Cancer specific Mucin-1 glycoforms are expressed on multiple myeloma

Present therapies cannot cure the large majority of patients with multiple myeloma (MM) and therefore new treatment strategies are imperative. This study analysed the different glycosylation profiles of Mucin-1 (MUC1) on MM and acute myeloid leukaemia (AML) cells using a series of anti-MUC1 antibodies. Seventy-three per cent of the MM patients had plasma cells that expressed the fully glycosylated forms of MUC1. In contrast to controls, normal bone marrow cells and AML cells, the differentiation-dependent and cancer-associated glycoforms of MUC1 were present on 59% and 36% MM tumour cells respectively. This indicated that aberrantly glycosylated MUC1 is a potential immunotherapeutic target in MM patients.     

Nonsecretory multiple myeloma

The clinical features and disease course of 29 consecutive multiple myeloma patients without monoclonal globulins are described. This variant accounted for 4.7% of all patients with this disease referred over a 17 year time span. Despite bone marrow plasmacytosis and multiple bone lesions in all, hemoglobin levels were less frequently depressed and immunoglobulin values more frequently preserved in comparison with typical myeloma patients. A low tumor mass was defined in 69%, in comparison with 24% of those with evidence of myeloma protein production. Such earlier disease contributed to the long median survival of 39 months in these patients, a duration about 1 year longer than that of typical patients.     

轻链型多发性骨髓瘤一例

患者,女性,61岁。因反复头昏,乏力,加重2个月入院。一年前,患者无明显诱因感头昏、乏力,伴活动后心悸,当时未行诊治。2个月前患者因受凉后出现咳嗽、咳痰,并发热,自服感冒药症状无缓解。且头昏、乏力加重,上一层楼即感心悸不适。查体:中度贫血貌,胸骨压痛,浅表淋巴结肿大,心肺(-),肝脾不大。实验室检查:Ｈｂ71ｇ/Ｌ,尿蛋白(),尿本周氏蛋白阳性;ＷＢＣ4.8×109/Ｌ,ＢＰＣ73×1012/Ｌ;ＩｇＧ6.14ｇ/Ｌ(8.00～15.50ｇ/Ｌ),ＩｇＡ0.16ｇ/Ｌ(0.74～2.86ｇ/Ｌ),ＩｇＭ0.21ｇ/Ｌ(0.62～2.26ｇ/Ｌ);抗λ血清和尿之间均出现一条明显沉淀线;尿素4.63ｍ…     

A staging system for multiple myeloma based on the morphology of myeloma cells

Abstract: The morphology of myeloma cells is reported to be one of the prognostic factors in multiple myeloma (MM) patients. We analyzed the prognostic factors, including morphological classification, in 292 patients with MM in order to select poor-risk patients who should be considered candidates for early intensive chemotherapy, including stem cell transplantation. Multivariate analysis was applied to 90 patients diagnosed between 1989 and 1996, because serum beta-2-microglobulin (β₂M) has been measured regularly since 1989, and showed that serum albumin, serum β₂M, and the morphology of myeloma cells predicted survival. According to these factors, patients were divided into 3 risk groups; a high-risk group (14%), a intermediate-risk group (46%) and a low-risk group (40%). There were significant differences between survival times in these 3 groups (median survival: high-risk, 16; intermediate-risk, 22; and low-risk, 44 months).     

Genetics of multiple myeloma

In recent years, we have seen an explosion in knowledge of the genetics and cytogenetics of the plasma-cell neoplasms. This chapter will deal with these advances and will place them in the integrative context of the pathophysiologic basis of the disease, and will discuss the important clinical implications of these abnormalities. We have learned that myeloma can be classified into increasingly definable subgroups that follow a basic global hierarchical grouping. All gene expression profiling strategies have come to similar conclusions and confirm the subgroups previously identified by karyotype, molecular cytogenetics and other genetic studies. At the top level there are two major pathogenetic pathways for the development of plasma cell tumors: one that is associated with hyperdiploidy and one that is characterized by the presence of chromosome translocations involving the immunoglobulin heavy chain locus (IgH). These translocations are seen in up to 60% of patients, but involve a common recurrent chromosome partner in only 40-50% of patients. Several genetic markers are now shown to be associated with a shortened survival. Of these, the most common ones include abnormalities (deletion and monosomy) of chromosome 13, the global state of hypodiploidy and abnormalities of chromosome 1. Many of the translocations observed in MM are also seen in monoclonal gammopathy of undetermined significance (MGUS), even in individuals without progression to full malignant disease for many years. The identification of critical genetic lesions will pave the way for the development of disease-targeted therapy.     

Chemokines in multiple myeloma

OBJECTIVE: In this article we focus on the role that chemokines and chemokine receptors play in the pathogenesis of multiple myeloma and the associated bone destructive process, and consider their utility as novel therapeutic targets for treating this devastating disease. METHODS: Current research on the role that chemokine and chemokine receptors play in the pathogenesis of myeloma is reviewed. RESULTS: The chemokines, MIP-1alpha, MCP-1, IL-8, and SDF-1, and their receptors play important roles in homing of MM cells, tumor growth, and bone destruction in myeloma. They are attractive therapeutic targets for treating myeloma patients. CONCLUSION: Addition of chemokine antagonists to current treatment regimens for myeloma should result in better therapeutic responses because of the loss of both the protective effect of the marrow microenvironment on the MM cells and the induction of osteoclast activity.     

Lenalidomide in multiple myeloma

For many years the treatment of multiple myeloma was limited to such regimens as melphalan-prednisone, high-dose dexamethasone, and vincristine-doxorubicin-dexamethasone (VAD). These combinations provided response rates of 45-55%, with complete remission rates of up to 10%. With the advent of thalidomide- and bortezomib-based combinations, response rates to induction therapy have risen to 85-95% in previously untreated patients and are associated with complete remission rates up to 25%. However, these agents are associated with such side-effects as somnolence, constipation and neuropathy. Lenalidomide, a thalidomide analog, was developed with the hope of improving both the efficacy and toxicity profile of thalidomide, and has subsequently shown significant clinical activity in patients with multiple myeloma. We describe the role of lenalidomide in patients with symptomatic multiple myeloma that is newly diagnosed, relapsed and/or refractory to other therapies, or concurrent with primary amyloidosis.     

Immunotherapy of multiple myeloma

The failure of chemotherapy to cure a significant proportion of multiple myeloma (MM) patients and increasing knowledge of tumor immunology and MM biology have generated considerable interest in immunotherapy for this lethal disease. Immunotherapy for MM can be divided into three broad categories: passive antibody-mediated immunotherapy, active specific immunization (vaccination), and adoptive T-cell immunotherapy. Early clinical trials using anti-CD20 monoclonal antibodies (mAbs) have met with limited success so far but have also suggested that selected patient subgroups may benefit from this treatment. The availability of a truly tumor-specific antigen such as immunoglobulin idiotype, the recent demonstration that MM cells process and present idiotype to T lymphocytes, and formal evidence of an antitumor effect of idiotypic vaccination in follicular lymphoma provide the framework for applying idiotypic vaccination in MM. The ability to generate ex vivo functional dendritic cells has made it possible to fuse them with patients' MM cells, thus producing a different type of customized vaccine. Dendritic cells are also a pivotal reagent to generate ex vivo MM-specific cytotoxic T lymphocytes (CTLs) to be reinfused into the patient for adoptive immunotherapy. This review summarizes achievements in MM immunotherapy based on data reported since 1998.     

Bortezomib in multiple myeloma

Multiple myeloma (MM) remains an incurable disease, and novel agents are therefore needed to improve outcome. Bortezomib is the first proteasome inhibitor to be approved by the US Food and Drug Administration and the European Agency for the Evaluation of Medicinal Products for the treatment of refractory/relapsed MM. Bortezomib has demonstrated significant anti-myeloma activity as a single agent in refractory/relapsed MM. When used in combination with other agents, responses have suggested the possibility of chemosensitization and synergy. All these facts have been the rationale for the use of bortezomib-based regimens as upfront treatment in young and elderly newly diagnosed MM patients. Furthermore, bortezomib does not appear to have an adverse effect on subsequent stem-cell collection. Bortezomib is well tolerated; most side-effects are only mild to moderate and manageable. Practical management of these side-effects is given so that they can be recognized and minimized by dose modification or concomitant therapy.     

Management of multiple myeloma

Summary There has been little progress in the treatment of patients with multiple myeloma, and the average survival time is still only about 3 years. Although there have been significant therapeutic advances in recent years, clinical trials have only just begun. The major concern is, of course, the achievement of major disease control (which can be equated with a cure). The data available to date indicate that this is possible only with the use of allogeneic bone marrow transplantation, with which a survival plateau of around 30% can be attained. The trials should perhaps include the sequential use of all regimens with established efficacy in refractory myeloma. Immunoconjugate therapy with either radioisotopes or cytotoxic agents could also be envisioned, and expansion with suitable biological agents such as interleukin-2 could be considered. There is a plethora of promising treatment possibilities and novel concepts that may improve the dismal outlook for patients with multiple myeloma.Supported in part by grants CA28771 and CA37161 from the National Cancer Institute, National Institutes of Health, Bethesda, MD 20205, USA