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https://www.readbyqxmd.com/read/28814763/spatial-genomic-heterogeneity-in-multiple-myeloma-revealed-by-multi-region-sequencing
#1
L Rasche, S S Chavan, O W Stephens, P H Patel, R Tytarenko, C Ashby, M Bauer, C Stein, S Deshpande, C Wardell, T Buzder, G Molnar, M Zangari, F van Rhee, S Thanendrarajan, C Schinke, J Epstein, F E Davies, B A Walker, T Meissner, B Barlogie, G J Morgan, N Weinhold
In multiple myeloma malignant plasma cells expand within the bone marrow. Since this site is well-perfused, a rapid dissemination of "fitter" clones may be anticipated. However, an imbalanced distribution of multiple myeloma is frequently observed in medical imaging. Here, we perform multi-region sequencing, including iliac crest and radiology-guided focal lesion specimens from 51 patients to gain insight into the spatial clonal architecture. We demonstrate spatial genomic heterogeneity in more than 75% of patients, including inactivation of CDKN2C and TP53, and mutations affecting mitogen-activated protein kinase genes...
August 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/28799436/immunotherapy-based-approaches-in-myelofibrosis
#2
Lucia Masarova, Srdan Verstovsek, Hagop Kantarjian, Naval Daver
Aberrant regulation of the immune system with up-regulation of pro-inflammatory cytokines contributes to disease pathophysiology in myelofibrosis (MF). Therapeutic options for MF associated anemia, thrombocytopenia, and bone marrow fibrosis remain limited. Areas covered: This review focuses on immune based therapies in MF, including immunomodulatory imide drugs (IMiDs), interferons, monoclonal antibodies and targeted agents (SL-401), and checkpoint inhibitors. Published literature was reviewed using available databases (PubMed, Cochrane, Scopus) and web pages (clinicaltrials...
August 11, 2017: Expert Review of Hematology
https://www.readbyqxmd.com/read/28792255/host-related-immunodeficiency-in-the-development-of-multiple-myeloma
#3
Talib Dosani, Sham Mailankody, Neha Korde, Elisabet Manasanch, Manisha Bhutani, Nishant Tageja, Mark Roschewski, Mary Kwok, Dickran Kazandjian, Rene Costello, Debra Burton, Yong Zhang, David Liewehr, Seth M Steinberg, Irina Maric, Ola Landgren
Host-related immunodeficiency is known to play a role in the development of multiple myeloma (MM) from its precursor conditions (monoclonal gammopathy of undetermined significance, MGUS, smoldering multiple myeloma, SMM). In order to understand the underlying immune changes in this process, we characterized immune patterns from MGUS to SMM to MM. We further sought to identify potential novel immune biomarkers that may predict progression of SMM to MM. We characterized patterns of circulating lymphocytes in 181 patients using multiparametric flow cytometry...
August 9, 2017: Leukemia & Lymphoma
https://www.readbyqxmd.com/read/28782633/plasma-cell-deficiency-in-humans-with-heterozygous-mutations-in-sec61a1
#4
Desirée Schubert, Marie-Christine Klein, Sarah Hassdenteufel, Andrés Caballero-Oteyza, Linlin Yang, Michele Proietti, Alla Bulashevska, Janine Kemming, Johannes Kühn, Sandra Winzer, Stephan Rusch, Manfred Fliegauf, Alejandro A Schäffer, Stefan Pfeffer, Roger Geiger, Adolfo Cavalié, Hongzhi Cao, Fang Yang, Yong Li, Marta Rizzi, Hermann Eibel, Robin Kobbe, Amy L Marks, Brian P Peppers, Robert W Hostoffer, Jennifer M Puck, Richard Zimmermann, Bodo Grimbacher
BACKGROUND: Primary antibody deficiencies (PAD) are the most frequent primary immunodeficiencies in humans. The genetic causes for PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide-conducting channel in the endoplasmic reticulum (ER) membrane. SEC61A1 is a target gene of XBP1s and strongly induced during plasma cell differentiation. OBJECTIVE: Characterization of a novel genetic defect and its pathological mechanism in eleven patients from two unrelated families with PAD...
August 3, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/28768640/clonal-expansion-and-interrelatedness-of-distinct-b-lineage-compartments-in-multiple-myeloma-bone-marrow
#5
Leo Hansmann, Arnold Han, Livius Penter, Michaela Liedtke, Mark M Davis
Multiple myeloma is characterized by the clonal expansion of malignant plasma cells in the bone marrow. But the phenotypic diversity and the contribution of less predominant B-lineage clones to the biology of this disease have been controversial. Here we asked whether cells bearing the dominant multiple myeloma immunoglobulin rearrangement occupy phenotypic compartments other than that of plasma cells. To accomplish this, we combined 13-parameter FACS index sorting and t-Stochastic Neighbor Embedding (t-SNE) visualization with high-throughput single-cell immunoglobulin sequencing to track selected B-lineage clones across different stages of human B-cell development...
August 2, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/28766538/-prognostic-value-of-1q21-amplification-in-multiple-myeloma
#6
T V Abramova, T N Obukhova, L P Mendeleeva, O S Pokrovskaya, E O Gribanova, V V Ryzhko, L A Grebenyuk, M V Nareyko, M V Solovyev, O M Votyakova, S M Kulikov, M A Rusinov, V G Savchenko
AIM: To determine the prevalence of amp1q21 and its relationship to the clinical manifestations of multiple myeloma (MM). SUBJECTS AND METHODS: In December 2009 to March 2016, a total 134 patients aged 30 to 81 years (median 57 years) underwent a pretreatment FISH-study of bone marrow (BM) with centromeric and locus-specific DNA probes to identify amp1q21, t(11;14), t(4;14), t(14;16), t(14;20), t(6;14), trisomies of chromosomes 5, 9, 15, del13q14, del17p13/TP53, and t(8q24)/cMYC...
2017: Terapevticheskiĭ Arkhiv
https://www.readbyqxmd.com/read/28763347/ex-vivo-induction-of-multiple-myeloma-specific-immune-responses-by-monocyte-derived-dendritic-cells-following-stimulation-by-whole-tumor-antigen-of-autologous-myeloma-cells
#7
Spyridoula Vasileiou, Ioannis Baltadakis, Sosanna Delimpasi, Maria-Helena Karatza, Konstantinos Liapis, Maria Garofalaki, Eirini Tziotziou, Zoe Poulopoulou, Dimitri Karakasis, Nicholas Harhalakis
The introduction of novel agents has significantly expanded treatment options for multiple myeloma (MM), albeit long-term disease control cannot be achieved in the majority of patients. Vaccination with MM antigen-loaded dendritic cells (DCs) represents an alternative strategy that is currently being explored. The aim of this study was to assess the immunogenic potential of ex vivo-generated monocyte-derived DCs (moDCs), following stimulation with the whole-antigen array of autologous myeloma cells (AMC). MoDCs were loaded with antigens of myeloma cells by 2 different methods: phagocytosis of apoptotic bodies from γ-irradiated AMC, or transfection with AMC total RNA by square-wave electroporation...
July 31, 2017: Journal of Immunotherapy
https://www.readbyqxmd.com/read/28761118/bortezomib-before-and-after-high-dose-therapy-in-myeloma-long-term-results-from-the-phase-iii-hovon-65-gmmg-hd4-trial
#8
H Goldschmidt, H M Lokhorst, E K Mai, B van der Holt, I W Blau, S Zweegman, K C Weisel, E Vellenga, M Pfreundschuh, M J Kersten, C Scheid, S Croockewit, R Raymakers, D Hose, A Potamianou, A Jauch, J Hillengass, M Stevens-Kroef, M S Raab, A Broijl, H W Lindemann, G M J Bos, P Brossart, M van Marwijk Kooy, P Ypma, U Duehrsen, R M Schaafsma, U Bertsch, T Hielscher, Le Jarari, H J Salwender, P Sonneveld
The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0...
July 4, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28760306/high-risk-multiple-myeloma-definition-and-management
#9
REVIEW
Nisha S Joseph, Silvia Gentili, Jonathan L Kaufman, Sagar Lonial, Ajay K Nooka
The prognosis of patients with multiple myeloma has significantly improved after the introduction of novel concepts of immunomodulation and proteasome inhibition in myeloma therapies. In conjunction with the use of high-dose therapy and autologous stem cell transplantation, these newer antimyeloma agents facilitated the augmentation of deeper responses and as a result, enhanced survival outcomes. Despite mounting clinical evidence that novel therapies may mitigate the poor prognostic impact of some predictors historically considered "harbingers of doom" in myeloma such as t(4;14), the benefit of these advances is less evident in patients who present with genetically defined high-risk features such as presence of chromosomal abnormalities del17p, t(14;16), or t(14;20), or among patients presenting with plasma cell leukemia...
July 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28758197/enhanced-immune-modulatory-effects-of-thalidomide-and-dexamethasone-co-treatment-on-t-cell-subsets
#10
Eun Jee Kim, Jae Geun Lee, Joon Ye Kim, Seung Hwan Song, Dong Jin Joo, Kyu Ha Huh, Myoung Soo Kim, Beom Seok Kim, Yu Seun Kim
Thalidomide (TM) has been reported to have anti-cancer and anti-inflammatory properties, and dexamethasone (DX) is known to reduce inflammation and inhibit production of inflammatory cytokines. Many studies have reported the combinatorial therapy of TM and DX is clinically used to treat multiple myeloma (MM) and lupus nephritis, but the mechanism responsible for its effects has not been elucidated. In this study, we determined that TM and DX co-treatment had an enhanced immune-modulatory effect on T cells through regulating expression of co-stimulatory molecules...
July 31, 2017: Immunology
https://www.readbyqxmd.com/read/28754858/melphalan-modifies-the-bone-microenvironment-by-enhancing-osteoclast-formation
#11
Ryan C Chai, Michelle M McDonald, Rachael L Terry, Nataša Kovačić, Jenny M Down, Jessica A Pettitt, Sindhu T Mohanty, Shruti Shah, Gholamreza Haffari, Jiake Xu, Matthew T Gillespie, Michael J Rogers, John T Price, Peter I Croucher, Julian M W Quinn
Melphalan is a cytotoxic chemotherapy used to treat patients with multiple myeloma (MM). Bone resorption by osteoclasts, by remodeling the bone surface, can reactivate dormant MM cells held in the endosteal niche to promote tumor development. Dormant MM cells can be reactivated after melphalan treatment; however, it is unclear whether melphalan treatment increases osteoclast formation to modify the endosteal niche.Melphalan treatment of mice for 14 days decreased bone volume and the endosteal bone surface, and this was associated with increases in osteoclast numbers...
July 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28751764/a-novel-bcma-cd3-bispecific-t-cell-engager-for-the-treatment-of-multiple-myeloma-induces-selective-lysis-in-vitro-and-in-vivo
#12
S Hipp, Y-T Tai, D Blanset, P Deegen, J Wahl, O Thomas, B Rattel, P J Adam, K C Anderson, M Friedrich
This corrects the article DOI: 10.1038/leu.2016.388.
July 28, 2017: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
https://www.readbyqxmd.com/read/28751289/a-new-case-of-ige-multiple-myeloma-with-review-of-literature
#13
Guillaume Vignon, Anne Sophie Cognée, François Carrere, Isabelle Masson, Florence Borde, Pierre Frédéric Augereau, Philippe Aucher, Franck Lellouche
IgE myeloma is an extremely rare disease characterized by frequent plasma cell leukemia, little monoclonal-spike on electrophoresis, an high incidence of t(11;14) translocation and a worse survival than those with common myelomas. We report here a new case of IgE myeloma and discuss clinical presentation, biological features and therapeutic option.
August 1, 2017: Annales de Biologie Clinique
https://www.readbyqxmd.com/read/28729550/anti-tumor-activity-and-immunotherapeutic-potential-of-a-bisphosphonate-prodrug
#14
Yoshimasa Tanaka, Masashi Iwasaki, Kaoru Murata-Hirai, Kenji Matsumoto, Kosuke Hayashi, Haruki Okamura, Tomoharu Sugie, Nagahiro Minato, Craig T Morita, Masakazu Toi
Bisphosphonates have benefits in breast cancer and multiple myeloma patients and have been used with adoptive immunotherapy with γδ T cells expressing Vγ2 Vδ2 TCRs. Although treatment with γδ T cells is safe, it has shown limited efficacy. Present bisphosphonates stimulate γδ T cells but were designed to inhibit bone resorption rather than treating cancer and have limited oral absorption, tumor cell entry, and cause bone side effects. The development of phosphate and phosphonate nucleotide prodrugs has led to important drugs for hepatitis C and HIV...
July 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28728165/active-multiple-myeloma-suppresses-and-typically-eliminates-coexisting-mgus
#15
John P Campbell, Jennifer L J Heaney, Sankalp Pandya, Zaheer Afzal, Martin Kaiser, Roger Owen, J Anthony Child, Walter Gregory, Gareth J Morgan, Graham H Jackson, Chris M Bunce, Mark T Drayson
BACKGROUND: Myeloma is consistently preceded by premalignant monoclonal gammopathy of undetermined significance (MGUS). In >5% of MGUS patients there is a second MGUS clone (biclonal gammopathy of undetermined significance; BGUS), yet, at myeloma diagnosis, presentation of biclonal gammopathy myeloma (BGMy) is considered less frequent, implying that myeloma eradicates coexisting MGUS. METHODS: In the largest study of its kind, we assessed BGMy frequency amongst 6399 newly diagnosed myeloma patients enrolled in recent UK clinical trials...
July 20, 2017: British Journal of Cancer
https://www.readbyqxmd.com/read/28702457/multiple-myeloma-cells-express-key-immunoregulatory-cytokines-and-modulate-the-monocyte-migratory-response
#16
Leonardo Freire-de-Lima, Ana Flávia Fernandes Ribas Nardy, Erivan Schnaider Ramos-Junior, Luciana Conde, Jéssica Santos Lemos, Leonardo Marques da Fonseca, Juliana Echevarria Lima, Angelo Maiolino, Alexandre Morrot
Multiple myeloma (MM) is a plasma cell disorder that still remains incurable. The immune dysfunction of the host is a striking characteristic of MM, leading to tumor growth and reducing the survival rate of patients. Monocytes are precursors of conventional dendritic cells (DCs), a major player in the immunity mechanisms driving protective T cell responses against tumor. Herein, we report that human MM RPMI 8226 cell line shows a pronounced chemoattractant activity for monocytes and also expresses enhanced levels of the leukocyte chemotactic cytokines CXCL12, CCL5, MIP-1β, and CXCL10 in association with elevated levels of both key immunoregulatory interleukins such as IL-4 and IL-10...
2017: Frontiers in Medicine
https://www.readbyqxmd.com/read/28692028/in-search-of-the-optimal-platform-for-post-allogeneic-sct-immunotherapy-in-relapsed-multiple-myeloma-a-systematic-review
#17
REVIEW
R Oostvogels, S M U Venema, M de Witte, R Raymakers, J Kuball, N Kröger, M C Minnema
Allogeneic stem cell transplantation (allo-SCT) has the potential to induce sustained remissions in patients with multiple myeloma (MM). Currently, allo-SCT is primarily performed in high-risk MM patients, most often in the setting of early relapse after first-line therapy with autologous SCT. However, the implementation of allo-SCT for MM is jeopardized by high treatment-related mortality (TRM) rates as well as high relapse rates. In this systematic review, we aimed to identify a safe allo-SCT strategy that has optimal 1-year results regarding mortality, relapse and severe GvHD, creating opportunities for post-transplantation strategies to maintain remissions in the high-risk group of relapsed MM patients...
July 10, 2017: Bone Marrow Transplantation
https://www.readbyqxmd.com/read/28690897/a-case-of-multiple-myeloma-presenting-with-diabetes-insipidus
#18
Rudrajit Paul, Aditya V Ruia, Asim Saha, Jayati Mondal, T J Sau, Indranil Thakur, Kunal Haldar
Multiple myeloma (MM) can present with involvement of the central nervous system in the form of nerve palsy, plasma cell masses or, rarely, with endocrinological effects due to involvement of the pituitary gland. Usually, in such cases, the disease has a rapid progression and poor prognosis. We report a 52-year-old man who was admitted to the Kolkata Medical College, Kolkata, India, in 2016 with a prolonged low-grade fever and hypernatremia. Shortly afterwards, the patient began to complain of increased urinary frequency and drowsiness...
May 2017: Sultan Qaboos University Medical Journal
https://www.readbyqxmd.com/read/28689001/immuno-oncologic-approaches-car-t-cells-and-checkpoint-inhibitors
#19
REVIEW
Francesca Gay, Mattia D'Agostino, Luisa Giaccone, Mariella Genuardi, Moreno Festuccia, Mario Boccadoro, Benedetto Bruno
Advances in understanding myeloma biology have shown that disease progression is not only the consequence of intrinsic tumor changes but also of interactions between the tumor and the microenvironment in which the cancer grows. The immune system is an important component of the tumor microenvironment in myeloma, and acting on the immune system is an appealing new treatment strategy. There are 2 ways to act toward immune cells and boost antitumor immunity: (1) to increase antitumor activity (acting on T and NK cytotoxic cells), and (2) to reduce immunosuppression (acting on myeloid-derived stem cells and T regulatory cells)...
June 17, 2017: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/28685821/pd-1-pd-l1-inhibitors-in-haematological-malignancies-update-2017
#20
REVIEW
Tomas Jelinek, Jana Mihalyova, Michal Kascak, Juraj Duras, Roman Hajek
The introduction of PD-1/PD-L1 pathway inhibitors is an important landmark in solid oncology with unprecedented practice-changing activity in various types of solid tumours. Among haematological malignancies, PD-1/PD-L1 inhibitors have been successful, so far, only in the treatment of classical Hodgkin lymphoma, which typically exhibits an over-expression of PD-1 ligands (PD-L1, PD-L2) due to alterations in chromosome 9p24.1. Such positive outcomes led to the US Food and Drug Administration approval of nivolumab use in relapsed Hodgkin lymphoma in 2016 as the first haematological indication...
July 6, 2017: Immunology
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