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Frontiers in Immunology 2021Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention... (Review)
Review
Mouse models of human cancer provide an important research tool for elucidating the natural history of neoplastic growth and developing new treatment and prevention approaches. This is particularly true for multiple myeloma (MM), a common and largely incurable neoplasm of post-germinal center, immunoglobulin-producing B lymphocytes, called plasma cells, that reside in the hematopoietic bone marrow (BM) and cause osteolytic lesions and kidney failure among other forms of end-organ damage. The most widely used mouse models used to aid drug and immunotherapy development rely on propagation of human myeloma cells in immunodeficient hosts (xenografting) or myeloma-like mouse plasma cells in immunocompetent hosts (autografting). Both strategies have made and continue to make valuable contributions to preclinical myeloma, including immune research, yet are ill-suited for studies on tumor development (oncogenesis). Genetically engineered mouse models (GEMMs), such as the widely known Vκ*MYC, may overcome this shortcoming because plasma cell tumors (PCTs) develop (spontaneously) in a highly predictable fashion and accurately recapitulate many hallmarks of human myeloma. Moreover, PCTs arise in an intact organism able to mount a complete innate and adaptive immune response and tumor development reproduces the natural course of human myelomagenesis, beginning with monoclonal gammopathy of undetermined significance (MGUS), progressing to smoldering myeloma (SMM), and eventually transitioning to frank neoplasia. Here we review the utility of transplantation-based and transgenic mouse models of human MM for research on immunopathology and -therapy of plasma cell malignancies, discuss strengths and weaknesses of different experimental approaches, and outline opportunities for closing knowledge gaps, improving the outcome of patients with myeloma, and working towards a cure.
Topics: Animals; Disease Progression; Humans; Immunotherapy; Mice; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma
PubMed: 34149703
DOI: 10.3389/fimmu.2021.667054 -
Deutsches Arzteblatt International Apr 2022Multiple myeloma (MM) is a malignant plasma-cell disease that arises on the basis of a so-called monoclonal gammopathy of undetermined significance (MGUS). The median... (Review)
Review
BACKGROUND
Multiple myeloma (MM) is a malignant plasma-cell disease that arises on the basis of a so-called monoclonal gammopathy of undetermined significance (MGUS). The median age at disease onset is over 70. In Germany, there are approximately eight new cases per 100 000 inhabitants per year, or about 6000 new patients nationwide each year.
METHODS
To prepare this clinical practice guideline, a systematic literature review was carried out in medical databases (MEDLINE, CENTRAL), guideline databases (GIN), and the search portal of the German Institute for Quality and Efficiency in Health Care (IQWiG). The recommendations to be issued were based on two international guidelines, 40 dossier evaluations and systematic reviews, 10 randomized controlled trials, and 37 observational studies and finalized in a structured consensus process.
RESULTS
Because of its prognostic relevance, the use of the International Staging System (ISS) is recommended to stage MM and related plasma-cell neoplasms. When symptomatic MM is diagnosed, it is recommended to determine the extent of skeletal involvement by whole-body computed tomography. The indications for treatment shall be determined on the basis of the SLiMCRAB criteria; in all patients with MM it is recommended to include the biological (rather than chronological) age in the decisionmaking process. In suitable patients, it is recommended that initial treatment includes high-dose therapy, followed by main - tenance treatment. Even without high-dose treatment, a median progression-free survival of more than three years can be achieved with combination therapies. For the treatment of relapse, combinations of three drugs are more effective than doublet regimens with a median progression-free survival ranging from 10 to 45 months, depending on the study and prior therapy. Following anti-myeloma therapy, it is recommended to promptly offer physical exercise adapted to individual abilities to all patients who have the potential for rehabilitation, so that their quality of life can be sustained and improved.
CONCLUSION
This new clinical practice guideline addresses, in particular, the modalities of care that can be offered in addition to systemic antineoplastic therapy. In view of the significant recent advances in the treatment of myeloma, affected patients' quality of life now largely depends on optimized interdisciplinary care.
Topics: Humans; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Neoplasm Recurrence, Local; Paraproteinemias; Quality of Life
PubMed: 35314026
DOI: 10.3238/arztebl.m2022.0149 -
Current Opinion in Nephrology and... May 2018The current review will discuss recent advances in our understanding of the pathology of C3 glomerulopathy and atypical haemolytic uremic syndrome (aHUS). (Review)
Review
PURPOSE OF REVIEW
The current review will discuss recent advances in our understanding of the pathology of C3 glomerulopathy and atypical haemolytic uremic syndrome (aHUS).
RECENT FINDINGS
C3 glomerulopathy and aHUS are associated with abnormalities of control of the alternative pathway of complement. Recent articles have provided new insights into the classification of C3 glomerulopathy and its relationship to idiopathic immune complex-mediated glomerulonephritis. They suggest that there may be considerable overlap in pathogenesis between these entities and have indicated novel ways in which classification may be improved. There is increasing evidence that monoclonal gammopathy may cause C3 glomerulopathy or aHUS in older patients and emerging evidence that treatment of the underlying plasma cell clone may ameliorate the kidney disease.
SUMMARY
Recent work has provided new insights into the causes of C3 glomerulopathy and aHUS, and the mechanism by which complement is dysregulated. This is of particular importance with the advent of new therapeutic agents which can specifically target different parts of the complement cascade.
Topics: Atypical Hemolytic Uremic Syndrome; Complement Activation; Complement C3; Complement Pathway, Alternative; Glomerulonephritis; Humans; Paraproteinemias
PubMed: 29517501
DOI: 10.1097/MNH.0000000000000412 -
Blood Cancer Journal Oct 2017Multiparameter flow cytometry (MFC) has become standard in the management of patients with plasma cell (PC) dyscrasias, and could be considered mandatory in specific... (Review)
Review
Multiparameter flow cytometry (MFC) has become standard in the management of patients with plasma cell (PC) dyscrasias, and could be considered mandatory in specific areas of routine clinical practice. It plays a significant role during the differential diagnostic work-up because of its fast and conclusive readout of PC clonality, and simultaneously provides prognostic information in most monoclonal gammopathies. Recent advances in the treatment and outcomes of multiple myeloma led to the implementation of new response criteria, including minimal residual disease (MRD) status as one of the most relevant clinical endpoints with the potential to act as surrogate for survival. Recent technical progress led to the development of next-generation flow (NGF) cytometry that represents a validated, highly sensitive, cost-effective and widely available technique for standardized MRD evaluation, which also could be used for the detection of circulating tumor cells. Here we review current applications of MFC and NGF in most PC disorders including the less frequent solitary plasmocytoma, light-chain amyloidosis or Waldenström macroglobulinemia.
Topics: Flow Cytometry; Humans; Paraproteinemias
PubMed: 29053157
DOI: 10.1038/bcj.2017.90 -
Blood Advances Aug 2019Recent years have witnessed a rapid growth in our understanding of the pathogenic property of monoclonal proteins. It is evident that some of these small monoclonal... (Review)
Review
Recent years have witnessed a rapid growth in our understanding of the pathogenic property of monoclonal proteins. It is evident that some of these small monoclonal proteins are capable of inducing end-organ damage as a result of their intrinsic physicochemical properties. Hence, an umbrella term, monoclonal gammopathy of clinical significance (MGCS), has been coined to include myriad conditions attributed to these pathogenic proteins. Because kidneys are the most commonly affected organ (but skin, peripheral nerves, and heart can also be involved), we discuss MGRS exclusively in this review. Mechanisms of renal damage may involve direct or indirect effects. Renal biopsy is mandatory and demonstration of monoclonal immunoglobulin in kidney, along with the corresponding immunoglobulin in serum or urine, is key to establish the diagnosis. Pitfalls exist at each diagnostic step, and a high degree of clinical suspicion is required to diagnose MGRS. Recognition of MGRS by hematologists and nephrologists is important, because timely clone-directed therapy improves renal outcomes. Autologous stem cell transplant may benefit selected patients.
Topics: Algorithms; Biopsy; Fluorescent Antibody Technique; Humans; Kidney Diseases; Monoclonal Gammopathy of Undetermined Significance; Paraproteinemias; Prevalence; Treatment Outcome
PubMed: 31409583
DOI: 10.1182/bloodadvances.2019031914 -
Cleveland Clinic Journal of Medicine Jan 2019
Topics: Bone Marrow; Humans; Paraproteinemias; Primary Health Care
PubMed: 30624180
DOI: 10.3949/ccjm.86b.01019 -
Frontiers in Immunology 2022Monoclonal gammopathy of clinical significance (MGCS) represents a new clinical entity referring to a myriad of pathological conditions associated with the monoclonal... (Review)
Review
Monoclonal gammopathy of clinical significance (MGCS) represents a new clinical entity referring to a myriad of pathological conditions associated with the monoclonal gammopathy of undetermined significance (MGUS). The establishment of MGCS expands our current understanding of the pathophysiology of a range of diseases, in which the M protein is often found. Aside from the kidney, the three main organ systems most affected by monoclonal gammopathy include the peripheral nervous system, skin, and eye. The optimal management of these MGUS-related conditions is not known yet due to the paucity of clinical data, the rarity of some syndromes, and limited awareness among healthcare professionals. Currently, two main treatment approaches exist. The first one resembles the now-established therapeutic strategy for monoclonal gammopathy of renal significance (MGRS), in which chemotherapy with anti-myeloma agents is used to target clonal lesion that is thought to be the culprit of the complex clinical presentation. The second approach includes various systemic immunomodulatory or immunosuppressive options, including intravenous immunoglobulins, corticosteroids, or biological agents. Although some conditions of the MGCS spectrum can be effectively managed with therapies aiming at the etiology or pathogenesis of the disease, evidence regarding other pathologies is severely limited to individual patient data from case reports or series. Future research should pursue filling the gap in knowledge and finding the optimal treatment for this novel clinical category.
Topics: Humans; Clinical Relevance; Monoclonal Gammopathy of Undetermined Significance; Multiple Myeloma; Health Personnel; Immunoglobulins, Intravenous
PubMed: 36505449
DOI: 10.3389/fimmu.2022.1045002 -
European Journal of Neurology Dec 2022We evaluated the clinical and neurophysiological efficacy of rituximab (RTX) in a neurophysiologically homogeneous group of patients with monoclonal gammopathy and...
Efficacy of rituximab in anti-myelin-associated glycoprotein demyelinating polyneuropathy: Clinical, hematological and neurophysiological correlations during 2 years of follow-up.
BACKGROUND AND PURPOSE
We evaluated the clinical and neurophysiological efficacy of rituximab (RTX) in a neurophysiologically homogeneous group of patients with monoclonal gammopathy and immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody (anti-MAG) demyelinating polyneuropathy.
METHODS
Twenty three anti-MAG-positive polyneuropathic patients were prospectively evaluated before and for 2 years after treatment with RTX 375 mg/m . The Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale (INCAT-ds), modified INCAT sensory score (mISS), Medical Research Council sum score, Patients' Global Impression of Change scale were used, IgM levels were assessed and extensive electrophysiological examinations were performed before (T0) and 1 year (T1) and 2 years (T2) after RTX treatment.
RESULTS
At T1 and T2 there was a significant reduction from T0 both in mISS and in INCAT-ds, with a p value < 0.001 in the inferential Friedman's test overall analysis. Ulnar nerve Terminal Latency Index and distal motor latency significantly changed from T0 to T1 and in the overall analysis (p = 0.001 and p = 0.002), and ulnar nerve sensory nerve action potential (SNAP) amplitude was significantly increased at T2 from T1, with a p value < 0.001 in the overall analysis. Analysis of the receiver-operating characteristic curves showed that a 41.8% increase in SNAP amplitude in the ulnar nerve at T2 from T0 was a fair predictor of a mISS reduction of ≥2 points (area under the curve 0.85; p = 0.005; sensitivity: 90.9%, specificity: 83.3%).
CONCLUSIONS
This study suggests that RTX is effective in patients with clinically active demyelinating anti-MAG neuropathy over 2 years of follow-up, and that some neurophysiological variables might be useful for monitoring this efficacy.
Topics: Humans; Rituximab; Follow-Up Studies; Polyneuropathies; Paraproteinemias; Immunoglobulin M; Autoantibodies
PubMed: 36083713
DOI: 10.1111/ene.15553 -
Clinics in Laboratory Medicine Dec 2017Plasma cell dyscrasia (PCD) is a heterogeneous disease that has seen a tremendous change in outcomes due to improved therapies. Over the past few decades,... (Review)
Review
Plasma cell dyscrasia (PCD) is a heterogeneous disease that has seen a tremendous change in outcomes due to improved therapies. Over the past few decades, multiparametric flow cytometry has played an important role in the detection and monitoring of PCDs. Flow cytometry is a high-sensitivity assay for early detection of minimal residual disease (MRD) that correlates well with progression-free survival and overall survival. Before flow cytometry can be effectively implemented in the clinical setting, sample preparation, panel configuration, analysis, and gating strategies must be optimized to ensure accurate results. Current consensus methods and reporting guidelines for MRD testing are discussed.
Topics: Flow Cytometry; Humans; Multiple Myeloma; Neoplasm, Residual; Paraproteinemias
PubMed: 29128071
DOI: 10.1016/j.cll.2017.08.001 -
Frontiers in Endocrinology 2023
Topics: Humans; Paraproteinemias
PubMed: 36733528
DOI: 10.3389/fendo.2023.1107283