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Clinics in Laboratory Medicine Sep 2023Flow cytometry plays a critical role in the diagnosis, prognostication, therapy response evaluation, and clinical management of plasma cell neoplasms. The review... (Review)
Review
Flow cytometry plays a critical role in the diagnosis, prognostication, therapy response evaluation, and clinical management of plasma cell neoplasms. The review summarizes how flow cytometry is used in the initial evaluation to distinguish primary and secondary clonal plasma cell populations from each other and from reactive plasma cells. We further illustrate the kinds of prognostic information the assessment can provide at diagnosis and disease follow-up of primary plasma cell neoplasms. Technical requirements for MRD assays and their use in therapy efficacy assessment and clinical decision-making in multi-myeloma are discussed.
Topics: Humans; Multiple Myeloma; Flow Cytometry; Neoplasms, Plasma Cell; Clinical Decision-Making
PubMed: 37481317
DOI: 10.1016/j.cll.2023.05.003 -
Cells Sep 2023G protein-coupled estrogen receptor 1 (GPER1) activation is emerging as a promising therapeutic strategy against several cancer types. While GPER targeting has been...
G protein-coupled estrogen receptor 1 (GPER1) activation is emerging as a promising therapeutic strategy against several cancer types. While GPER targeting has been widely studied in the context of solid tumors, its effect on hematological malignancies remains to be fully understood. Here, we show that GPER1 mRNA is down-regulated in plasma cells from overt multiple myeloma (MM) and plasma cell leukemia patients as compared to normal donors or pre-malignant conditions (monoclonal gammopathy of undetermined significance and smoldering MM); moreover, lower GPER1 expression associates with worse overall survival of MM patients. Using the clinically applicable GPER1-selective agonist G-1, we demonstrate that the pharmacological activation of GPER1 triggered in vitro anti-MM activity through apoptosis induction, also overcoming the protective effects exerted by bone marrow stromal cells. Noteworthy, G-1 treatment reduced in vivo MM growth in two distinct xenograft models, even bearing bortezomib-resistant MM cells. Mechanistically, G-1 upregulated the miR-29b oncosuppressive network, blunting an established miR-29b-Sp1 feedback loop operative in MM cells. Overall, this study highlights the druggability of GPER1 in MM, providing the first preclinical framework for further development of GPER1 agonists to treat this malignancy.
Topics: Humans; Multiple Myeloma; Hematologic Neoplasms; Smoldering Multiple Myeloma; Plasma Cells; MicroRNAs
PubMed: 37759449
DOI: 10.3390/cells12182226 -
Seminars in Cancer Biology Jul 2023Obesity is a global pandemic that has been associated with the development of breast, endometrial, large intestine, renal, esophageal, and pancreatic cancer. Obesity is... (Review)
Review
Obesity is a global pandemic that has been associated with the development of breast, endometrial, large intestine, renal, esophageal, and pancreatic cancer. Obesity is also involved in the development of cardiovascular disease and type 2 diabetes mellitus. Recently, an increase in the incidence of obesity-related cancers has been reported. Multiple myeloma (MM) is the second most common hematological malignancy, after lymphoma. The aim of this review is to examine the epidemiological data on obesity and MM, assess the effect of obesity on MM outcomes, evaluate the possible mechanisms through which obesity might increase the incidence of MM and provide the effects of obesity management on MM. Current evidence indicates that obesity may have an impact on the progression of monoclonal gammopathy of undetermined significance (MGUS) to MM and increase the prevalence of MM. However, data regarding the effect of obesity on MGUS incidence are controversial; further studies are needed to examine whether obesity affects the development of MGUS or the progression of MGUS to MM. In addition, obesity affects MM outcomes. Increased BMI is associated with decreased survival in patients with MM, while data regarding the effect of obesity on newly diagnosed MM subjects and autologous stem cell transplantation are limited. Interestingly, the obesity paradox may also apply to patients with relapsed/refractory MM who are overweight or obese, because they may have a survival advantage. The pathophysiological pathways linking obesity to MM are very complicated and include bone marrow adipose tissue; adipokines, such as adiponectin, leptin, resistin, and visfatin; inflammatory cytokines and growth factors, such as TNF-α and IL-6; hormones including insulin and the insulin-like growth factor system as well as sex hormones. In terms of the effect of pharmacological management of obesity, orlistat has been shown to alter the proliferation of MM cells, whereas no data exist on glucagon-like peptide-1 receptor agonists, naltrexone/bupropion, or phentermine/topiramate. Bariatric surgery may be associated with a reduction in the incidence of MM, however, further studies are needed.
Topics: Humans; Multiple Myeloma; Diabetes Mellitus, Type 2; Hematopoietic Stem Cell Transplantation; Transplantation, Autologous; Obesity; Disease Progression
PubMed: 37030643
DOI: 10.1016/j.semcancer.2023.04.003 -
International Journal of Cancer Oct 2023Multiple myeloma (MM) is a relapsing clonal plasma cell malignancy and incurable thus far. With the increasing understanding of myeloma, highlighting the critical... (Review)
Review
Multiple myeloma (MM) is a relapsing clonal plasma cell malignancy and incurable thus far. With the increasing understanding of myeloma, highlighting the critical importance of the immune system in the pathogenesis of MM is essential. The immune changes in MM patients after treatment are associated with prognosis. In this review, we summarize currently available MM therapies and discuss how they affect cellular immunity. We find that the modern anti-MM treatments enhance antitumour immune responses. A deeper understanding of the therapeutic activity of individual drugs offers more effective treatment approaches that enhance the beneficial immunomodulatory effects. Furthermore, we show that the immune changes after treatment in MM patients can provide useful prognostic marker. Analysing cellular immune responses offers new perspectives for evaluating clinical data and making comprehensive predictions for applying novel therapies in MM patients.
Topics: Humans; Multiple Myeloma; Immunotherapy; Neoplasm Recurrence, Local; Plasma Cells; Immunity, Cellular
PubMed: 37306091
DOI: 10.1002/ijc.34609 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2023Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor... (Review)
Review
Secondary antibody deficiency (SAD) is a subtype of secondary immunodeficiency characterized by low serum antibody concentrations (hypogammaglobulinemia) or poor antibody function. SAD is common in patients with multiple myeloma (MM) due to underlying disease pathophysiology and treatment-related immune system effects. Patients with SAD are more susceptible to infections and infection-related morbidity and mortality. With therapeutic advancements improving MM disease control and survival, it is increasingly important to recognize and treat the often-overlooked concurrent immunodeficiency present in patients with MM. The aims of this review are to define SAD and its consequences in MM, increase SAD awareness, and provide recommendations for SAD management. Based on expert panel discussions at a standalone meeting and supportive literature, several recommendations were made. Firstly, all patients with MM should be suspected to have SAD regardless of serum antibody concentrations. Patients should be evaluated for immunodeficiency at MM diagnosis and stratified into management categories based on their individualized risk of SAD and infection. Infection-prevention strategy education, early infection reporting, and anti-infective prophylaxis are key. We recommend prophylactic antibiotics or immunoglobulin replacement therapy (IgRT) should be considered in patients with severe hypogammaglobulinemia associated with a recurrent or persistent infection. To ensure an individualized and efficient treatment approach is utilized, patient's immunoglobin G concentration and infection burden should be closely monitored throughout treatment. Patient choice regarding route and IgRT treatment is also key in reducing treatment burden. Together, these recommendations and proposed management algorithms can be used to aid physician decision-making to improve patient outcomes.
Topics: Humans; Multiple Myeloma; Agammaglobulinemia; Immunologic Deficiency Syndromes; Immunization, Passive; Antibodies
PubMed: 37353432
DOI: 10.1016/j.clml.2023.05.008 -
Haematologica Dec 2023Multiple Myeloma (MM) is a plasma cell neoplasm originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in...
Multiple Myeloma (MM) is a plasma cell neoplasm originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in understanding the pathogenesis of MM and improving treatment is a lack of immunocompetent mouse models. We previously developed the IL6Myc mouse that generates plasmacytomas at 100% penetrance that phenotypically resemble aggressive MM. Using comprehensive genomic analysis, we found that the IL6Myc tumors resemble aggressive MM by RNA and protein expression. We also found that IL6Myc tumors accumulated fusions and missense mutations in genes that overlap significantly with human myeloma, indicating that the mouse is good model for studying disease etiology. Lastly, we derived cell lines from IL6Myc tumors that express cell surface markers typical of MM and readily engraft into mice, home to the bone marrow, and induce osteolytic disease. The cell lines may be useful in developing immunotherapies directed against BAFF-R and TACI, though not BCMA, and may also be a good model for studying dexamethasone resistance. These data indicate that the IL6Myc model is useful for studying development of aggressive MM and for developing new treatments against such forms of the disease.
Topics: Mice; Humans; Animals; Multiple Myeloma; Bone Marrow
PubMed: 37439384
DOI: 10.3324/haematol.2022.282538 -
The Lancet. Oncology Aug 2023
Topics: Humans; Multiple Myeloma; Receptors, Chimeric Antigen; Point-of-Care Systems; T-Lymphocytes; Immunotherapy, Adoptive
PubMed: 37414061
DOI: 10.1016/S1470-2045(23)00269-3 -
Clinical Advances in Hematology &... Sep 2023Multiple myeloma (MM) is a clonal plasma cell dyscrasia and the most common form of primary bone marrow cancer. Nearly 35,000 new cases of MM are diagnosed in the United... (Review)
Review
Multiple myeloma (MM) is a clonal plasma cell dyscrasia and the most common form of primary bone marrow cancer. Nearly 35,000 new cases of MM are diagnosed in the United States each year. MM is a slowly progressive illness that remains incurable. The median survival for patients with MM is approximately 7 years, during which these patients suffer substantial morbidity. Despite the introduction of new drugs and immune-based therapies, many patients unfortunately relapse and require further therapies. Therefore, it is becoming increasingly important to be able to accurately and quickly determine changes in a patient's clinical status. Assessments of monoclonal protein and serum free light chain levels are the most common tests now available for monitoring patients with MM; however, these assays have several drawbacks. Modern radiologic techniques such as positron emission tomography and computed tomography are better than standard radiographs but are costly and cumbersome. Serum B-cell maturation antigen is a new biomarker for both the diagnosis and prognosis of MM. Assessment of measurable residual disease is becoming an important endpoint. The creation of better ways to predict outcomes and promptly and accurately monitor changes for patients with MM should lead to improved quality of life and longer survival.
Topics: Humans; Multiple Myeloma; Quality of Life; Antibodies, Monoclonal; B-Cell Maturation Antigen; Neoplasm, Residual
PubMed: 37647495
DOI: No ID Found -
EMBO Molecular Medicine Apr 2024B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here...
B-cell maturation antigen (BCMA), expressed in plasmablasts and plasma cells, could serve as a promising therapeutic target for autoimmune diseases. We reported here chimeric antigen receptor (CAR) T cells targeting BCMA in two patients with highly relapsed and refractory myasthenia gravis (one with AChR-IgG, and one with MuSk-IgG). Both patients exhibited favorable safety profiles and persistent clinical improvements over 18 months. Reconstitution of B-cell lineages with sustained reduced pathogenic autoantibodies might underlie the therapeutic efficacy. To identify the possible mechanisms underlying the therapeutic efficacy of CAR-T cells in these patients, longitudinal single-cell RNA and TCR sequencing was conducted on serial blood samples post infusion as well as their matching infusion products. By tracking the temporal evolution of CAR-T phenotypes, we demonstrated that proliferating cytotoxic-like CD8 clones were the main effectors in autoimmunity, whereas compromised cytotoxic and proliferation signature and profound mitochondrial dysfunction in CD8 Te cells before infusion and subsequently defect CAR-T cells after manufacture might explain their characteristics in these patients. Our findings may guide future studies to improve CAR T-cell immunotherapy in autoimmune diseases.
Topics: Humans; Immunotherapy, Adoptive; Multiple Myeloma; B-Cell Maturation Antigen; Cell Lineage; Myasthenia Gravis; T-Lymphocytes; Immunoglobulin G
PubMed: 38409527
DOI: 10.1038/s44321-024-00043-z -
Journal of Clinical Oncology : Official... Jan 2024
Topics: Humans; Multiple Myeloma
PubMed: 37847871
DOI: 10.1200/JCO.23.02017