment with thalidomide.
Second response to lower-dose thalidomide in a patient with multiple myeloma.
Reduced duration of cytopenias following melphalan conditioning and autografting for multiple myeloma.
Secondary extramedullary plasmacytoma involving the pancreas.
Multidetector CT of the spine in multiple myeloma: comparison with MR imaging and radiography.
The labelling index of primitive plasma cells determines the clinical behaviour of patients with myelomatosis.
In multiple myeloma, only a single stage of neoplastic plasma cell differentiation can be identified by VLA-5 and CD45 expression.
Interleukin-2 activation of haematopoietic stem cells.
Relapsed multiple myeloma.
Bone disease in myeloma.
Plasma cell crystalline inclusions.
Newly diagnosed multiple myeloma.
Solitary bone plasmacytoma and extramedullary plasmacytoma.
Nursing care of patients with multiple myeloma: a paradigm for the needs of special populations.
Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.
Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma.
Real-time polymerase chain reaction in multiple myeloma: quantitative analysis of tumor contamination of stem cell harvests.
Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma.
Dose escalation therapy in previously untreated patients with multiple myeloma following Z-Dex induction treatment.
FGFR3 dysregulation in multiple myeloma: frequency and prognostic relevance.
Qualitative and quantitative polymerase chain reaction detection of the residual myeloma cell contamination after positive selection of CD34+
The endogenous granulocyte colony-stimulating factor response following autologous peripheral blood stem cell transplantation is impaired in
[Importance of selected laboratory indicators in the differential diagnosis and monitoring of multiple myeloma]
Dermatomyositis and sarcoid-like reaction associated with multiple myeloma treated effectively by high-dose chemotherapy and autologous
Evaluation and appraisal of randomized controlled trials in myeloma.
Multiple myeloma.
[An accidental finding: Kahler's disease]
Plasmacytoma of the temporal bone: management with a combination of surgery and radiotherapy.
[Dynamic contrast-enhanced MRI for evaluating bone marrow microcirculation in malignant hematological diseases before and after
Oxaliplatin (L-OHP) treatment of human myeloma cells induces in vitro growth inhibition and apoptotic cell death.
Influence of thalidomide on Bcl2 expression and proangiogenic cytokine levels in short-term culture of peripheral blood and bone marrow
[Stratification of myeloma patients according to prognostic factors]
[Effect of autologous peripheral blood stem cell transplantation for multiple myeloma: a multi-institutional survey]
[Allogeneic stem cell transplantation with non-myeloablative or reduced-intensity conditioning for multiple myeloma]
[Thalidomide for the treatment of refractory multiple myeloma]
[Effect of bisphosphonate on myeloma bone disease]
Multiple myeloma in young persons.
Biased Iglambda expression in hypermutated IgD multiple myelomas does not result from receptor revision.
The cholesterol lowering drug lovastatin induces cell death in myeloma plasma cells.
Mistaken identity?
Multiple myeloma: evolving genetic events and host interactions.
The effects of anemia in hematologic malignancies: more than a symptom.
High-dose chemotherapy and autologous CD34-positive blood stem cell transplantation for multiple myeloma in an HIV carrier.
Multiple myeloma.
Smoldering, asymptomatic stage 1, and indolent myeloma.
Immunocytochemistry reveals RANKL expression of myeloma cells.
CT-pathologic correlation in a case of solitary plasmacytoma of the rib.
Antisense strategy shows that Mcl-1 rather than Bcl-2 or Bcl-x(L) is an essential survival protein of human myeloma cells.
Repair of DNA interstrand crosslinks as a mechanism of clinical resistance to melphalan in multiple myeloma.
Dendritic cells are functionally defective in multiple myeloma: the role of interleukin-6.
Thalidomide-associated gynecomasty in a patient with multiple myeloma.
Mechanisms associated with cell adhesion mediated drug resistance (CAM-DR) in hematopoietic malignancies.
Cytological diagnosis of multiple myeloma in a 13-year-old boy.
Extramedullary plasmacytoma: clinical and histopathologic study.
[Solitary plasmacytoma of the head and neck. Report of 3 cases and review of the literature]
Therapeutical aspects of the plasmocytoma localized at the level of head and neck.
Isotype class switching and the pathogenesis of multiple myeloma.
[A case report of IgD myeloma]
Epileptic seizures after autologous peripheral blood progenitor infusion in a patient treated with high-dose chemotherapy for myeloma.
The use of hypotensive technique in conjunction with brachial plexus block anesthesia for surgery of the upper extremity.
Skeletal clues apparently distinguishing Waldenstrom's macroglobulinemia from multiple myeloma and leukemia.
Proteasome inhibitor holds promise for patients with refractory multiple myeloma.

1
UI - 11880703
AU - Huff CA; Jones RJ
TI - Bone marrow transplantation for multiple myeloma: where we are today.
SO - Curr Opin Oncol 2002 Mar;14(2):147-51
AD - Johns Hopkins University, Department of Oncology, Baltimore, Maryland 21231, USA. Huffca@jhmi.edu
Multiple myeloma is incurable with standard chemotherapy. Autologous transplantation appears to offer a modest survival advantage over standard dose chemotherapy, but most patients subsequently relapse. Through the induction of graft-versus-tumor activity, allogeneic bone marrow transplantation can lead to long-term disease-free survival, and cure in some patients with myeloma. Transplant-related mortality after allogeneic bone marrow transplantation is high. Many patients are ineligible for this approach because of advanced age, comorbid illnesses, and extensive previous chemotherapy. Ongoing investigations endeavor to reduce regimen-related mortality through nonmyeloablative preparative regimens while maintaining immunologic antitumor activity through donor lymphocytes, which have significant graft-versus-myeloma activity. Early reports demonstrate lower rates of transplant related mortality; however, graft-versus-host disease rates are high and can preclude the administration of graded donor lymphocyte infusions, which may optimize the therapeutic index of graft-versus-host reactivity.

2
UI - 11972511
AU - Yi Q; Desikan R; Barlogie B; Munshi N
TI - Optimizing dendritic cell-based immunotherapy in multiple myeloma.
SO - Br J Haematol 2002 May;117(2):297-305
AD - Myeloma and Transplantation Research Center, University of Arkansas for Medical Science, 4301 West Markham Street, Little Rock, AR 72205, USA. YiQing@uams.edu
Vaccination with idiotype protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. These studies used immature DCs, which are less potent at activating T cells and could differentiate to macrophages once the cytokines were withdrawn. After intravenous administration, DCs accumulate in the lungs and liver for up to 48 h, thus reducing their potential to migrate to lymphoid organs and interact with T cells. To improve the efficacy of DC vaccination in myeloma, we investigated the use of idiotype-pulsed mature DCs administered subcutaneously. Five patients (three IgG and two IgA myeloma) with stable partial remission following high-dose chemotherapy were enrolled. DC vaccines were administered three times at 2-week intervals at least 4 months post transplantation. Idiotype-specific T-cell responses, detected using enzyme-linked immunospot (ELISPOT) (four patients) and proliferation (two patients) assays, were elicited in four and anti-idiotypic B-cell responses in all five patients. The cytokine-secretion profile of activated T cells demonstrated a type-1 response. A 50% reduction in serum M-component was observed in one immunologically responding patient that persisted for 6 months and stable disease (for 6 months) resulted in the other three patients. The remaining patient without an immune response to the vaccination relapsed. No major side-effects were noted. Thus, subcutaneous administration of idiotype-pulsed mature DCs induced idiotype-specific T- and B-cell responses. Current efforts are geared towards optimizing the conditions of DC generation and administration, and the development of in vitro assays to monitor the cytotoxicity of the T cells.

3
UI - 11972522
AU - Blade J; Filella X; Montoto S; Bosch F; Rosinol L; Coca F; Gine E; Nadal
TI - E; Aymerich M; Rozman M; Montserrat E Interleukin 6 and tumour necrosis factor alpha serum levels in monoclonal gammopathy of undetermined significance.
SO - Br J Haematol 2002 May;117(2):387-9
AD - Institute of Hematology and Oncology, Farreras-Valenti Postgraduate School of Hematology, University of Barcelona, Villaroel 170, 08036 Barcelona, Spain. jblade@clinic.ub.es
The objectives of the present study were to compare the interleukin 6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) serum levels of individuals with monoclonal gammopathy of undetermined significance (MGUS) with those of healthy controls, and to ascertain the predictor value of these cytokines in the evolution from MGUS to multiple myeloma. After a median follow-up of 7 years from the initial cytokine measurements, nine patients with MGUS have evolved to a malignant condition. The actuarial probability of malignant transformation in patients with increased IL-6 and TNF-alpha was not significantly higher than in those with normal values.

4
UI - 12010810
AU - Mitsiades N; Mitsiades CS; Poulaki V; Chauhan D; Richardson PG;
TI - Hideshima T; Munshi N; Treon SP; Anderson KC Biologic sequelae of nuclear factor-kappaB blockade in multiple myeloma: therapeutic applications.
SO - Blood 2002 Jun 1;99(11):4079-86
AD - Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
The transcription factor nuclear factor-kappaB (NF-kappaB) confers significant survival potential in a variety of tumors. Several established or novel anti-multiple myeloma (anti-MM) agents, such as dexamethasone, thalidomide, and proteasome inhibitors (PS-341), inhibit NF-kappaB activity as part of their diverse actions. However, studies to date have not delineated the effects of specific inhibition of NF-kappaB activity in MM. We therefore investigated the effect of SN50, a cell-permeable specific inhibitor of NF-kappaB nuclear translocation and activity, on MM cells. SN50 induced apoptosis in MM cell lines and patient cells; down-regulated expression of Bcl-2, A1, X-chromosome-linked inhibitor-of-apoptosis protein (XIAP), cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, and survivin; up-regulated Bax; increased mitochondrial cytochrome c release into the cytoplasm; and activated caspase-9 and caspase-3, but not caspase-8. We have previously demonstrated that tumor necrosis factor-alpha (TNF-alpha) is present locally in the bone marrow microenvironment and induces NF-kappaB-dependent up-regulation of adhesion molecules on both MM cells and bone marrow stromal cells, with resultant increased adhesion. In this study, TNF-alpha alone induced NF-kappaB nuclear translocation, cIAP-1 and cIAP-2 up-regulation, and MM cell proliferation; in contrast, SN50 pretreatment sensitized MM cells to TNF-alpha-induced apoptosis and cleavage of caspase-8 and caspase-3, similar to our previous finding of SN50-induced sensitization to apoptosis induced by the TNF-alpha family member TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. Moreover, SN50 inhibited TNF-alpha-induced expression of another NF-kappaB target gene, intercellular adhesion molecule-1. Although the p38 inhibitor PD169316 did not directly kill MM cells, it potentiated the apoptotic effect of SN50, suggesting an interaction between the p38 and NF-kappaB pathways. Our results therefore demonstrate that NF-kappaB activity in MM cells promotes tumor-cell survival and protects against apoptotic stimuli. These studies provide the framework for targeting NF-kappaB activity in novel biologically based therapies for MM.

5
UI - 12010818
AU - Qiang YW; Kopantzev E; Rudikoff S
TI - Insulinlike growth factor-I signaling in multiple myeloma: downstream elements, functional correlates, and pathway cross-talk.
SO - Blood 2002 Jun 1;99(11):4138-46
AD - Laboratory of Cellular and Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255, USA.
In multiple myeloma cells, insulinlike growth factor-I (IGF-I) activates 2 distinct signaling pathways, mitogen-activated protein kinase (MAPK) and phosphoinositol 3-kinase (PI-3K), leading to both proliferative and antiapoptotic effects. However, it is unclear through which of these cascades IGF-I regulates these different responses. The present studies identify a series of downstream targets in the PI-3K pathway, including glycogen synthase kinase-3beta, p70S6 kinase, and the 3 members of the Forkhead family of transcription factors. The contribution of the MAPK and PI-3K pathways and, where possible, individual elements to proliferation and apoptosis was evaluated by means of a series of specific kinase inhibitors. Both processes were regulated almost exclusively by the PI-3K pathway, with only minor contributions associated with the MAPK cascade. Within the PI-3K cascade, inhibition of p70S6 kinase led to significant decreases in proliferation and protection from apoptosis. Activation of p70S6 kinase could also be prevented by MAPK inhibitors, indicating regulation by both pathways. The Forkhead transcription factor FKHRL1 was observed to provide a dual effect in that phosphorylation upon IGF-I treatment resulted in a loss of ability to inhibit proliferation and induce apoptosis. The PI-3K pathway was additionally shown to exhibit cross-talk and to regulate the MAPK cascade, as inhibition of PI-3K prevented activation of Mek1/2 and other downstream MAPK elements. These results define important elements in IGF-I regulation of myeloma cell growth and provide biological correlates critical to an understanding of growth-factor modulation of proliferation and apoptosis.

6
UI - 12043695
AU - Urbauer E; Kaufmann H; Nosslinger T; Raderer M; Drach J
TI - Thromboembolic events during treatment with thalidomide.
SO - Blood 2002 Jun 1;99(11):4247-8

7
UI - 12043696
AU - Lee FC
TI - Second response to lower-dose thalidomide in a patient with multiple myeloma.
SO - Blood 2002 Jun 1;99(11):4248; discussion 4249

8
UI - 12043699
AU - Devine SM; Jahagirdar B; van Besien K
TI - Reduced duration of cytopenias following melphalan conditioning and autografting for multiple myeloma.
SO - Blood 2002 Jun 1;99(11):4251-2; discussion 4252

10
UI - 12034612
AU - Mahnken AH; Wildberger JE; Gehbauer G; Schmitz-Rode T; Blaum M; Fabry U;
TI - Gunther RW Multidetector CT of the spine in multiple myeloma: comparison with MR imaging and radiography.
SO - AJR Am J Roentgenol 2002 Jun;178(6):1429-36
AD - Department of Radiology, University Hospital, University of Technology, Pauwelsstr. 30, D-52074 Aachen, Germany.
OBJECTIVE: The purpose of this study was to compare multidetector CT (MDCT) of the thoracic and lumbar segments of the spine with MR imaging and conventional radiography for bone lesion detection and for evaluating the risk of vertebral fracture in multiple myeloma. SUBJECTS AND METHODS: Eighteen patients with multiple myeloma stage III (according to the criteria of Durie and Salmon) underwent MDCT, conventional radiography, and MR imaging of the lumbar and thoracic spine. MDCT was performed using a standard protocol with no contrast material. Source images were reconstructed using an effective slice thickness of 3 mm with an overlapping reconstruction increment (0.8 mm). Secondary coronal and sagittal multiplanar reformations were exclusively used for establishing the diagnosis. Findings were compared with those of MR imaging and conventional radiography. RESULTS: In all patients, coronal and sagittal multiplanar reformations depicted the extent of osseous destruction and provided detailed information about osseous infiltration and potential bone instability. Compared with conventional radiography, an additional 24 affected vertebrae, 15 additional vertebral fractures, and six vertebrae at further risk of fracture were detected on MDCT. Compared with MR imaging, three additional endangered vertebrae were detected on MDCT. MR imaging alone would have lead to an understaging of five (27.8%) of 18 patients. Using combined radiography and MR imaging, disease in three (16.7%) of 18 patients would have been understaged. CONCLUSION: MDCT seems to be preferable to conventional radiography in evaluating bone destruction in multiple myeloma. In combination with MR imaging, detailed information for staging these tumors is obtained. For the initial staging in patients with multiple myeloma, MDCT in combination with MR imaging seems to be the method of choice.

11
UI - 8757512
AU - Joshua D; Petersen A; Brown R; Pope B; Snowdon L; Gibson J
TI - The labelling index of primitive plasma cells determines the clinical behaviour of patients with myelomatosis.
SO - Br J Haematol 1996 Jul;94(1):76-81
AD - Institute of Haematology, Royal Prince Alfred Hospital, Sydney, Australia.
For patients with multiple myeloma the most important laboratory correlate of prognosis and disease activity is the bromodeoxyuridine (BrdUrd) plasma cell labelling index (LI). However, the traditional immunofluorescent microscope LI technique, like other manual enumeration assays, can suffer from poor precision and accuracy. In this study the LI of different subpopulations of plasma cells (CD38++) as determined by flow cytometry was correlated with disease state. The mean LI of the total CD38++ population was significantly higher (2.7 +/- 0.4%) than the LI determined by the traditional slide technique (0.6 +/- 0.1%) for 65 samples tested. Primitive plasma cells (CD38++, CD45++) had a higher labelling index than mature plasma cells (CD38++, CD45-) (7.0 +/- 1.3% v 1.8% +/- 0.3%) and in one patient the LI of the primitive plasma cells was 46%. In addition, the LI of the mature plasma cells was lower than the total plasma cell population. As expected, there was a significant difference between the LI of patients in plateau phase and progressive disease but this difference was greatest when the LI of the primitive plasma cells was studied (9.2 +/- 2.9% v 2.2 +/- 0.7%; z = 19.9, P < 0.001). This study has raised some concerns about the sensitivity and accuracy of the traditional labelling index and has shown that the increased LI associated with progressive disease is almost entirely attributable to an increase in the LI of the primitive plasma cell subpopulation and that the LI of primitive plasma cells provides a more clinically significant correlation with disease status than the traditional assay.

12
UI - 11380472
AU - Rawstron AC; Barrans SL; Blythe D; English A; Richards SJ; Fenton JA;
TI - Davies FE; Child JA; Jack AS; Morgan GJ In multiple myeloma, only a single stage of neoplastic plasma cell differentiation can be identified by VLA-5 and CD45 expression.
SO - Br J Haematol 2001 Jun;113(3):794-802
AD - HMDS, The General Infirmary at Leeds, Leeds, UK. andy.rawstron@newscientist.net
The nature of the proliferating fraction in myeloma is still not known and understanding the characteristics of this fraction is central to the development of effective novel therapies. However, myeloma plasma cells typically show a very low rate of proliferation and this complicates accurate analysis. Although the level of CD45 and/or VLA-5 has been reported to identify proliferating 'precursor' plasma cells, there are discrepancies between these studies. We have therefore used a rigorous sequential gating strategy to simultaneously analyse cycle status and immunophenotype with respect to CD45, VLA-5 and a range of other integrin molecules. In 11 presentation myeloma patients, the proliferative fraction was distributed evenly between CD45+ and CD45- cells, however, cycling plasma cells were consistently VLA-5-. There was close correlation between the expression of VLA-5 and a range of other integrin molecules (CD11a, CD11c, CD103), as well as the immunoglobulin-associated molecules CD79a/b (Spearman, n = 10, P < 0.0001). In short-term culture, cells that were initially VLA-5-showed increasing VLA-5 expression with time. However, simultaneous analysis of the DNA-binding dye 7-amino-actinomycin D demonstrated that this was not as a result of differentiation, as VLA-5+ plasma cells were all non-viable. This was confirmed in freshly explanted plasma cells from nine patients. Discrete stages of plasma cell differentiation could not be distinguished by the level of CD45 or VLA-5 expression. The results indicate that there is a single stage of plasma cell differentiation, with the phenotype CD38+CD138+VLA-5-. These findings support the hypothesis that neoplastic bone marrow plasma cells represent an independent, self-replenishing population.

13
UI - 12050948
AU - Hajek R; Koristek Z; Vinklarkova J; Janovska E; Klabusay M; Doubek M;
TI - Dvorakova D; Bourkova L; Dusek L; Buchler T; Adler J; Adam Z; Penka M; Mayer J; Vorlicek J Interleukin-2 activation of haematopoietic stem cells.
SO - Acta Med Austriaca 2002;29(2):61-7
AD - Department of Internal Medicine-Hematooncology, Department of Clinical Hematology, University Hospital Brno, Bohunice, Jihlavska 20, CZ-639 00 Brno, Czech Republic. r.hajek@fnbrno.cz
BACKGROUND: Recent findings concerning the role of immunity in the eradication of residual malignant disease after autologous haematopoietic stem cell transplantation have led to extensive studies of T-cell and natural killer (NK) mediated anti-tumour effects. Interleukin 2 (IL-2) activation of autologous bone marrow (BM) or peripheral blood stem cells (PBSC) before transplantation is one of the methods of adoptive cell therapy. METHODS: Autologous BM of patients with chronic myelogenous leukaemia (n = 11) and PBSC of patients with multiple myeloma (n = 14) were activated by IL-2 in laboratory conditions with the aim of evaluating the feasibility of this method, the activation of T and NK cells, recovery of active progenitor cells, microbial contamination, and reduction of malignant cell content. RESULTS: Samples of BM (mean 2.6 x 10(6) cells) and PBSC (mean 10.3 x 10(6) cells) were cultured in complete culture medium with IL-2 (6000 Ul/ml) for 24 h. The recovery of CD34+ cells and CFU-GM was 82.5% and 51.5%, respectively, for BM, and 85% and 86%, respectively, for PBSC (mean values). No purging effect was detected by flow cytometry and a small decline in malignant cell contamination was observed by quantitative PCR in BM samples. No microbial contamination occurred during the sample processing. CONCLUSIONS: The described in vitro activation of BM and peripheral blood stem cells using IL-2 was evaluated as a safe and reliable method suitable for clinical application.

14
UI - 12057126
AU - Pandit S; Vesole DH
TI - Relapsed multiple myeloma.
SO - Curr Treat Options Oncol 2001 Jun;2(3):261-9
AD - Division of Hematology/Oncology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, WI 53226, USA.
The treatment of relapsed multiple myeloma remains a challenge for clinicians. Most salvage therapies result in transient responses, with median survival from relapse ranging from 6 to 18 months. No randomized trials comparing salvage therapies have been performed. In the absence of a "gold standard" salvage therapy, relapsed patients should be considered for clinical trials. In light of the recent observation that thalidomide alone brings about a 30% to 35% response rate with manageable toxicities, this is the most promising single agent available to treat relapsed disease. The maximum effective dose appears to be 400 mg/d; virtually all responses are evident within 2 months of starting therapy. Combination therapy of thalidomide with pulse dexamethasone or other chemotherapeutic agents has shown promise in pilot trials. Even with thalidomide-responsive disease, the response duration is brief, ranging from 3 to 6 months. Therefore, the authors recommend that patients under the age of 78 years who have acceptable physiologic organ function, chemotherapy-sensitive disease, third-party financial coverage, and adequate hematopoietic stem cells be considered for high-dose therapy with autologous hematopoietic stem cell transplant. High-dose therapy with hematopoietic stem cell transplant provides the highest response rate, response duration, and survival compared with historical controls treated with conventional therapy. Patients under the age of 70 years who have human leukocyte antigen-compatible donors should be considered for immune-based therapy using nonmyeloablative preparative regimens with allogeneic hematopoietic stem cell transplant.

15
UI - 12057127
AU - Berenson JR
TI - Bone disease in myeloma.
SO - Curr Treat Options Oncol 2001 Jun;2(3):271-83
AD - Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
The major clinical manifestation of multiple myeloma results from osteolytic bone destruction. The only currently Food and Drug Administration-approved drug for the treatment of the bony complications of multiple myeloma is monthly intravenous pamidronate at a dose of 90 mg infused over 4 hours. Recent studies have shown the safety of 2-hour infusions. A randomized trial comparing pamidronate to placebo continued to show benefits throughout the 21-month trial. Although the duration of therapy has not been firmly determined, it is likely that discontinuation of this drug will be met by enhanced bone loss and an increased risk of bony complications for these patients. Thus, it is recommended that the drug be continued indefinitely. Support for this recommendation also comes from the reduced bone density observed in women with postmenopausal osteoporosis following the withdrawal of bisphosphonate treatment. Recent attempts to give higher doses, more frequent infusions (every 2 weeks or less), or more rapid infusions (1 hour or less) of pamidronate have occasionally been associated with albuminuria and azotemia. These modifications should therefore be avoided. Importantly, the drug can be safely administered at 90 mg monthly to patients with poor renal function. The use of pamidronate for myeloma patients without lytic bone involvement or with Durie-Salmon stages I or II disease has not been evaluated. However, it is recognized that most patients with earlier stages of disease or without lytic bone involvement also develop bony complications. There is no reason to believe that these patients would not benefit from monthly intravenous infusions of pamidronate. The potential antimyeloma effect of this agent is another reason to administer this drug in these types of patients. Thus, it is our practice to administer monthly pamidronate to myeloma patients regardless of stage or bone involvement. However, trials evaluating oral bisphosphonates have produced inconsistent clinical results, probably as a result of the erratic and scanty poor absorption as well as poor oral tolerability of these drugs. Although these oral agents may be useful in some patients, it is impossible to identify which myeloma patients will benefit from orally administered bisphosphonates. The more potent nitrogen-containing bisphosphonate zoledronic acid more effectively reverses hypercalcemia of malignancy than pamidronate, and it appears promising in reducing bone loss in cancer patients. However, its efficacy in preventing skeletal complications is still being evaluated. Many other types of new agents are in early clinical trials, but their efficacy remains unproven at the present time.

16
UI - 12087975
AU - Gruszecki AC; Reddy VV
TI - Plasma cell crystalline inclusions.
SO - Arch Pathol Lab Med 2002 Jun;126(6):755
AD - Department of Pathology, University of Alabama, Birmingham 35233, USA. agruszec@path.uab.edu

17
UI - 12057069
AU - Weber DM
TI - Newly diagnosed multiple myeloma.
SO - Curr Treat Options Oncol 2002 Jun;3(3):235-45
AD - University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Box #429, Houston, TX 77030, USA. dmweber@mdanderson.org
Melphalan combined with prednisone (MP) has been accepted as the standard therapy for previously untreated multiple myeloma (MM) because most studies demonstrate only a modest survival benefit of combination chemotherapy regimens when compared with MP. There have been modest gains with more intensive myeloablative regimens in combination with blood stem cell support, particularly for patients with early primary refractory disease who subsequently achieve partial remission, and for the approximately 25% to 35% of patients achieving complete remission. To preserve the ability to adequately collect stem cells, the use of alkylating agents, such as melphalan, should be limited in the previously untreated patient with myeloma (including those older than 65 years of age) who is a candidate for myeloablative therapy. Pulse dexamethasone-containing regimens provide rapid responses and may be considered the first regimens of choice. Although vincristine/doxorubicin/dexamethasone (VAD) produces responses in approximately 50% to 70% of patients with previously untreated multiple myeloma, use early in the disease has not improved survival. Outside of a specific study protocol, this regimen may be best reserved for patients with refractory (particularly relapsing) disease. Notable exceptions include patients with renal failure or plasma cell leukemia in whom the rapid responses provided by VAD may avoid potentially permanent, serious complications. Recently, new agents with novel mechanisms of action (ie, thalidomide, immunomodulatory drugs, proteosome inhibitors) have demonstrated activity in resistant myeloma. Because these agents are likely to show activity alone or in combination, newly diagnosed patients and previously untreated patients should be considered for clinical trials. Thalidomide/dexamethasone has already produced response rates of 65% to 75% in previously untreated patients. Its ease of administration along with stem cell preservation are likely to make this, followed by myeloablative therapy with stem cell support, the treatment of choice for untreated myeloma as confirmatory studies are completed.

18
UI - 12057071
AU - Dimopoulos MA; Hamilos G
TI - Solitary bone plasmacytoma and extramedullary plasmacytoma.
SO - Curr Treat Options Oncol 2002 Jun;3(3):255-9
AD - Department of Clinical Therapeutics, University of Athens School of Medicine, 227 Kifissias Avenue, Kifissia, Athens 14561, Greece. mdimop@med.uoa.gr
Solitary bone and extramedullary plasmacytomas are rare plasma cell proliferative disorders. Their diagnosis is based on histologic confirmation of monoclonal plasma cell infiltration of a single disease site and on the exclusion of systemic myeloma. For both entities, the treatment of choice is localized radiotherapy. With modern radiotherapy and with a total dose of at least 4000 cGy, the risk for local recurrence is less than 5%. There is no role for systemic chemotherapy in the management of these disorders. Approximately 30% of patients with solitary bone plasmacytoma (SBP) remain disease-free for several years; some of these patients may be cured. Patients with the best prognosis are those in whom the monoclonal protein disappears by 1 year after radiotherapy. The prognosis of patients with solitary extramedullary plasmacytoma (SEP) appears to be better than for patients with SBP because approximately 70% of patients with SEP remain disease-free at 10 years. With more sensitive staging procedures, the diagnosis of SBP and SEP may become less common, but the number of patients with prolonged stability and cure may increase.

19
UI - 11899375
AU - Rice D; Sheridan CA
TI - Nursing care of patients with multiple myeloma: a paradigm for the needs of special populations.
SO - Clin J Oncol Nurs 2001 May-Jun;5(3):89-93
AD - Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 USA. ricer@mskcc.org
Multiple myeloma, a B cell malignancy that has its peak incidence in the elderly and affects African Americans more frequently than Caucasians, may be used as a paradigm to examine the concerns of special populations. Special populations are those who are medically underserved or medically underrepresented. Using this disease entity to focus on concerns of special populations and access to healthcare systems, the oncology nurse can formulate an approach to cancer care with a broader view of patients from special populations and their needs and goals.

20
UI - 12036884
AU - Mitsiades N; Mitsiades CS; Poulaki V; Chauhan D; Richardson PG;
TI - Hideshima T; Munshi NC; Treon SP; Anderson KC Apoptotic signaling induced by immunomodulatory thalidomide analogs in human multiple myeloma cells: therapeutic implications.
SO - Blood 2002 Jun 15;99(12):4525-30
AD - Department of Adult Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Thalidomide (Thal) achieves responses even in the setting of refractory multiple myeloma (MM). Although increased angiogenesis in MM bone marrow and the antiangiogenic effect of Thal formed the empiric basis for its use in MM, we have shown that Thal and its immunomodulatory analogs (IMiDs) directly induce apoptosis or growth arrest of MM cells, alter adhesion of MM cells to bone marrow stromal cells, inhibit the production of cytokines (interleukin-6 and vascular endothelial growth factor) in bone marrow, and stimulate natural killer cell anti-MM immunity. In the present study, we demonstrate that the IMiDs trigger activation of caspase-8, enhance MM cell sensitivity to Fas-induced apoptosis, and down-regulate nuclear factor (NF)-kappa B activity as well as expression of cellular inhibitor of apoptosis protein-2 and FLICE inhibitory protein. IMiDs also block the stimulatory effect of insulinlike growth factor-1 on NF-kappa B activity and potentiate the activity of TNF-related apoptosis-inducing ligand (TRAIL/Apo2L), dexamethasone, and proteasome inhibitor (PS-341) therapy. These studies both delineate the mechanism of action of IMiDs against MM cells in vitro and form the basis for clinical trials of these agents, alone and coupled with conventional and other novel therapies, to improve outcome in MM.

21
UI - 12036895
AU - Bellucci R; Alyea EP; Weller E; Chillemi A; Hochberg E; Wu CJ; Canning
TI - C; Schlossman R; Soiffer RJ; Anderson KC; Ritz J Immunologic effects of prophylactic donor lymphocyte infusion after allogeneic marrow transplantation for multiple myeloma.
SO - Blood 2002 Jun 15;99(12):4610-7
AD - Center for Hematologic Oncology and Department of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Reconstitution of T-cell immunity after bone marrow transplantation (BMT) is often delayed, resulting in a prolonged period of immunodeficiency. Donor lymphocyte infusion (DLI) has been used to enhance graft-versus-leukemia activity after BMT, but the effects of DLI on immune reconstitution have not been established. We studied 9 patients with multiple myeloma who received myeloablative therapy and T-cell-depleted allogeneic BMT followed 6 months later by infusion of lymphocytes from the same donor. DLI consisted of 3 x 10(7) CD4(+) donor T cells per kilogram obtained after in vitro depletion of CD8(+) cells. Cell surface phenotype of peripheral lymphocytes, T-cell receptor (TCR) V beta repertoire, TCR rearrangement excision circles (TRECs), and hematopoietic chimerism were studied in the first 6 months after BMT and for 1 year after DLI. These studies were also performed in 7 patients who received similar myeloablative therapy and BMT but without DLI. Phenotypic reconstitution of T and natural killer cells was similar in both groups, but patients who received CD4(+) DLI developed increased numbers of CD20(+) B cells. TCR V beta repertoire complexity was decreased at 3 and 6 months after BMT but improved more rapidly in patients who received DLI (P =.01). CD4(+) DLI was also associated with increased numbers of TRECs in CD3(+) T cells (P <.001) and with conversion to complete donor hematopoiesis (P =.05). These results provide evidence that prophylactic infusion of CD4(+) donor lymphocytes 6 months after BMT enhances reconstitution of donor T cells and conversion to donor hematopoiesis as well as promoting antitumor immunity.

22
UI - 12063019
AU - Ladetto M; Omede P; Sametti S; Donovan JW; Astolfi M; Drandi D; Volpato
TI - F; Giaccone L; Giaretta F; Palumbo A; Bruno B; Pileri A; Gribben JG; Boccadoro M Real-time polymerase chain reaction in multiple myeloma: quantitative analysis of tumor contamination of stem cell harvests.
SO - Exp Hematol 2002 Jun;30(6):529-36
AD - Divisione Universitaria di Ematologia, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy. marco.ladetto@unito.it
OBJECTIVE: Autologous transplantation of bone marrow (BM) and peripheral blood progenitor cells (PBPC) is commonly used for treatment of multiple myeloma (MM). Although both stem cell sources harbor residual clonal cells, a quantitative evaluation of their level of tumor contamination (LTC) still needs to be performed through highly accurate and reproducible approaches. In this study, we used a validated real-time polymerase chain reaction (PCR) strategy to evaluate LTC of BM and PBPC samples obtained from MM patients. MATERIALS AND METHODS: The patients underwent two different mobilization courses (defined as early or late course) following two cycles of cyclophosphamide 5 g/m(2). LTC was evaluated by measuring the number of clonal immunoglobulin heavy-chain rearrangements followed by normalization of samples using the GAPDH gene. RESULTS: Overall, 26 PBPC and 12 BM samples were analyzed. Main results are as follows. 1) PBPC harvests are less contaminated than BM samples taken immediately after each mobilization course (median difference 2.68 logs; range 1.7 to 4.6) (p < 0.0001). 2) LTC of PBPC harvests has only minimal variation among different leukaphereses performed during the same mobilization course (median difference 0.45 logs; range 0.22 to 1.2). 3) No difference was observed among PBPC and BM samples obtained after the late mobilization course as compared to the early mobilization course (median reduction 0.21 logs; range -0.39 to 1.3) (p = 0.84). 4) In PBPC but not in BM samples, there is a clear overestimation of the percentage of plasma cells when flow cytometric evaluation of CD38(bright) cells is compared to real-time PCR results. This suggests that in PBPC, most CD38(bright) cells do not belong to the neoplastic clone. CONCLUSIONS: Real-time PCR using the IgH rearrangement proved an effective tool for monitoring LTC in stem cell harvests from MM patients. The smaller LTC of PBPC harvests supports the role of PBPC as stem cell rescue for MM patients compared to BM cells.

23
UI - 11940485
AU - Tosi P; Zamagni E; Cellini C; Ronconi S; Patriarca F; Ballerini F; Musto
TI - P; Di Raimondo F; Ledda A; Lauria F; Masini L; Gobbi M; Vacca A; Ria R; Cangini D; Tura S; Baccarani M; Cavo M Salvage therapy with thalidomide in patients with advanced relapsed/refractory multiple myeloma.
SO - Haematologica 2002 Apr;87(4):408-14
AD - Istituto di Ematologia e Oncologia Medica "L. e A. Seragnoli", Policlinico S. Orsola, via Massarenti 9, 40138 Bologna, Italy. ptosi@med.unibo.it
BACKGROUND AND OBJECTIVES: Few therapeutic options are presently available for patients with multiple myeloma (MM) who relapse after autologous or allogeneic stem cell transplantation, or for patients who are refractory to conventional chemotherapy and not eligible for salvage high-dose therapy. Thalidomide, a glutamic acid derivative with anti-angiogenic properties, has been recently proposed as an effective therapy for patients with advanced refractory disease. The aim of this study was to evaluate the activity of thalidomide in a large series of patients (46 males/19 females) from 8 Italian institutions were treated with thalidomide. Twenty-six patients had relapsed after autologous stem cell transplantation, either single (n = 12) or double (n= 12); 38 patients had shown disease progression after >= 2 lines of conventional chemotherapy, 2 patients had relapsed after allotransplant, one single patient had not received previous treatment. Sixty-one (93.8%) patients were in stage III, median b2 microglobulin was 2.9 mg/L, and median bone marrow plasma cell infiltration was 50%. Thalidomide was initially administered at a dose of 100 mg/day; if well tolerated, the dose was to be increased serially by 200mg every other week to a maximum of 800 mg/day. RESULTS: The median administered dose of thalidomide was 400 mg/day. WHO grade > II toxic effects were constipation (52%), lethargy (34%), skin rash (11%), peripheral neuropathy (14%) and leukopenia (3%). Sixty patients are presently evaluable for response; of these, 17 (28.3%) showed > or = 50% reduction in serum or urinary M protein concentration and 11 (18.3%) showed > or = 25% tumor reduction, for a total response rate averaging 46.6%. After a median of 8 months' follow-up, 15/28 patients are alive and progression-free (at 2 to 16 months), 12 patients have relapsed, and 1 patient died of pulmonary edema while still in partial remission. Among pre-treatment variables that were analyzed for their potential relationship with tumor response, only the concentration of vascular endothelial growth factor (VEGF) in the conditioned media obtained upon culture of bone marrow plasma cells was statistically significant. Plasma cells from patients who responded favorably to thalidomide secreted a significantly lower amount of VEGF than plasma cells from resistant patients (126.45 165 pg/mL vs 227.11 70 pg/mL, p=0.04). INTERPRETATION AND CONCLUSIONS: These data confirm that thalidomide is active in patients with advanced relapsed/refractory MM and represent the basis for ongoing clinical trials aimed at testing the role of this drug as front line therapy for newly diagnosed disease.

24
UI - 12028028
AU - Clark AD; Douglas KW; Mitchell LD; McQuaker IG; Parker AN; Tansey PJ;
TI - Franklin IM; Cook G Dose escalation therapy in previously untreated patients with multiple myeloma following Z-Dex induction treatment.
SO - Br J Haematol 2002 Jun;117(3):605-12
AD - Academic Transfusion Medicine Unit, Department of Medicine, University of Glasgow, Glasgow, Scotland, UK.
A phase I-II study of high-dose (HD) alkylating agents in newly diagnosed patients with multiple myeloma after maximum response to Z-Dex (idarubicin, dexamethasone) therapy and DHAP (cisplatin, HD cytosine arabinoside, dexamethasone), stem cell mobilization is reported. Twenty-six patients, median age 56 years (range 42-66), completed Z-Dex chemotherapy and peripheral blood stem cells (PBSC) were mobilized with DHAP. Patients then preceded to cyclophosphamide (HD Cy: 6 g/m(2)) with granulocyte colony-stimulating factor followed by busulphan-melphalan-conditioned PBSC autograft. Interferon alpha was introduced at 3 months post transplant as maintenance therapy. Six patients failed to complete the full protocol. Median time from diagnosis to transplantation was 8 months (range 6-12). Mean CD34+ cell dose collected was 15.8 x 10(6)/kg (CI 11.8, 19.8). Median time from DHAP to HD-Cy was 6 weeks (range 4-12) and from HD-Cy to transplant was 8 weeks (range 6-12). The median follow-up was 36 months (range 6-63). On an intent-to-treat basis, the response rates were three complete response (CR, 12%), 21 partial response (PR, 80%) and two stable disease (SD, 8%) post Z-Dex, five CR (19%) and 21 PR (81%) post HD-Cy, and 14 CR (54%) and 12 PR (46%) post transplant. The treatment-related mortality (TRM) was 4% (1 patient). Median overall survival (OS) and progression-free survival (PFS) have not been reached; estimated values were 60 and 48 months respectively. The 3-year OS and PFS were 72% and 62%. Actuarial 5-year OS and event-free survival were 49% and 32%. DHAP produces effective PBSC mobilization and sequential HD therapy, including autologous PBSCT, in patients who received Z-Dex; this offers significant durable disease response rates with acceptable TRM.

25
UI - 12028033
AU - Rasmussen T; Hudlebusch HR; Knudsen LM; Johnsen HE
TI - FGFR3 dysregulation in multiple myeloma: frequency and prognostic relevance.
SO - Br J Haematol 2002 Jun;117(3):626-8
AD - Department of Haematology L 54P4, Herlev Hospital, University of Copenhagen, DK-2730 Herlev, Denmark. thra@herlevhosp.kbhamt.dk
The t(4:14) translocation affects two potential oncogenes, FGFR3 and MMSET, in multiple myeloma (MM). We investigated the frequency of FGFR3 dysregulation and its prognostic value in MM. FGFR3 mRNA levels were determined in 110 diagnostic bone marrow (BM) samples from MM patients. In addition, selected BM samples were screened for elevated MMSET mRNA levels. 14.5% (16/110) of MM BM samples showed dysregulated FGFR3 expression. Follow-up of 76 MM patients showed no significant difference between FGFR3 dysfunction and survival (P = 0.3) or correlation with known prognostic factors. Further, no linear relation was observed between FGFR3 and MMSET levels.

26
UI - 12028036
AU - Voena C; Locatelli G; Castellino C; Omede P; Ladetto M; Zappone E;
TI - Milani R; Perfetti V; Boccadoro M; Pileri A; Lusso P; Villa C; Malnati M; Corradini P Qualitative and quantitative polymerase chain reaction detection of the residual myeloma cell contamination after positive selection of CD34+ cells with small- and large-scale Miltenyi cell sorting system.
SO - Br J Haematol 2002 Jun;117(3):642-5
AD - Department of Haematology, Laboratory of Molecular Haematology, Istituto H.S. Raffaele, Milan, Italy.
The purging efficacy of the Miltenyi sorting system was evaluated by qualitative and TaqMan quantitative polymerase chain reaction (PCR) in myeloma patients, using immunoglobulin genes. After small-scale selection, qualitative PCR showed that in 6 of 12 leukaphereses myeloma cells were no longer detectable. Envisaging a possible clinical application, the leukaphereses from three patients underwent large-scale selection. Qualitative PCR showed that myeloma cells were still detectable. Quantitative PCR, performed in two patients, showed a tumour depletion of 1 and 2 logs respectively. Although numbers are small, the promising results obtained with small-scale selection were not reproduced in large-scale experiments.

27
UI - 12028037
AU - Morris TC; Magill MK; Drake M; Price S; Ranaghan L; Bridget S; Jordan
TI - AE; Irvine AE The endogenous granulocyte colony-stimulating factor response following autologous peripheral blood stem cell transplantation is impaired in patients with myeloma.
SO - Br J Haematol 2002 Jun;117(3):646-9
AD - Department of Haematology, Belfast City Hospital, Lisburn Road, Belfast BT9 7AB, Northern Ireland, UK. curly.morris@bll.n-i.nhs.uk
Granulocyte colony-stimulating factor (G-CSF) levels were studied in 23 patients (10 myeloma, 13 relapsed Hodgkin's disease, non-Hodgkin's lymphoma or germ cell tumours), post autologous peripheral blood stem cell transplantation (PBSCT). The two groups had similar previous chemotherapy and numbers of CD34+ cells transplanted. All patients received G-CSF by inj

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