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Background: Prognosis of multiple myeloma (MM) patients with extramedullary disease (EMD) remains poor. T cell dysfunction and an immunosuppressive environment have been reported in the bone marrow (BM) of MM patients. However, the immunosuppressive microenvironment and immune checkpoint receptors (ICRs) on CD8+ T cells in the EMD tissue of newly diagnosed MM (NDMM) patients have not been thoroughly studied. Methods: We investigated the expression levels of T cell immunoglobulin mucin-domain-containing-3 (TIM-3) and T-cell immunoglobulin and ITIM domain (TIGIT) on CD8+ T cells and the expression of their ligands (Galectin-9 and CD155) on myeloma cells in EMD tissue of NDMM patients. The expression levels of TIM-3 and TIGIT on T cells and their ligands (Galectin-9 and CD155) on myeloma cells were analyzed by multicolored fluorescent flow cytometry in the peripheral blood (PB), BM, and EMD tissue. Additionally, the expression of ICRs was compared among PB, BM, and EMD tissue. Results: The expression levels of TIGIT and TIM-3 on CD8+ T cell subsets, including CD8+ Naïve T (TN) cells and CD8+ terminally differentiated effector memory T (TEMRA) cells, were significantly higher in EMD than in PB (p < 0.05 for all). The expression levels of TIGIT and TIM-3 on CD8+ TN cells were higher in EMD than in BM (p < 0.05 for all). There were no differences in Galectin-9 and CD155 expression on myeloma cells among PB, BM, and EMD tissue. Conclusion: Our data add new evidence that T cells express increased TIGIT and TIM-3, suggesting that there may be T-cell exhaustion in EMD of patients with MM. [ABSTRACT FROM AUTHOR]

Background: Non-secretory multiple myeloma is a sporadic type of multiple myeloma with the proliferation of monoclonal plasmocytes in the bone marrow that cannot secrete or synthesize immunoglobulins. Its prevalence as a hematologic malignancy is low, and it is usually diagnosed by demonstration of monoclonal plasma cells ≥ 10% in the bone marrow with negative results on serum and urine electrophoresis and immunofixation studies. Methods: We present a case report where the patient's serum and whole blood samples were received in the study laboratory to evaluate the complete hemogram and metabolic profile. The metabolic and hematological profiles were deranged, subsequent to which the patient's clinical history was obtained from the treating clinician. It was discovered that the patient had presented with long-term weakness and back ache and was advised routine investigations along with magnetic resonance imaging (MRI) of the spine, which revealed the presence of osteolytic lesions. Following this, a gammopathy panel was requested. Results: Serum protein capillary electrophoresis and immunofixation electrophoresis revealed a normal pattern without any noticeable bands, distortions, or suspicious regions. However, the findings of the comprehensive gammopathy panel were suggestive of non-secretory multiple myeloma. Conclusion: In the absence of a detailed and meticulous work-up, a case of non-secretory multiple myeloma can be easily misdiagnosed. Here, we discuss the case in detail, the diagnostic pitfalls associated with it, and the role of serum free light chain assays in its diagnosis. [ABSTRACT FROM AUTHOR]

• MST1 expression is high in myeloma cells. • MST1 anticorrelates with transcriptional activator with PDZ-binding motif (TAZ) expression in multiple myeloma cell lines and patient samples. • Inhibition of MST1 upregulates TAZ and its targets. • Pharmacologic or genetic inhibition of MST1 increases cell death in human myeloma cell lines (HMCLs). • Downregulating MST1 sensitizes HMCLs to frontline antimyeloma therapeutics. We have previously reported that transcriptional activator with PDZ-binding motif (TAZ) functions as a tumor suppressor in multiple myeloma (MM). MST1 is a serine-threonine kinase upstream of the Hippo-signaling pathway that functions as a tumor suppressor in many non-hematologic malignancies. However, its role in hematologic malignancies, including MM is still poorly understood. In this article, we provide evidence that MST1 expression is higher in MM and negatively correlates with TAZ expression in both cell lines and patient samples. High MST1 expression was associated with poor clinical outcomes. Genetic or pharmacologic inhibition of MST1 leads to increased TAZ expression and cell death. Importantly, MST1 inhibitors sensitize myeloma cells to frontline antimyeloma agents—lenalidomide and dexamethasone. Taken together, our data reveal a key role for MST1 in MM pathogenesis and provide evidence to explore the therapeutic potential of using MST inhibitors to upregulate TAZ expression in MM to promote response to anticancer agents. [ABSTRACT FROM AUTHOR]

Over the past decade, 2 strategies have advanced the treatment of patients with multiple myeloma and its precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not have been treated. Second, there is widespread enthusiasm for treating high-risk, smoldering multiple myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. Although early treatment adds cost and therapeutic burden, it remains unknown whether survival and health-related quality of life are improved by early treatment. Herein, we consider the implications of diagnostic expansion in multiple myeloma.

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Macroglossia is a rare clinical situation, that can cause of sever complications, as undernutrition even obstruction of upper airways. Causes are many and the diagnostic approach must be rigorous, by eliminating in the first place hematologic malignancy of myeloma or tumor. Management is first-line medical. The use of possible surgery must be discussed on a case-by-case basis, depending on etiology, complications and prognosis of mac)rolossia. From a clinical case, we purpose in this article, focus on the diagnostic approach and therapeutic of macroglossia acquired from the adult and especially during AL amyloidosis. [ABSTRACT FROM AUTHOR]

We investigated the predictive role for serum free light chain ratio (FLCr) ≥100, bone marrow plasma cell (BMPC) ≥60%, and evolving biomarkers through group-based trajectory modeling (GBTM) as high-risk defining events in 273 smoldering multiple myeloma (SMM) patients with a median follow-up of 74 months. FLCr ≥100 was confirmed as a marker for high-risk progression with a median time to progression (TTP) of 40 months with a 44% risk of progression of disease (PD) at 2 years; however, 44% of FLCr ≥100 also did not progress during follow-up. For patients with BMPC ≥60% by core biopsy, the median TTP was 31 months with a 2-year PD of 41%. GBTM established high-risk trajectories for evolving hemoglobin (eHb; characterized as a 1.57 g/dL decrease in hemoglobin), evolving m-protein (eMP; 64% increase in m-protein), and evolving differences in FLC (edFLC; 169% increase in dFLC) within 1 year of diagnosis associated with a decreased median TTP and an increased 2 year rate of PD. Of all the variables examined, we identify a model where immunoparesis, eHb, eMP, and edFLC were significant predictors for ultra-high-risk progression with a median TTP of only 13 months with 3 or more variables present. Our results not only confirm a more modest 2 year PD associated with FLCr ≥100 and BMPC ≥60 but also suggest that eHb, eMP, and edFLC may help identify an ultra-high-risk SMM group.

Key message: Two candidate genes (Csa6G046210 and Csa6G046240) were identified by fine-mapping gsb-s6.2 for gummy stem blight resistance in cucumber stem. Gummy stem blight (GSB) is a serious fungal disease caused by Didymella bryoniae, that affects cucumber yield and quality worldwide. However, no GSB-resistant genes have been identified in cucumber cultivars. In this study, the wild cucumber accession 'PI 183967' was used as a source of resistance to GSB in adult stems. An F2 population was mapped using resistant line 'LM189' and susceptible line 'LM6' derived from a cross between 'PI 183967' and '931'. By developing InDel and SNP markers, the gsb-s6.2 QTL on Chr. 6 was fine-mapped to a 34 kb interval harboring six genes. Gene Expression analysis after inoculation showed that two candidate genes (Csa6G046210 and Csa6G046240) were induced and differentially expressed between the resistant and susceptible parents, and may be involved in disease defense. Sequence alignment showed that Csa6G046210 encodes a multiple myeloma tumor-associated protein, and it harbored two nonsynonymous SNPs and one InDel in the third and the fourth exons, and two InDels in the TATA-box of the basal promoter region. Csa6G046240 encodes a MYB transcription factor with six variants in the AP2/ERF and MYB motifs in the promoter. These two candidate genes lay the foundation for revealing the mechanism of GSB resistance and may be useful for marker-assisted selection in cucumber disease-resistant breeding. [ABSTRACT FROM AUTHOR]

Ixazomib is an oral proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of relapsed/refractory multiple myeloma (MM). Approval in the United States, Europe, and additional countries was based on results from the phase III TOURMALINE‐MM1 (C16010) study. Here, joint population pharmacokinetic/pharmacodynamic time‐to‐event (TTE) and discrete time Markov models were developed to describe key safety (rash and diarrhea events, and platelet counts) and efficacy (myeloma protein [M‐protein] and progression‐free survival [PFS]) outcomes observed in TOURMALINE‐MM1. Models reliably described observed safety and efficacy results; prior immunomodulatory drug therapy and race were significant covariates for diarrhea and rash events, respectively, whereas M‐protein dynamics were sufficiently characterized using TTE models of relapse and dropout. Moreover, baseline M‐protein was identified as a significant covariate for observed PFS. The developed framework represents an integrated approach to describing safety and efficacy with MM therapy, enabling the simulation of prospective trials and potential alternate dosing regimens. [ABSTRACT FROM AUTHOR]

Objectives: Myeloma is characterised by the presence of monoclonal immunoglobulin (M‐protein) and the free light chain (FLC) in blood. We investigated whether these M‐proteins and FLC are detectable in myeloma patients' saliva to evaluate its utility for non‐invasive screening and monitoring of haematological malignancies. Methods: A total of 57 patients with monoclonal gammopathy and 26 age‐matched healthy participants provided paired serum and saliva samples for immunoglobulin characterisation and quantification. Results: Myeloma patients had IgG or IgA M‐protein levels ranging up to five times and FLC levels up to a thousand times normal levels of polyclonal immunoglobulins. Despite these highly elevated levels, only two IgG and no IgA M‐proteins or FLC could be detected in paired saliva samples. Most patients had reduced levels of serum polyclonal immunoglobulins, but all had normal levels of salivary IgA. Conclusions: Immunoglobulin transfer from blood is not determined by levels in the systemic circulation and more likely dictated by periodontal inflammation and the integrity of the oral epithelium. Immunoglobulins secreted by bone marrow plasma cells do not substantially enter saliva, which represents a poor medium for myeloma diagnosis. These findings, along with normal salivary IgA levels despite systemic immunoparesis, support a strong partitioning of oral from systemic humoral immunity. [ABSTRACT FROM AUTHOR]

Multiple myeloma is an incurable malignancy that initiates from a bone marrow resident clonal plasma cell and acquires successive mutational changes and genomic alterations, eventually resulting in tumor burden accumulation and end-organ damage. It has been recently recognized that myeloma secondary genomic events result in extensive sub-clonal heterogeneity both in localized bone marrow areas and circulating peripheral blood plasma cells. Rare genomic subclones, including myeloma initiating cells, could be the drivers of disease progression and recurrence. Additionally, evaluation of rare myeloma cells in blood for disease monitoring has numerous advantages over invasive bone marrow biopsies. To this end, an unbiased method for detecting rare cells and delineating their genomic makeup enables disease detection and monitoring in conditions with low abundant cancer cells. In this study, we applied an enrichment-free four-plex (CD138, CD56, CD45, DAPI) immunofluorescence assay and single-cell DNA sequencing for morphogenomic characterization of plasma cells to detect and delineate common and rare plasma cells and discriminate between normal and malignant plasma cells in paired blood and bone marrow aspirates from five patients with newly diagnosed myeloma (N = 4) and monoclonal gammopathy of undetermined significance (n = 1). Morphological analysis confirms CD138+CD56+ cells in the peripheral blood carry genomic alterations that are clonally identical to those in the bone marrow. A subset of altered CD138+CD56- cells are also found in the peripheral blood consistent with the known variability in CD56 expression as a marker of plasma cell malignancy. Bone marrow tumor clinical cytogenetics is highly correlated with the single-cell copy number alterations of the liquid biopsy rare cells. A subset of rare cells harbors genetic alterations not detected by standard clinical diagnostic methods of random localized bone marrow biopsies. This enrichment-free morphogenomic approach detects and characterizes rare cell populations derived from the liquid biopsies that are consistent with clinical diagnosis and have the potential to extend our understanding of subclonality at the single-cell level in this disease. Assay validation in larger patient cohorts has the potential to offer liquid biopsy for disease monitoring with similar or improved disease detection as traditional blind bone marrow biopsies. [ABSTRACT FROM AUTHOR]

Objective. To explore the effect of autologous stem cell transplantation combined with modified VTD regimen on elderly patients with multiple myeloma and its influence on miRNA cytokines. Methods. The data of 42 elderly patients with multiple myeloma who were treated in our hospital from May 2010 to June 2018 were retrospectively analyzed, and they were divided into the combined group (autologous stem cell transplantation combined with improved VTD scheme, n = 25) and the control group (improved VTD scheme, n = 17) according to different treatment schemes, and the clinical efficacy of the two groups was compared. The levels of CD3+, CD4+, CD4+/CD8+, and Treg were measured in the two groups. The expression levels of miRNA-15a, miRNA-16, and miRNA-21 in the bone marrow fluid of the two groups were measured before and after treatment. The levels of M protein and myeloma cells in the two groups were detected. Comparing the incidence of adverse reactions between the two groups, the Kaplan-Meier method was used for survival analysis. Results. The total effective rate of the combined group (84.00%) was higher than that of the control group (52.94%), and the difference was statistically significant (P < 0.05). After treatment, the levels of CD3+, CD4+, CD4+/CD8+, Treg, miRNA-15a, and miRNA-16 in the combined group were higher than those in the control group, and the levels of miRNA-21, M protein, and myeloma cells were lower than those in the control group, with statistical significance (P < 0.05). There was no significant difference in adverse reactions between the two groups (P > 0.05). The first, second, and third year survival rates of group A (96.00%, 88.00%, and 80.00%) were significantly higher than those of the control group (70.59%, 58.82%, and 47.06%), and the difference was statistically significant (P < 0.05). Conclusion. Autologous stem cell transplantation combined with a modified VTD regimen can effectively improve the immune function and survival rate of elderly patients with multiple myeloma, which is safe and effective. [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs, including the Contergan derivatives lenalidomide and pomalidomide have significantly improved the therapy of hematologic malignancies such as multiple myeloma. New targeted therapeutic options The discovery that multiple myeloma cells can be attacked by targeting the proteins CD98hc and LAT1 opens up new possibilities for innovative therapies in this currently incurable cancer. [Extracted from the article]

Objetive: To describe the atypical histopathologic presentation in bone marrow of multiple myeloma. Case Report: We present the case of a 75-yearold male who manifested low back pain of variable intensity associated with decreased urinary flow, for which he went to the emergency room. On physical examination, vital functions were within normal parameters with generalized decrease in adipose tissue and earthy pallor, the rest of the examination being non-contributory. Bone marrow studies showed 13% of plasma cells with tetranucleated neoplastic cells with 1 and 2 nucleoli, basophilic cytoplasm with presence of vacuoles, which was corroborated in flow cytometry with pathological phenotype in relation to plasma cell neoplasia. The patient receives a therapeutic regimen with cyclophosphamide, dexamethasone and thalidomide. Conclusion: Tetranucleated presentation is a rare histopathologic variant of multiple myeloma, so this peculiar finding should be appreciated in the microscopic diagnosis of this clinical entity. [ABSTRACT FROM AUTHOR]

Background and Objectives: Anemia during peripheral blood stem cells (PBSCs) transplant is considered a bad prognostic marker. The study aimed to determine whether pretransplant anemia influence peritransplant transfusion requirements in myeloma patients. Methods: Myeloma patients planned for PBSC transplant were stratified based on hemoglobin levels at time of mobilization, PBSC collection, and PBSC infusion. Univariate and multivariate analysis was performed to study the predictors for good mobilization, adequate CD34 yield by apheresis, and red blood cell (RBC) transfusion in the peritransplant period. Results: Of 67 patients, the prevalence of anemia at mobilization, PBSC collection, and PBSC infusion was 37%, 58%, and 70%, respectively. Eighty-five percent had good mobilization with peripheral blood CD34 count of 50 cells/µl (8-123) and 81% had adequate CD34 yield with first apheresis. Thirty-two percent patients received peritransplant RBC transfusion with the median of one unit (range: 0-5). Anemia on the day of infusion did influence the RBC transfusions in the peritransplant period (P = 0.03). Conclusion: One third of myeloma patients require RBC transfusion support in the peritransplant period. We identified pretransplant anemia neither influenced mobilization nor PBSC collection but increased the risk for RBC transfusion in the peritransplant period. [ABSTRACT FROM AUTHOR]

Nuclear export proteins such as exportin-1 (XPO1) transport tumor-suppressor proteins and other growth-regulatory proteins from the nucleus to the cytoplasm. Overexpression of XPO1 has been observed in several cancers and correlates with shorter event-free and overall survival in multiple myeloma. Selinexor was developed as an oral first-in-class selective inhibitor of nuclear export (SINE) that inhibits XPO1. Preclinical studies in tumor cell lines and mouse models have demonstrated the efficacy of selinexor both as a single agent and in various combinations with known active antimyeloma agents. Results from the pivotal phase II STORM trial led to the US FDA approval of selinexor with dexamethasone in penta-refractory myeloma. Because of the feasibility of combining selinexor with other active antimyeloma agents, the multiarm STOMP trial was initiated and is ongoing, with impressive response rates reported in some of the combination arms thus far. The registrational phase III BOSTON trial demonstrated the superiority of selinexor in combination with bortezomib and dexamethasone as compared with bortezomib and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) who have received one to three prior anti-MM regimens. The toxicity profile of selinexor is well established and predictable and may be significant unless managed aggressively and preemptively. The most common side effects are thrombocytopenia, anemia, neutropenia, fatigue, nausea, anorexia, and weight loss. Hyponatremia and cataracts seem to be class effects. Other SINE compounds are now being studied in efforts to discover agents that will potentially be better tolerated. Eltanexor is an investigational SINE compound that has shown a more positive toxicity profile in preclinical studies, with reduced central nervous system penetration and gastrointestinal side effects, and is now undergoing clinical investigation. These and other trials will further clarify the role of these innovative agents in the therapeutic advancement of RRMM. [ABSTRACT FROM AUTHOR]

[Display omitted] • Aberrant STAT3 activation can promote neoplastic transformation by affecting cellular proliferation, invasion, metastasis, angiogenesis, and anti-apoptosis induction. • Fangchinoline abrogated protein expression levels of STAT3 and upstream signals (JAK1/2 and Src) in different tumor cells. • Fangchinoline inhibited the levels of various tumorigenic markers and promoted marked apoptosis through degradation of PARP and caspase-3. • Fangchinoline attenuated the level of STAT3 and upstream signals and suppressed the level of anti- apoptotic proteins in xenograft mice model. The development of cancer generally occurs as a result of various deregulated molecular mechanisms affecting the genes that can control normal cellular growth. Signal transducer and activator of transcription 3 (STAT3) pathway, once aberrantly activated can promote carcinogenesis by regulating the transcription of a number of oncogenic genes. Here, we evaluated the impact of fangchinoline (FCN) to attenuate tumor growth and survival through modulation of oncogenic STAT3 signaling pathway using diverse tumor cell lines and a xenograft mouse model. To evaluate the action of FCN on STAT3 cascade, protein levels were analyzed by Western blot analysis and electrophoretic mobility shift assay (EMSA). Translocation of STAT3 was detected by immunocytochemistry. Thereafter, FCN-induced ROS was measured by GSH/GSSG assay and H2DCF-DA. FCN-induced apoptosis was analyzed using Western blot analysis and flow cytometry for various assays. Finally, anti-cancer effects of FCN in vivo was evaluated in a myeloma model. We noted that FCN abrogated protein expression levels of STAT3 and upstream signals (JAK1/2 and Src). In addition, FCN also attenuated DNA binding ability of STAT3 and its translocation into the nucleus. It altered the levels of upstream signaling proteins, increased SHP-1 levels, and induced substantial apoptosis in U266 cells. FCN also promoted an increased production of reactive oxygen species (ROS) and altered GSSG/GSH ratio in tumor cells. Moreover, FCN effectively abrogated tumor progression and STAT3 activation in a preclinical myeloma model. Overall, this study suggests that FCN may have a tremendous potential to alter abnormal STAT3 activation and induce cell death in malignant cells along with causing the suppression of pathogenesis and growth of cancer through a pro-oxidant dependent molecular mechanism. [ABSTRACT FROM AUTHOR]

As no unified treatment protocol or evidence yet exists for plasmapheresis without plasma, this study explored the outcomes of using 4% human albumin (ALB) solution as a replacement solution in patients undergoing plasma exchange for multiple myeloma (MM) patients with acute kidney injury (AKI). This study was prospectively registered (ChiCTR2000030640 and NCT05251896). Bortezomib-based chemotherapy plus therapeutic plasmapheresis (TPP) with 4% human ALB solution was assessed for three years in patients with MM aged >18 years, with AKI according to the Kidney Disease Improving Global Outcomes criteria, and without previous renal impairment from other causes. The primary endpoints were changes in renal function over 18 weeks and survival outcomes at 36 months. The secondary endpoints were the incidence of adverse reactions and symptom improvement. Among the 119 patients included in the analysis, 108 experienced renal reactions. The M protein (absolute changes: median -12.12%, interquartile ranges (IQRs) -18.62 to -5.626) and creatine (median -46.91 μmol/L, IQR -64.70 to -29.12) levels decreased, whereas the estimated glomerular filtration rate (eGFR) increased (median 20.66 mL/(min·1.73 m 2 ), IQR 16.03-25.29). Regarding patient survival, 68.1% and 35.3% of patients survived for >12 and >36 months, respectively. The three symptoms with the greatest relief were urine foam, poor appetite, and blurred vision. All 11 patients (7.6%) who experienced mild adverse reactions achieved remission. In conclusion, in MM patients with AKI, plasma-free plasmapheresis with 4% human ALB solution and bortezomib-based chemotherapy effectively alleviated light chain damage to kidney function while improving patient quality of life.

Ralstonia pickettii is an opportunistic bacillus found in Pseudomonas species, with the ability to induce systemic infections. We report the case of a 69-year-old man, with a clinical history of myeloma, Type IIdiabetes, renal failure (grade IV), and colon cancer, that developed a severe bacterial infection, with acute asthenia and a fever, that appeared at the end of dialysis. Using theMALDI-TOF technology, the bacillus Ralstonia pickettii was identified, and an antimicrobial treatment was quickly started with a rapid microbiological remission. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the role of SIRT3 and inflammatory factors in bortezomib-induced peripheral neuropathy (PN). This prospective observational cohort study included a total of 159 patients of multiple myeloma patients during June 2016 to June 2019. All patients received the strategy of bortezomib and dexamethasone and were further divided into the PN group and the non-PN group. Serum SIRT3, CRP, IL-6 and TNF-α levels were measured by enzyme-linked immunosorbent assay (ELISA). During the study period, 76 (47.8%) patients developed PN. The inflammatory factors all gradually decreased and SIRT3 levels were gradually increased after treatment by bortezomib combined with dexamethasone compared with the baseline. The levels of all inflammatory factors were markedly higher, while SIRT3 levels were lower in PN patients compared with the non-PN patients at the same time point after treatment. In PN grade III patients, the serum levels of CRP, IL-6 and TNF-α were significantly higher, while serum levels of SIRT3 were markedly lower than the grade I–II patients. SIRT3 was negatively correlated with CRP, IL-6 and TNF-α. After nursing treatment and reduction of bortezomib dose, the levels of SIRT3 significantly increased, while levels of inflammatory decreased in PN patients with grade III. SIRT3 and inflammatory factors showed the potential for diagnosis of bortezomib-induced PN. Besides, SIRT3, IL-6 and TNF-α were the independent risk factors for MM patients developing PN after treatment of bortezomib. Higher inflammatory factors and lower SIRT3 might be associated with the development of bortezomib-induced PN in multiple myeloma patients, which might be reversed by decreased bortezomib dose and proper nursing treatment. [ABSTRACT FROM AUTHOR]

A 14‐year‐old male castrated Pomeranian was found to be hypercalcaemic and hyperglobulinaemic during investigation of anorexia and haematochezia. Ionised hypercalcaemia, increased serum parathyroid hormone concentration, normophosphatemia and a parathyroid nodule found on cervical ultrasound examination were diagnostic for primary hyperparathyroidism (PHPT). Thoracic radiographs revealed ovoid lytic lesions in multiple bones. To investigate the hyperglobulinaemia, serum electrophoresis and immunoglobulin (Ig) quantification were performed, revealing an IgA biclonal gammopathy. Bone marrow cytopathology confirmed multiple myeloma (MM). Following bilateral parathyroidectomy, the dog's hypercalcaemia resolved, and pulse‐dose chemotherapy with prednisone and melphalan was initiated to treat MM. To the authors' knowledge, this is a unique case report of simultaneous PHPT and MM in the veterinary literature, diseases that are rarely reported concurrently in humans. This case highlights the need to thoroughly investigate multiple problems when they are not explained by a single diagnosis. [ABSTRACT FROM AUTHOR]

The signaling lymphocytic activation molecule F7 (CS-1) enables the selective killing of the myeloma cells with minimal side effects on the healthy tissue. In this study, we have modelled the 3D structure of CS-1 followed by performing molecular dynamic simulations. To develop a potential CS-1 modulator, a virtual screening of the 'Bioactive Compound Database' was conducted. The screening results have given three interacting regions. The best representative structure of each class and mode of action were revealed. Our study suggests compounds ICG-001, Avanafil, and BPTES, as novel drug candidates at the CS-1 protein target. The molecular dynamic simulation study reveals that the resulted compounds provide different binding patterns over the CS-1 Ig-like V-type domain in which Avanafil and BPTES provide stable interactions with their binding environment located at the bc-hi loops clefts and bc-fg loops clefts, respectively. In contrast, compound ICG-001 shows more flexible and transient non-binding interaction due to the vast binding region over β-sheet strands consisting of H, C and D during the simulation timeline. We conclude that the identified compounds seem to be the best candidates to design a series of new compounds with the ability to bind to CS-1 with potential binding activity to its target. [ABSTRACT FROM AUTHOR]

Childhood acute lymphoblastic leukemia (ALL) has an origin in the fetal period which may distinguish it from ALL diagnosed later in life. We wanted to test whether familial risks differ in ALL diagnosed in the very early childhood from ALL diagnosed later. The Swedish nation-wide family-cancer data were used until year 2016 to calculate standardized incidence ratios (SIRs) for familial risks in ALL in three diagnostic age-groups: 0–4, 5–34 and 35 + years. Among 1335 ALL patients diagnosed before age 5, familial risks were increased for esophageal (4.78), breast (1.42), prostate (1.40) and connective tissue (2.97) cancers and leukemia (2.51, ALL 7.81). In age-group 5–34 years, rectal (1.73) and endometrial (2.40) cancer, myeloma (2.25) and leukemia (2.00, ALL 4.60) reached statistical significance. In the oldest age-group, the only association was with Hodgkin lymphoma (3.42). Diagnostic ages of family members of ALL patients were significantly lower compared to these cancers in the population for breast, prostate and rectal cancers. The patterns of increased familial cancers suggest that BRCA2 mutations could contribute to associations of ALL with breast and prostate cancers, and mismatch gene PMS2 mutations with rectal and endometrial cancers. Future DNA sequencing data will be a test for these familial predictions. [ABSTRACT FROM AUTHOR]

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) are limited. Daratumumab in combination with bortezomib and dexamethasone is a promising new treatment. The aim of this analysis was to assess the outcomes of daratumumab-bortezomib-dexamethasone (DVd) combination for the treatment of patients with RRMM in a real-world setting. All consecutive RRMM patients who received at least two cycles of DVd treatment between December 2016 and July 2020 were identified. We analyzed the clinical characteristics and survival of 47 patients treated at 7 Slovak centers outside of the clinical trials. The median age was 65 years (range, 35 to 83). The median (range) number of lines of therapy per patient was 3 (2-6). All patients were previously exposed to PIs (proteasome inhibitors) and IMIDs (immunomodulatory drugs), the majority of patients (70.2%) had double refractory (IMIDs and PI) disease and 72.3% of patients were refractory to their last therapy. Most patients presented with high-risk characteristics, including 25.6% adverse cytogenetics and 25.5% extramedullary disease. The majority of patients responded with an overall response rate of 78%, we found complete response in 3, very good partial response in 22, partial response in 12, minor response or stable disease in 9, and progressive disease in 1 patient. After a median follow-up period of 8 months, the median progression-free survival was 10 months. There was a longer progression-free survival in those with 2 vs. >2 prior treatments, with equally good effectivity in standard-risk and high-risk cytogenetic groups. The adverse events were usually mild, none leading to permanent drug interruptions. Daratumumab- bortezomib-based combinations are efficacious and safe regimens in RRMM patients in the real-world setting. This is the first analysis in Slovakia addressing the DVd combination outside of the clinical trial setting. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a malignant plasma cell neoplasm, requiring the integration of clinical examination, laboratory and radiological investigations for diagnosis. Detection and isotypic identification of the monoclonal protein(s) and measurement of other relevant biomarkers in serum and urine are pivotal analyses. However, occasionally this approach fails to characterize complex protein signatures. Here we describe the development and application of next generation mass spectrometry (MS) techniques, and a novel adaptation of immunofixation, to interrogate non-canonical monoclonal immunoproteins. Immunoprecipitation immunofixation (IP-IFE) was performed on a Sebia Hydrasys Scan2. Middle-down de novo sequencing and native MS were performed with multiple instruments (21T FT-ICR, Q Exactive HF, Orbitrap Fusion Lumos, and Orbitrap Eclipse). Post-acquisition data analysis was performed using Xcalibur Qual Browser, ProSight Lite, and TDValidator. We adapted a novel variation of immunofixation electrophoresis (IFE) with an antibody-specific immunosubtraction step, providing insight into the clonal signature of gamma-zone monoclonal immunoglobulin (M-protein) species. We developed and applied advanced mass spectrometric techniques such as middle-down de novo sequencing to attain in-depth characterization of the primary sequence of an M-protein. Quaternary structures of M-proteins were elucidated by native MS, revealing a previously unprecedented non-covalently associated hetero-tetrameric immunoglobulin. Next generation proteomic solutions offer great potential for characterizing complex protein structures and may eventually replace current electrophoretic approaches for the identification and quantification of M-proteins. They can also contribute to greater understanding of MM pathogenesis, enabling classification of patients into new subtypes, improved risk stratification and the potential to inform decisions on future personalized treatment modalities. [ABSTRACT FROM AUTHOR]

Fatty acid binding proteins (FABPs) transport fatty acids (FA) into cells as an energy source, and their inhibition suppressed tumor proliferation in solid tumors. Multiple myeloma (MM) is a hematologic malignancy, known for disrupted protein metabolism including high proteasome activity, where proteasome inhibitors made a dramatic improvement in its treatment. Recent discovery found FABPs as a novel metabolic pathway in MM, which will have an impact on understanding the biology and on therapeutic application in MM. [ABSTRACT FROM AUTHOR]

Introduction: Stage classification is an important underpinning of management in patients with cancer and rests on a combination of three components-T for tumor extent, N for nodal involvement, and M for distant metastases. This article details the revision of the N and the M components of thymic epithelial tumors for the ninth edition of the TNM classification of malignant tumors proposed by the Thymic Domain of the International Association for the Study of Lung Cancer Staging and Prognostic Factors Committee., Methods: The N and M components of the eighth edition staging system were verified by a large international collaborative data source through a data-driven analysis. A total of 9147 cases were included for analysis, including 7662 thymomas, 1345 thymic carcinomas, and 140 neuroendocrine thymic tumors., Results: Lymph node involvement rates were 1.5% in thymomas and 17.6% and 27.7% in thymic carcinomas and neuroendocrine thymic tumors, respectively. Rates of lymph node metastasis were increasingly higher in tumors with higher T stage and higher-grade histologic type. Survival analysis validated the differences in the N and M categories proposed in the eighth edition staging system. Good discrimination in overall survival was detected among pathologic (p)N and pM categories in patients with thymoma and thymic carcinoma., Conclusions: No changes are proposed from the eighth edition for the N and M components. The proposed stage classification will provide a useful tool for management of the disease among the global thymic community., (Copyright © 2023 International Association for the Study of Lung Cancer. All rights reserved.)

Isatuximab, a monoclonal antibody (mAb) of immunoglobulin G (IgG) isotype, specifically targets the cluster of differentiation 38 antigen overexpressed in malignant plasma cells. Isatuximab is used to treat multiple myeloma (MM), characterized by the excessive production of abnormal "myeloma proteins" (M‐proteins) that may interact with therapeutic IgG mAb on the neonatal Fc receptor (FcRn)‐mediated recycling pathway. The clinical pharmacology profile of isatuximab was investigated by population pharmacokinetics (PKs) modeling in 476 patients with MM who received 1–20 mg/kg isatuximab either as single agent or in combination with pomalidomide‐dexamethasone in 4 clinical trials. Isatuximab PKs were characterized by a two‐compartment model with parallel time‐varying linear clearance (CL) and nonlinear elimination. Due to a mechanism‐based drug‐disease interaction, patients secreting IgG M‐protein exhibited a twofold lower drug exposure compared with patients with non‐IgG MM. No dose adjustment was required based on MM immunoglobulin type because efficacy and safety profiles were comparable between IgG and non‐IgG MM subpopulations. β2‐microglobulin, body weight, sex, drug material, and race have a limited effect on drug exposure and do not require any dose adjustment. A typical 50% decrease in linear CL from initial treatment to steady‐state was predicted, and this decrease correlated with the best overall response rate and was slower for patients with IgG MM. These findings suggest that the time‐dependent effect of isatuximab is likely mediated by a combined factor of both disease state evolution and the perturbation of the FcRn‐mediated recycling pathway. [ABSTRACT FROM AUTHOR]

Purpose: To identify the clinical usefulness of serum M protein and to establish a rationale for regular follow-up with serum protein electrophoresis in solitary plasmacytoma. Materials and Methods: Sixty-nine patients with solitary plasmacytoma and solitary plasmacytoma with minimal marrow involvement according to the International Myeloma Working Group criteria were retrospectively reviewed. Results: At a median follow-up of 6.2 years, 5-year local control (LC), 5-year multiple myeloma-free survival (MMFS), 5-year failure-free survival (FFS), and 5-year overall survival (OS) were 82.6%, 44.1%, 41.8%, and 85.1%, respectively. Among the patients whose initial serum M protein was present or not evaluated, 37.3% of patients showed disappearance of serum M protein after various treatment. MMFS of these patients were comparable to non-secretory plasmacytoma with undetectable levels of M protein, and significantly better than patients with persistent M protein. Increase of serum M protein =0.1 g/dL was most predictive of treatment failure with area under the curve of 0.731. Conclusion: Patients who eventually showed persistence of serum M protein after treatment showed worse MMFS and FFS compared to those whose serum M protein disappeared or who had initially non-secretory disease. The increase of serum M protein level =0.1 g/dL from current nadir was predictive of treatment failure. Therefore, regular follow-up with serum M protein is highly recommended especially unless the patient had initially non-secretory disease. [ABSTRACT FROM AUTHOR]

Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of selinexor for management of relapsed multiple myeloma (MM). Data Sources: A literature search was performed of PubMed and MEDLINE databases (January 1, 2000, to November 14, 2019), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from US National Institutes of Health ClinicalTrials.gov. Queries were performed using key words selinexor, SINE, XPO1, and Xpovio.Study Selection/Data Extraction: Human and animal studies related to the pharmacology, pharmacokinetics, efficacy, and safety of selinexor were identified. Data Synthesis: Although numerous advances have been made in MM management, there remains an unmet need for treatment of heavily relapsed/refractory disease. Selinexor is a first-in-class selective inhibitor of nuclear export, which, through inhibition of exportin-1, causes accumulation of tumor suppressor proteins, reduction in oncoproteins, and apoptosis of plasma cells. Selinexor exhibited an overall response in 26% of patients with multiply relapsed MM. Median progression-free survival was 3.7 months, and overall survival was 8.6 months. Common adverse effects include thrombocytopenia, neutropenia, fatigue, and nausea. Ongoing studies are investigating combination therapies utilizing selinexor. Relevance to Patient Care and Clinical Practice: This review describes the efficacy, safety, and clinical applicability of selinexor, a novel agent with potential to meet an unmet need in refractory MM. Conclusion: Selinexor has demonstrated activity in a heavily refractory patient population. Given the adverse effect profile and associated costs, additional studies are needed to further elucidate the appropriate clinical scenario and combinations for selinexor use. [ABSTRACT FROM AUTHOR]

The article focuses on a study which found antibody shrank fast-growing non-Hodgkin lymphoma tumors in 46 of 124 patients in whom other treatments had failed. It mentions engineered cells, known as chimeric antigen receptor (CAR) T cells and clinical trial suggested a bispecific antibody might work equally well on myeloma, another blood cancer. It also mentions cancer drugs are such monoclonal antibodies, including the breast cancer drug trastuzumab, better known as Herceptin.

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The Maf proteins, including c-Maf, MafA, and MafB, are critical transcription factors in myelomagenesis. Previous studies demonstrated that Maf proteins are processed by the ubiquitin-proteasome pathway, but the mechanisms remain elusive. This study applied MS to identify MafB ubiquitination-associated proteins and found that the ubiquitin-specific protease USP7 was present in the MafB interactome. Moreover, USP7 also interacted with c-Maf and MafA and blocked their polyubiquitination and degradation. Consistently, knockdown of USP7 resulted in Maf protein degradation along with increased polyubiquitination levels. The action of USP7 thus promoted Maf transcriptional activity as evidenced by luciferase assays and by the up-regulation of the expression of Maf-modulated genes. Furthermore, USP7 was up-regulated in myeloma cells, and it was negatively associated with the survival of myeloma patients. USP7 promoted myeloma cell survival, and when it was inhibited by its specific inhibitor P5091, myeloma cell lines underwent apoptosis. These results therefore demonstrated that USP7 is a deubiquitinase of Maf proteins and promotes MM cell survival in association with Maf stability. Given the significance of USP7 and Maf proteins in myeloma genesis, targeting the USP7/Maf axle is a potential strategy to the precision therapy of MM. [ABSTRACT FROM AUTHOR]

Context: The fluctuations of proteins in multiple myeloma (MM) are well-known markers for checking the status of the patients.Aims: The objective of this study was to examine three proteins that have an important role in disease progression.Subjects and Methods: The study was performed with two groups: 30 MM stage I patients' (14 females/16 males; aged 60.83 ± 12.38 years) as case group and 40 healthy individuals (18 females/22 males; aged 57.65 ± 6.43 years) as control group. Both groups have been matched in gender and age. Bone sialoprotein (BSP), osteopontin (OPN), and β2-microglobulin (β2M) were measured with an enzyme-linked immunosorbent assay.Results: Serum BSP levels of MM-I patients was significantly higher than that of healthy controls (29.24 ± 5.57 vs. 20.89 ± 3.67, P = 0.001). OPN levels of MM-I patients were significantly lower than that of healthy individuals (12.03 ± 3.45 vs. 19.35 ± 4.67, P = 0.001). β2M levels of patients and controls were similar (1.49 ± 0.67 vs. 1.29 ± 0.55, P = 0.193).Conclusions: The results suggested that myeloma cells may affect the production of BSP and OPN, which possibly contributes to osteoclastic bone resorption in MM-I patients. Their levels may be a useful biomarker for assessing bone destruction in MM-I patients and distinguishing MM-I from healthy individuals. [ABSTRACT FROM AUTHOR]

Purpose: To describe the ophthalmic manifestations of amyloidosis and the corresponding therapeutic measures.Methods: The 178 patients included in the study had different types of amyloidosis, diagnosed at a single internal medicine institution (Bari, Italy). To provide a comprehensive review of the types of amyloidosis that can be associated with ocular involvement, the images and clinical descriptions of patients with amyloidosis structurally related to gelsolin, keratoepithelin and lactoferrin were obtained in collaborations with the ophthalmology departments of hospitals in Mainz (Germany) and Helsinki (Finland).Results: Overall, ocular morbidity was detected in 41 of the 178 patients with amyloidosis (23%). AL amyloidosis was diagnosed in 18 patients with systemic disease, 3 with multiple myeloma, and 11 with localized amyloidosis. AA amyloidosis was detected in 2 patients with rheumatoid arthritis and 3 with Behçet syndrome, and transthyretin amyloidosis in 4 patients. The treatment of AL amyloidosis is based on chemotherapy to suppress the production of amyloidogenic L-chains and on surgical excision of orbital or conjunctival masses. AA amyloidosis is managed by targeting the underlying condition. Vitreous opacities and additional findings of ocular involvement in patients with transthyretin amyloidosis indicate the need for pars plana vitrectomy. Gelsolin amyloidosis, characterized by lattice corneal amyloidosis and polyneuropathy, results in recurrent keratitis and corneal scarring, such that keratoplasty is inevitable. In patients with lattice corneal dystrophies associated with amyloid deposits of keratoepithelin fragments, corneal transparency is compromised by deposits of congophilic material in the subepithelial layer and deep corneal stroma. Patients with established corneal opacities are treated by corneal transplantation, but the prognosis is poor because recurrent corneal deposits are possible after surgery. In patients with gelatinous drop-like dystrophy, the amyloid fibrils that accumulate beneath the corneal epithelium consist of lactoferrin and can severely impair visual acuity. Keratoplasty and its variants are performed for visual rehabilitation.Conclusion: A routine ophthalmic follow-up is recommended for all patients with established or suspected amyloidosis, independent of the biochemical type of the amyloid. Close collaboration between the ophthalmologist and the internist will facilitate a more precise diagnosis of ocular involvement in amyloidosis and allow the multidisciplinary management of these patients.Abbreviations: CD: corneal dystrophy; CLA: corneal lattice amyloidosis; CNS: central nervous system; CT: computed tomography; FAP: familial amyloidotic polyneuropathy; GDLCD: gelatinous drop-like corneal dystrophy; GLN: gelsolin; LCD: lattice corneal dystrophy; MRI: magnetic resonance imaging; OLT: orthotopic liver transplantation; TEM: transmission electron microscopy; TGFBI: transforming growth factor β induced; TTR: transthyretin. [ABSTRACT FROM AUTHOR]