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[New aspects in the clinical course determination and therapy in multiple myeloma].

Multiple myeloma can be regarded as model disease for quantification of tumor mass, investigation of tumor cell kinetics and of tumor response to therapy. The quantification of the tumor cell number allows evaluation of prognosis and monitoring of disease as well as of therapy induced responses. Treatment of multiple myeloma is primarily based on the alkylating drugs cyclophosphamide and melphalan. In recent years other cytostatic substances, also effective in the treatment of this disorder have been introduced. However, the sensitivity determination of the individual myeloma stem cells seems to be the only possible method which possibly increases the response rate significantly. In accordance with these considerations we have, in preliminary clinical investigations, observed a good correlation between the in vitro determined cytostatic drug sensitivity and the in vivo response to therapy. Further progress in the treatment of multiple myeloma is to be expected with the introduction of interferon into the therapeutic regimen. Administration of this glycoprotein has resulted in significant reduction of tumor mass in more than half of all patients treated up to this time.

Antineoplastic Agents↗

[Selected renal complications during the course of multiple myeloma].

Multiple myeloma is the most frequent dysproteinemia leading to nephropathy. The aim of the study was to analyse this complication in patients treated in nephrological departments. The study was performed in 83 patients (45 M, 38 F) aged 47-82 years in whom a diagnosis of multiple myeloma was based on clinical manifestation (weakness, subfebrile states, bone aches, loss of body weight, recurrent infections of urinary and respiratory tracts), increased number of plasmocytes in bone-marrow, presence of monoclonal protein in serum and/or urine and lesions in bone system. In a significant number of the studied patients the disease was revealed while diagnosing proteinuria as well as searching for a reason of elevated erythrocyte sedimentation rate or proteinogram abnormalities. The obtained results indicate that signs of nephropathy in the course of multiple myeloma may be the first visible symptoms of the disease. Proteinuria was observed in 79.5% of the studied patients. Bence-Jones protein was found in 41% of individuals and features of renal failure in different stages of development in 67%. Dialysis therapy was started in 3 patients with acute and 7 patients with chronic renal failure.

Aged↗

[Salvage therapy with proteasome inhibitor bortezomib for relapsed and refractory multiple myeloma].

Multiple myeloma is a malignant disease with high incidence in middle-aged and old-aged population. Bortezomib is a proteasome inhibitor which target mainly is NF-kappaB. This observation is to study the clinical treatment effect of bortezomib in one relapsed multiple myeloma (MM) patient and one primary refractory MM patient. The first patient diagnosed as IgA IIIA stage, whose state of disease became worse after 8 months of autologous peripheral blood stem cell transplantation. And the disease became further aggressive with 4 courses of chemical therapy regimen including methylprednisolone, Arsenic trioxide, dexamethasone, cyclophosphamide, mitoxantrone, VM-26. Myeloma cells in bone marrow and abnormal monoclonal immunoglobulin in blood plasma both increased. Bone destruction became severe, and there was a plasmacytoma about 5 x 6 cm on the patient's right upper chest wall. Therefore, the patient received therapy of bortezomib combined with doxrubicin, dexamethasone and thalidomide (VADT). After one course of therapy with this VADT regimen, IgA in blood plasma decreased from 54 g/L to 6.6 g/L, and abnormal plasma cells in bone marrow decreased from 40% to 0.6%, and plasmacytoma on the patient's right upper chest wall almost absorbed. But there was no obvious clinical effect after the second course of therapy of VADT, and the disease status became progressive again. The second patient was MM patient with a light chain kappa type, III B stage. There was no any effect after two courses of VAD therapy and one course of MOFP therapy. The patient acquired near complete remission after one course of treatment with VADT. Quantity of kappa protein in urine reduced from 24 - 30 g/24 hours to 1.12 g/24 hours. Blood creatinine reduced from 475.3 micromol/L to 124.2 micromol/L. Beta2-MG reduced from 161g/L to 64 g/L. And this patient got complete remission after three consecutive VADT therapy. The mainly side effects of the bortezomib regimen in the first patient include markedly lassitude, diarrhea, numbness of the end of extremities, marked increase of LDH. All the side effects could be tolerated and became disappeared after contraposing treatment and stopping the bortezomib regimen therapy. The second patient complicated with severe subacute left hemiplegia after the bortezomib dose had been increased to 1.45 mg/m2 at the third time of the first VADT course and the complication became worst at the following day. The upper limb muscle strength was only 1 grade and the lower limb muscle strength was 2 grade. Then the condition improved with the support therapy and gradually recovered after two weeks. Therefore, bortezomib is an effective target drug for therapy in refractory multiple myeloma, and more attentions to the side effects should be paid in order to deal with those side effects in time.

Adult↗

Pneumococcemia as the presenting feature of multiple myeloma.

Multiple myeloma is associated with a susceptibility to bacterial infections, specifically for encapsulated organisms such as Streptococcus pneumoniae. However, severe bacterial infection as the initial presentation of this disease has been rarely reported. The most common presenting features are anemia, lytic lesions, hypercalcemia, and renal failure. We report two cases of pneumococcal bacteremia as the initial manifestation of an underlying multiple myeloma. The first case is of a 68-year-old woman with pneumococcal pneumonia and bacteremia, presenting with a white blood cell count of 900/microL and mild anemia. Further work-up disclosed monoclonal IgG kappa and 50% plasma cells in bone marrow. Her course was complicated by acute renal failure requiring hemodialysis. The second patient is a 57-year-old man presenting with acute pneumococcal meningitis and bacteremia. Due to prior bacterial epiglottitis, further work-up disclosed IgG lambda monoclonal spike and 40% plasma cells in bone marrow. Both cases responded to antibiotic therapy without complications. These two cases add to the few patients described in the literature with pneumococcemia as the first sign of multiple myeloma. Features that were common in most of these cases, and that should lead to a suspicion of myeloma in an otherwise asymptomatic patient, are S. pneumoniae bacteremia, leukopenia, mild anemia, history of prior bacterial infections, and indirect evidence of a paraproteinemia, such as increased total protein levels with low albumin.

Aged↗

[Proteasome inhibition: a new therapeutic approach for the treatment of multiple myeloma].

Multiple myeloma is the second most common hematologic malignancy with currently 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 offer cure for the disease. Introduction of thalidomide into the therapeutic arsenal provided a breakthrough in the treatment of refractory and/or relapsing disease, however, clinical experience indicated need for alternative treatments for thalidomide resistant disease as well as for intolerant patients. Proteasome inhibitors, hallmarked by bortezomib may represent one of the much needed therapeutic options. The results of the SUMMIT investigation that involved 202 heavily pretreated patients were convincing enough to prompt the FDA to register this drug for the treatment of multiple myeloma. Its European registration is also underway. In this review, the proteasome and its inhibition as a pharmacotherapeutic avenue are introduced. The most important clinical studies employing bortezomib and its combinations are also detailed. It is the hope of the authors that bortezomib and its derivatives will soon belong to the clinical armory against multiple myeloma.

Animals↗

[A case report of variant form of multiple myeloma].

Multiple myeloma is usually manifested with multiple destructive bone lesion, plasmacytosis and monoclonal protein. Here in we report a case of IgA (lambda) multiple myeloma with hepatomegaly and anemia but without bone lesions. Differential diagnostic points among lymphoma, amyloidosis, cancer and heavy chain disease are discussed.

Anemia↗

Recent advances in the treatment of multiple myeloma.

Multiple myeloma, a clonal B-cell malignancy, accounts for 10% of all hematologic cancers. In patients with multiple myeloma, median survival is approximately 30 to 36 months with conventional therapy, but high-dose chemotherapy resulted in better outcomes in a mature randomized trial. Pamidronate and other bisphosponates, used as supportive therapy, effectively reduce the incidence of skeletal events and decrease pain. They also have a role in disease control. Ongoing trials are now addressing such issues as further intensification with tandem transplantations, timing of transplantation, and decrease of malignant cell reinfusion by positive selection. Important laboratory observations have better defined the malignant clone and its interaction with the microenvironment. These observations will be important for the treatment of myeloma in the future.

Antineoplastic Agents↗

Hypercalcemia in two cats with multiple myeloma.

Multiple myeloma is a rare malignancy in cats. While hypercalcemia is reported frequently in association with myeloma in humans and dogs, it has not been reported in cats. Two cats with hypercalcemia and multiple myeloma were treated with alkylating agents and corticosteroids. One cat was a long-term (16 months) survivor.

Adrenal Cortex Hormones↗

Enhanced T cell suppression is directed toward sensitive circulating B cells in multiple myeloma.

Multiple myeloma, a disorder typically accompanied by monoclonal immunoglobulin excess and hypogammaglobulinemia was evaluated to delineate the status of T cell regulation on malignant B cell proliferation. Intact T cells and T cell subsets previously noted by us to be suppressor (T gamma) and helper (T non-gamma) were isolated from 10 controls and 10 myeloma patients. Various concentrations of control and patient T cell subsets were mixed with control and patient B cells and stimulated with PWM. T cell effect on B cell proliferation as measured by [3H]thymidine incorporation was then determined. Myeloma T gamma cells were more effective than control T gamma cells in suppressing control or myeloma B cell [3H]thymidine incorporation. Interestingly, myeloma B cells, when added to myeloma T gamma cells, were suppressed to a greater extent than were control B cells when mixed with a similar concentration of myeloma T gamma cells. These in vitro studies suggest a complexity of B and T cell abnormalities in multiple myeloma; first, the myeloma B cells are extremely sensitive to T gamma cell suppression, and second, myeloma T gamma cells have excessive suppressor capacity. It is yet unclear whether these results are associated with an immunoregulatory response to this malignancy or represent part of the basic disease process.

B-Lymphocytes↗

The involvement of adhesion molecules in the biology of multiple myeloma.

Multiple myeloma represents a B cell malignancy characterized by a monoclonal proliferation of plasma cells. A striking feature of the disease is the tendency of the malignant plasma cells to affect mainly the bone marrow environment and to invade the peripheral blood only in the terminal stage. The growth of myeloma plasma cells is believed to be regulated by a functional interplay between the tumor cells and the bone marrow stroma, involving the action of various cytokines. This growth control is most probably mediated by close cellular contact of the myeloma cells and marrow stromal components. Therefore it can be assumed that myeloma plasma cells possess the ability to interact with the bone marrow stroma. Until now the adhesive mechanisms that may underlie this interaction, remain undetermined. We investigated the expression of several adhesion molecules on bone marrow plasma cells in myeloma patients and normal controls. Normal as well as malignant plasma cells were found to be strongly positive for the intercellular adhesion molecule ICAM-1, the fibronectin receptor VLA-4 and the lymphocyte homing receptor CD44. In addition, a much weaker expression of the second fibronectin receptor VLA-5, the laminin receptor VLA-6 and the vitronectin receptor CD51 was demonstrated. In contrast to normal plasma cells, myeloma cells can also express the neural cell adhesion molecule N-CAM. In this report we discuss the possible role of adhesion molecules in the pathogenesis and clinical evolution of multiple myeloma.

B-Lymphocytes↗

Markers of multiple hematopoietic-cell lineages in multiple myeloma.

Multiple myeloma is considered a cancer of mature plasma cells. Recent studies, however, suggest the possible involvement of early B cells and the expression of myelomonocytic antigens by myeloma cells. Using flow cytometry, we searched for evidence of the expression of genes specific for different hematopoietic lineages by tumor cells in bone marrow aspirates from 27 patients with aneuploid multiple myeloma. In addition to features characteristic of myeloma cells, we found evidence of the frequent expression by myeloma tumor cells of the pre-B-cell antigen CALLA (common acute lymphocytic leukemia antigen) (in specimens from 58 percent of patients) and of megakaryocytic (88 percent), myelomonocytic (65 percent), and erythroid (39 percent) surface markers. The proportion of tumor cells expressing the different markers varied among patients, from 2 to 100 percent of recognizable tumor cells. We conclude that cells of multiple lineages are involved in myeloma--a finding that is consistent with the hypothesis that there is a common primary neoplastic lesion for all hematologic cancers.

Aneuploidy↗

Expression and function of chemokine receptors in human multiple myeloma.

Multiple myeloma (MM) is a B cell tumor characterized by its selective localization in the bone marrow. The mechanisms that contribute to the multiple myeloma cell recruitment to the bone marrow microenvironment are not well understood. Chemokines play a central role for lymphocyte trafficking and homing. In this study we have investigated expression and functional importance of chemokine receptors in MM-derived cell lines and primary MM cells. We found that MM cell lines express functional CCR1, CXCR3 and CXCR4 receptors, and some also CCR6. Although only a minority of the cell lines responded by calcium mobilization after agonist stimulation, a migratory response to the CCR1 ligands RANTES and MIP-1 alpha was obtained in 5/6 and 4/6, respectively, of the cell lines tested. Five out of six cell lines showed a response to the CXCR4 ligand SDF-1. In addition, 3/6 cell lines migrated in response to MIP-3 alpha and IP-10, ligands for CCR6 and CXCR3, respectively. The expression of CXCR4 and CCR1 and the migration to their ligands, SDF-1, and RANTES and MIP-1 alpha, respectively, were also demonstrated in primary MM cells. These findings suggest that chemokine receptor expression and the migratory capacity of MM cells to their ligands are relevant for the compartmentalization of MM cells in the bone marrow.

Calcium↗

Pneumococcaemia as a presenting sign in 3 cases of multiple myeloma.

Multiple myeloma was diagnosed in 3 patients following episodes of pneumococcaemia associated with neutropenia and decreased serum concentration of normal immunoglobulins. Severe pneumococcal infection is commonly encountered during the course of multiple myeloma, but has not been stressed as a presenting feature of the disease.

Aged↗

Matrix metalloproteinases in multiple myeloma.

Multiple myeloma is a deadly malignancy characterized by plasma cell infiltration of bones. The resulting effect is painful "punched-out" lesions where bone is eroded and filled with myeloma cells that suppress and replace the normal marrow components. Recently it has been shown that myeloma cells produce matrix-metalloproteinase-9 (MMP-9) and MMP-2 and that accumulation of MMP-9 protein is suppressed upon expression of the heparan sulfate proteoglycan, syndecan-1. In this review, we briefly consider the potential roles for MMPs in the pathogenesis of multiple myeloma. MMPs likely have major roles in: 1) the infiltration of bone and other tissues by the myeloma cells; 2) the osteolytic bone destruction caused by overly active osteoclasts, 3) extracellular matrix remodeling by bone marrow stromal cells; 4) promoting the invasion of the endothelial cells that form neoangiogenic blood vessels necessary to sustain tumor foci; and 5) promoting the growth of myeloma cells. Effective and safe synthetic inhibitors of MMPs are available and these may prove useful in limiting the growth and spread of myeloma cells. In addition, recent insights into the suppression of MMP-9 by syndecan-1 may suggest new strategies for treatment of myeloma.

Animals↗

Antisense p53 transduction leads to overexpression of bcl-2 and dexamethasone resistance in multiple myeloma.

Multiple myeloma is a malignant proliferation of plasma cells which fail to undergo apoptosis. To understand events associated with lack of apoptosis in these cells, we studied effect of antisense p53 gene transduction in a multiple myeloma cell line, ARH77. Adeno-associated virus was used as a vector to introduce p53 cDNA in an antisense orientation driven by a herpes virus thymidine kinase promoter. We observed, that an antisense p53 (p53as) transduced cell line showed marked reduction in p53 mRNA and protein expression and increased growth when compared to the control cell lines transduced with neomycin-resistance gene or untransduced cells. There was a concomitant up-regulation of bcl-2 expression by over five-fold in p53as-transduced cells compared with controls; while there was no significant change in expression of c-myc and IL-6, genes implicated in myeloma growth. We measured apoptosis in the transduced cells by DNA end-labeling reaction which revealed decrease in apoptosis from 15.6% in control cells to 1.6% in p53as-transduced cells. Additionally, the p53as cells over expressing bcl-2 also showed resistance to killing by dexamethasone. In summary, our data demonstrates that loss of p53 function leads to myeloma cell progression and resistant phenotype through bcl-2-related mechanisms.

Apoptosis↗

Current therapy for multiple myeloma.

Multiple myeloma is an incurable plasma cell malignancy that accounts for 10% of all hematologic cancers. For decades the mainstay of therapy has been the use of melphalan and prednisone; with this regimen, the median survival is approximately 3 years. Recently, important advances were made that have substantially altered the manner in which patients with myeloma are treated. Newly diagnosed patients with good performance status are now treated with autologous stem cell transplantation, resulting in improved survival. Because of the increasing use of transplantation as initial therapy, several therapeutic issues have emerged: the role of tandem transplantation, early vs delayed transplantation, and the role of allogeneic transplantation. The pronounced activity of thalidomide in patients with refractory myeloma represents another important advance. This has prompted the study of several novel agents in the treatment of myeloma, at least 2 of which appear promising. Supportive care measures also have improved, including the use of bisphosphonates to prevent osteolytic lesions. The purpose of this review is to summarize recent advances and provide an evidence-based approach to the treatment of multiple myeloma.

Antineoplastic Combined Chemotherapy Protocols↗

[Anesthetic experiences in 3 patients with multiple myeloma].

Multiple myeloma which occurs mostly in aged people is a neoplastic proliferation of plasma cells characterized by immunoglobulin disorders. It presents various kinds of signs and complications depending on its stage and involved organs, and these complications often require surgical treatment. Risk factors to be considered include renal failure, hemorrhagic tendency, increased susceptibility to infections, hyperviscosity syndrome, anemia, and hypercalcemia. We report 5 anesthetic experiences in 3 cases with multiple myeloma.

Aged↗

The temporal bone in multiple myeloma.

Multiple myeloma is a malignant disease of the skeleton. Anatomically, any bone may ultimately come to be involved in a given case. In a literature review, no published series of temporal bone findings have been reported. In this study, oto-histopathologic changes associated with multiple myeloma are analyzed and reported in 15 temporal bones from 8 patients. The bone marrow of 13 temporal bones was involved by the tumor. Osteolysis was evident in 11 temporal bones. Serous otitis media (SOM) or purulent otitis media (POM) was seen in 13 ears with 12 showing mastoid effusions. Eight ears exhibited pathological changes in inner ears, including degeneration of the organ of Corti, atrophy of stria vascularis, decreased ganglion cells, and labyrinthine hydrops. The inner ear changes were most severe in 2 patients who had otologic symptoms. Infiltration of myeloma cells was not apparent in the middle ear mucosa or the inner ears.

Aged↗