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PubMedDate not supplied

Chromosome 1 abnormalities in multiple myeloma.

Multiple myeloma (MM) is a malignancy of the terminally-differentiated B cells and accounts for 10% of all hematological malignancies. Chromosome 1 aberrations are frequently described, the short arm being preferentially involved in deletions and the long arm in gains. The abnormalities were identified in the bone marrow of 37 MM patients by conventional cytogenetics. Fluorescence in situ hybridization (FISH) was used to confirm the presence of the abnormalities and to better characterize them. Chromosome 1 abnormalities were grouped into 4 categories: balanced translocations, deletions, amplifications and jumping translocations (JT). Breakpoints involved in balanced translocations were randomly distributed. The smallest region of overlap for deletions was 1p11 --> 1p21 (present in 27% of the patients) and for gains 1q31 --> 1qter (present in 54% of the patients). The whole long arm was found to be the donor segment for the majority of patients with JT, the most frequent recipients being chromosomes 16 and 19. Our results share some similarities with those obtained for 143 published patients studied by FISH. Band 1p21 was found to be frequently deleted, leading to the assumption that a 1p deletion could lead to hemizygosity of at least 1 tumor suppressor gene. Two regions of 1q showed preferential gains: q12 to q22 and q31 to q42; these amplifications could induce the overexpression of 1 or more oncogenes. In conclusion, our results confirm that chromosome 1 abnormalities play an important role in the pathogenesis of multiple myeloma.

Chromosome Aberrations↗

PubMed2003

Management of renal dysfunction in multiple myeloma.

Multiple myeloma is frequently associated with renal dysfunction. In addition, it has been shown that the presence of renal failure indicates a higher tumor burden and consequently more aggressive disease. Patients who are diagnosed with renal insufficiency should be aggressively treated because reversal of renal insufficiency results in survival outcomes similar to patients who have normal renal function at diagnosis. However, the presence of renal impairment could add significantly to the morbidity of these patients and make it difficult to tolerate aggressive treatment regimens. Therefore, the treatment approach to this group of patients should include a thorough understanding of the feasibility and outcomes of the various antimyeloma treatments that are available, including newer options such as thalidomide. We recommend the following sequence of treatment in newly diagnosed patients with multiple myeloma with renal insufficiency (creatinine > 2 mg/dL): correction of hypercalcemia with full-dose bisphosphonates in patients with hypercalcemia, induction therapy that may be initiated before correction of hypercalcemia with bolus VAD (vincristine 2 mg, doxorubicin 40 mg/m(2), dexamethasone 40 mg on days 1-4, 9-12, and 17-20), and stem cell collection (cyclophosphamide 2.5-3 g/m(2)) with high-dose melphalan (140-150 mg/m(2)) with autologous stem cell transplant. Dialysis support should be considered whenever necessary for all newly diagnosed patients if renal function does not improve with aggressive initial therapy. For patients who develop renal insufficiency later in the course of the disease, therapeutic options need to be tailored to the patient's treatment history, disease status, and performance status.

Antineoplastic Agents↗

PubMed1995

Engineered anti-CD38 monoclonal antibodies for immunotherapy of multiple myeloma.

Multiple myeloma is a malignancy of plasma cells for which there is no effective treatment. To develop an immunotherapeutic agent, we have raised a high affinity mAb (AT13/5) against CD38, one of the few well-characterized surface Ags present on myeloma cells. Since murine monoclonals have many disadvantages as human therapeutics, we prepared two engineered forms of the Ab: a CDR-grafted humanized IgG1 and a chimeric FabFc2 (mouse Fab cross-linked to two human gamma 1 Fc). To retain affinity in the humanized Ab, a number of changes were required to the human framework regions of the heavy chain. In particular, through systematic mutagenesis and computer modeling, we identified a critical interaction between the side chains of residues 29 and 78, which may be important for the humanization of other Abs. The properties of the humanized IgG1 and FabFc2 constructs were compared in a series of in vitro tests. Both constructs efficiently directed Ab-dependent cellular cytotoxicity against CD38-positive cell lines, but C was activated only poorly. Neither construct caused down-modulation of CD38, nor did they affect the NADase activity of CD38. Despite their differing structures, both Abs showed similar activity in most assays, although the humanized IgG1 was more potent at inducing monocyte cytotoxicity. These data represent the first direct comparison of CDR-grafted and chimeric FabFc2 forms of the same Ab, and offer no support for the perceived advantages of the FabFc2. These Abs show promise for therapy of multiple myeloma and other diseases involving CD38-positive cells.

ADP-ribosyl Cyclase↗

PubMed1995

[Evaluation of treatment of anemia with erythropoietin in patients with multiple myeloma].

Multiple myeloma is very frequently associated with anaemia which has the character of hypo-proliferative anaemia of chronic diseases. In this type of anaemia the erythropoietin formation is frequently inadequate. According to data in the literature pharmacological doses of erythropoietin lead to an increase of the haemoglobin concentration in blood. Erythropoietin (Eprex Cilag) was administered to 11 patients whose haemoglobin concentration was lower than 100 g/l. The results from 10 patients were finally evaluated. During the first month all patients were given erythropoietin - 150 U/kg three times per week. Unless during the first month of treatment the haemoglobin concentration increased by 10 g/l, the dose was doubled to 300 U/kg. In patients where the haemoglobin value had risen above 120 g/l, the authors assessed an individual maintenance dose. In case three-month erythropoietin treatment did not lead to an increase of haemoglobin by 20 g/l as compared with the baseline value, erythropoietin administration was discontinued. The haemoglobin concentration increased by 20 g/l in a total of 8 (80%) of 10 evaluated patients. In all five patients where the haemoglobin concentration increased by 20 g/l during the first month, the endogenous erythropoietin concentration was less than 60 U/l. In another three patients the mentioned therapeutic response was recorded only during the 2nd or 3rd month of treatment after the erythropoietin dose had been increased. These three patients had higher baseline concentrations of endogenous erythropoietin, 100 to 350 U/l. During treatment no undesirable effects of erythropoietin were observed. Erythropoietin is a useful drug for anaemic patients with the diagnosis of multiple myeloma. According to the results of the authors work and data in the literature it is obvious that in patients with endogenous serum erythropoietin below 100 U/l a rapid riae of haemoglobin can be observed already during the first month. Patients with a higher baseline concentration of endogenous erythropoietin (100 to 500 U/l) respond less frequently to treatment and larger doses of erythropoietin must be administered. In patients with an erythropoietin value above 500 U/l there is a minimal probability that a response will be produced.

Adult↗

PubMed1995

Therapy of anemia in patients with multiple myeloma.

Multiple myeloma is very frequently associated with anemia which has the character of hypoproliferative anemia of chronic diseases. In this type of anemia there is often insufficient production of endogenous erythropoietin. According to literature pharmacological doses of erythropoietin result in the increase of blood hemoglobin concentration. Erythropoietin (Eprex Cilag) was given to 11 patients whose hemoglobin concentration in blood was lower than 100 g/l. 10 patients could be evaluated at the end of the study. Within the first month all patients were given erythropoietin in the dose of 150 U/kg 3 times a week. The dose was doubled, when the blood hemoglobin concentration did not increase by more than 10 g/l within the first month. In patients with hemoglobin level above 120 g/l we were trying to find the individual maintenance dose. In patients who had not reached a blood hemoglobin concentration increase of at least 20 g/l, as compared with the initial level, further erythropoietin administration was stopped. The concentration of hemoglobin increased of 20 g/l in 8 (80%) out of 10 patients evaluated. All 5 patients who responded within the first month, had had pretreatment concentration of endogenous erythropoietin below 60 U/l. Three other patients had not been responding before their dose of erythropoietin was increased in the 2nd and 3rd months of therapy. The therapy response appeared only in the 2nd and the 3rd months of treatment. These 3 patients had higher pretreatment concentrations of endogenous erythropoietin, from 100 to 350 U/l. During the treatment no adverse effects of erythropoietin were observed. Erythropoietin is a useful drug for anemic patients with the diagnosis of multiple myeloma. According to the results mentioned above and also according to the data from literature it is evident that in patients with the endogenous blood erythropoietin value below 100 U/l it is possible to expect a sudden rise in hemoglobin concentration already within the first month. Patients with a higher concentration of endogenous erythropoietin (100 to 500 U/l) respond to the therapy less frequently and for the increase in hemoglobin it is necessary to give higher doses of erythropoietin. Patients with the initial value of erythropoietin above 500 U/l are not likely to respond.

Adult↗

PubMed2002

Expression of parathyroid hormone-related protein (PTHrP) in multiple myeloma.

Multiple myeloma is a plasma cell neoplasia often associated with multiple skeletal lesions and hypercalcemia. Several cytokines, including interleukin (IL)-1, IL-6 and tumor necrosis factor-beta (TNF-beta), derived from myeloma cells are thought to accelerate osteoclastic bone resorption and cause hypercalcemia through a paracrine mechanism. We report on a case of a 69-year-old man with multiple myeloma associated with hypercalcemia and advanced osteolytic lesions. After bisphosphonate treatment and MP (melphalan and prednisolone) therapy, the patient's serum calcium level was successfully but transiently recovered to the normal range. Biochemical analysis showed a remarkable increase in serum parathyroid hormone-related protein (PTHrP; 3.7 pmol/L) and IL-6 (22.0 pg/mL). On the other hand, parathyroid hormone and 1alpha,25(OH)2 vitamin D3 were suppressed. By immunohistochemistry and in situ hybridization on aspiration-biopsied bone marrow clot sections, PTHrP mRNA and protein were detected in the cytoplasm of myeloma cells. The rate of PTHrP-positive myeloma cells was estimated to be at least one-third. Since PTHrP can, as an endocrine factor, systemically act on bone and kidney, hypercalcemia in this case might have been caused through both local osteolytic hypercalcemia and humoral hypercalcemia of malignancy mechanisms.

Aged↗

PubMed2000

Recent advances in multiple myeloma.

Multiple myeloma is the second most common hematologic malignancy, with approximately 15,000 new cases each year in the United States. Our understanding of the pathophysiology underlying myeloma continues to expand, but the cause of this plasma cell dyscrasia remains unclear. Though controversy remains regarding a possible viral cause of myeloma, evidence suggesting a role for the human herpesvirus-8 is mounting. The roles of cytogenetic abnormalities as well as aberrant angiogenesis and cytokine expression in the etiology of myeloma continue to be explored and may lead to future therapeutic strategies. Transplantation in myeloma is rarely curative but offers clinical benefit not only for young but possibly for older myeloma patients as well. Newer bisphosphonates may offer greater ease of administration, improved efficacy, and possibly even enhanced antitumor effect. Finally, thalidomide offers significant clinical benefit to patients with myeloma previously refractory to multiple agents, and its role in early stages of the disease is under investigation.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2026

Comprehensive Analyses of SOX7 Provide Novel Insights on Its Tumor Suppressor Role and Its Target Genes with Therapeutic Implications in Multiple Myeloma.

Multiple myeloma (MM) is an incurable hematological malignancy. SOX7, located within the recurrently deleted 8p23.1 region in MM, is suggested to act as a tumor suppressor. We characterized SOX7 through genetic, epigenetic, and functional analyses in MM cell lines. SOX7 was frequently silenced due to deletion and/or promoter hypermethylation. Ectopic SOX7 expression in KMS-18 and MM.1S cell lines caused a progressive decline in SOX7-transduced cells and induced G1 cell cycle arrest and/or apoptosis. Although SOX7 re-expression did not enhance bortezomib efficacy, treatment with the pan-histone deacetylase inhibitor panobinostat induced G1 arrest, promoted apoptosis, and increased SOX7 expression in MM.1S cells. Whole-transcriptome sequencing identified G1/S progression-related Wnt/β-catenin pathway genes as major SOX7-regulated targets, while ChIP-Seq analysis revealed widespread genomic SOX7 occupancy in MM.1S. Flow cytometric analysis of permeabilized bone marrow tumor cells from newly diagnosed and relapsed MM patients demonstrated generally low SOX7 protein expression. Collectively, these results indicate that SOX7 functions as a tumor suppressor in MM, and its inactivation promotes cell cycle progression. The anti-myeloma effects of panobinostat in MM.1S cells may be partially mediated through SOX7 induction.

Multiple Myeloma↗

PubMed2006

Vincristine, doxorubicin, and dexamethasone or thalidomide plus dexamethasone for newly diagnosed patients with multiple myeloma?

Multiple myeloma (MM) is a malignant plasma cell tumor that is distributed at multiple sites within the bone marrow compartments. High-dose dexamethasone regimens [including vincristine, doxorubicin, and dexamethasone (VAD) chemotherapy] induce rapid responses, and have resulted in improved survival for many patients when followed by intensive therapy with autologous stem cell support early in the disease course. However, VAD have several disadvantages including the need for an intravenous indwelling catheter, which predisposes patients to catheter-related sepsis and thrombosis; most of the activity of VAD was from high-dose dexamethasone component. We enrolled all patients who fulfilled entire criteria for MM during the period between January 1997 and December 2005. The present study is a descriptive, retrospective, longitudinal, and observational one. The frequency of response (CR, VGPR/NCR, and PR) in the group of thalidomide and dexamethasone was 84.3% (CR 18.75% VGPR/NCR 18.75%, and PR 46.8%) being higher than VAD, 55% (CR 16%, VGPR/NCR 5%, and PR 34%). P = 0.0005. In summary, we conclude Thal/dex is an effective therapy in newly diagnosed MM inducing objective responses in over 84.3%.

Aged↗

PubMed1997

[Prognostic factors of multiple myeloma].

Multiple myeloma is a heterogeneous disease with survival ranging from a few months to many years. Several clinical parameters (S beta 2-M) are a direct expression of the tumor burden and have been shown by univariate analysis to be related to patient survival. Durie and Salmon developed a myeloma staging system that analyzed the presenting clinical features, response to treatment and survival duration. But this classification is not related to the intrinsic malignancy (labeling index). Many new parameters (genetic alterations, plasma cell evaluation; serum marqueurs, immune dysregulation) related to patient response to chemotherapy and survival duration have been identified. However, they have not yet been included in standard staging and compared with the recognized prognostic parameters in multivariate analysis. There is a need to create a new international myeloma staging system based on biological features of the disease.

Humans↗

PubMed2005

Role of allogeneic stem cell transplantation in multiple myeloma.

Multiple myeloma is currently incurable using standard treatment regimens. While the introduction of high-dose chemotherapy with autologous stem cell rescue has been shown to increase overall survival when compared with chemotherapy alone, this strategy is palliative. Allogeneic stem cell transplantation provides the potential for long-term disease-free survival in a small proportion of patients, although its application has been limited by procedure-related mortality, reflecting the intensive myeloablative conditioning given. Recently, reduced intensity conditioning regimens have been developed in an attempt to reduce toxicity whilst preserving the allogeneic graft-versus-myeloma effect, therefore maintaining the potential for disease eradication. This review aims to examine the current position of allogeneic transplantation in the management of myeloma.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1997

Detection of multidrug resistance gene expression in multiple myeloma.

Multiple myeloma is a disease which is generally considered responsive to chemotherapy; however, essentially all patients who respond to drug treatment will relapse and die of drug-resistant disease. This disease is therefore considered a paradigm for studying the development of acquired drug resistance in the clinic. Natural product agents are frequently used in the treatment of myeloma, especially vincristine and doxorubicin. Studies using human myeloma cell lines have shown that the MDR1 gene product, P-glycoprotein (Pgp), is responsible for conferring drug resistance to natural products and glucocorticoids. We have developed assays to measure the expression of MDR1/Pgp in human myeloma specimens. These assays include immunocytochemistry, flow cytometry, and RT/PCR. Human myeloma cell lines, 8226/Dox, that are resistant to natural product agents and overexpress MDR1/Pgp are important for standardizing results and offer a means of comparing inter- and intra-patient results. Assays which measure both the presence and function of Pgp are necessary to determine the role of Pgp in clinical drug resistance in patients with myeloma.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMedDate not supplied

The presence of circulating clonal CD19+ cells in multiple myeloma.

Multiple myeloma (MM) is a B-cell malignancy characterized by the expansion of mature plasma cells (PC) localized in the bone marrow (BM). Several studies have identified circulating clonotypic CD19+ cells at a differentiation stage preceding the PC. The level of circulating clonotypic CD19+ cells is highly variable but generally low. Circulating clonotypic cells respond well to induction therapy, although a small subset within the CD19 compartment is resistant even to high-dose chemotherapy. The clonal CD19+ cells represent an ongoing differentiating population ranging from memory B-cells to plasmablasts. However, a clonal relationship gives no proof of malignant potential, and whether or not clonotypic precursor cells are involved in the disease process is a subject of intense debate. Translocations involving the immunoglobulin locus (14q32) are an early non-transforming event common to both monoclonal gammopathy of undetermined significance (MGUS) and MM introduced at the memory B-cell level. At the plasmablast stage, a phenotypic transformation occurs with downregulation of CD19 and upregulation of myeloma specific markers such as CD56, CD117 and CD28. Translocations involving the isotype-switch machinery and the introduction of tumor-specific markers at the plasmablast stage suggest that the clonal CD19+ memory B-cells and CD19+ plasmablasts are non-malignant, but immortalized relatives that gave rise to myeloma. A final proof of the malignant potential of CD19+ clonotypic cells might await the identification of the molecular events causing the transformation in myeloma.

Antigens, CD19↗

PubMed2006

Thalidomide in multiple myeloma.

Multiple myeloma is an incurable bone marrow cancer, the treatment of which is notoriously difficult. Only modest advances have been achieved using complex polychemotherapeutic regimens, transplant strategies and supportive therapy. In 1999, when new drugs for myeloma were urgently needed, thalidomide was introduced and opened up a completely new line of therapy for the disease. Although the mechanism of action is not yet completely understood, thalidomide has demonstrated efficacy in patients with refractory, relapsed myeloma, even in late-stage cases. This article reviews the current knowledge of thalidomide in myeloma treatment, focusing especially on the possible mechanisms of action, clinical results and adverse events of this drug.

Humans↗

PubMed1992

The epidemiology of multiple myeloma.

Multiple myeloma is a relatively rare cancer that primarily affects older individuals. In the United States, the highest rates of myeloma are found in black individuals and these rates continue to outpace the rate of myeloma in white individuals. The causes of myeloma are largely unknown. The strongest potential risk factors include radiation and agricultural exposures.

Environmental Exposure↗

PubMed2000

Autologous and allogeneic stem cell transplantation in multiple myeloma.

Multiple myeloma is still an incurable disease. The standard conventional chemotherapy comprises melphalan and prednisone (MP). Combination chemotherapy regimens could not improve the median survival of 36 months observed with MP. In the French IFM90 study, HD therapy with TBI plus melphalan 140 mg/m2 was shown to prolong overall survival and progression-free survival compared to conventional treatment. Nonetheless, most patients eventually succumb due to disease progression. Allogeneic transplantation may induce long-term remissions and even cure, but is hampered by a high transplantation-related mortality (TRM). Currently, efforts are made to reduce this TRM and to evaluate the graft-versus-myeloma effect.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Immunogenicity and cross-reactivity with idiotypic IgA of VH CDR3 peptide in multiple myeloma.

Multiple myeloma idiotypic protein is clone-specific and therefore represents an ideal tumour antigen for immune targeting. In this study we determined whether a synthetic peptide corresponding to the autologous idiotypic VH CDR3 sequence could elicit peptide-specific immune responses in a patient with IgA myeloma. Not unlike B-cell lymphoma, the immune repertoire of the patient contained T cells capable of mounting proliferative and cytotoxic responses to antigen-presenting cells loaded with the CDR3 peptide. Furthermore, the T cells were also able to secrete interferon-gamma upon peptide rechallenge. Antigen recognition by peptide-primed T cells was MHC dependent and could be blocked by antibodies to both monomorphic MHC class I and class II molecules. These results therefore indicate the presence of T-cell epitopes on the VH CDR3 sequence. In addition, CDR3 peptide-primed T cells were also able to mount similar immune responses when rechallenged with the intact IgA idiotypic protein, suggesting that functional T-cell epitopes had been derived from the CDR3 sequence of the idiotypic protein. Our results therefore provide a new perspective to the immunogenicity of the idiotypic protein in myeloma.

Cell Division↗

PubMed2006

Ten years and counting: so what do we know about t(4;14)(p16;q32) multiple myeloma.

Multiple myeloma is a genetically heterogenous disease with a wide variety of characterized genetic aberrations. Until recently, the impact of these aberrations on patient outcome was not known. However, in the last 5-10 years, several genetic markers have been linked to patient outcome. One of the strongest predictors of outcome identified to date is t(4;14)(p16;q32). Although this translocation is tightly linked to chromosome 13 deletions, another poor prognosis marker, it is becoming apparent that the translocation and not the deletion of 13 is the important factor. Unfortunately, despite the known association with outcome, an understanding of the mechanism(s) whereby the translocation contributes to developing and maintaining this aggressive form of myeloma remains elusive.

Carrier Proteins↗