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Autologous stem-cell transplantation and agents such as thalidomide, lenalidomide, and bortezomib have changed the management of myeloma and extended overall survival. This review discusses both the biologic features and the management of multiple myeloma. Multiple myeloma is a neoplastic plasma-cell disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow microenvironment, monoclonal protein in the blood or urine, and associated organ dysfunction. 1 It accounts for approximately 1% of neoplastic diseases and 13% of hematologic cancers. In Western countries, the annual age-adjusted incidence is 5.6 cases per 100,000 persons. 2 The median age at diagnosis is approximately 70 years; 37% of patients are younger than 65 years, 26% are between the ages of 65 and 74 years, and 37% are 75 years of age or older. 2 , 3 In recent years, the . . .

Waldenström's macroglobulinemia is a lymphoplasmacytic lymphoma. Genetic analysis has revealed a common mutation (L265P) in MYD88 in more than 90% of patients with this disease. The mutation appears to activate NF-κB. Waldenström's macroglobulinemia is an IgM-secreting lymphoplasmacytic lymphoma (LPL). 1 , 2 Clinical manifestations of Waldenström's macroglobulinemia include cytopenia resulting from bone marrow infiltration by lymphoplasmacytic cells, paraprotein-related cryoglobulinemia, the cold agglutinin syndrome, demyelinating neuropathy, and symptomatic hyperviscosity. 3 The oncogenic basis of Waldenström's macroglobulinemia has not been defined. Familial clustering of Waldenström's macroglobulinemia and other B-cell disorders suggests that genetic factors play a role in the pathogenesis of Waldenström's macroglobulinemia in certain patients. 4 – 6 IgM monoclonal gammopathy of unknown significance (MGUS) is characterized by the presence of a monoclonal IgM protein and the absence of bone marrow disease involvement on histologic examination. 1 IgM . . .

In patients ineligible for transplantation, the combination of lenalidomide and dexamethasone with lenalidomide maintenance until disease progression achieved significantly improved progression-free survival, as compared with melphalan, prednisone, and thalidomide therapy. For patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation, the standard therapy is melphalan and prednisone (MP) combined with either thalidomide (MPT) or bortezomib (VMP). 1 – 10 Lenalidomide (Revlimid, Celgene) is an immunomodulatory drug that, in combination with dexamethasone, is a standard treatment option for patients with multiple myeloma who have received at least one prior therapy as approved by the Food and Drug Administration and the European Medicines Agency. 7 – 13 In a randomized trial that included both younger and older patients with newly diagnosed multiple myeloma, lenalidomide plus low-dose dexamethasone was associated with fewer adverse . . .

Thalidomide and the immunomodulatory drug, lenalidomide, are therapeutically active in hematological malignancies. The ubiquitously expressed E3 ligase protein cereblon (CRBN) has been identified as the primary teratogenic target of thalidomide. Our studies demonstrate that thalidomide, lenalidomide and another immunomodulatory drug, pomalidomide, bound endogenous CRBN and recombinant CRBN–DNA damage binding protein-1 (DDB1) complexes. CRBN mediated antiproliferative activities of lenalidomide and pomalidomide in myeloma cells, as well as lenalidomide- and pomalidomide-induced cytokine production in T cells. Lenalidomide and pomalidomide inhibited autoubiquitination of CRBN in HEK293T cells expressing thalidomide-binding competent wild-type CRBN, but not thalidomide-binding defective CRBN YW/AA . Overexpression of CRBN wild-type protein, but not CRBN YW/AA mutant protein, in KMS12 myeloma cells, amplified pomalidomide-mediated reductions in c-myc and IRF4 expression and increases in p21 WAF-1 expression. Long-term selection for lenalidomide resistance in H929 myeloma cell lines was accompanied by a reduction in CRBN, while in DF15R myeloma cells resistant to both pomalidomide and lenalidomide, CRBN protein was undetectable. Our biophysical, biochemical and gene silencing studies show that CRBN is a proximate, therapeutically important molecular target of lenalidomide and pomalidomide.

In patients 65 or younger with multiple myeloma, high-dose consolidation therapy was associated with longer survival and more myelotoxicity than conventional-dose therapy. Lenalidomide maintenance improved progression-free survival but not overall survival. High-dose chemotherapy plus autologous stem-cell transplantation, as compared with conventional chemotherapy, prolongs progression-free survival and overall survival among patients with newly diagnosed multiple myeloma. 1 – 4 and it is currently the standard of care for patients who are younger than 65 years of age. However, since autologous stem-cell transplantation has substantial toxic effects and requires prolonged hospitalization, the comparison with less toxic, orally administered treatments is important. Immunomodulatory drugs and proteasome inhibitors have significantly improved outcomes in patients, regardless of whether they are eligible for transplantation. 5 – 18 These improvements have raised questions about the role of transplantation in comparison with conventional . . .

Lenalidomide maintenance after stem-cell transplantation significantly prolonged progression-free and event-free survival in patients with multiple myeloma. At 4 years, overall survival was similar in the lenalidomide-treated and placebo-treated groups. During the past decade, high-dose chemotherapy with autologous stem-cell transplantation has become the standard treatment for newly diagnosed myeloma in patients younger than 65 years of age. However, the median duration of response after this procedure does not exceed 3 years, and few patients remain free of the disease for more than 10 years. 1 – 4 Relapses are due to the failure of high-dose chemotherapy to eradicate all myeloma cells. Maintenance treatments have been proposed to control the proliferation of residual malignant cells after transplantation. For many years, interferon with or without glucocorticoids was used, 1 , 2 , 5 but this approach was . . .

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures less than 37°C and produce organ damage through two main pathways: vascular sludging (hyperviscosity syndrome, mainly in type I cryoglobulinaemia) and immune-mediated mechanisms (principally vasculitis, in mixed cryoglobulinaemia). Cryoglobulinaemia is associated with many illnesses, which can be broadly grouped into infections, autoimmune disorders, and malignancies; the most common cause is infection with hepatitis C virus. Mixed cryoglobulinaemic syndrome is diagnosed when a patient has typical organ involvement (mainly skin, kidney, or peripheral nerve) and circulating cryoglobulins. Cutaneous purpura is the most common manifestation of cryoglobulinaemic vasculitis. The most frequently affected internal organs are the peripheral nerves, kidneys, and joints. The course varies widely and prognosis is influenced by both cryoglobulinaemic damage to vital organs and by comorbidities associated with underlying diseases. More than 90% of cases of cryoglobulinaemia have a known underlying cause; therefore treatment is focused on the cause of the disorder rather than merely symptomatic relief. Studies suggest that both combined or sequential antiviral therapies and targeted biological treatments might be more effective than monotherapy.

Certain clinical features predict progression from smoldering to overt multiple myeloma. Patients with high-risk features who were treated with lenalidomide and dexamethasone were less likely to have disease progression and had a higher rate of survival than untreated patients. Smoldering multiple myeloma is a plasma-cell proliferative disorder characterized by a monoclonal component of at least 3 g per deciliter, a level of plasma-cell infiltration into bone marrow of at least 10%, or both features. 1 Currently, patients with smoldering myeloma are not treated until symptomatic disease develops. 2 In the past, few drugs were effective against myeloma, and the available treatments, mainly alkylating agents, led to concerns about long-term toxicity. Attempts at early intervention with alkylating agents, 3 – 5 bisphosphonates, 6 – 8 antagonists of the receptor of interleukin-1β, 9 or thalidomide 10 – 13 failed to show a significant benefit. Although the risk of progression to . . .

Promising new drugs are being evaluated for treatment of multiple myeloma (MM), but their impact should be measured against the expected outcome in patients failing current therapies. However, the natural history of relapsed disease in the current era remains unclear. We studied 286 patients with relapsed MM, who were refractory to bortezomib and were relapsed following, refractory to or ineligible to receive, an IMiD (immunomodulatory drug), had measurable disease, and ECOG PS of 0, 1 or 2. The date patients satisfied the entry criteria was defined as time zero (T 0 ). The median age at diagnosis was 58 years, and time from diagnosis to T 0 was 3.3 years. Following T 0 , 213 (74%) patients had a treatment recorded with one or more regimens (median=1; range 0–8). The first regimen contained bortezomib in 55 (26%) patients and an IMiD in 70 (33%). A minor response or better was seen to at least one therapy after T 0 in 94 patients (44%) including ⩾partial response in 69 (32%). The median overall survival and event-free survival from T 0 were 9 and 5 months, respectively. This study confirms the poor outcome, once patients become refractory to current treatments. The results provide context for interpreting ongoing trials of new drugs.

Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. BRAF and other links to multiple myeloma Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Chapman et al . have used next-generation sequencing to compare 38 multiple myeloma genomes with those of normal cells from the same patients. The disease involves mutations of genes with roles in protein translation, histone methylation and blood coagulation. In terms of clinically relevant findings, unexpected activating mutations were found in the kinase BRAF, inhibitors of which have recently shown dramatic clinical activity. This suggests that BRAF inhibitors should be evaluated in patients with BRAF-mutated multiple myeloma. Multiple myeloma, a malignancy of plasma cells, remains incurable and is poorly understood. Using next-generation sequencing of several multiple myeloma genomes reveals that this disease involves mutations of genes involved in protein translation, histone methylation and blood coagulation. The study suggests that BRAF inhibitors should be evaluated in multiple myeloma clinical trials.