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  • VAD followed by VMCP: an alternative regimen for multiple myeloma.
    Med Oncol 2002;19(2):105-8 by Wadhwa J, Kumar L, Kochupillai V.
    In patients with multiple myeloma, a good complete response rate and disease-free survival may be achieved with sequential chemotherapy using VAD and VMCP, which is an alternative effective and less expensive treatment regimen. This regimen thus assumes particular significance in developing nations like India, where the majority of patients with myeloma cannot afford the cost of high-dose chemotherapy with stem cell rescue.

  • Expression of MDR1/P-glycoprotein, the multidrug resistance protein MRP, and the lung-resistance protein LRP in multiple myeloma.
    Med Oncol 2002;19(2):87-104. Author: Schwarzenbach H.
    The purpose of this study was to determine the incidence of three genes associated with multidrug resistance (MDR) in multiple myeloma in relation to treatment status. MDR1/Pgp (P-glycoprotein) expression was detected in 41% of 93 myeloma samples. Generally, the incidence of MDR1/Pgp expression was higher in pretreated samples, and treatments with doxorubicin and/or vincristine were more effective in MDR1/Pgp expression than with alkylating agents. A significant association was observed between MDR1 /Pgp-positiveness and the ability of verapmil to increase doxorubicin sensitivity, suggesting functional relevance of MDR1/Pgp expression. MRP (multidrug resistance protein) expression was detected in 20.5% of 88 myeloma samples, in 26% at the mRNA level analyzed by quantitative reverse transriptase-polymerase chain reaction, and in only 3 of 79 samples by immunohistochemistry. LRP (lung-resistance protein) protein expression was observed in 12.5% of 72 myeloma samples. MRP and LRP expression was similar in samples with and without prior therapy. Approximately 80% of the myeloma samples with detectable mRNA expression of MDRI and MRP exhibited low expression levels corresponding to < 10% of the Pgp- and MRP-overexpressing multidrug-resistant human myeloma cell lines 8226/Dox6 and 8226/DOXint40c, respectively. Some normal bone marrow samples showed higher levels of MRP mRNA as compared to myeloma specimens, whereas MDRI mRNA expression in normal bone marrow was much lower (< or = 5%) than that in 8226/Dox6. These findings indicate a requirement to develop single-cell assays for MRP detection in multiple myeloma that are more sensitive than immunohistochemistry and might be useful to evaluate the incidence of genes associated with MDR.

  • Consolidation therapy of multiple myeloma with thalidomide-dexamethasone after intensive chemotherapy.
    IMF Scientific Advisor, Raymond Alexanian, Weber D, Giralt S, Delasalle K.
    The University of Texas M.D. Anderson Cancer Center, Houston, Texas, US

    Background:
    After myeloablative therapy for multiple myeloma, progression-free survival is shorter for disease in partial remission rather than complete remission. In an attempt to induce more frequent complete remission, we assessed thalidomide-dexamethasone in patients with stable partial remission after intensive therapy. PATIENTS AND METHODS: Twenty-one patients with multiple myeloma were identified with disease in stable partial remission after prior intensive therapy. Thalidomide-dexamethasone was given within 15 months after intensive therapy provided myeloma protein production had been reduced by >75% to a constant level for at least 4 months. Thalidomide was begun at a dose of 100 mg each evening, with increments of 50 mg every 7 days to a maximum of 300 mg. Dexamethasone was given concurrently in a dose of 20 mg/m(2) each morning for 4 days on days 1-4, 9-12 and 17-20, with resumption on day 35. The combination was continued for at least 3 months and patients with marked reduction of myeloma were maintained on thalidomide alone until disease progression.

    Results:
    Marked further reduction of myeloma by at least 90% occurred in 12 patients (57%), including four (19%) with disease converted to complete remission. Disease has progressed in six of 21 patients, whose median total remission was 22 months. Common side effects of constipation, fatigue, paresthesias and dry skin were mild, dose-related and reversible.

    Conclusions:
    The combination of thalidomide-dexamethasone reduced tumor mass markedly in 57% of patients with stable, residual disease after myeloablative therapy. Such an effect may produce longer disease-free survival and/or preserve tumor sensitivity to later retreatment with previously effective drugs.


  • avb3 integrin engagement enhances cell invasiveness in human multiple myeloma
    Roberto Ria, Angelo Vacca, Domenico Ribatti, Francesco Di Raimondo, Francesca Merchionne, Franco Dammacco
    Correspondence: Professor Angelo Vacca, M.D., Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, Policlinico, piazza Giulio Cesare 11, 70124 Bari, Italy. Phone: +39.080.5593106. Fax: +39.080.5478820.

    Background and Objectives.
    In multiple myeloma (MM), the mechanisms used by plasma cells to invade locally and metastasize are thought to be similar to those developed by solid tumors and include cell proliferation and secretion of extracellular matrix (ECM)&endash;degrading enzymes following adhesion to ECM proteins. We studied these mechanisms in fresh bone marrow plasma cells of patients with MM after adhesion to the ECM proteins vitronectin (VN) and fibronectin (FN).

    Design and Methods.
    The ability of bone marrow plasma cells to adhere to VN and FN and the consequent formation of focal adhesion plaques on the cell surface, their composition and phosphorylation of several signal transduction proteins, cell proliferation and secretion of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) and urokinase-type plasminogen activator (uPA) were studied.

    Results.
    Plasma cells adhered to immobilized VN and FN. Adhesion was fully prevented by neutralizing anti-avb3 integrin antibody. Integrin engagement caused aggregation of the plaques, which contained the b3 integrin subunit, some cytoskeletal proteins, tyrosine kinases, the Grb-2 adapter protein, and mitogen-activated protein (MAP) kinase. Free and immobilized VN and FN stimulated cell proliferation and the production and the release of uPA, and increased the release of the activated forms of MMP-2 and MMP-9 in an avb3 integrin-dependent manner.

    Interpretation and Conclusions.
    This ability of myeloma plasma cells to interact with VN and FN via avb3 integrin engagement suggests a novel mechanism for their invasion and spreading, since this interaction allows them to adhere to the substratum and enhances their proliferation and protease secretion.

  • Oral melphalan at diagnosis hampers adequate collection of peripheral blood progenitor cells in multiple myeloma
    IMF Advisor Mario Boccadoro, Antonio Palumbo, Sara Bringhen, Franco Merletti, Giovannino Ciccone, Lorenzo Richiardi, Cecilia Rus, Alessandra Bertola, Luisa Giaccone, Paola Omedè, Pellegrino Musto, Alessandro Pileri
    Background and Objectives.
    Since optimal collection of peripheral blood progenitor cells (PBPC) remains crucial for high-dose therapy in patients with multiple myeloma (MM) in relapse phase or refractory to chemotherapy, we evaluated several variables that may influence mobilization.

    Design and Methods.
    Eighty-nine patients who underwent a standard mobilization procedure with cyclophosphamide (3 g/m2) and growth factors entered the study. A composite collection totalling at least 2x106 CD34+/kg was defined as a sufficient yield: 59 patients achieved an adequate collection. A reliable factor to predict adequate yields was prior therapy: an adequate collection was obtained in 92% of patients treated with conventional non-alkylating therapy (VAD-based regimens), in 56% treated with oral melphalan and in 23% who had received intravenous melphalan.

    Results.
    The three groups were similar for most clinical features. After adjustment for several potential confounders, the probability of an adequate PBPC collection remained higher in the group treated with non-alkylating agents, with an odds ratio (OR) of 6.14 (95% confidence interval, CI=1.34, 28.13) and lower in those treated with intravenous melphalan (OR=0.08; CI=0.01-0.61), when compared to the group treated with oral melphalan. Among the other prognostic factors (stage, percentage of bone marrow plasma cells, b2-microglobulin, labeling index, isotype, monoclonal component, Bence-Jones proteinuria) evaluated at diagnosis, there was no clear association with progenitor cell yield.

    Interpretation and Conclusions.
    In conclusion, patients who are potential candidates for high-dose therapy with PBPC support should not receive conventional alkylating therapy, even orally. Alternatively, progenitor cells should be collected early in the course of MM.

  • Interstitial deletions at the long arm of chromosome 13 may be as common as monosomies in multiple myeloma. A genotypic study.
    Josep F. Nomdedéu, Adriana Lasa, Josep Úbeda, Giuseppe Saglio, Mar Bellido, Sílvia Casas, Maria J. Carnicer, Anna Aventín, Anna Sureda, Jorge Sierra, Montserrat Baiget|
    Background and Objectives.
    Deletions at the long arm of chromosome 13, mostly at the q14, and monosomy of chromosome 13 are described to be common in multiple myeloma (MM). 13q- has been associated with an adverse outcome and it has been proposed as one of the most important prognostic factors for MM patients. Deletions of 13q14 are rare in monoclonal gammopathy of undetermined significance (MGUS) and are thus believed to be associated with the development of the full myeloma phenotype.

    Design and Methods.
    A genotyping analysis on purified neoplastic plasma cells was performed on 14 consecutive MM cases to determine the minimally deleted region at chromosome 13. Freshly obtained bone marrow was analyzed by flow cytometry in order to establish the percentage of plasma cell infiltration (CD38+BB4+CD56+/-CD19-). Neoplastic enrichment was carried out using BB4 coatedimmunomagnetic beads. This method allowed us to monitor the enrichment process. DNA obtained from the enriched neoplastic population and DNA from the clean fraction was amplified using combination sets of chromosomes 12 and 13. Amplimers were run on acrylamide gels, analyzed by automatic fluorescence quantification, and their size determined using the software programs Genescan and Genotyper.

    Results.
    In 11 patients electropherograms were suggestive of loss of heterozygosity (LOH) for polymorphic markers located at the long arm of chromosome 13. Four patients showed monosomy and 7 had interstitial deletions in the telomeric region. LOH was not evidenced at chromosome 12 in any sample. The minimal region with deletion was defined by the markers D13S159 (13q32.2, centromeric) and D13S1267 (13q32.3, telomeric). A gene with a potentiallypathogenic role may be located in this very small region. Three patients did not show LOH at chromosome 13 by genotypic analysis; however, in one of these, proximal deletion at the long arm of chromosome 13 (13q2.1-2.2) was demonstrated by comparative genomic hybridization (CGH).

    Interpretation and Conclusions.
    These findings suggest that interstitial deletions of the long arm of chromosome 13 may be more common than previously recognized. The methodologic approach reported in this work may simplify LOH analysis in MM patients. The potential uses of genotyping analysis in risk stratification remain to be investigated.

  • Adenovirus transduction to effect CD40 signalling improves the immune stimulatory activity of myeloma cells
    Asad Bashey, Mark J. Cantwell, Thomas J. Kipps
    British Journal of Haematology
    Vol. 118 Issue 2 Page 506 August 2002
    Neoplastic plasma cells from patients with myeloma fail to stimulate an effective anti-myeloma immune response, which may be in part due to their deficient expression of immune accessory molecules.

  • A molecular study of the t(4;14) in multiple myeloma.
    Kathryn Sibley, James A. L. Fenton, Ann M. Dring, Andrew J. Ashcroft, Andrew C. Rawstron, IMF Scientific Advisor Gareth J. Morgan
    British Journal of Haematology
    Vol. 118 Issue 2 Page 514 August 2002

    Summary.
    The t(4;14) translocation is found in approximately 10% of myeloma patients and results in the deregulation of at least two genes, MMSET and fibroblast growth factor receptor 3 (FGFR3), with the formation of a fusion product between MMSET and the immunoglobulin heavy chain (IgH) locus and overexpression of FGFR3. We have analysed a series of 80 patient samples, comprising 67 multiple myeloma (MM) cases and 13 monoclonalgammopathy of undetermined significance (MGUS) cases, using RT-PCR to detect IgH-MMSET fusions. The t(4;14) translocation was detected in 7/67 (10%) myeloma cases and all seven expressed FGFR3 which was not seen in t(4;14)-negative myeloma cases. In the MGUS cases, a similar proportion of t(4;14)-positive cases was found (2/13; 15%), but none of these expressed FGFR3. All patients with detectable FGFR3 expressed both the FGFR3 IIIb and FGFR3 IIIc isoforms, the result of alternative splicing in the ligand binding domain, and exon-deleted variants of FGFR3. We also identified a cryptic splice site in MMSET which results in a 277 amino acid deletion downstream of the breakpoint on der(4). FGFR3 mutation analysis revealed no mutations in the presenting myeloma or MGUS samples. However, we also had access to paired presentation and relapse samples which had been taken from a patient 13months apart. Both samples had the t(4;14) translocation and overexpressed FGFR3, but only the relapse sample possessed the K650E mutation in the kinase domain of FGFR3. This suggests that targeted mutation in the translocated FGFR3 gene when under the control of the immunoglobulin promoters can occur and may provide one mechanism for disease progression.

  • GM-CSF and IL-12 production by malignant plasma cells promotes cell-mediated immune responses against monoclonal Ig determinants in a light chain myeloma model"
    H. R. GALEA & M. COGNÉ
    Clinical and Experimental Immunology
    Volume 129 Issue 2 Page 247 - August 2002

    Immune responses towards malignant plasma cells have clearly been demonstrated in the course of monoclonal B cell dyscrasias and shown to be mostly specific for idiotypic determinants of the monoclonal immunoglobulin (Ig). These responses are specifically efficient against lymphoma cells expressing a membrane form of the monoclonal Ig. In myeloma, such immune responses are often weak and a number of strategies are currently assayed in order to boost the cell-mediated responses against the secreted monoclonal Ig. The use of cytokines promoting Th1 responses could be helpful for the induction of anti-tumour immunity and the control of residual disease in patients treated with myeloablative therapy, and such strategies need to be evaluated.

    In a light chain myeloma model where the monoclonal Ig can only be secreted, we tried to induce protective immune responses through immunization of animals with transfected malignant plasma cells. An expression plasmid encoding GM-CSF and IL-12 proved to be highly efficient for the induction of both cytotoxic and proliferative responses after immunization of animals with transfected and irradiated tumour cells. Anti-tumour immunization according to this protocol was successful in protecting 93·4% of the animals against a subsequent tumour challenge.

  • B 2-microglobulin as a negative growth regulator of myeloma cells
    Rui Min, Zhongkui Li, Joshua Epstein, IMF Scientific Advisor Bart Barlogie and Qing Yi
    British Journal of Haematology
    Volume 118 Issue 2 Page 495 - August 2002

    Summary.
    High 2-microglobulin (2m) levels in myeloma correlate with poor prognosis. We hypothesized that 2m may affect myeloma cell growth and survival. In this study, we examined the in vitro effects of 2m on myeloma cells. Primary myeloma cells freshly isolated from patients and myeloma cell lines were used, cultured in the presence of 2m, and monitored for growth and survival. 2m suppressed the growth of primary tumour cells and myeloma cell lines (ARK-RS, ARP-1, RPMI-8226, U266, ARH-77 and IM-9). High concentrations of 2m induced apoptosis and cell cycle arrest. 2m-induced apoptosis was dependent on activation of a caspase cascade, inhibited by interleukin 6, and did not involve the surface death receptors, as receptor-neutralizing antibodies had no inhibitory effect. 2m-induced growth arrest was associated with downregulation of cyclins A and D2. Surprisingly, anti-2m antibodies did not block the effect of 2m but were synergistic with 2m, resulting in 90% growth inhibition and 70% apoptosis of myeloma cells. Whereas 2m treatment resulted in slight upregulation of surface 2m and major histocompatibility complex class I -chain expression, treatment of myeloma cells with anti-2m antibodies alone or with 2m resulted in significant downregulation of surface 2m and class I molecules, suggesting that class I molecules may be involved in signal transduction. Our data demonstrate that 2m plays an important role in regulating the growth and survival of myeloma cells in vitro and warrants further investigation to delineate the mechanisms of 2m and anti-2m antibody-induced growth regulation of myeloma cells.