Monoclonal Gammopathy Of Undetermined Significance Research Articles

The effects of short-term, progressive exercise training on disease activity in smouldering multiple myeloma and monoclonal gammopathy of undetermined significance: a single-arm pilot study.

High levels of physical activity are associated with reduced risk of the blood cancer multiple myeloma (MM). MM is preceded by the asymptomatic stages of monoclonal gammopathy of undetermined significance (MGUS) and smouldering multiple myeloma (SMM) which are clinically managed by watchful waiting. A case study (N = 1) of a former elite athlete aged 44 years previously indicated that a multi-modal exercise programme reversed SMM disease activity. To build from this prior case study, the present pilot study firstly examined if short-term exercise training was feasible and safe for a group of MGUS and SMM patients, and secondly investigated the effects on MGUS/SMM disease activity. In this single-arm pilot study, N = 20 participants diagnosed with MGUS or SMM were allocated to receive a 16-week progressive exercise programme. Primary outcome measures were feasibility and safety. Secondary outcomes were pre- to post-exercise training changes to blood biomarkers of MGUS and SMM disease activity- monoclonal (M)-protein and free light chains (FLC)- plus cardiorespiratory and functional fitness, body composition, quality of life, blood immunophenotype, and blood biomarkers of inflammation. Fifteen (3 MGUS and 12 SMM) participants completed the exercise programme. Adherence was 91 ± 11%. Compliance was 75 ± 25% overall, with a notable decline in compliance at intensities > 70% V̇O2PEAK. There were no serious adverse events. There were no changes to M-protein (0.0 ± 1.0g/L, P =.903), involved FLC (+ 1.8 ± 16.8mg/L, P =.839), or FLC difference (+ 0.2 ± 15.6mg/L, P =.946) from pre- to post-exercise training. There were pre- to post-exercise training improvements to diastolic blood pressure (- 3 ± 5 mmHg, P =.033), sit-to-stand test performance (+ 5 ± 5 repetitions, P =.002), and energy/fatigue scores (+ 10 ± 15%, P =.026). Other secondary outcomes were unchanged. A 16-week progressive exercise programme was feasible and safe, but did not reverse MGUS/SMM disease activity, contrasting a prior case study showing that five years of exercise training reversed SMM in a 44-year-old former athlete. Longer exercise interventions should be explored in a group of MGUS/SMM patients, with measurements of disease biomarkers, along with rates of disease progression (i.e., MGUS/SMM to MM). https://www.isrctn.com/ISRCTN65527208 (14/05/2018).

Long Term Remission of Capillary Leak Syndrome Associated with Monoclonal Gammopathy with Progression to Multiple Myeloma After Autologous Stem Cell Transplantation: a Case Report and Review of the Literature.

Clarkson's disease is a very rare entity characterised by acute episodes of systemic oedema and severe hypotension associated with paraproteinaemia. Its classical treatment relies on methylxanthine combined with terbutaline. Although this prophylactic therapy reduces the mortality rate, relapses are frequent. Eighty percent of patients with Clarkson's disease present with monoclonal gammopathy of unknown significance (MGUS). The risk of progression to multiple myeloma is 1% per year. Here, we present a 49-year-old woman who suffered multiple such episodes requiring treatment in the intensive care unit. Treatment with terbutaline and theophylline was ineffective. She was diagnosed with multiple myeloma (MM) 8 years after the first of these acute episodes. Antimyeloma treatment with bortezomib and dexamethasone was started, followed by autologous haemopoietic transplantation, with no further acute episodes since then. Our case is, to our knowledge, unique because eradication of MM was followed by complete disappearance of acute episodes of capillary leakage. Our case report is also the first to support the use of bortezomib and dexamethasone in this setting. Furthermore, autologous peripheral blood progenitor cell transplantation consolidated the MM stringent complete remission achieving a very long progression-free survival (> 11 years) of both MM and Clarkson's disease.

Cytogenetic, Clinical, Hematologic, Demographic, Immunohistochemical, and Flow Cytometry Characteristics of Patients with Plasma Cell Neoplasm in Five Years: A First Report from Iran.

The aggregation of clonal plasma cells causes plasma cell neoplasms, which vary in severity and clinical outcomes. The present research focused on the epidemiological, clinical, immunologic, and cytogenetic characteristics of plasma cell neoplasms. In this five-year retrospective cross-sectional study, demographic information such as age and sex, calcium elevation, renal insufficiency, anemia, and bone lesion (CRAB) characteristics, as well as laboratory data including bone marrow and peripheral blood film results, immunohistochemistry, flow cytometry, and cytogenetic study outcomes were collected at Shiraz University of Medical Sciences, Shiraz, Iran. The collected data were analyzed using SPSS Statistics software (version 20.0). Descriptive statistics were reported as numbers, percentages, and mean±SD. 417 newly diagnosed plasma cell neoplasm patients were confirmed by bone marrow or other tissue biopsy tests. 279 patients were men (66.9%). The most prevalent age group was 60-64 years old (18.46%). Plasma cell myeloma (PCM) affected 355 (85.13%) patients, while monoclonal gammopathy of undetermined significance (MGUS) affected 6 (1.43%) patients. Solitary plasmacytoma was seen in 56 (13.42%) patients. At the time of diagnosis, 119 (33.52%) of 355 PCM patients were asymptomatic, whereas 236 (66.47%) patients had at least one CRAB symptom, 55 (15.49%) had two or more, and 14 (3.94%) had three or more. There were 7 (1.97%) cases of amyloidosis. Cytogenetic abnormalities were found in 51.28% (40/78) of the patients. Twenty-one individuals (52.5%) were hyperdiploid with multiple trisomy, while 19 (47.50%) were not. When diagnosed, Iranian PCM patients might have more advanced disease. PCM was more prevalent in young adults, and hyperdiploid was the most common cytogenetic finding in this investigation.

Clinical Significance of Serum Free Light Chain in Monoclonal Gammopathy

To investigate the expression and clinical significance of serum free light chain (sFLC) in patients with monoclonal gammopathy (MG). The peripheral blood of 98 patients with MG and 30 healthy volunteers were collected. The level of sFLC was detected by immunoturbidimetry, and the value of sFLC in diagnosis, disease severity, and efficacy evaluation was analyzed. Among 98 MG patients, there were 58 males and 40 females, 45 cases of monoclonal gammopathy of renal significance (MGRS), 33 cases of monoclonal gammopathy of undetermined significance (MGUS), 20 cases of hematological malignancy (HM), 58 cases of IgG type, 26 cases of IgA type, 7 cases of IgM type, 5 cases of light chain type, 2 cases of non-secreting type, 35 cases of κ type, 63 cases of λ type, 53 cases of renal insufficiency, 45 cases of normal renal function. The expression levels of sFLC-κ and sFLC-λ in MG patients were significantly higher than those of the control group (P <0.01). The expression levels of sFLC-κ and sFLC-λ in HM patients were significantly higher than MGRS and MGUS patients, and in MGRS patients were also significantly higher than MGUS patients (P <0.05). Patients with abnormal renal function had higher expression levels of sFLC-κ and sFLC-λ than patients with normal renal function (P <0.01). sFLC-κ and sFLC-λ were positively correlated with the expression level of globulin (r =0.392, r =0.435) and β2-MG (r =0.403, r =0.468) in MG patients, as well as serum creatinine in patients with abnormal renal function (r =0.586, r =0.631), while no significant correlation was found with age, sex, albumin, lactate dehydrogenase, and serum calcium. After treatment, the levels of sFLC-κ and sFLC-λ were significantly decreased (P <0.01). sFLC is significantly elevated in MG patients and can be quickly detected with high sensitivity, which is helpful for the diagnosis of disease type, judgment of disease severity, and evaluation of therapy.

Establishing Monoclonal Gammopathy of Undetermined Significance as an Independent Pre-Disease State of Multiple Myeloma Using Raman Spectroscopy, Dynamical Network Biomarker Theory, and Energy Landscape Analysis.

Multiple myeloma (MM) is a cancer of plasma cells. Normal (NL) cells are considered to pass through a precancerous state, such as monoclonal gammopathy of undetermined significance (MGUS), before transitioning to MM. In the present study, we acquired Raman spectra at three stages-834 NL, 711 MGUS, and 970 MM spectra-and applied the dynamical network biomarker (DNB) theory to these spectra. The DNB analysis identified MGUS as the unstable pre-disease state of MM and extracted Raman shifts at 1149 and 1527-1530 cm-1 as DNB variables. The distribution of DNB scores for each patient showed a significant difference between the mean values for MGUS and MM patients. Furthermore, an energy landscape (EL) analysis showed that the NL and MM stages were likely to become stable states. Raman spectroscopy, the DNB theory, and, complementarily, the EL analysis will be applicable to the identification of the pre-disease state in clinical samples.

Monoclonal immunoglobulin as a prognostic factor for the severity of bone damage in paraproteinemic hemoblastoses and Waldenström’s macroglobulinemia

Aim. Identify risk factors for the development of osteodestructive syndrome. To determine the relationship between the types of secreted monoclonal immunoglobulin (paraprotein) and the severity of osteodestructive syndrome in patients with paraproteinemic hemoblastoses (PH) and Waldenström’s macroglobulinemia (WM).Materials and methods. A retrospective analysis of data from 116 patients with PH and WM was performed. 104 patients (89.6 %) were diagnosed with multiple myeloma. Less commonly observed were WM (in 8 patients – 6.9 %), plasma cell leukemia (in 2 patients – 1.8 %), solitary plasmacytoma and monoclonal gammopathy of unknown significance were diagnosed in one case (0.9 %) each. According to the severity of osteodestructive syndrome, all patients were divided into 4 groups. The first group (0) included patients who did not have osteodestructive changes in the bones. In patients of the second group, a mild degree (I) osteodestructive process was observed, and in patients from the third and fourth groups – moderate (II) and severe (III) degrees, respectively. All patients underwent protein electrophoresis followed by immunofixation to determine the type of paraprotein and its concentration in serum and urine.Results. In the majority of patients, paraproteins were detected in the blood – Gκ (35.1 %), Gλ (24.6 %), Bence Jones protein λ-type (BJλ) (14.9 %); in urine – BJλ protein (14.9 %) and Bence Jones protein κ-type (BJκ) (28.1 %). Secretion of other types of paraproteins in the blood was less frequently detected – Aκ (9.6 %), Aλ (7.0 %), Mκ (3.5 %), Mλ (3.5 %), Dλ (2.6 %), BJκ (4.4 %). Osteodestructive syndrome of I and II severity was diagnosed in 43 (37.1 %) and 40 (34.5 %) patients, respectively; lytic destruction of III degree was less frequently detected in 20 (17.2 %) patients, in 13 (11.2 %) patients osteodestruction was not detected (degree 0). It was noted that a higher degree of destruction (II, III) was observed in patients with multiple myeloma occurring with paraproteinemia Dλ and BJλ in the blood, as well as hypercalcemia. Osteodestructive syndrome of the lowest degree (0, I) was diagnosed in patients with the secretion of monoclonal proteins Ak and Mλ. There was no statistically significant relationship between the type of secretion of paraproteins Gκ, Gλ, Aλ, Mκ, BJκ in the blood, as well as proteins BJκ and BJλ in the urine and the severity of the osteodestructive process.Conclusion. The results obtained in the study make it possible to identify risk groups, and parameters such as the type of paraprotein, the concentration of calcium in the blood serum can be considered as prognostic factors when assessing the severity of osteodestructive syndrome in patients with PH and WM.

Stromal alterations in patients with monoclonal gammopathy of undetermined significance, smoldering myeloma, and multiple myeloma

AbstractThe hallmark of multiple myeloma (MM) is a clonal plasma cell infiltration in the bone marrow accompanied by myelosuppression and osteolysis. Premalignant stages such as monoclonal gammopathy of undetermined significance (MGUS) and asymptomatic stages such as smoldering myeloma (SMM) can progress to MM. Mesenchymal stromal cells (MSCs) are an integral component of the bone marrow microenvironment and play an important role in osteoblast differentiation and hematopoietic support. Although stromal alterations have been reported in MM contributing to hematopoietic insufficiency and osteolysis, it is not clear whether alterations in MSC already occur in MGUS or SMM. In this study, we analyzed MSCs from MGUS, SMM, and MM regarding their properties and functionality and performed messenger RNA sequencing to find underlying molecular signatures in different disease stages. A high number of senescent cells and a reduced osteogenic differentiation capacity and hematopoietic support were already present in MGUS MSC. As shown by RNA sequencing, there was a broad spectrum of differentially expressed genes including genes of the BMP/TGF-signaling pathway, detected already in MGUS and that clearly increases in patients with SMM and MM. Our data may help to block these signaling pathways in the future to hinder progression to MM.

Bone marrow adipocytes provide early sign for progression from MGUS to multiple myeloma.

Multiple Myeloma (MM) is the second most common hematological malignancy and is characterized by clonal expansion of malignant plasma cells in the bone marrow. In spite of recent advances in the field of MM, the disease has remained incurable. MM is preceded by a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS), with a risk of progression to MM of 1% per year. Establishing a scalable approach that refines the identification of MGUS patients at high risk of progression to MM can transform the clinical management of the disease, improve the patient's quality of life, and will have significant socioeconomic implications. Here, we provide evidence that changes in the bone marrow adipose tissue (BMAT) provide an early sign for progression from MGUS to MM. We employed AI-assisted histological analysis of unstained bone marrow biopsies from MGUS subjects with or without progression to MM within 10 years (n = 24, n = 17 respectively). Although the BMAT fraction was not different between the two groups, bone marrow adipocyte (BMAd) density was decreased in MGUS patients who developed MM, compared to non-progressing MGUS patients. Importantly, the distribution profile for BMAd size and roundness was significantly different between the two groups, indicating a shift toward increased BMAd size and roundness in MGUS patients who developed MM. These early changes in the BMAT could serve as valuable early indicators for the transition from MGUS to MM, potentially enabling timely interventions and personalized treatment strategies. Finally, the AI-based approach for histological characterization of unstained bone marrow biopsies is cost-effective and fast, rendering its clinical implementation feasible.

Mass spectrometry-detected MGUS is associated with obesity and other novel modifiable risk factors in a high-risk population

AbstractMonoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition of multiple myeloma with few known risk factors. The emergence of mass spectrometry (MS) for the detection of MGUS has provided new opportunities to evaluate its risk factors. In total, 2628 individuals at elevated risk for multiple myeloma were enrolled in a screening study and completed an exposure survey (PROMISE trial). Participant samples were screened by MS, and monoclonal proteins (M-proteins) with concentrations of ≥0.2 g/L were categorized as MS-MGUS. Multivariable logistic models evaluated associations between exposures and MS outcomes. Compared with normal weight (body mass index [BMI] of 18.5 to <25 kg/m2), obesity (BMI of ≥30 kg/m2) was associated with MS-MGUS, adjusting for age, sex, Black race, education, and income (odds ratio [OR], 1.73; 95% confidence interval [CI], 1.21-2.47; P = .003). High physical activity (≥73.5 metabolic equivalent of task (MET)-hours per week vs <10.5 MET-hours per week) had a decreased likelihood of MS-MGUS (OR, 0.45, 95% CI, 0.24-0.80; P = .009), whereas heavy smoking and short sleep had increased likelihood of MS-MGUS (>30 pack-years vs never smoker: OR, 2.19; 95% CI, 1.24-3.74; P = .005, and sleep <6 vs ≥6 hours per day: OR, 2.11; 95% CI, 1.26-3.42; P = .003). In the analysis of all MS-detected monoclonal gammopathies, which are inclusive of M-proteins with concentrations of <0.2 g/L, elevated BMI and smoking were associated with all MS-positive cases. Findings suggest MS-detected monoclonal gammopathies are associated with a broader range of modifiable risk factors than what has been previously identified. This trial was registered at www.clinicaltrials.gov as #NCT03689595.

O-02 Inactivation of KDM1A with the concurrent presence of MGUS in a patient with GIP-dependent Cushing's syndrome and the vanishing effect of octreotide therapy

Abstract Introduction Glucose-dependent insulinotropic peptide (GIP)-dependent primary bilateral macronodular adrenal hyperplasia (PBMAH) is a rare cause of Cushing's syndrome. It has germline genetic predisposition and requires for personalized approaches to investigation and therapy. We aimed to present the rare case of a GIP-dependent PBMAH patient with unusually severe cortisol secretion and a KDM1A inactivation with an accompanying haematological co-morbidity related to that mutation. Clinical Case A 41-year-old woman presented with a 5-kg weight gain in last 6 months, irritability and fatique. Physical examination revealed elevated blood pressure, increased supraclavicular fat pads, and abdominal obesity. The cortisol level was 25.9 (6.7-22.6) µg/dL in the morning, 16.9 µg/dL in the late night, and 6.5 µg/dL in the morning after an overnight 1 mg of dexamethasone. Urinary free cortisol (UFC) level was also elevated to 2150 (58-403) µg/24-h. The early morning plasma ACTH level was 1.5 (7-63) pg/mL. Abdominal imaging revealed 29×23 mm adenomas on the right and 46×35 mm on the left with high fat content. Cortisol was stimulated by the administration of mixed meals (+537%) but not by TRH, GnRH, metoclopramide or upright posture. The response to mixed meals was blunted by pretreatment with subcutaneous 100 mg octreotide. Following the patient's diagnosis of GIP-dependent PBMAH, octreotide LAR therapy was initiated. Although inducing a significant acute suppression of UFC and improvement in symptoms during the first 3 months, the UFC began to rise due to the resistance in the following period (Figure 1). After 9 months of octreotide LAR treatment, left adrenalectomy was performed according to the adrenal volumetric assessment. Histopathology was reported as diffuse macronodular adrenal hyperplasia without internodular atrophy. Even though the patient had a unilateral adrenalectomy, adrenal insufficiency occurred in the postoperative period. Subsequently, the patient has been closely monitored and followed up with a physiological, divided-dose hydrocortisone replacement regimen for 7 months. A germline heterozygous variant in the KDM1A gene in the patient's blood sample and a recurrent deletion in the short p arm of chromosome 1 harboring the KDM1A locus in the adrenal sample were identified. When screened for diseases associated with the KDM1A mutation, monoclonal gammopathy of undetermined significance (MGUS) was detected in the patient with mild anemia, and genetic counseling was also provided. Conclusion The management of GIP-dependent PBMAH remains controversial, and further therapeutic options are under investigation. Due to the very limited number of case reports and the heterogeneous nature of the disease, special features of our case, which are severe cortisol excess, accompanying MGUS, the vanishing effect of octreotide, and adrenal insufficiency after unilateral adrenalectomy, might contribute to the existing literature.Figure 1.Urinary free cortisol levels following octreotide therapyUFC: Urinary free cortisol, ULN: Upper limit normal, LAR: Long acting release

Prior cancer and risk of monoclonal gammopathy of undetermined significance: a population-based study in Iceland and Sweden.

There is some evidence that a prior cancer is a risk factor for the development of multiple myeloma (MM). If this is true, prior cancer should be associated with a higher prevalence or increased progression rate of monoclonal gammopathy of undetermined significance (MGUS), the precursor of MM and related disorders. Those with a history of cancer might therefore constitute a target population for MGUS screening. This two-part study is the first study to evaluate a relationship between MGUS and prior cancers. First, we evaluated whether prior cancers were associated with having MGUS at the time of screening in the Iceland Screens Treats or Prevents Multiple Myeloma (iStopMM) study that includes 75,422 individuals screened for MGUS. Next, we evaluated the association of prior cancer and the progression of MGUS to MM and related disorders in a population-based cohort of 13,790 Swedish individuals with MGUS. A history of prior cancer was associated with a modest increase in the risk of MGUS (odds ratio=1.10; 95% confidence interval: 1.00-1.20). This excess risk was limited to prior cancers in the year preceding MGUS screening. A history of prior cancer was associated with progression of MGUS, except for myeloid malignancies which were associated with a lower risk of progression (hazard ratio=0.37; 95% confidence interval: 0.16-0.89; P=0.028). Our findings indicate that a prior cancer is not a significant etiological factor in plasma cell disorders. The findings do not warrant MGUS screening or different management of MGUS in those with a prior cancer.

Development and validation of a diagnostic nomogram model for predicting monoclonal gammopathy of renal significance

In patients with kidney disease, the presence of monoclonal gammopathy necessitates the exploration of potential causal relationships. Therefore, in this study, we aimed to address this concern by developing a nomogram model for the early diagnosis of monoclonal gammopathy of renal significance (MGRS). Univariate and multivariate logistic regression analyses were employed to identify risk factors for MGRS. Verification and evaluation of the nomogram model's differentiation, calibration, and clinical value were conducted using the receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis. The study encompassed 347 patients who underwent kidney biopsy, among whom 116 patients (33.4%) were diagnosed with MGRS and 231 (66.6%) with monoclonal gammopathy of undetermined significance. Monoclonal Ig-related amyloidosis (n = 86) and membranous nephropathy (n = 86) was the most common renal pathological type in each group. Notably, older age, abnormal serum-free light chain ratio, and the absence of microscopic hematuria were identified as independent prognostic factors for MGRS. The areas under the ROC curves for the training and verification sets were 0.848 and 0.880, respectively. In conclusion, the nomogram model demonstrated high accuracy and clinical applicability for diagnosing MGRS, potentially serving as a valuable tool for noninvasive early MGRS diagnosis.

Toward Precision Medicine for Patients with Multiple Myeloma

Multiple myeloma (MM), the second most common hematologic malignancy, is a plasma cell neoplasm that arises from a precursor, monoclonal gammopathy of undetermined significance (MGUS), which may or may not be previously diagnosed. Smoldering multiple myeloma (SMM), another precursor of MM, lacks myeloma-defining events and end-organ damage that are diagnostic of MM in the appropriate clinical settings. Newly diagnosed MM (NDMM) is highly heterogeneous genetically and clinically with very variable survival outcomes ranging from a few months to over a decade. Despite this heterogeneity, treatment outcomes have improved significantly in the last two decades, with overall survival improving continuously due to novel classes of drugs approved for treating MM. However, due to the immense heterogeneity, the quest for a cure will almost certainly require individualized patient evaluation and management at every level for every factor influencing patient quality of life and survival, including most importantly determining upfront the progression risks in the precursor states and prognostic risks for progression or relapse in NDMM. Toward that goal, this paper briefly describes, including a historical perspective, current concepts, and recent advances in NDMM for students, researchers, and clinical practitioners. The topics discussed include an overview of the epidemiology, current diagnostic criteria, including for distinguishing MGUS, SMM, and MM, refractory and relapsed MM, staging and prognosis of MM, treatment response criteria, including measurable residual disease evaluation, improvements in survival, current standards for treating NDMM, and disparities and inequities in receiving care in ethnic minority populations for treatment of MM, followed by progress in evaluating the risk of progression in MGUS and SMM, and finally, the genomics of MM, SMM, and MGUS since integrating disease biology in assessing and precisely managing all risk factors and achieving equity in treating all patients would help to achieve that precision medicine goal for a cure.

Monoclonal Gammopathies of Undetermined Significance and Abnormal Serum Protein Rates Prevelance in Blood Donors: For Improved Transfusion Safety

ABSTRACT Background and Objectives: Protein abnormalities include monoclonal gammopathies of undetermined significance (MGUS) and malignant lymphoplasmacytic tumors such as multiple myeloma (MM), Waldenström macroglobulinemia, and amyloid light-chain amyloidosis. MGUS prevalence increases with age, especially in individuals over 50. MGUS progresses to various lymphoplasmacytic diseases, including smoldering MM and MM. Almost all blood donors (BDs) are asymptomatic but some of them could present protein abnormalities. Our objective was to assess the prevalence and impact of protein abnormalities and monoclonal gammopathies (MGs) on transfusion safety among BDs in Morocco. Methods: Two hundred eighty-one serum samples were collected from BDs aged over 40 years old. Total serum protein measurement and protein electrophoresis were performed using the Architect ci8200 and Capillarys-2-Piercing automated systems, respectively. Immunofixation was conducted using hydrates. Results: Protein levels ranged between 59 and 87 g/L (average = 71.69 ± 4.96 g/L). Our results showed 195 (69.39%) normal profiles, 6 (2.13%) MGs, 14 (4.98%) heterogeneous restriction of γ-globulins, and 66 other abnormalities (23.48%) regarding the levels of albumin and proteins from alpha and beta fractions. Conclusion: Our preliminary results appeal to blood transfusion professionals regarding ethical considerations and transfusion safety. BDs with abnormal protein levels should benefit systematically from diagnostic tests and therapies.

CDK6 protein expression is associated with disease progression and treatment resistance in multiple myeloma.

Multiple myeloma (MM) is a heterogeneous malignancy of plasma cells. Despite improvement in the prognosis of MM patients after the introduction of many new drugs in the past decades, MM remains incurable since most patients become treatment-resistant. Cyclin-dependent kinase 6 (CDK6) is activated in many types of cancer and has been associated with drug resistance in MM. However, its association with disease stage, genetic alterations, and outcomehas not been systematically investigated in large cohorts. Here, we analyzed CDK6 expression using immunohistochemistry in 203 formalin-fixed paraffin-embeddedsamples of 146 patients and four healthy individuals. We found that 61.5% of all MM specimens express CDK6 at various levels. CDK6 expression increased with the progression of disease with a median of 0% of CDK6-positive plasma cells in monoclonal gammopathy of undetermined significance (MGUS) (n = 10) to 30% in newly diagnosed MM (n = 78)and up to 70% in relapsed cases (n = 55). The highest median CDK6 was observed in extramedullary myeloma (n = 12), a highly aggressive manifestation of MM. Longitudinal analyses revealed that CDK6 is significantly increased in lenalidomide-treated patients but not in those who did not receive lenalidomide. Furthermore, we observed that patients who underwent lenalidomide-comprising induction therapy had significantly shorter progression-free survival when their samples were CDK6 positive. These data support that CDK6 protein expression is a marker for aggressive and drug-resistant disease and describes a potential drug target in MM.

The Involvement of LAG-3positive Plasma Cells in the Development of Multiple Myeloma.

The Lymphocyte-Activation Protein 3 (LAG-3) inhibitory receptor is expressed on regulatory plasma cells (PCs). Micro-environmental cells that express LAG-3 were found to be increased during the progression of smoldering multiple myeloma (SMM). To assess the possible role of LAG-3 expression on regulatory PCs in patients with plasma cell dyscrasia. Purified Cluster of Differentiation 138 (CD138+) PCs from patients with premalignant conditions, active multiple myeloma (MM), and controls were analyzed for the expression of LAG-3 by flow cytometry. Autologous CD8+T cells were incubated with sorted LAG-3pos or LAG-3neg PCs for 24 h. The expression of granzyme (Grz) in CD8+T cells was assessed by flow cytometry. LAG-3 expression on PCs in active MM (newly diagnosed and relapse refractory MM) was significantly increased compared to monoclonal gammopathy of undetermined significance (MGUS)/ SMM. Grz expression was significantly decreased in CD8+T cells incubated with CD138+LAG-3pos PCs, compared to CD138+LAG-3neg PCs in patients with plasma cell dyscrasia, n = 31, p = 0.0041. LAG-3 expression on malignant PCs can be involved in the development of MM from MGUS by decreasing the expression of Grz in CD8+T cells.

Monoclonal Gammopathy of Undetermined Significance in General Practice

Background: In addition to progression to lymphoproliferative diseases, patients with monoclonal gammopathy of undetermined significance (MGUS) appear to suffer from other types of comorbidities although the extent to which MGUS contributes to these comorbidities is unclear. The aim of this study is to evaluate the presence of patients with MGUS who attend general practice (GP) in our healthcare area, as well as to describe the comorbidities and abnormal blood test results associated with these patients.Methods: A retrospective study was carried out, where demographic data, comorbidities, and results of some analytical parameters were collected from 1201 patients who visited their general practice physician: 201 patients with a monoclonal protein detected, and 1000 patients without presence of monoclonal protein.Main findings: Out of the 6307 proteinograms performed on patients from GP, 201 presented an M-protein (3.2%). The presence of MGUS increased with age and was significantly higher in men than in women (55.7% vs 44.3%, p&lt;0.05). We found that the most frequently associated comorbidities with MGUS are renal and cardiovascular diseases, osteoporosis and bone lesions, anemia, and hyperlipidemia. There was a significant association between MGUS and the following blood parameters: hemoglobin, leukocytes, neutrophils, monocytes, proteins, albumin, globulin and creatinine; as well as for the indices neutrophil-to-lymphocyte, monocyte-to-lymphocyte and albumin-to-globulin ratio.Principal conclusions: We conclude that MGUS is a common premalignant plasma cell disorder in general practice patients, the prevalence of which increases with age. Likewise, a series of blood parameters and comorbidities associated with MGUS that support the need to implement a program for early detection and monitoring of MGUS was described.Key words: MGUS, paraprotein, general practice, comorbidities

Clinico-pathological profile of patients with plasma cell neoplasms with special reference to bone marrow fibrosis and amyloid deposition.

To clarify the significance of bone marrow fibrosis and amyloid deposition in plasma cell neoplasm, a retrospective cross-sectional study for a period of 3 years was conducted. Patients who underwent bone marrow aspiration and biopsy with suspicion of plasma cell neoplasms were included in the study. The bone marrow findings were correlated with clinical profile of the patient along with biochemical parameters, cytogenetics, Fluorescent in situ hybridization (FISH) wherever available. A total of 273 bone marrow aspirates and biopsies of patients with suspected plasma cell neoplasms were analyzed. There were 181 male patients and 92 female patients (Male: Female = 1.96: 1). There were 245 cases of multiple myeloma (89.7%), 8 cases of primary amyloidosis (2.9%) and 6 monoclonal gammopathy of undetermined significance (MGUS) (2.1%), 5 cases of plasmacytoma (1.8%) and 4 cases of smouldering myeloma (1.4%), 5 cases of POEMS syndrome (1.8%). Bone marrow fibrosis was noted in 12 patients at diagnosis (4.3%). Among the parameters studied, only the mean Hemoglobin was significantly low in patients with marrow fibrosis. Amyloid deposition in various organs including bone marrow, kidney, liver etc., were noted in 17 patients overall (6.2%). In conclusion, the incidence of fibrosis (4.3%) and amyloidosis (6.2%) associated with plasma cell neoplasms were much lower in our study as compared to published studies.

Monoclonal Gammopathy of Undetermined Significance and Smoldering Myeloma

Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smoldering Myeloma (SMM) describe pre-malignant conditions that are defined by the presence of monoclonal immunoglobulin production. They are found in up to 3% of individuals over the age of 50 with a rate of progression to multiple myeloma or other related malignancy of approximately 1% per year. Accurate diagnosis and risk-stratification are paramount to prevent end-organ damage and determine follow-up intervals. With the data currently available, treatment for MGUS is not recommended. Patients with newly diagnosed high- risk SMM should be referred to a centre and therapy with lenalidomide plus/minus dexamethasone for 2 years or participation in a clinical trial should be discussed.

Short-Chain Fatty Acid Production by Gut Microbiota Predicts Treatment Response in Multiple Myeloma.

The gut microbiota plays important roles in health and disease. We questioned whether the gut microbiota and related metabolites are altered in monoclonal gammopathies and evaluated their potential role in multiple myeloma and its response to treatment. We used 16S rRNA sequencing to characterize and compare the gut microbiota of patients with monoclonal gammopathy of undetermined significance (n = 11), smoldering multiple myeloma (n = 9), newly diagnosed multiple myeloma (n = 11), relapsed/refractory multiple myeloma (n = 6), or with complete remission (n = 9). Short-chain fatty acids (SCFA) were quantified in serum and tested in cell lines. Relevant metabolites were validated in a second cohort of 62 patients. Significant differences in alpha- and beta diversity were present across the groups and both were lower in patients with relapse/refractory disease and higher in patients with complete remission after treatment. Differences were found in the abundance of several microbiota taxa across disease progression and in response to treatment. Bacteria involved in SCFA production, including Prevotella, Blautia, Weissella, and Agathobacter, were more represented in the premalignant or complete remission samples, and patients with higher levels of Agathobacter showed better overall survival. Serum levels of butyrate and propionate decreased across disease progression and butyrate was positively associated with a better response. Both metabolites had antiproliferative effects in multiple myeloma cell lines. We demonstrate that SCFAs metabolites and the gut microbiota associated with their production might have beneficial effects in disease evolution and response to treatment, underscoring its therapeutic potential and value as a predictor.