Genetic correlation between multiple myeloma and chronic lymphocytic leukaemia provides evidence for shared aetiology

The clustering of different types of B-cell malignancies in families raises the possibility of shared aetiology. To examine this, we performed cross-trait linkage disequilibrium (LD)-score regression of multiple myeloma (MM) and chronic lymphocytic leukaemia (CLL) genome-wide association study (GWAS) data sets, totalling 11,734 cases and 29,468 controls. A significant genetic correlation between these two B-cell malignancies was shown (Rg = 0.4, P = 0.0046). Furthermore, four of the 45 known CLL risk loci were shown to associate with MM risk and five of the 23 known MM risk loci associate with CLL risk. By integrating eQTL, Hi-C and ChIP-seq data, we show that these pleiotropic risk loci are enriched for B-cell regulatory elements and implicate B-cell developmental genes. These data identify shared biological pathways influencing the development of CLL and, MM and further our understanding of the aetiological basis of these B-cell malignancies

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

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

Correction to: Nature Communications; https://doi.org/10.1038/s41467-018-04989-w, published online 13 September 2018

Non-Invasive Imaging Provides Spatiotemporal Information on Disease Progression and Response to Therapy in a Murine Model of Multiple Myeloma

Background: Multiple myeloma (MM) is a B-cell malignancy, where malignant plasma cells clonally expand in the bone marrow of older people, causing significant morbidity and mortality. Typical clinical symptoms include increased serum calcium levels, renal insufficiency, anemia, and bone lesions. With standard therapies, MM remains incurable; therefore, the development of new drugs or immune cell-based therapies is desirable. To advance the goal of finding a more effective treatment for MM, we aimed to develop a reliable preclinical MM mouse model applying sensitive and reproducible methods for monitoring of tumor growth and metastasis in response to therapy. Material and Methods: A mouse model was created by intravenously injecting bone marrow-homing mouse myeloma cells (MOPC-315.BM) that expressed luciferase into BALB/c wild type mice. The luciferase in the myeloma cells allowed in vivo tracking before and after melphalan treatment with bioluminescence imaging (BLI). Homing of MOPC-315.BM luciferase+ myeloma cells to specific tissues was examined by flow cytometry. Idiotype-specific myeloma protein serum levels were measured by ELISA. In vivo measurements were validated with histopathology. Results: Strong bone marrow tropism and subsequent dissemination of MOPC-315.BM luciferase+ cells in vivo closely mimicked the human disease. In vivo BLI and later histopathological analysis revealed that 12 days of melphalan treatment slowed tumor progression and reduced MM dissemination compared to untreated controls. MOPC-315.BM luciferase+ cells expressed CXCR4 and high levels of CD44 and a4b1 in vitro which could explain the strong bone marrow tropism. The results showed that MOPC-315.BM cells dynamically regulated homing receptor expression and depended on interactions with surrounding cells. Conclusions: This study described a novel MM mouse model that facilitated convenient, reliable, and sensitive tracking of myeloma cells with whole body BLI in living animals. This model is highly suitable for monitoring the effects of different treatment regimens

Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

In this retrospective study, we analyzed the outcomes of 129 patients who underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and had a history of probable or proven invasive aspergillosis (IA), of whom 57 (44%) received a reduced-intensity conditioning (RIC). Overall, 27 patients with IA progressed after the allo-HSCT (cumulative incidence [CumInc] at 2 years, 22%). The variables that increased the 2-year CumInc of IA progression were (1) longer duration of neutropenia after transplantation; (2) advanced status of the underlying disease; and (3) less than 6 weeks from start of systemic anti-Aspergillus therapy and the allo-HSCT. In addition, (4) conventional myeloablative conditioning increased the risk of progression early after transplantation (before day 30) only, while 3 variables increased the risk beyond day 30 were (5) cytomegalovirus disease; (6) bone marrow or cord blood as source of stem cells; and (7) grades II to IV acute graft-versus-host disease (GVHD). A risk model for progression was generated, defined as low (0-1 risk factors, 6% incidence), intermediate (2-3 risk factors, 27% incidence), or high risk (> or = 3 risk factors, 72% incidence [P < .001]). These findings may help in the interpretation and design of future studies on secondary prophylaxis of IA after an allo-HSCT

Perspectives on the Risk-Stratified Treatment of Multiple Myeloma

Blood cancer discovery34273-28

Perspectives on the Risk-Stratified Treatment of Multiple Myeloma

Blood cancer discovery34273-28

Perspectives on the Risk-Stratified Treatment of Multiple Myeloma.

The multiple myeloma treatment landscape has changed dramatically. This change, paralleled by an increase in scientific knowledge, has resulted in significant improvement in survival. However, heterogeneity remains in clinical outcomes, with a proportion of patients not benefiting from current approaches and continuing to have a poor prognosis. A significant proportion of the variability in outcome can be predicted on the basis of clinical and biochemical parameters and tumor-acquired genetic variants, allowing for risk stratification and a more personalized approach to therapy. This article discusses the principles that can enable the rational and effective development of therapeutic approaches for high-risk multiple myeloma