Longitudinal fluorescence in situ hybridization reveals cytogenetic evolution in myeloma relapsing after autologous transplantation

To investigate cytogenetic evolution after upfront autologous stem cell transplantation for newly diagnosed myeloma we retrospectively analyzed fluorescence in situ hybridization results of 128 patients with paired bone marrow samples from the time of primary diagnosis and at relapse. High-risk cytogenetic abnormalities (deletion 17p and/or gain 1q21) occurred more frequently after relapse (odds ratio: 6.33; 95% confidence interval: 1.86–33.42; P<0.001). No significant changes were observed for defined IGH translocations [t(4;14); t(11;14); t(14;16)] or hyperdiploid karyotypes between primary diagnosis and relapse. IGH translocations with unknown partners occurred more frequently at relapse. New deletion 17p and/or gain 1q21 were associated with cytogenetic heterogeneity, since some de novo lesions with different copy numbers were present only in subclones. No distinct baseline characteristics were associated with the occurrence of new high-risk cytogenetic abnormalities after progression. Patients who relapsed after novel agent-based induction therapy had an increased risk of developing high-risk aberrations (odds ratio 10.82; 95% confidence interval: 1.65–127.66; P=0.03) compared to those who were treated with conventional chemotherapy. Survival analysis revealed dismal outcomes regardless of whether high-risk aberrations were present at baseline (hazard ratio, 3.53; 95% confidence interval: 1.53–8.14; P=0.003) or developed at relapse only (hazard ratio, 3.06; 95% confidence interval: 1.09–8.59; P=0.03). Our results demonstrate cytogenetic evolution towards high-risk disease after autologous transplantation and underline the importance of repeated genetic testing in relapsed myeloma (EudraCT number of the HD4 trial: 2004-000944-26)

an interim analysis from the prospective GMMG-MM5 trial

We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight into the biological basis of MM.</p

Political travel across the ‘Iron Curtain’ and Communist youth identities in West Germany and Greece in the 1970s and 1980s

This article explores tours through the Iron Curtain arranged by West German and Greek pro-Soviet Communist youth groups, in an attempt to shed light on the transformation of European youth cultures beyond the ‘Americanisation’ story. It argues that the concept of the ‘black box’, employed by Rob Kroes to describe the influence of American cultural patterns on Western European youth, also applies to the reception of Eastern Bloc policies and norms by the Communists under study. Such selective reception was part of these groups’ efforts to devise a modernity alternative to the ‘capitalist’ one, an alternative modernity which tours across the Iron Curtain would help establish. Nevertheless, the organisers did not wish such travel to help eliminate American/Western influences on youth lifestyles entirely: the article analyses the excursions’ aims with regard to two core components of youth lifestyles in Western Europe since the 1960s, which have been affected by intra-Western flows, the spirit of ‘doing one’s own thing’ and transformations of sexual practices. The article also addresses the experience of the travellers in question, showing that they felt an unresolved tension: the tours neither served as a means of Sovietisation nor as an impulse to develop an openly anti-Soviet stance.PostprintPeer reviewe

Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma

Genome-wide association studies (GWAS) have transformed our understanding of susceptibility to multiple myeloma (MM), but much of the heritability remains unexplained. We report a new GWAS, a meta-analysis with previous GWAS and a replication series, totalling 9974 MM cases and 247,556 controls of European ancestry. Collectively, these data provide evidence for six new MM risk loci, bringing the total number to 23. Integration of information from gene expression, epigenetic profiling and in situ Hi-C data for the 23 risk loci implicate disruption of developmental transcriptional regulators as a basis of MM susceptibility, compatible with altered B-cell differentiation as a key mechanism. Dysregulation of autophagy/apoptosis and cell cycle signalling feature as recurrently perturbed pathways. Our findings provide further insight

Antibiotic Prophylaxis or Granulocyte-Colony Stimulating Factor Support in Multiple Myeloma Patients Undergoing Autologous Stem Cell Transplantation

We compare, in this manuscript, antibiotic prophylaxis versus granulocyte-colony stimulating factor (G-CSF) support as anti-infective strategies, in patients with multiple myeloma (MM), undergoing high-dose therapy followed by autologous stem cell transplantation (HDT/ASCT). At our institution, antibiotic prophylaxis after HDT/ASCT in MM was stopped in January 2017 and replaced by G-CSF support in March 2017. Consecutive MM patients who received HDT/ASCT between March 2016 and July 2018 were included in this single-center retrospective analysis. In total, 298 patients and 353 individual cases of HDT/ASCT were evaluated. In multivariate analyses, G-CSF support was associated with a significantly shortened duration of severe leukopenia &lt; 1/nL (p &lt; 0.001, hazard ratio (HR) = 16.22), and hospitalization (estimate = −0.19, p &lt; 0.001) compared to antibiotic prophylaxis. Rates of febrile neutropenia, need of antimicrobial therapy, transfer to intensive care unit, and death, were similar between the two groups. Furthermore, antibiotic prophylaxis was associated with a significantly increased risk for the development of multidrug resistant bacteria especially vancomycin-resistant Enterococcus faecium compared to G-CSF support (odds ratio (OR) = 17.38, p = 0.01). Stop of antibiotic prophylaxis as an anti-infective strategy was associated with a reduction in overall resistance rates of bacterial isolates. These results indicate that G-CSF support should be the preferred option in MM patients undergoing HDT/ASCT

Proof of the concept to use a malignant B cell line drug screen strategy for identification and weight of melphalan resistance genes in multiple myeloma

In a conceptual study of drug resistance we have used a preclinical model of malignant B-cell lines by combining drug induced growth inhibition and gene expression profiling. In the current report a melphalan resistance profile of 19 genes were weighted by microarray data from the MRC Myeloma IX trial and time to progression following high dose melphalan, to generate an individual melphalan resistance index. The resistance index was subsequently validated in the HOVON65/GMMG-HD4 trial data set to prove the concept. Biologically, the assigned resistance indices were differentially distributed among translocations and cyclin D expression classes. Clinically, the 25% most melphalan resistant, the intermediate 50% and the 25% most sensitive patients had a median progression free survival of 18, 32 and 28 months, respectively (log-rank P-value  = 0.05). Furthermore, the median overall survival was 45 months for the resistant group and not reached for the intermediate and sensitive groups (log-rank P-value  = 0.003) following 38 months median observation. In a multivariate analysis, correcting for age, sex and ISS-staging, we found a high resistance index to be an independent variable associated with inferior progression free survival and overall survival. This study provides clinical proof of concept to use in vitro drug screen for identification of melphalan resistance gene signatures for future functional analysis