In multiple myeloma, c-MYC is activated and contributes to the malignant phenotype. Targeting MYC by short hairpin RNA induced cell death in myeloma cell lines; however, cell lines are generated from ...samples taken in advanced stages of the disease and may not reflect patient cells adequately. In this study, we used the selective small molecule inhibitor of MYC-MAX heterodimerization, 10058-F4, on myeloma cell lines as well as primary myeloma cells, and we show that inhibition of c-MYC activity efficiently induces myeloma cell death. Moreover, in cocultures of cell lines with bone marrow stromal cells from myeloma patients, the inhibitor still induces apoptosis. Our results provide further evidence that myeloma cells are addicted to c-MYC activity and that c-MYC is a promising therapeutic target in multiple myeloma.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Patients with newly diagnosed multiple myeloma (NDMM) show heterogeneous outcomes, and approximately 60% of them are at intermediate-risk according to the Revised International Staging system ...(R-ISS), the standard-of-care risk stratification model. Moreover, chromosome 1q gain/amplification (1q+) recently proved to be a poor prognostic factor. In this study, we revised the R-ISS by analyzing the additive value of each single risk feature, including 1q+.
The European Myeloma Network, within the HARMONY project, collected individual data from 10,843 patients with NDMM enrolled in 16 clinical trials. An additive scoring system on the basis of top features predicting progression-free survival (PFS) and overall survival (OS) was developed and validated.
In the training set (N = 7,072), at a median follow-up of 75 months, ISS, del(17p), lactate dehydrogenase, t(4;14), and 1q+ had the highest impact on PFS and OS. These variables were all simultaneously present in 2,226 patients. A value was assigned to each risk feature according to their OS impact (ISS-III 1.5, ISS-II 1, del(17p) 1, high lactate dehydrogenase 1, and 1q+ 0.5 points). Patients were stratified into four risk groups according to the total additive score: low (Second Revision of the International Staging System R2-ISS-I, 19.2%, 0 points), low-intermediate (II, 30.8%, 0.5-1 points), intermediate-high (III, 41.2%, 1.5-2.5 points), high (IV, 8.8%, 3-5 points). Median OS was not reached versus 109.2 versus 68.5 versus 37.9 months, and median PFS was 68 versus 45.5 versus 30.2 versus 19.9 months, respectively. The score was validated in an independent validation set (N = 3,771, of whom 1,214 were with complete data to calculate R2-ISS) maintaining its prognostic value.
The R2-ISS is a simple prognostic staging system allowing a better stratification of patients with intermediate-risk NDMM. The additive nature of this score fosters its future implementation with new prognostic variables.
How the marriage of Industry 4.0 and the Circular Economy can radically transform waste management-and our world Do we really have to make a choice between a wasteless and ...nonproductive world or a wasteful and ultimately self-destructive one? Futurist and world-renowned waste management scientist Antonis Mavropoulos and sustainable business developer and digital strategist Anders Nilsen respond with a ringing and optimistic "No!" They explore the Earth-changing potential of a happy (and wasteless) marriage between Industry 4.0 and a Circular Economy that could-with properly reshaped waste management practices-deliver transformative environmental, health, and societal benefits. This book is about the possibility of a brand-new world and the challenges to achieve it. The fourth industrial revolution has given us innovations including robotics, artificial intelligence, 3D-printing, and biotech. By using these technologies to advance the Circular Economy-where industry produces more durable materials and runs on its own byproducts-the waste management industry will become a central element of a more sustainable world and can ensure its own, but well beyond business as usual, future. Mavropoulos and Nilsen look at how this can be achieved-a wasteless world will require more waste management-and examine obstacles and opportunities such as demographics, urbanization, global warming, and the environmental strain caused by the rise of the global middle class. · Explore the new prevention, reduction, and elimination methods transforming waste management · Comprehend and capitalize on the business implications for the sector · Understand the theory via practical examples and case studies · Appreciate the social benefits of the new approach Waste-management has always been vital for the protection of health and the environment. Now it can become a crucial role model in showing how Industry 4.0 and the Circular Economy can converge to ensure flourishing, sustainable-and much brighter-future.
In this study we set out to investigate whether anti PDL1 or PD-1 treatment targeting the immune system could be used against multiple myeloma. DCs are important in regulating T cell responses ...against tumors. We therefore determined PDL1 and PDL2 expression on DC populations in bone marrow of patients with plasma cell disorders using multicolour Flow Cytometry. We specifically looked at CD141+ and CD141- myeloid and CD303+ plasmacytoid DC. The majority of plasma cells (PC) and DC subpopulations expressed PDL1, but the proportion of positive PDL1+ cells varied among patients. A correlation between the proportion of PDL1+ PC and CD141+ mDC was found, suggesting both cell types could down-regulate the anti-tumor T cell response.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Summary Background Immune thrombocytopenia is characterised by immune-mediated destruction and suboptimum production of platelets. Despite the absence of supporting evidence, rituximab is frequently ...used off-label in patients with immune thrombocytopenia. We aimed to assess the efficacy of rituximab as compared with placebo as a splenectomy-sparing treatment in patients who were previously treated with corticosteroids. Methods In this multicentre, randomised, double-masked, placebo-controlled trial, we enrolled corticosteroid unresponsive adult patients (aged ≥18 years) with primary immune thrombocytopenia and a platelet count of less than 30 × 109 platelets per L. Patients were randomly assigned (1:1) to four weekly infusions of 375 mg/m2 rituximab or placebo. Concurrent treatment with corticosteroids only was allowed during the study. The primary endpoint was rate of treatment failure within 78 weeks—a composite of splenectomy or meeting criteria for splenectomy after week 12 if splenectomy was not done, assessed in all patients who received at least one dose of study treatment. Secondary endpoints were response rates, relapse rates, and duration of response. Efficacy endpoints were assessed with the Kaplan-Meier method. Safety endpoints were assessed in all patients who received at least one dose. This trial is registered with ClinicalTrials.gov , number NCT00344149. Findings Between Aug 17, 2006, and June 30, 2011, we enrolled 112 patients. 32 (58%) of 55 patients in the rituximab group and 37 (69%) of 54 patients in the placebo group had treatment failure within 78 weeks (Kaplan-Meier cumulative incidence 46% for rituximab vs 52% for placebo (hazard ratio HR 0·89, 95% CI 0·55–1·45; p=0·65). The cumulative incidence of overall response was 81% in the rituximab group versus 73% in the placebo group (p=0·15) and complete response was 58% in the rituximab group versus 50% in the placebo group (p=0·12). Of those achieving an overall response, 68% relapsed in the rituximab group and 78% relapsed in the placebo group, and of those achieving complete response, 50% relapsed in the rituximab group and 62% relapsed in the placebo group. Time to relapse in the rituximab group was longer in patients who achieved overall response (36 vs 7 weeks; p=0·01) but not complete response (76 vs 49 weeks; p=0·19). Rates of bleeding were similar in the two groups (21 38% in the rituximab group vs 27 50% in the placebo group; p=0·08) as were rates of infection (22 40% vs 13 24%; p=0·09). Interpretation Despite no reduction in the rate of long-term treatment failure with rituximab, a small benefit cannot be ruled out, as suggested by an apparently longer duration of response and numerically higher response rates with rituximab. Funding South-East Regional Health Authority and Østfold Hospital, Norway; Roche, France; and Roche, Norway.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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Population‐based studies from high‐quality nationwide cancer registries provide an important alternative to clinical trials in the assessment of the impact of modern myeloma treatment. Based ...on data from the Cancer Registry of Norway, we investigated trends in incidence and relative survival (RS) for 10 524 patients in three age groups diagnosed between 1982 and 2017. Nationwide myeloma drug consumption statistics were obtained from the Norwegian Institute of Public Health. Patients aged <65 years had a steady increase in both 5‐ and 10‐year RS across all calendar periods from 1982. For patients aged 65–79 years, RS was stable until the calendar period 1998–2002, followed by an improvement in both 5‐ and 10‐year RS. The 5‐year RS for patients aged ≥80 years also increased significantly between the first and the last calendar period. In conclusion, we demonstrate a significant improvement in 5‐year RS in all age groups. Improved RS in patients aged ≥80 years at the time of diagnosis is only rarely described in other population‐based studies. For patients aged ≥65 years, the improvement in RS coincides with the introduction of modern drugs, whereas patients aged <65 years had an ongoing improvement before the introduction of autologous stem‐cell transplant.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Plasma cell disorders (PCDs) are identified in the clinical lab by detecting the monoclonal immunoglobulin (M-protein) which they produce. Traditionally, serum protein electrophoresis methods have ...been utilized to detect and isotype M-proteins. Increasing demands to detect low-level disease and new therapeutic monoclonal immunoglobulin treatments have stretched the electrophoretic methods to their analytical limits. Newer techniques based on mass spectrometry (MS) are emerging which have improved clinical and analytical performance. MS is gaining traction into clinical laboratories, and has replaced immunofixation electrophoresis (IFE) in routine practice at one institution. The International Myeloma Working Group (IMWG) Mass Spectrometry Committee reviewed the literature in order to summarize current data and to make recommendations regarding the role of mass spectrometric methods in diagnosing and monitoring patients with myeloma and related disorders. Current literature demonstrates that immune-enrichment of immunoglobulins coupled to intact light chain MALDI-TOF MS has clinical characteristics equivalent in performance to IFE with added benefits of detecting additional risk factors for PCDs, differentiating M-protein from therapeutic antibodies, and is a suitable replacement for IFE for diagnosing and monitoring multiple myeloma and related PCDs. In this paper we discuss the IMWG recommendations for the use of MS in PCDs.
Summary Background Lenalidomide has been linked to second primary malignancies in myeloma. We aimed to pool and analyse available data to compare the incidence of second primary malignancies in ...patients with and without lenalidomide exposure. Methods We identified relevant studies through a search of PubMed and abstracts from the American Society of Clinical Oncology, American Society of Hematology, and the International Myeloma Workshop. Randomised, controlled, phase 3 trials that recruited patients with newly diagnosed multiple myeloma between Jan 1, 2000, and Dec 15, 2012, and in which at least one group received lenalidomide were eligible for inclusion. We obtained individual patient data (age, sex, date of diagnosis, allocated treatment and received treatment, duration of treatment and cause of discontinuation, maintenance treatment, date of first relapse, date of second primary malignancy diagnosis, type of second primary malignancy, date of death or last contact, and cause of death) by direct collaboration with the principal investigators of eligible trials. Primary outcomes of interest were cumulative incidence of all second primary malignancies, solid second primary malignancies, and haematological second primary malignancies, and were analysed by a one-step meta-analysis. Findings We found nine eligible trials, of which seven had available data for 3254 patients. 3218 of these patients received treatment (2620 had received lenalidomide and 598 had not), and were included in our analyses. Cumulative incidences of all second primary malignancies at 5 years were 6·9% (95% CI 5·3–8·5) in patients who received lenalidomide and 4·8% (2·0–7·6) in those who did not (hazard ratio HR 1·55 95% CI 1·03–2·34; p=0·037). Cumulative 5-year incidences of solid second primary malignancies were 3·8% (95% CI 2·7–4·9) in patients who received lenalidomide and 3·4% (1·6–5·2) in those that did not (HR 1·1 95% CI 0·62–2·00; p=0·72), and of haematological second primary malignancies were 3·1% (95% CI 1·9–4·3) and 1·4% (0·0–3·6), respectively (HR 3·8 95% CI 1·15–12·62; p=0·029). Exposure to lenalidomide plus oral melphalan significantly increased haematological second primary malignancy risk versus melphalan alone (HR 4·86 95% CI 2·79–8·46; p<0·0001). Exposure to lenalidomide plus cyclophosphamide (HR 1·26 95% CI 0·30–5·38; p=0·75) or lenalidomide plus dexamethasone (HR 0·86 95% CI 0·33–2·24; p=0·76) did not increase haematological second primary malignancy risk versus melphalan alone. Interpretation Patients with newly diagnosed myeloma who received lenalidomide had an increased risk of developing haematological second primary malignancies, driven mainly by treatment strategies that included a combination of lenalidomide and oral melphalan. These results suggest that alternatives, such as cyclophosphamide or alkylating-free combinations, should be considered instead of oral melphalan in combination with lenalidomide for myeloma. Funding Celgene Corporation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Activins are members of the TGF-β family of ligands that have multiple biological functions in embryonic stem cells as well as in differentiated tissue. Serum levels of activin A were found to be ...elevated in pathological conditions such as cachexia, osteoporosis and cancer. Signaling by activin A through canonical ALK4-ACVR2 receptor complexes activates the transcription factors SMAD2 and SMAD3. Activin A has a strong affinity to type 2 receptors, a feature that they share with some of the bone morphogenetic proteins (BMPs). Activin A is also elevated in myeloma patients with advanced disease and is involved in myeloma bone disease.
In this study we investigated effects of activin A binding to receptors that are shared with BMPs using myeloma cell lines with well-characterized BMP-receptor expression and responses. Activin A antagonized BMP-6 and BMP-9, but not BMP-2 and BMP-4. Activin A was able to counteract BMPs that signal through the type 2 receptors ACVR2A and ACVR2B in combination with ALK2, but not BMPs that signal through BMPR2 in combination with ALK3 and ALK6.
We propose that one important way that activin A regulates cell behavior is by antagonizing BMP-ACVR2A/ACVR2B/ALK2 signaling.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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