Rafael Fonseca

..In addition, the low number of in vitro or in vivo models significantly challenges extensive analysis. In this manuscript, we review the molecular basis of this disease...

..Ongoing clinical trials continue to address the role of long term maintenance therapy. Understanding the proper management of these agents is paramount to providing patients disease control and yet minimizing side effects from treatment...

..More importantly it provides further compelling evidence that MM is composed of subgroups of patients categorized according to their underlying genomic aberrations...

..By using an alkylator-free consolidation and reserving stem cell transplantation until the time of relapse, we hope that these treatment strategies will further prolong the survival of patients with myeloma...

..These patients do not have a worsened prognosis as previously thought...

..Areas in need of further study were identified. The study of the genetic aberrations will likely form the platform for targeted therapy for the disease...

..In addition, information on proliferative activity of plasma cells may be of value. The introduction of novel methods of prognostication should be strongly considered in all clinical trials...

..Novel treatments, such as bortezomib, oblimersen sodium, perifosine and others are being evaluated...

..This group proposes that genetic testing needs to be incorporated into daily clinical practice and also as an essential component of all ongoing and future clinical trials...

..It is likely that in the future, knowledge of the cytogenetic composition will be an integral part of the evaluation of myeloma patients...

..Both 1q21 gain and increase gene expression level were significantly associated with reduced survival. However, neither is an independent prognostic marker in MM on multivariate Cox proportional hazard analysis...

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..The classification of MM into hyperdiploidy and nonhyperdiploidy is dictated largely by the recurrent (primary) IgH translocations in the latter...

..To determine the long-term effects of a combined regimen of lenalidomide and dexamethasone (Rev-Dex) on time to progression, progression-free survival, and overall survival (OS) in patients with multiple myeloma...

..INTERPRETATION AND CONCLUSIONS: The median time to disease progression in patients with multiple myeloma who receive initial therapy with Thal/Dex and who do not undergo ASCT is 18 months...

..3% vs 9.2%, P = .058) and peripheral neuropathy (10.4% vs 0.9%, P < .001). Len/dex appears well-tolerated and more effective than thal/dex. Randomized trials are needed to confirm these results...

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..It is well tolerated with few side effects. CyBorD warrants continued investigation as treatment for AL...

..In conclusion, CyBorD demonstrated superior responses and less frequent serious toxicity but more neuropathy when compared to RD and CRD. Importantly, 80% of patients treated with modern therapeutic approaches are alive at 4years...

..CONCLUSIONS: Thalidomide is useful in the treatment of patients with relapsed multiple myeloma and produced durable response in approximately one third of patients, with median response duration of nearly 1 year...

..These results need confirmation in larger, prospectively designed studies...

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..Outside a randomized clinical trial, these results present the strongest data supporting the role of PBSCT in selected patients with AL...

..Prognostic factors for the progression and outcome of this disease are unclear...

..CRd is an effective and well-tolerated regimen for upfront therapy of MM with high response rates and excellent 2-year OS, and is suitable for long-term therapy...

..Pomalidomide overcomes resistance in myeloma refractory to both lenalidomide and bortezomib. This trial is registered at http://ClinicalTrials.gov, number NCT00558896...

..This study validates the high-risk features defined by FISH and CG in the Mayo risk-stratification model for patients with MM predominantly treated with novel therapies based on immunomodulatory agents...

..02). Angiogenesis is increased in solitary plasmacytoma and is a significant predictor of progression to myeloma and provides further evidence of its importance in the pathogenesis of myeloma...

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..Others have reported that N-terminal pro-brain natriuretic peptide (NT-proBNP) is a valuable prognostic marker. We sought to develop a staging system for patients with AL...

..This percentage (40%) is remarkably similar to the percentage of hyperdiploid MM reported in the literature, suggesting that hyperdiploid MM may originate early during disease evolution...

..Similar translocations are found in both MGUS and MM, including t(4;14)(p16.3;q32) and t(14;16)(q32;q23). Moreover, Delta 13 is common in MGUS and unlikely to play a predominant role in the evolution of MGUS to MM...

..Autologous stem cell transplant should be considered in all eligible patients with relapsed disease...

..Patients ended treatment due to progressive disease (18 patients), death (3) and other (2). The data suggest that imatinib is not an active agent in patients with relapsed or refractory multiple myeloma...

..We conclude that the degree of bone marrow angiogenesis is a prognostic marker in patients with multiple myeloma and does not decrease significantly after therapy...

..We report, to our knowledge, the first phase II trial of pomalidomide administered in combination with low-dose dexamethasone for the treatment of relapsed or refractory multiple myeloma...

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..We conclude that pomalidomide appears to be a valuable drug covering an unmet clinical need in patients with previously treated AL. The trial is registered at www.clinicaltrials.gov as NCT00558896...

..Based on the current findings, we conclude that the presence of trisomies in patients with t(4;14), t(14;16), t(14;20), or p53 deletion abnormalities in MM ameliorates the usual adverse impact associated with these prognostic markers...

..Furthermore, the signatures that defined these clusters may provide a basis for tailoring treatment to individual patients...

..74, 0.7, and 0.7, respectively. Here we demonstrate the prognostic value for GEP risk stratification in a group of patients primarily treated with novel agents. This trial was registered at www.clinicaltrials.gov as #NCT00098475...

..Thus, IL6 and its downstream signaling may be of biologic importance in WM. Further elucidation of the role of IL-6 in WM is warranted as this may offer a potential therapeutic avenue...

..The area of minimal deletion was between 6q23 and 6q24.3, but the deletion usually encompassed a large fragment of the 6q arm. These results indicate that 6q- can distinguish WM from IgM MGUS and is likely to be a secondary event...

..This set of recommendations represents such an effort-the development of a set of consensus guidelines by a group of experts to manage patients with newly diagnosed disease based on an interpretation of the best available evidence...

..Three patients had IgH translocation t(11;14)(q13;q32). No abnormalities were seen at 17p13(p53). The monosomy 13 is in line with other plasma cell disorders while the low prevalence of hyperdiploidy and abnormalities at 14q32 is unique...

..01; IL-6, 24% versus 70% at 2 years, P = 0.01). None of the other parameters predicted response or PFS, and no significant changes in cytokine levels occurred with therapy...

..Moreover, these cell lines will provide an invaluable tool to better understand AL, from the combined perspectives of amyloidogenic protein structure and amyloid formation, genetics, and cell biology...

..To determine the clinical and laboratory features of newly diagnosed multiple myeloma...

..In summary, CRBN is an essential requirement for IMiD activity and a possible biomarker for the clinical assessment of antimyeloma efficacy...

..The trial was registered at www.clinicaltrials.gov (NCT00564889)...

..5% vs. 4.2%, P = 0.129) were higher with Rd. Results of this case-matched analysis suggest that there is significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results...

..008). The prognostic value of circulating PBPCs may help select treatment for patients with AL...

..However, WM tumor cells, which appear to be diploid or near diploid, often have deletions of 6q21...

..The presence of t(4;14) identifies a subset of patients whose time to progression is only 8.2 months. These patients receive minimal benefit from autologous stem cell transplantation and are candidates for novel therapeutic approaches...

..03). The presence of Delta13 is an important and independent adverse prognostic factor in newly diagnosed MM and is associated with specific biological features...

..In conclusion, FS associated with monoclonal gammopathy does not appear to confer an additional risk of subsequent evolution to MM. ESRD occurs late in the disease process...

..This study provides new insight into the molecular profile of clonal plasma cells and its functional relevance in the pathogenesis of light chain amyloidosis...

..5 years. This must be remembered when making treatment decisions for these patients and must be factored in when assessing the efficacy of new therapies...

..Beta2-microglobulin > or =4 mg/l was associated with a threefold increase in the risk of death when added to the prognostic model. We describe a simple prognostic model for overall survival for newly diagnosed patients with WM...

..Human myeloma cell lines with higher CI are more responsive to treatment with a novel aurora kinase inhibitor. Aurora kinase may represent novel therapeutic targets in these patients with very poor prognosis...

..These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma...

..The objective of this study was to test cladribine (2-CDA) alone and in combination with rituximab in patients with mantle cell lymphoma (MCL)...

..Little, however, is known about cytogenetic abnormalities in patients with light chain amyloidosis...

..Thalidomide, an agent with antiangiogenic properties, is effective in relapsed myeloma. We report the results of a study combining thalidomide and dexamethasone as initial therapy for myeloma...

..To determine whether bone marrow (BM) angiogenesis progressively increases along the spectrum of plasma cell disorders ranging from monoclonal gammopathy of undetermined significance (MGUS) to advanced myeloma...

..Median time on the study was 72 days, range was 25 to 333 days. All 12 have withdrawn from the study (side-effects, 6; progression, 4; and death, 2 patients). AL patients do not tolerate high dose thalidomide...

..1 deletion and in the more favorable genetic subtype characterized by the presence of 13q14.1 deletion. This aCGH study adds information on the association between poor trial response and increasing genetic complexity as CLL progresses...

..The remaining 20% are characterised by absence of IgH expression; we aimed to assess prevalence of a corresponding precursor entity, light-chain MGUS...

..Rev/Dex is a highly active regimen with manageable side effects in the treatment of newly diagnosed myeloma...

..These data support targeted repression of cyclin D genes as a therapeutic strategy for human malignancies...

..Despite minor differences, our results suggest that shipment of samples did not significantly affect these quality determinants in aggregate...

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..Factors predicting an initial increase in IgM levels could not be identified...

..High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide...

..On further analysis, the prognostic impact of 1p31-32 loss is due to shortening of post-relapse survival as there is no impact on complete response rates and progression-free survival...

..Deletions of these two regions are uncommon in WM, being more common in the late stages of the disease, thus unlikely playing a role in primary disease pathogenesis...

..Importantly, we recommend that all clinical trials now adopt routine genetic testing and risk stratification...

..Having found deletions of the long arm of chromosome 6 as the only recurrent aberration, we speculate that a gene involved in B-cell maturation or survival at this locus may be inactivated as a cause of WM...

..2%) of those had translocation (11;14)(q13;q32) for an overall prevalence of the abnormality of 55%. IgH translocations are common in AL, especially the t(11;14)(q13;q32)...

..Although not conclusive, this result lends further support to the hypothesis that angiogenesis is a relevant therapeutic target in myeloma...

..A phase I first-in-human study was conducted to characterize the safety, tolerability, pharmacokinetic, and pharmacodynamic properties of the anti-insulinlike growth factor 1 receptor (IGF-IR) monoclonal antibody CP-751,871...

..Additional features of the syndrome often develop, but the complications of classic multiple myeloma rarely develop...

..The presence of renal disease, on the other hand, was associated with improved survival. Therefore, identification of the clonal VL gene in AL has important implications in determining clinical outcome...

..Testing should be done 2-3 months after the initial recognition of SMM. If the results are stable, the patient should be followed every 4-6 months for 1 year and, if stable, every 6-12 months...

..Using this system, 49%, 38%, and 13% of patients were in stage I, stage II, and stage III, respectively. Determining levels of circulating biomarkers may be the most powerful tool for staging patients with AL undergoing PBSCT...

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..This study tested whether temsirolimus (previously known as CCI-779), an inhibitor of the mammalian target of rapamycin kinase that regulates cyclin D1 translation, could produce tumor responses in patients with MCL...

..These guidelines were developed in the Interest of patient safety and will be reexamined as new data emerge regarding risks and benefits...

..Additionally, mutational clusterspots were identified at specific positions in the nucleotide and deduced protein sequence that could potentially contribute to destabilizing interactions resulting in a propensity to form amyloid...

..The serum immunoglobulin FLC ratio is an important additional determinant of clinical outcome in patients with SMM...

..No anti-myeloma activity was observed in vivo. As administered, flavopiridol has disappointing activity as a single agent in advanced myeloma...

..To determine if thalidomide plus dexamethasone yields superior response rates compared with dexamethasone alone as induction therapy for newly diagnosed multiple myeloma...

..This paper provides consensus guidelines for the use of this important assay, in the diagnosis and management of clonal PCD...

..As mice that lack GRK6 are healthy, inhibition of GRK6 represents a uniquely targeted novel therapeutic strategy in human multiple myeloma...

..The median survival of symptomatic patients is 65 months. Patients without symptoms should not be treated...

..Angiogenesis is correlated with the plasma cell labeling index but not the bone marrow plasma cell percentage. A simple visual grading of angiogenesis is an efficient alternative to microvessel density estimation...

..A system including both these risk factors allows better prediction of outcome...

..To describe presenting clinical manifestations, long-term disease complications, prognostic indicators, and outcome of pregnancy for women younger than 50 years with essential thrombocythemia...

..We conclude that M-FISH can be effective in complete characterization of critical gene rearrangements in haematological disorders...

..This article addresses the extent to which eligibility to undergo HSCT is a favorable prognostic feature and explores prognostic factors within the subset of eligible patients...

..In high-risk patients, upfront bortezomib results in response rates that are comparable to those reported for unselected cohorts, but single agent bortezomib is not sufficient as primary therapy...

..4. To establish the prognostic significance of delta13 in MM patients undergoing high-dose chemotherapy with stem cell support and contrast this to the effect of delta13 on survival in MM patients treated with conventional chemotherapy. ..

..Variables will also be studied using a multiple-variable model to test them as independent predictors. ..

..PUBLIC HEALTH RELEVANCE: This grant proposal aims to better define which treatments should be given to which genetic subtypes of myeloma, to provide optimal and risk adapted therapy for patients. ..