Clonal Proliferation Of Plasma Cells Research Articles

Essential procedures of single-cell RNA sequencing in multiple myeloma and its translational value

Multiple myeloma (MM) is a malignant neoplasm characterized by clonal proliferation of abnormal plasma cells. In many countries, it ranks as the second most prevalent malignant neoplasm of the hematopoietic system. Although treatment methods for MM have been continuously improved and the survival of patients has been dramatically prolonged, MM remains an incurable disease with a high probability of recurrence. As such, there are still many challenges to be addressed. One promising approach is single-cell RNA sequencing (scRNA-seq), which can elucidate the transcriptome heterogeneity of individual cells and reveal previously unknown cell types or states in complex tissues. In this review, we outlined the experimental workflow of scRNA-seq in MM, listed some commonly used scRNA-seq platforms and analytical tools. In addition, with the advent of scRNA-seq, many studies have made new progress in the key molecular mechanisms during MM clonal evolution, cell interactions and molecular regulation in the microenvironment, and drug resistance mechanisms in target therapy. We summarized the main findings and sequencing platforms for applying scRNA-seq to MM research and proposed broad directions for targeted therapies based on these findings.

Comprehensive Characterization of the Bone Marrow Microenvironment Transcriptional Remodeling in the Progression from MGUS to Smoldering and Multiple Myeloma

Multiple Myeloma (MM) is a hematological malignancy characterized by the abnormal proliferation and accumulation of clonal plasma cells (PCs) in the bone marrow (BM). Despite significant advances in treating MM patients, most patients eventually relapse and succumb to the disease. Understanding the mechanisms driving progression from precursor conditions into clinically active MM may contribute to implementing early curative approaches. Accumulating evidence indicates that the tumor formation and progression process is influenced not only by the malignant cells but also by the microenvironment components and interconnectedness between them. However, the understanding of the contribution of the non-immune BM microenvironment (BME) to disease progression and relapse remains largely unknown. Our aim was to identify the transcriptional changes in the endothelial cells (ECs) and mesenchymal stromal cells (MSCs) during the transition from premalignant stages to MM to identify potential mechanisms of transformation and therapeutic targets. To this end, ECs and MSCs were immunophenotypically isolated from BM samples of healthy aged donors (n=19) and patients with (MGUS, n=10), Smoldering Multiple Myeloma (SMM, n=13), and MM (n=36). Bulk RNA sequencing analysis of ECs revealed enrichment in terms related to cell cycle and fatty acid metabolism in MGUS, SMM, and MM patients compared to old adults. Indeed, a selective upregulation of pathways associated with calcium signaling, cytokines, and angiogenesis was detected in ECs from MM patients. Regarding MSCs, our results revealed an increase in bone remodeling, inflammation, oxidative defense, and DNA damage repair in MM patients. Interestingly, during the transition from MGUS to SMM, MSCs exhibited enrichment in functions associated with cell morphogenesis and epithelial transition, while lipid-related functions were decreased. To gain a deeper understanding, single-cell RNA sequencing analysis of BME and PCs was performed in unique immunocompetent murine models recapitulating the principal clinical, genetic, and immunological characteristics of MGUS and MM patients (Larrayoz et al., 2023). Using as a reference a previous BME characterization in mice we conducted (Ye et al., 2022) and in line with findings in human patients, our results unveiled a compromised BME characterized by the angiogenic profile of ECs and the increase in the immune-related state of MSCs associated with the progression of the disease. Furthermore, MGUS ECs displayed enrichment in ion homeostasis, immune response, and cell signaling-related pathways compared to healthy controls. While MM ECs exhibited a significant increase in immune terms, migration, and vascular-related pathways when compared to MGUS ECs, indicating a more angiogenic functional profile. Moreover, MSCs in the MGUS stage depicted significant activation of pathways related to immune defense, detoxification, lipid metabolism, and bone remodeling. Likewise, genes upregulated in MM MSCs were associated with calcium signaling, cytokines, and interferon response-related pathways, demonstrating the inflammatory signature of MSCs that may be in relation to the immune exhaustion underlying MM transformation. Finally, subsequent single-cell derived cell-to-cell interaction analysis using Liana was conducted to characterize the interactions between malignant PCs and their niche and delineate the communication dynamics of the tumor-BM ecosystem. Our results showed that PCs interact with ECs mainly through Itga1 and Cd44, while they communicate with MSCs mainly via Egfr and Sdc1. Remarkably, the interactions initiated during the MGUS stage between ECs and PCs persisted, and MM-specific interactions were involved in adhesion, migration, and angiogenesis pathways. In the crosstalk between PCs and MSCs, MGUS-specific interactions were associated with fat and bone-related processes. In contrast, MM-specific interactions were related to the extracellular matrix, collagen organization, and immune-related processes. In conclusion, our findings provide several novel insights into the transcriptional profiles of the non-immune BME during MM disease progression as well as the cellular interactions established with malignant PCs that can drive a pro-MM environment. Additional analyses are ongoing to further comprehend the BME's remodeling through MM development.

Blood-Based Diagnostic Assay for λ Light Chain Amyloidosis through Quantification of an Amyloidogenicity-Indicating Neo-Epitope

Light chain amyloidosis (AL) is a rare, progressive, and often fatal protein misfolding disease. AL is caused by aberrant clonal plasma cell proliferation, where excess amounts of amyloidogenic monoclonal Free Light Chain (FLC) are produced, secreted into the circulation, misfolded and deposted as amyloid fibrils in various vital organs, such as the heart, kidney, liver, and nerves. The involed lambda (λ) FLC accounts for ~75% of all AL cases. Amyloidogenic FLCs (aFLCs) are believed to be the toxic species contributing to AL disease pathology. Specific quantification of aFLCs can provide critical guidance in clinical practice but has been hampered by the LCs sequence diversity as well as the lack of tests that are able to differentiate between circulating normal polyclonal FLCs and aFLCs. Contrary to non-amyloidogenic, aFLCs are kinetically and oftentimes thermodynamically unstable. aFLCs are prone to misfolding and formation of pathogenic conformations such as non-native structures, proteolytic fragments, soluble aggregates, and amyloid fibrils. We exploited such characteristics of aFLCs by applying limited proteolysis using Proteinase K, where less stable λ aFLC proteins readily yield a 23KDa fragment composed of the homodimeric LC constant domain (dLCCD) linked by a disulfide bond. Formation of the dLCCD fragment reveals a highly conserved, novel, cryptic epitope at the N-terminus of the fragment. We have generated monoclonal antibodies (mAbs) that explicitly bind to such novel epitope and developed immunoassays for the specific detection and sensitive quantification of λ aFLCs in biological samples. Western blot or Meso Scale Discovery (MSD) analyses were employed to detect and quantify dLCCD signal using the dLCCD mAbs on plasma samples from randomly selected, treatment naïve and λ-restricted cases with biopsy-proven AL amyloidosis before and after exposure to optimized proteolytic conditions. Tissue amyloid deposits of λ-type were confirmed in most AL cases. Informed consent for data and plasma sample collections were obtained from the Institutional Review Boards and in accordance with the Declaration of Helsinki. Multiple myeloma (MM) plasma samples of unknown LC restriction type, treatment or amyloid deposits status and normal volunteer control samples were purchased from BioIVT (USA). A set of representative results based on three runs are shown in Fig. 1. As little as 2 µL of biofluid was used for each assay. Upon limited proteolysis, dLCCD signal was detected in 32 of 35 AL plasmas, including two samples from patients with AL-associated IgM lymphoplasmacytic lymphoma (LPL). Of the three dLCCD negative AL samples, one presented with monoclonal IgAλ, and two cases were bi-clonal on serum immunofixation electrophoresis. dLCCD signal was not detected in 18 of 19 MM plasma samples. Similarly, dLCCD signal was undetectable in 23 normal plasmas. Overall, the dLCCD signals detected in AL plasmas were 10x-200x above that of normal control and most MM samples (Fig. 1). The low limit of quantification of the MSD assay was ~0.4 ng/dL (1.4 pM), with >500x dynamic range, enabling sensitive and robust quantification of λ aFLCs in biosamples. Analysis of Proteinase K recognition potential of the cleavage site of 389 λ LC sequences from the AL-Base, a database of amyloidogenic LC sequences (https://wwwapp.bumc.bu.edu/BEDAC_ALBase/) predicted that the dLCCD assay can detect λ aFLCs in up to 99% of λ AL patients, irrespective of the FLC sequences. This was confirmed with the 100% detection rate of the dLCCD signal in a validation cohort of 35 additional monoclonal λ-restricted AL samples. In summary, we have developed a quantitative blood-based immunoassay that is sensitive and highly specific for λ aFLC irrespective of the protein sequences. The preliminary data demonstrates the potential of our assay for AL diagnostics. Additional clinical applications for future exploration will include (i) monitoring and early detection of AL amyloidosis in plasma cell dyscrasias (monoclonal gammopathy of unknown significance, MM, and smoldering MM) and lymphoproliferative disorders, including LPL; and (ii) clinical management of patients with AL amyloidosis via the assessment and monitoring of minimal residual disease and therapeutic responses. The utility of the dLCCD assay in the quantification of λ aFLCs in bi-clonal AL cases warrants further investigation.

Geographic Prevalence Patterns and Modifiable Risk Factors for Monoclonal Gammopathy of Undetermined Significance

Monoclonal gammopathy of undetermined significance (MGUS) is a pre-malignant plasma cell disorder with an etiology that is incompletely understood. Modifiable risk factors and genetic predispositions likely interact to increase MGUS risk in specific individuals and populations. Identifying geographic prevalence patterns and modifiable risk factors is critical for understanding the etiology of MGUS. The aim of this review was to outline original research on MGUS prevalence across geographic locations and modifiable risk factors. We conducted a systematic review of 39 eligible studies from PubMed®, Embase®, and Web of Science® written in English and published by February 2023. Our protocol was registered in accordance with PROSPERO guidelines. Studies were synthesized using Research Electronic Data Capture and appraised using the National Heart, Lung, and Blood Institute study quality assessment tools. The prevalence of MGUS ranged from 0.24% to 9% across geographic locations. Modifiable risk factors for MGUS include infections, autoimmune diseases, chronic inflammatory conditions, lifestyle factors, environmental exposures, and ionizing radiation. Therefore, the development of MGUS may be related to chronic antigenic stimulation and genetic aberrations that promote clonal proliferation of plasma cells. Prospective studies assessing gene–environment interactions are needed to further define risk factors for MGUS and inform screening and preventative strategies.

The Effect of a Six-Week Nordic Walking Training Cycle on Oxidative Damage of Macromolecules and Iron Metabolism in Older Patients with Multiple Myeloma in Remission-Randomized Clinical Trial.

Multiple myeloma (MM) is an incurable hematologic malignancy originating from clonal plasma cell proliferation within the bone marrow, predominantly affecting older individuals. While anemia serves as a diagnostic criterion for MM, it often ameliorates upon achieving disease remission. Iron metabolism parameters have emerged as potential prognostic indicators in MM. Notably, physical exercise has been established to influence iron metabolism. This study aimed to assess alterations in serum iron, ferritin, and transferrin concentrations, as well as leukocyte gene expression, in MM patients undergoing a six-week cycle of Nordic walking training. Thirty patients divided into an exercise group (NW, n = 15, mean age 63.1 ± 8.4 years) and a control group (CG, n = 15, mean age: 63.5 ± 3.6 years) completed the study protocol. Blood samples were collected at baseline, after three and six weeks of training, and after nine weeks. Serum ferritin, transferrin, and iron concentrations were measured, along with the leukocyte expression of genes. Additionally, serum oxidative damage marker levels were determined. Following the Nordic walking training cycle, a declining trend in serum ferritin concentrations was observed. Intracellular mRNA levels of genes associated with iron metabolism were positively influenced by the training regimen, indicating the potential impact of this physical activity on gene expression and ferritin concentrations. Although positive trends were noted, extended training periods might be requisite for significant changes. To conclude, moderate-intensity exercise induces favorable shifts in the analyzed parameters among MM patients, potentially influencing disease progression. Consequently, Nordic walking training is a safe recommendation for MM patients, though sustained training beyond six weeks could be necessary for notable effects on iron metabolism factors.

Molecular and immunological mechanisms of clonal evolution in multiple myeloma.

Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of clonal plasma cells in the bone marrow (BM). It is known that early genetic mutations in post-germinal center B/plasma cells are the cause of myelomagenesis. The acquisition of additional chromosomal abnormalities and distinct mutations further promote the outgrowth of malignant plasma cell populations that are resistant to conventional treatments, finally resulting in relapsed and therapy-refractory terminal stages of MM. In addition, myeloma cells are supported by autocrine signaling pathways and the tumor microenvironment (TME), which consists of diverse cell types such as stromal cells, immune cells, and components of the extracellular matrix. The TME provides essential signals and stimuli that induce proliferation and/or prevent apoptosis. In particular, the molecular pathways by which MM cells interact with the TME are crucial for the development of MM. To generate successful therapies and prevent MM recurrence, a thorough understanding of the molecular mechanisms that drive MM progression and therapy resistance is essential. In this review, we summarize key mechanisms that promote myelomagenesis and drive the clonal expansion in the course of MM progression such as autocrine signaling cascades, as well as direct and indirect interactions between the TME and malignant plasma cells. In addition, we highlight drug-resistance mechanisms and emerging therapies that are currently tested in clinical trials to overcome therapy-refractory MM stages.

Differential Diagnosis and Therapeutic Advances in Multiple Myeloma: A Review Article.

Multiple myeloma (MM) is a hematologic malignancy characterized by the abnormal clonal proliferation of plasma cells that may result in focal bone lesions, renal failure, anemia, and/or hypercalcemia. Recently, the diagnosis and treatment of MM have evolved due to a better understanding of disease pathophysiology, improved risk stratification, and new treatments. The incorporation of new drugs, including proteasome inhibitors, immunomodulatory drugs, anti-CD38 antibodies and high-dose chemotherapy followed by hematopoietic stem cell transplantation, has resulted in a significant improvement in patient outcomes and QoL. In this review, we summarize differential diagnoses and therapeutic advances in MM.

Association of monoclonal gammopathy of undetermined significance and C3 glomerulopathy.

Monoclonal gammopathy of undetermined significance (MGUS) is usually an asymptomatic pre-malignant condition caused by the proliferation of clonal plasma cells. Often considered a benign condition, it has the potential to progress to malignant plasma cell or lymphoproliferative disorders. Moreover, MGUS can rarely cause glomerular disease by activating the alternative complement pathway resulting in immunoglobulin-negative C3-positive glomerulonephritis called C3 glomerulopathy. Because of its rarity, the diagnosis might not be considered by the treating physicians, leading to delayed diagnosis or misdiagnosis. Untreated C3 glomerulopathy can lead to irreversible glomerular damage and end-stage renal failure, and a high index of suspicion is essential for timely diagnosis and management. Here, we present the case of a patient with a prior diagnosis of MGUS who presented with proteinuria and microscopic haematuria and was diagnosed with C3 glomerulopathy. The patient had complete resolution of the disease after receiving treatment with a combination of dexamethasone, lenalidomide and bortezomib for the underlying MGUS.

Unlocking Drug Resistance in Multiple Myeloma: Adipocytes as Modulators of Treatment Response.

Multiple myeloma (MM) is an incurable hematological malignancy characterized by the clonal proliferation of malignant plasma cells. Despite the development of a diverse array of targeted drug therapies over the last decade, patients often relapse and develop refractory disease due to multidrug resistance. Obesity is a growing public health threat and a risk factor for multiple myeloma, although the mechanisms by which obesity contributes to MM growth and progression have not been fully elucidated. In the present study, we evaluated whether crosstalk between adipocytes and MM cells promoted drug resistance and whether this was amplified by obesity. Human adipose-derived stem cells (ASCs) from nineteen normal (BMI = 20-25 kg/m2), overweight (25-30 kg/m2), or obese (30-35 kg/m2) patients undergoing elective liposuction were utilized. Cells were differentiated into adipocytes, co-cultured with RPMI 8226 or U266B1 multiple myeloma cell lines, and treated with standard MM therapies, including bortezomib or a triple combination of bortezomib, dexamethasone, and lenalidomide. We found that adipocytes from overweight and obese individuals increased cell adhesion-mediated drug resistance (CAM-DR) survival signals in MM cells, and P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP) drug transporter expression. Further, co-culture enhanced in vitro angiogenesis, MMP-2 activity, and protected MM cells from drug-induced decreases in viability. In summary, we provide an underlying mechanism by which obesity can impair the drug response to MM and allow for recurrence and/or disease progression.

Multiple Myeloma: Case of a “Moving” Sternal Wire

Multiple myeloma generally occurs in older adults, with the clonal proliferation of plasma cells and accumulation of monoclonal protein resulting in a broad range of clinical manifestations and complications, including hypercalcemia, renal dysfunction, anaemia, and bone destruction (termed CRAB features). A 64-year-old man with no history of malignancy presented with an enlarging precordial lump occurring three years post-sternotomy for uneventful coronary artery bypass grafting surgery. Initial investigations showed anaemia and impaired renal function. Multimodal imaging performed for further evaluation showcases the radio-pathological features which can be encountered in haematological malignancy. Subsequent percutaneous biopsy confirmed an underlying plasma cell neoplasm, and a diagnosis of multiple myeloma was achieved. The prompt resolution of the lesions upon the initiation of treatment highlights the importance of early diagnosis and treatment.

Tamponnade cardiaque : première manifestation du myélome multiple : à propos d'un cas et revue de la littérature

Multiple myeloma is a hematologic malignancy characterized by clonal proliferation of plasma cells, mainly in bone marrow. Extramedullary disease is reported in many cases and may occur at diagnosis, at progression, or during relapse phase. Pericardial involvement is a rare condition that usually occurs with advanced-stage disease.We report a rare case of 76-year-old women with plasma cell-based pericardial effusion with cardiac tamponade as a form of presentation of multiple myeloma and discuss it in the light of literature.Diagnosis was established by pericardial fluid cytology. The patient received systemic chemotherapy, according to MPT protocol.

#5788 MONOCLONAL GAMMOPATHY OF RENAL SIGNIFICANCE: A SINGLE CENTER EXPERIENCE

Abstract Background and Aims Monoclonal gammopathy of renal significance is an organ-threatening manifestation of paraproteinemia. It can be secondary to the clonal proliferation of either plasma cells or mature B-lymphocytes. The underlying clonal disorder does not meet the current hematologic criteria for immediate myeloma-specific therapy. With the advent of routine use of light chain detection by immunofluroscence technique in tissue biopsy, more cases of monoclonal gammopathy of renal significance are being diagnosed but there remains a therapeutic uncertainty. Data regarding the prognosis and outcomes of the various clinical manifestations of monoclonal gammopathy of renal significance is limited due to its rarity and under diagnosis. MGRS if left untreated can lead to end-stage renal disease and premature death. Method This is a retrospective study conducted at the Institute of Nephro-urology, Bangalore by retrieving the data from the digital medical records of our institute. Demographic and clinical details of the patients diagnosed with monoclonal gammopathy of renal significance from 1 st January 2018 to 31 st October 2022 were collected. Myeloma related light chain cast nephropathy was excluded from the study. Follow-up data were collected usingout patient data base, through telephone, and from the records at the cancer institute where the patient was referred post-diagnosis at our institute. The data collected was entered in excel and analyzed using SPSS software version 27.0. Results Fifty eight patients (n = 52) were diagnosed with the disease during the study period. MGRS contributed to 1.27% of all the renal biopsies conducted at our institute during the study period. The mean age of the study population was 52.1 with 95% CI [48.5 to 55.6] with a male: female ratio of 1.36:1 and 36.5% (n = 19) ofstudy cohort aged above 60 years. Among clinical presentations CKD (n = 23) was the main clinical presentation followed by AKI, Nephrotic syndrome, Nephritic syndrome and RPGN as the other presentations. Dialysis requirement was noted in 35% at initial presentation. Most common histiopathological presentation was Amyloidosis (n = 15) followed by Light chain deposition disease LCDD (n = 14), monoclonal non-amyloid deposition disease NADD (n = 6), Light chain proximal tubulopathy LCPT (n = 5), Proliferative glomerulonephritis with monoclonal immunoglobulin deposition disease PGNMIDD (n = 9) and others (n = 3). The patient survival at the time of analysis was 22.7% and death censored renal survival was 80%. Conclusion MGRS contributed to 1.27% of all the renal biopsies conducted at our institute during the study period. Because of its variable clincal presentation,one needs high degree of clinical suspicion for early diagnosis. MGRS unlike MGUS carries significant morbidity and mortality.

Multiple Facets of Multiple Myeloma in Kidney Biopsy: A Multicenter Retrospective Study.

Multiple myeloma is a type of plasma cell dyscrasia, which causes clonal proliferation of plasma cells and deposition in various organ systems. At presentation, 50% of patients with multiple myeloma have kidney dysfunction, which is considered a poor prognostic indicator. Data on the histopathological manifestations of multiple myeloma are sparse. To look at the kidney histopathological lesions in patients with the clinical diagnosis of multiple myeloma. A retrospective analysis of all kidney biopsies in patients with the clinical diagnosis of multiple myeloma was performed from June 1, 2020 to May 30, 2022, from three tertiary care nephrology referral centers. A total of 61 patients with multiple myeloma and biopsy-proven kidney involvement were included in the study. The mean age at presentation was 55.39 ± 11.91 years, with male predominance (male to female ratio -1.6:1). The most common lesion on kidney biopsy was myeloma cast nephropathy (72.1%), followed by light chain deposition disease (21.3%) and AL amyloidosis (18%). About 26% of patients had dual lesions on kidney biopsy, 3% had three types of lesions on kidney biopsy In 48% of patients, the diagnosis of multiple myeloma was made only after the kidney biopsy. Patients with multiple myeloma and kidney involvement should be biopsied as the type of histopathological lesion influences the treatment options and prognosis.

Identifying associations between race and gender in the incidence and mortality of patients with multiple myeloma.

e20052 Background: Multiple Myeloma (MM) is a plasma cell malignancy due to proliferation of malignant clonal plasma cells. Prior studies have shown that overall incidence of MM was 8.47 per 100,000 individuals. It has also been seen that the incidence of MM has trended upwards in non-Hispanic white (NHW) males and non-Hispanic blacks (NHB) across all age groups. This retrospective, database-driven population study sought to further assess racial and gender-based differences in the trends of the incidence of MM and mortality from MM. Methods: Data obtained from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) registry 17 were available to assess trends of multiple myeloma incidence and mortality from 2000 to 2019. Trends were described as average annual percentage change (APC) rates. Results: A total of 102,467 MM patients were identified in this data set; 56,508 (55.1%) were males and 45,949 (44.8%) were female. The distribution of MM by race was as follows (in order from highest to lowest): Non-Hispanic White [NHW] patients was 63.2% (N = 64,776), Non-Hispanic Black [NHB] patients was 18.6% (n = 19,099), Hispanic patients was 11.6 % (11,841), Non-Hispanic Asian [NHA] patients was 5.6% (5,769), and Non-Hispanic American Indian [NHAI]/Alaska Native patients was 0.5% (523). Incidence of MM (cases per 100,000 persons) was highest in males (7.5; 95% CI: 7.5, 7.6) and blacks (13; 95% CI: 12.8, 13.2). Overall trend in the incidence of MM has increased significantly for all gender and ethnicity groups over the period from 2000-2019, except for NHA patients. The incidence-based mortality of MM was highest in male (5.2; 95% CI: 5.2, 5.3) and black (8.7; 95% CI: 8.5, 8.8) patients. The overall incidence-based mortality increased significantly in males APC 4.1% (95% CI: 2.2,5.9; p < 0.001), females APC 3.6% (95% CI, 1.8,5.5; p < 0.001) and all ethnicities - NHW patients APC 4.1%, (95% CI, 2.2,6.0; p < 0.001), NHB (APC 4.2%, 95% CI, 2.1,6.3; P < 0.001), NHAI (APC 4.7%, 95% CI, -2.2,7.2; p < 0.001), NHA (APC 3.0%, 95% CI: 0.8,5.2; P = 0.009) and Hispanic (APC 2.9, 95% CI:1.1,4.7; P = 0.003). Conclusions: Population-based trends in MM incidence and mortality, as reported in this study, were increased commensurate with prior reports. Of note, mortality was noted to be highest amongst the NHB and male populations, indicating a need for further research focused efforts in this potentially high-risk population.

Myelomatous Meningitis - a diagnostic and therapeutic challenge

Multiple myeloma is a malignant disease, which consists of the clonal proliferation of plasma cells that will lead to the accumulation of a monoclonal protein in the serum and/or urine, with organic damage. Extramedullary involvement is found in approximately 5% of cases of myeloma. Multiple myeloma with determination in the central nervous system is extremely rare and is associated with a bad prognosis. A targeted treatment scheme for this complication is not described, but the therapeutic approach should follow the same steps as in the case of other lymphoproliferative diseases with neurological involvement ( association of intrathecal chemotherapy applications cytarabine and methotrexate, with systemic treatment and depending on the response local radiotherapy should be performed). The occurrence of extramedullary disease in the evolution of multiple myeloma is a complication associated with a poor prognosis.

An overview of pim kinase as a target in multiple myeloma.

Multiple myeloma (MM) is the second common hematologic malignancy manifesting as a clonal proliferation of plasma cells in the bone marrow. In recent years, high expression and activity of pim kinase have been found to be associated with both the progression and prognosis of a significant proportion of malignant diseases. Therefore, pim kinase has become a potential therapeutic target in the treatment of MM and some pim kinase inhibitors have demonstrated good efficacy in clinical trials. Based on nearly the entire literature searched from PubMed in the field of pim kinase in MM, the paper concluded how pim kinase got involved in the proliferation of myeloma cells, the progression of bone disease infiltration, and even in the regulation of the immune microenvironment. Next as a very promising drug, the effectiveness of pim kinase inhibitors as single agents or in combination with other drugs in the treatment of MM was also summarized. Our analysis will guide the clinical use of pim kinase inhibitors for managing tumor load and bone disease in MM patients.

LncRNA FEZF1-AS1 accelerates multiple myeloma progression by regulating IGF2BP1/BZW2 signaling.

Multiple myeloma (MM) is the second largest hematological tumor with clonal proliferation of malignant plasma cells. Growing reports have revealed that the dysregulation of long non-coding RNA (lncRNA) is involved in the MM progression. Nevertheless, lncRNA FEZF1 antisense RNA 1 (FEZF1-AS1) remain not deeply explored. The RNA transcripts and protein level of MM-associated molecule were measured by quantitative real-time polymerase chain reaction or western blot assays, respectively. The clinical correlation was analyzed by Pearson analysis. Molecular interactions among lncRNA FEZF1-AS1, basic leucine zipper and W2 domain 2 (BZW2) and insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) were verified by RNA immunoprecipitation and RNA pull-down assays. The survival of MM cells was detected by cell counting kit-8 and flow cytometry assays. Xenograft tumor in vivo was performed to assess tumor growth. The RNA transcripts of lncRNA FEZF1-AS1, BZW2 and IGF2BP1 were upregulated in MM samples compared to those in healthy donors. Knockdown of lncRNA FEZF1-AS1 could inhibit the proliferation and induce cell apoptosis in vitro and in vivo. Besides, lncRNA FEZF1-AS1 could maintain the stability of BZW2 mRNA by interacting IGF2BP1. Moreover, BZW2 silence also downregulated the proliferation but enhanced apoptosis of MM cells, while BZW2 overexpression had an opposite role, which dramatically reversed the regulatory roles of lncRNA FEZF1-AS1. Altogether, lncRNA FEZF1-AS1 facilitated MM development by regulating IGF2BP1/BZW2 signaling, suggesting that lncRNA FEZF1-AS1 might be a candidate for MM treatment.

Identification and Targeting of Mutant Neoantigens in Multiple Myeloma Treatment.

Multiple myeloma (MM) is malignant disease characterized by the clonal proliferation of plasma cells in the bone marrow, leading to anemia, immunosuppression, and other symptoms, that is generally hard to treat. In MM, the immune system is likely exposed to neoplasia-associated neoantigens for several years before the tumor onset. Different types of neoantigens have been identified. Public or shared neoantigens derive from tumor-specific modifications often reported in several patients or across diverse tumors. They are intriguing therapeutic targets because they are frequently observed, and they have an oncogenic effect. Only a small number of public neoantigens have been recognized. Most of the neoantigens that have been identified are patient-specific or "private", necessitating a personalized approach for adaptive cell treatment. It was demonstrated that the targeting of a single greatly immunogenic neoantigen may be appropriate for tumor control. The purpose of this review was to analyze the neoantigens present in patients with MM, and to evaluate the possibility of using their presence as a prognostic factor or as a therapeutic target. We reviewed the most recent literature on neoantigen treatment strategies and on the use of bispecific, trispecific, and conjugated antibodies for the treatment of MM. Finally, a section was dedicated to the use of CAR-T in relapsed and refractory patients.

Isolated Progression of Multiple Myeloma into the Extramedullary Plasmacytoma of Dura Mater: A Case Report and Review of the Literature

Multiple myeloma (MM) is a disease caused by the uncontrolled proliferation of clonal plasma cells in bone marrow. Extramedullary plasma cell infiltrations may occur at the time of diagnosis but usually arise during systemic disease progression. Central nervous system (CNS) plasmacytomas are extremely rare (less than 1% of patients with MM) and usually occur as a result of systemic disease progression. The frequency of extramedullary progression to CNS without simultaneous systemic progression is not known. Here, we present a challenging case in which local disease progression to CNS occurred without any signs of systemic progression. The extramedullary plasmacytoma originated from the dura mater of the brain mimicking a brain tumor. We review and discuss further treatment options that are available in such rare clinical scenarios in relation to the treatment already undertaken.

Pulmonary hypertension in patients with multiple myeloma: A comprehensive review.

Multiple myeloma (MM) is a common hematological malignancy resulting from clonal proliferation of plasma cells and is defined by criteria set forth by the international myeloma working group. Pulmonary hypertension (PH) is defined by an elevated mean pulmonary artery pressure >20 mmHg measured during right heart catheterization. Echocardiography-diagnosed PH is relatively common in patients with MM and has been associated with increased mortality, morbidity, and poor stem cell transplant outcomes. PH in patients with MM (PH-MM) is usually multifactorial in origin. MM disease-specific factors, host comorbidities, and treatment-related adverse effects are the key factors for the development of PH-MM. Pragmatically, patients with PH-MM can be grouped into either (i) PH in patients with a new diagnosis of MM or (ii) PH that develops or worsens along the way of MM treatment. In the latter group, drug-induced PH, venous thromboembolism, pulmonary veno occlusive disease, and cardiotoxicity should be considered as possible causes. PH-MM should be evaluated and managed in a multidisciplinary setting. Select individuals with PH-MM could be considered for pulmonary vasodilators at PH-specialized centers.