Multitargeted therapies for multiple myeloma

Multiple myeloma (MM) comprises 1% of all malignancies and 10% of all hematological malignancies. MM is a malignancy of plasma cells in the bone marrow where complex and dynamic interactions with the bone marrow microenvironment lead to tumor progression, skeletal destruction and angiogenesis. Despite the discovery of several novel treatments against MM, including the proteasome inhibitor bortezomib, it is considered to be an incurable disease with an average 4–5 years overall survival.     

Prognostic value of periostin in multiple solid cancers: A systematic review with meta-analysis

Previous studies have shown that the expression of periostin (POSTN) is significantly correlated with prognosis in multiple solid cancers. However, the function of POSTN in tumorigenesis and its relationship with clinical outcomes have not been systematically summarized and analyzed. Thus, a meta-analysis was performed to evaluate the prognostic pertinence of POSTN in solid cancer. We conducted a systematic search in the PubMed, EMBASE, Web of Science, and Cochrane library databases, and a total of 10 studies were used to assess the association of POSTN expression and patients’ overall survival (OS) and disease-free survival (DFS). The hazard ratio (HR) or odds ratio (OR) and their corresponding 95% confidence intervals (95% CIs) were further calculated to estimate the association between POSTN and relevant clinical parameters of solid cancer patients. The pooled results indicated that POSTN overexpression was associated with poor OS (HR = 2.35, 95% CI = 1.88–2.93, p < .00001) and DFS (HR = 2.70, 95% CI = 2.00–3.65, p < .00001) in a cohort of 993 patients with cancer. Subsequent analyses showed that the positive expression ratio of POSTN was evidently higher in cancer tissues than in normal tissues (OR = 7.44, 95% CI = 3.66–13.95, p < .00001). In addition, subgroup analysis showed that POSTN was related to microvascular invasion (OR = 5.09, 95% CI = 3.07–8.44, p < .00001), tumor differentiation (OR = 2.03, 95% CI = 1.41–2.91, p = .0001), and lymph node metastasis (OR = 3.05, 95% CI = 2.01–4.64, p < .00001). These data showed that POSTN could be a credible prognostic biomarker and a potential therapeutic target in human solid cancer.     

Antigen-specific therapies in multiple sclerosis

Multiple sclerosis is the major neurological disease of young adults in the western world, affecting about 1 per 1,000. It is characterised by chronic or recurrent lesions of inflammatory damage in the white matter of the central nervous system. Within such lesions, the protective myelin sheath is stripped off axons by infiltrated macrophages which leads to impaired conductivity. The inflammatory process most likely starts by activation of helper T cells directed against local myelin antigens. Currently, efforts are directed at specifically blocking such myelin-reactive helper T cells in order to control the disease. In this chapter, immunological features of multiple sclerosis and the experimental animal model for the disease, experimental allergic encephalomyelitis, are discussed. Next, an overview is presented on myelin antigens that have been suggested to play a role as target antigens in MS. Finally, strategies are discussed that are currently employed to selectively block the activation of T-cells reactive against myelin antigens.     

Intracytoplasmic immunofluorescence in multiple myeloma

A new intracytoplasmic immunofluorescence staining procedure has been investigated to detect and quantify myeloma cells by means of flow cytometry. Freshly harvested bone marrow aspirations from 12 patients with multiple myeloma were treated with collagenase and Triton X-100, and incubated with different specimens of fluoro-isothiocyanate-marked antihuman immunoglobulins. DNA-staining was then done with propidium iodide. Biparametric evaluation in a cytofluorograph 6300A/FC 200 showed a characteristic cluster distribution of normal and pathological immunoglobulin-producing cells. This intracytoplasmic fluorochromic staining procedure may be significant for the specific identification of nonsecretive immunocytomas, which cannot be detected by serodiagnostic methods.     

DC in multiple myeloma immunotherapy

Therapy for patients with multiple myeloma (MM) is currently unsatisfactory and most patients eventually succumb to relapsed disease. DCs are a subset of leukocytes with the capacity to initiate and control the adaptive immune response against many cancers, including MM. In MM patients, in vivo DC function is often abnormal, however, it appears that it can be restored by in vitro manipulation. This has led to the development of DC immunotherapy for MM patients. We review the background research leading to the recognition of an anti-MM immune response, and discuss abnormalities in DC function, potential tumor-associated Ags, and the results of clinical trials of DC immunotherapy in MM patients.     

Therapy of multiple myeloma

Multiple myeloma (MM) is a haematological malignancy characterised by the clonal expansion of malignant plasma cells within the bone marrow. It accounts for 10% of all haematological malignant diseases and 1% of all malignancies. The median age of patients at the time of the diagnosis is 70 years. The characteristic clinical features of MM are bone marrow failure, susceptibility to infections, bone pain, pathological bone fractures, hypercalcaemia, and renal failure. Though MM is currently incurable, the important progress in chemotherapy has resulted in an improvement in survival from a median of 7 months in the 1950-ies to about 3 years today. Advances in the diagnosis and in supportive treatment of infections, hypercalcaemia, and renal failure also contributed to the prolongation of survival. For decades, the gold standard of treatment had been oral melphalan alone or in combination with prednisolone. Combination chemotherapy has not improved overall survival (OS), but these regimens have led to the prolongation of event-free survival (EFS) and also to a better quality of life. High-dose chemotherapy with haemopoietic stem cell rescue resulted in a great improvement in EFS as well as OS. For those very few who have an HLA-compatible donor and are under 55, allogeneic bone marrow transplantation offers the best hope of survival but comes at a greatly increased risk of toxicity. There are conflicting data in the literature concerning the role of interferon-alpha; it seems to be able to prolong the duration of the plateau phase. Current treatment is moving towards an approach using sequential therapy. This involves induction therapy proceeding to high-dose chemotherapy with some form of stem-cell rescue. Bisphosphonates reduce hypercalcaemia, bone pain and can inhibit bone destruction. They also possess a direct antitumor activity. The better understanding of the pathomechanism of the disease gives the opportunity of the application of new therapeutic modalities such as antagonising the effect of interleukin-6 (IL-6), or idiotypic vaccination.     

Management of multiple myeloma

There has been no improvement in the treatment of multiple myeloma (MM) during the last decades and two meta-analyses of randomized trials recorded no significant survival benefit for combination chemotherapy compared to the classic melphalan-prednisone combination. However the past 15 years has seen several innovative strategies which have dramatically modified the management of MM. In younger patients, high-dose therapy with autologous stem cell transplantation is considered to be superior to conventional chemotherapy and is used as part of front-line therapy. A number of issues have been addressed in recent trials in order to improve the results of autologous transplantation (source of stem cells, conditioning regimen, impact of double transplants, maintenance therapy). Bisphosphonates reduce the incidence of skeletal-related events and improve the quality of life. Recombinant erythropoietin reduces red blood cell transfusion need and improves the quality of life. Thalidomide has been introduced more recently. Phase II studies with thalidomide alone or combined with dexamethasone have shown impressive response rates and this drug is currently being evaluated as part of front-line therapy. Finally, analysis of prognostic factors such as beta 2 microglobulin and cytogenetics define subgroups of patients with a completely different outcome and help the process of selecting therapeutics strategies.     

Management of multiple myeloma

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.     

Acute renal failure in multiple myeloma

Two cases of acute renal failure complicating multiple myeloma are reported. In both, the renal failure preceded the diagnosis of multiple myeloma. In one case oliguria occurred after performance of a venogram; renal function returned to normal after two weeks of intermittent peritoneal dialysis, emphasizing the reversibility of the renal failure in some cases.     

Impaired NHEJ function in multiple myeloma

Multiple myeloma (MM) is characterized by multiple chromosomal aberrations. To assess the contribution of DNA repair to this phenotype, ionizing radiation was used to induce DNA double strand breaks in three MM cell lines. Clonogenic survival assays showed U266 (SF4 = 15.3 + 6.4%) and RPMI 8226 (SF4 = 12.6.0 + 1.7%) were radiation sensitive while OPM2 was resistant (SF4 = 78.9 + 4.1%). Addition of the DNA-PK inhibitor NU7026 showed the expected suppression in radiation survival in OPM2 but increased survival in both radiation sensitive cell lines. To examine non-homologous end joining (NHEJ) repair in these lines, the ability of protein extracts to support in vitro DNA repair was measured. Among the three MM cell lines analyzed, RPMI 8226 demonstrated impaired blunt ended DNA ligation using a ligation-mediated PCR technique. In a bacterial based functional assay to rejoin a DNA break within the β-galactosidase gene, RPMI 8226 demonstrated a 4-fold reduction in rejoining fidelity compared to U266, with OPM2 showing an intermediate capacity. Ionizing radiation induced a robust γ-H2AX response in OPM2 but only a modest increase in each radiation sensitive cell line perhaps related to the high level of γ-H2AX in freshly plated cells. Examination of γ-H2AX foci in RPMI 8226 cells confirmed data from Western blots where a significant number of foci were present in freshly plated untreated cells which diminished over 24 h of culture. Based on the clonogenic survival and functional repair assays, all three cell lines exhibited corrupt NHEJ repair. We conclude that suppression of aberrant NHEJ function using the DNA-PK inhibitor NU7026 may facilitate access of DNA ends to an intact homologous recombination repair pathway, paradoxically increasing survival after irradiation. These data provide insight into the deregulation of DNA repair at the site of DNA breaks in MM that may underpin the characteristic genomic instability of this disease.