Prognosis Of Multiple Myeloma Patients Research Articles

Improved survival of multiple myeloma patients treated with autologous transplantation in the modern era of new medicine.

New drugs for multiple myeloma (MM) have dramatically improved patients’ overall survival (OS). Autologous stem cell transplantation (ASCT) remains the mainstay for transplant‐eligible MM patients. To investigate whether the post‐ASCT prognosis of MM patients has been improved by new drugs, we undertook a retrospective observational analysis using the Transplant Registry Unified Management Program database in Japan. We analyzed 7323 patients (4135 men and 3188 women; median age, 59 years; range 16‐77 years) who underwent upfront ASCT between January 2007 and December 2018. We categorized them by when they underwent ASCT according to the drugs’ introduction in Japan: group 1 (2007‐2010), group 2 (2011‐2016), and group 3 (2017‐2018). We compared the groups’ post‐ASCT OS. The 2‐year OS rates (95% confidence interval [CI]) of groups 1, 2, and 3 were 85.8% (84.1%‐87.4%), 89.1% (88.0%‐90.1%), and 92.3% (90.0%‐94.2%) (P < .0001) and the 5‐year OS (95% CI) rates were 64.9% (62.4%‐67.3%), 71.6% (69.7%‐73.3%), and not applicable, respectively (P < .0001). A multivariate analysis showed that the post‐ASCT OS was superior with these factors: age less than 65 years, performance status 0/1, low International Staging System (ISS) stage, receiving SCT for 180 days or less post‐diagnosis, better treatment response pre‐ASCT, later year of ASCT, and receiving SCT twice. A subgroup analysis showed poor prognoses for the patients with unfavorable karyotype and poor treatment response post‐ASCT. The post‐ASCT OS has thus improved over time (group 1 < 2 < 3) with the introduction of new drugs for MM. As the prognosis of high‐risk‐karyotype patients with ISS stage III remains poor, their treatment requires improvement.

P-081: A novel circulating miRNA involved in T cell senescence of multiple myeloma patients

<h3>Background</h3> Many circulating miRNAs were reported as biomarkers of multiple myeloma (MM),but the functions of these circulating miRNAs are not clarified recently. The aim of this work is to identify novel biomarkers of circulating miRNAs in diagnosis and prognosis for MM and reveal their function in the pathogenesis of MM. <h3>Methods</h3> MiRNAs profiling in serum(n=15) and MM cells(CD138+, n=10) were analyzed by RNA-sequencing of MM patients. The common dysregulated miRNAs(P<0.05) were identified via Veen Diagram analysis in serum and MM cells between MM patients and healthy donors, then validated by RT-PCR. ROC analysis and Kaplan-Meier(K-M) analysis were performed to evaluate the differently expressed circulating miRNAs in diagnosis and prognosis in MM patients, respectively. Exosomes of serum were isolated and characterized by dynamic light scattering, transmission microscopy, and western blot analysis. <h3>Results</h3> There were stable and specific miRNA expression profiles in serum and tumor cells of MM patients. The miRNA profiling of MM serum showed that there were 74 differential circulating miRNAs(P<0.05), among which 56 miRNAs(75.7%) were down-regulated and 18 miRNAs were up-regulated(24.3%). MiRNA profiling of MM cells showed that there were 376 miRNAs differentially expressed(P<0.05), of which 87(23.1%) were down-regulated and 289(76.9%) were up-regulated. Veen analysis found 36 common dysregulated miRNAs both in serum and tumor cells of MM. There were 22.3% of differential miRNAs located on chromosome 1 and 17. Five circulating miRNAs(miR-27b-3p, miR-145-3p, miR-628-3p, miR-342-5p and miR-30e-3p) were further confirmed differentially expressed in MM patients(n=201) by RT-PCR. K-M analysis showed that MM patients with low level of miR-27b, miR-145, and miR-628 had shortened PFS and OS. Strikingly, comparing to the decreased level of miR-27b in MM patients serum, miR-27b was enriched in the exosome of serum. MM patients with low level of serum miR-27b displayed lower CD3+T cells and CD3+CD4+T cells in peripheral blood. Our further study found increased proportation of senescent T cells in MM patients with low level of serum miR-27b, especially in CD8+T cells. In order to confirm T cell senescent phenotype, PBMCs were co-cultured with MM patients serum exosomes which mimic the in vivo situation. Flow cytometry analysis showed the CD28 expression was notably decreased on the CD3+ T cells in the co-culture group. In addition, RT-PCR and flow cytometry analysis showed that overexpression of miR-27b significantly down-regulated the level of CD28 in jurkat cells, a T cell line. These findings suggested an immune suppressive microenvironment in MM patients with lower level of serum miR-27b. <h3>Conclusion</h3> Circulating miRNA works as a usful biomarker in diagnosis and prognosis of MM. Strigently, serum miR-27b is a novel circulating miRNA involved in T cell senescence of multiple myeloma patients which indicated the poor outcome of patients with MM.

Baseline lncRNA PCAT1 high expression and its longitude increment during induction therapy predict worse prognosis in multiple myeloma patients.

BackgroundLong noncoding RNA PCAT1 (lnc‐PCAT1) involves in the proliferation and drug sensitivity of multiple myeloma (MM), while its prognostic role in MM patients is still obscure. This study aimed to explore the association of lnc‐PCAT1 with MM risk, clinical characteristics, treatment response, progression‐free survival (PFS), and overall survival (OS).MethodsA total of 83 symptomatic MM patients were enrolled in this study. Additionally, 30 healthy bone marrow donors as health controls were also recruited. Bone marrow plasma cell samples of MM patients and health donors were collected. Lnc‐PCAT1 in bone marrow plasma cells was detected by reverse transcription‐quantitative polymerase chain reaction.ResultsLnc‐PCAT1 was increased in MM patients than in health donors (p < 0.001), and receiver operating characteristic (ROC) curve showed that lnc‐PCAT1 had excellent capability of discriminating MM patients from health donors (area under curve: 0.932, 95% confidence interval: 0.889–0.976). In MM patients, lnc‐PCAT1 was correlated with bone lesion (p = 0.024), higher β2‐MG (p = 0.005), LDH (p = 0.037), and presence of Del (17p) (p = 0.029). Lnc‐PCAT1 was also associated with poor ISS stage (p = 0.013) and R‐ISS stage (p = 0.005). Besides, lnc‐PCAT1 was reduced after treatment (p < 0.001); meanwhile, lnc‐PCAT1 before treatment was correlated with lower CR (p = 0.046) but not ORR (p = 0.185). Additionally, lnc‐PCAT1 after treatment was associated with lower CR (p = 0.003) and ORR (p = 0.010). Furthermore, baseline Inc‐PCAT1 high and Inc‐PCAT1 increase after treatment were correlated with worse PFS and OS (all p < 0.05).ConclusionLnc‐PCAT1 dysregulation serves as a biomarker for diagnosis and prognosis for MM.

PRL-3 promotes a positive feedback loop between STAT1/2-induced gene expression and glycolysis in multiple myeloma.

Over 34 000 patients are diagnosed yearly with multiple myeloma (MM), which remains a fatal malignancy. Expression of the phosphatase PRL-3 is associated with poor prognosis in MM patients, and Vandsemb etal. have demonstrated that PRL-3 contributes to enhanced MM cell fitness through activation of a glycolysis-associated feedback loop. PRL-3 resulted in increased expression of signal transducer and activator of transcription 1 (STAT1) and 2 (STAT2) and increased glycolysis. Increased glucose metabolism in turn activated STAT1/2 and interferon 1-related genes. This discovery advances the MM field by providing a new potential treatment avenue. Comment on: https://doi.org/10.1111/febs.16058.

An interactive nomogram based on clinical and molecular signatures to predict prognosis in multiple myeloma patients.

Although novel drugs and treatments have been developed and improved, multiple myeloma (MM) is still recurrent and difficult to cure. In the present study, the magenta module containing 400 hub genes was determined from the training dataset of GSE24080 through weighted gene co-expression network analysis (WGCNA). Then, using the least absolute shrinkage and selection operator (Lasso) analysis, a fifteen-gene signature was firstly selected and the predictive performance for overall survival (OS) was favorable, which was identified by Receiver Operating Characteristic (ROC) curves. The risk score model was constructed based on survival-associated fifteen genes from the Lasso model, which classified MM patients into high-risk and low-risk groups. Areas under the curve (AUC) of ROC curve and log-rank test showed that the high-risk group was correlated to the dismal survival outcome of MM patients, which was also identified in testing dataset of GSE9782. The calibration plot, the AUC value of the ROC curve and Concordance-index showed that the interactive nomogram with risk score could favorably predict the probability of multi-year OS of MM patients. Therefore, it may help clinicians make a precise therapeutic decision based on the easy-to-use tool of the nomogram.

The CRBN, CUL4A and DDB1 Expression Predicts the Response to Immunomodulatory Drugs and Survival of Multiple Myeloma Patients

Immunomodulatory drugs (IMiDs) are effective in the treatment of multiple myeloma (MM), myelodysplastic syndrome with deletion of chromosome 5q and other haematological malignancies. Recent studies showed that IMiDs bind to cereblon (CRBN), a substrate receptor of the CRL4–CRBN complex, to induce the ubiquitination and degradation of IKZF1 and IKZF3 in MM cells, contributing to their anti-myeloma activity. We aimed to determine whether the CRL4–CRBN complex proteins’ expression predicts the prognosis of MM patients treated with IMiDs. Here, we evaluated the expression of CRL4–CRBN complex proteins and their downstream targets with immunohistochemistry (IHC) staining in 130 bone marrow samples from MM patients treated with thalidomide or lenalidomide-based regimens. We found that the expression of CRBN and CUL4A was associated with the superior IMiD-based treatment response (p = 0.007 and p = 0.007, respectively). Moreover, the CUL4A expression was associated with improved PFS (HR = 0.66, 95% CI 0.44–0.99; p = 0.046) and DDB1 expression showed a negative impact on OS both in the univariate (HR = 2.75, 95% CI 1.65–4.61; p = 0.001) and the multivariate (HR 3.67; 95% CI 1.79–7.49; p < 0.001) analysis. Overall, our data suggest that the expression of DDB1, CUL4A and CRBN assessed by IHC predicts the clinical course of MM patients and identifies patients with a high probability of responding to IMiD-based therapy.

The Prognosis and Predictive Value of Complement C3 in Patients with Multiple Myeloma

To investigate the effect of complement C3 on the prognosis of patients with multiple myeloma (MM), and to establish a predictive model to evaluate the overall survival. Eighty newly diagnosed MM patients were enrolled, and clinical characteristics, such as sex, age, platelet count, white blood cell count, ISS stage, FISH, levels of kappa and lammda chain, complement C3 and C4 were retrospectively analyzed. Cox regression model was used for univariate and multivariate analysis about risk factors that affecting the prognosis of the MM patients. A nomogram based on C3 level was established for predicting the prognosis of MM patients. The average age of the MM patients was 63.15±10.41, including 36 males and 44 females. The median overall survival (OS) was 36.3 months, and the median progression-free survival (PFS) was 35.2 months, the 3-year OS rate and PFS rate of the MM patients were 67.5% and 52.5%, respectively. The variants selected by univariate analysis were put into multivariate regression model, the result showed that C3 level ≥0.7 U/L and PLT count <100×109/L were the independent risk factors for OS. Nomogram based on C3 level, PLT count as well as β2-protein level showed an excellent accuracy in estimating prognosis of MM (C-index: 0.775). Patients with C3 level≥0.7 U/L or PLT count <100×109/L show poor prognosis. Nomogram based on the two variants can estimate overall survival of MM patients and provide suggestions to clinical decision.

The Influence of CONUT Score on the Prognosis of Patients with Multiple Myeloma

To explore the influence of controlling nutritional status (CONUT) score on the prognosis of newly diagnosed patients with multiple myeloma (MM). The clinical data 119 patients with MM who were diagnosed according to the international myeloma diagnostic criteria in Lanzhou University Second Hospital from April 2010 to October 2018 were collected and retrospectively analyzed. The relationship between clinical indexes, including age, sex, MM type, absolute lymphocyte count (ALC), absolute neutrophil count (ANC), absolute monocyte count (AMC), hemoglobin (Hb), platelet (PLT), β2-microglobulin (β2-MG), lactate dehydrogenase (LDH), albumin (ALB), globulin (GLO), cholesterol (CHO), serum creatinine (Scr), etc, and CONUT score was discussed to explore the prognostic value of these indicators. SPSS 25.0 software was used for statistical analysis. Progression-free survival(PFS) and overall survival (OS) between different subgroups were calculated by Kaplan-Meier curves and difference between survival curves was detected by Log-rank tests. Receiver operating characteristic (ROC) curve was used to estimate the most discriminative cutoff value of CONUT score for predicting OS. Mann-Whitney U test was used for non-parametric samples, and chi-square test for categorical variables. Univariate and multivariate analysis were performed by using COX proportional hazards model to identify factors associated with OS. Compared with high-scoring group, low-scoring group had a better OS ［median OS was 43.3 months and 127.67 months, respectively, 95% confidence interval (CI): 57.065-78.345, P=0.038］. At the same time, the low-scoring group also had higher level of ALC, ANC, AMC, Hb, PLT, ALB, and CHO but lower of GLO. Multivariate survival analysis showed that age (HR=1.027, 95%CI: 1.000-1.054, P=0.048), AMC (HR=11.284, 95%CI: 22.968-42.897, P<0.001), CONUT score (HR=1.198, 95%CI: 1.036-1.385, P=0.015), M protein (non-IgG/IgG type) type (HR=0.503, 95%CI: 0.259-0.977, P=0.043) were independent factors affecting the prognosis of MM patients. The CONUT score as an immune-nutrition score is a convenient and easy-to-obtain index to effectively predict the prognosis of MM patients.

Coagulation Indexes and Their Prognostic Significance in Patients with Multiple Myeloma

To analyze the relationship between coagulation indexes and prognosis of patients with multiple myeloma (MM). A total of 99 newly diagnosed MM patients treated in Gansu Provincial Hospital from October 2017 to October 2019 were enrolled. Plasma thromboplastin time (TT), prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), D-dimer (D-D), platelet (PLT), and other laboratory indexes were detected. The relationship between coagulation indexes and clinical characteristics of MM patients was analyzed. The differences in survival rates among MM patients with different levels of coagulation indexes were compared, and the effect of each clinical index on the prognosis of MM patients was analyzed by univariate and multivariate. Each coagulation index was correlated to sex, disease classification and stage, and β2-MG level of MM patients. Disease stage and β2-MG level were positively correlated with coagulation indexes, which means that patients with late-stage disease or high β2-MG, IgA and IgG levels were more likely to develop into coagulation disorders (P<0.05). The survival rate of patients with MM exhibiting elevated PT, FIB, and D-D levels was significantly lower (P<0.05). Univariate and multivariate analysis showed that each coagulation index was the influencing factor on the follow-up outcomes of MM patients, in which FIB was an independent prognostic factor. Coagulation function is correlated with multiple clinical indicators of patients with MM and plays an important role in their prognosis.

Circular RNA_0000190 and its target microRNA-767-5p are dysregulated, and they are related to risk stratification as well as prognosis in multiple myeloma patients.

This study aimed to explore the correlation between circular RNA_0000190 (circ_0000190) and microRNA-767-5p (miR-767-5p), and their correlations with biochemical indices, risk stratification, treatment response, and survival in multiple myeloma (MM) patients. Bone marrow (BM) plasma cells of 86 MM patients (during standard diagnostic procedures) and 30 healthy donors (HDs) (examination of the eligibility for BM transplantation) were obtained, among which circ_0000190 and miR-767-5p expressions were detected using reverse transcription quantitative polymerase chain reaction. In MM patients, Durie-Salmon stage and International Staging System (ISS) stage were assessed. Clinical responses (including complete response (CR) and objective response rate (ORR)) were assessed. The progression-free survival (PFS) and overall survival (OS) were calculated. Circ_0000190 was decreased, but miR-767-5p was increased in MM patients compared with HDs. Circ_0000190 was negatively correlated with miR-767-5p in both HDs and MM patients. In MM patients, circ_0000190 was negatively correlated with ISS stage, serum creatinine, beta-2-microglobulin, and lactate dehydrogenase but was positively correlated with albumin. Whereas an opposite trend in miR-767-5p was observed. Regarding clinical response, circ_0000190 had the value for predicting increased ORR, while miR-767-5p had the value for predicting decreased CR and ORR. Circ_0000190 high expression was correlated with better PFS and OS, while miR-767-5p high expression was correlated with worse PFS and OS. Multivariate Cox's analyses revealed circ_0000190 high expression as an independent factor predicting better OS. Circ_0000190 and its target miR-767-5p are dysregulated, and they are related to risk stratification and prognosis in MM patients.

Expression quantitative trait loci of genes predicting outcome are associated with survival of multiple myeloma patients.

Gene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype-tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10-7 either in EBV-transformed B-lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression-free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4-rs1992292, TBRG4-rs2287535 and ENTPD1-rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta-analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4-rs1992292 is associated with OS (hazard ratio=1.14, 95% confidence interval 1.04-1.26, P=.007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP, and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib.

Simple SummaryThe mRNA expression of nine previously described genes that may affect resistance to multiple myeloma (MM), viz., ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1, was compared between bortezomib-refractory and bortezomib-sensitive patients. RPL5 was the only gene to be significantly down-regulated in MM patients compared with non-MM individuals, while POMP was significantly up-regulated in the bortezomib-refractory patients. Multivariate analysis found the best independent predictors of progression-free survival to be high PSMB5 and CXCR expression and autologous stem cell transplantation, and that high expression of POMP and RPL5 were associated with shorter survival.Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM); however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The aim of our study is to assess the expression of previously described genes that may influence the resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1) and prognosis of MM patients. mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival.

Visceral adipose tissue glucose uptake is linked to prognosis in multiple myeloma patients: An exploratory study

The use of computerized tomography to opportunistically assess body composition has highlighted abnormalities such as low muscle mass and high adiposity may be hidden conditions in cancer patients. However, the role of skeletal muscle (SM), subcutaneous (SAT) and visceral (VAT) adipose tissue glucose uptake measured by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)-CT on patient prognostication is unclear. Patients with multiple myeloma (MM) with satisfactory image frame for assessing body composition and for semi-quantification of SM, SAT and VAT glucose uptakes were included. Plasmatic pro-inflammatory cytokine and adipokine levels were measured. High VAT mean standardized uptake value (SUV) at baseline was associated with shorter event-free survival (EFS) (hazard ratio [HR]: 7.89; 95% confidence interval [CI], 1.58-39.30; P=0.012) and overall survival (OS) (HR, 15.24; 95% CI, 2.69-86.30; P=0.002) among patients with newly diagnosed MM, even after adjustment for covariates. The highest tertile of VAT SUV was significantly correlated with worse MM-EFS (HR for the highest vs the lowest tertile 3.71; 95% CI, 1.22-10.56; Ptrend=0.035) and mortality (HR, 4.41; 95% CI, 1.28-12.77; Ptrend=0.019). Notably, patients with higher VAT SUV presented with lower VAT area, VAT index, higher SAT SUV, and higher number of individuals with visceral obesity (all P<0.01). Additionally, we found a negative correlation between VAT mean SUV with leptin (R2=0.20, P=0.003); no correlations were detected between VAT mean SUV and resistin, tumor necrosis factor (TNF) or interleukin (IL)-6. Functional VAT activity estimated by 18F-FDG PET-CT is a relevant prognostic factor in MM patients, specifically, a higher VAT SUV might be an early biomarker of cancer cachexia in these patients.

The Expression of CD40/CD40L in MM Patients and Its Significance to the Prognosis of MM Patients

To explore the expression of CD40/CD40L in multiple myeloma(MM) patients and its influence on prognosis. Thirty patients with MM treated in Cangzhou People's Hospital from May 2016 to June 2017 were selected and divided into MM group, then 30 healthy people with a physical examination in our hospital at the same time were selected as the normal group. The serum CD40/CD40L levels of the patients in the two groups was detected by flow cytometry, and its correlation with the lymphocyte population, pathological grade and prognostic significance of MM patients was anaysis. The expression of CD40 in serum of the patients in MM group was significantly higher than those in normal group (P<0.05). The expression of CD40L in serum of the patients in MM group showed no significant difference as compared with those in normal group (P>0.05). The levels of CD40 and CD40L in the patients before and after chemotherapy showed no difference(P>0.05). The levels of Ts and NK cells in the patients of MM group were lower than those in normal group (P<0.05). The proportion of total B lymphocytes, Th and Th/Ts cells between the two groups showed no significant difference (P>0.05). The CD40 level was correlated with the serum total B lymphocyte level of the patients in MM group (r=0.877, P=0.005). There was a correlation with CD40L and Th cells in the serum of MM patients (r=-0.783, P=0.035). The expression of serum CD40 in the patients at phase III-IV was higher than those of the patients at phase I-II, the levels of serum CD40L in MM patients at different periods showed no significant difference(P>0.05). The survival rate of MM patients with high CD40 expression was lower than that of MM patients with low CD40 expression (χ2=1.639, P=0.201). The high level CD40 was the main factor affecting the prognosis of MM patients (95%CI: 1.156-4.125). The increasing of CD40 level in MM patients is related to the pathological grade of the patients. Chemotherapy can reduce the level of CD40. The increasing of CD40 is an important factor for the poor prognosis of MM patients. CD40L level is not meaningful for MM treatment and prognosis.

Suppression of steroid 5\u03b1-reductase type I promotes cellular apoptosis and autophagy via PI3K/Akt/mTOR pathway in multiple myeloma

Steroid 5α-reductase type I (SRD5A1) is a validated oncogene in many sex hormone-related cancers, but its role in multiple myeloma (MM) remains unknown. Based on gene expression profiling (GEP) of sequential MM samples during the disease course, we found that the aberrant expression of SRD5A1 was correlated with progression and poor prognosis in MM patients. In this study, the oncogenic roles of SRD5A1 were validated in human MM cell lines (ARP1 and H929) and the xenograft MM model as well as the 5TMM mouse model. MTT and flow cytometry were used to assess MM cell proliferation, cell cycle, and apoptosis post inducible knockdown SRD5A1 by lentivirus-mediated short-hairpin RNA (shRNA). Transcriptomic sequencing, immunofluorescence, and western blot were used to investigate the effects of SRD5A1 suppression on cell apoptosis and autophagy. Mechanistically, SRD5A1 downregulation simultaneously regulated both the Bcl-2 family protein-mediated apoptosis and the autophagic process via PI3K/Akt/mTOR signaling pathway in MM cells. Meanwhile, the autophagy inhibitor (3-methyladenine) and SRD5A1 inhibitor (Dutasteride) were utilized to evaluate their anti-myeloma effect. Thus, our results demonstrated that SRD5A1 downregulation simultaneously regulated both the apoptosis and the autophagic process in MM cells. The dual autophagy–apoptosis regulatory SRD5A1 may serve as a biomarker and potential target for MM progression and prognosis.

Value of Neutrophil/Lymphocyte Ratio and Monocyte/Lymphocyte Ratio in the Prognosis of Patients with Multiple Myeloma

To investigate the effect of neutrophil/lymphocyte ratio (NLR) and monocyte/lymphocyte ratio (MLR) in the valuation prognosis of patients with multiple myeloma (MM). The clinical data of 82 patients with initially diagnosed MM admitted to Gansu Provincial People's Hospital was analyzed retrospectively. NLR and MLR were calculated based on blood routine results respectively. The optimal cut-off point of NLR and MLR was determined according to the ROC curve, and the patients were divided into the high NLR/MLR group and the low NLR/MLR group. The general data, biochemical indicators and prognosis of the patients in each groups were compared respectively. The prognostic significance of the high NLR/MLR group and the low NLR/MLR group in patients between different treatment regimens and different clinical characteristics were analyzed. Risk stratification was designed based on NLR and high MLR as two risk factors, and the effect of risk factors, on the prognosis of MM patients were compared. ROC curve analysis determined that the optimal cut-off point of NLR was 3.1 (sensitivity 75%, specificity 70.7%) and the optimal cut-off point of MLR was 0.34 (sensitivity 83.3%, specificity 53.4%). The lactate dehydrogenase (LDH) and mean platelet volume (MPV) were correlated to NLR and MLR (P<0.05). There were no significant difference in age, sex, serum calcium (Ca), β 2-microglobulin (β 2-MG), albumin (Alb), hemoglobin (Hb), platelet (PLT), serum creatinine (Cr), bone marrow plasma cell ratio and ISS stage between the two groups (P>0.05). The OS rate of patients with higher NLR and MLR was lower than those with low NLR and MLR and showed poor prognosis; Further analysis showed that there were statistically significant differences in OS time among patients with different MLR and NLR in the new drug treatment group and the traditional chemotherapy group, as well as patients in different age stratification groups, different β 2-MG stratification groups and different serum creatinine stratification groups. Patients with 2 risk factors showed a poorer prognosis than those with 0-1 risk factor. Elevated NLR and MLR are associated with poor prognosis in MM patients and may serve as the cost-effective and readily available prognostic biomarkers.

Prognostic Value of R-ISS Staging Combined with "Multiple-Hits" in Patients with Multiple Myeloma

To analyze the prognostic value of R-ISS staging combined with "Multiple-Hits" in patients with multiple myeloma (MM), and to detected the effect of different "Multiple- Hits" combinations to the prognosis of the patients. The 220 MM patients treated in the hematology department of People's Hospital of Xinjiang Uygur Autonomous Region from April 2013 to October 2019 were enrolled and retrospective analyzed. All the patients were detected by FISH. The effects of R-ISS staging combined with "Multiple-Hits" and different "Multiple-Hits" combinations to the prognosis of the patients were compared. For the patients at R-ISS stage II and III, the median progression-free survival (PFS) time, overall survival (OS) time and duration of response (DOR) time in "Multiple-Hits" patients were all shorter than those without high-risk cytogenetic abnormality (HRCA) and those with only one type of HRCA (P<0.05), while the TTR (time to response) was significantly prolonged (P<0.05). For the prognosis of the patients among the three different "Multiple-Hits" combinations(1q21+ combined with del(17p), 1q21+ combined with t(14;16) and combined 1q21+ combined with t(4;14)), 1q21+ combined with del(17p) showed the worst prognosis. The patients with Different "Multiple-Hits" combinations shows different prognosis. The R-ISS staging combination with "Multiple-Hits" is more conducive to accurately judging the prognosis of MM patients.

Clinical Analysis of 46 Cases of Multiple Myeloma with Extramedullary Disease

To investigate the effect of clinical baseline data on prognosis in patients with multiple myeloma (MM) complicated by extramedullary disease (EMD). The clinical data of 46 MM patients with EMD were retrospectively analyzed. The clinical data and survival prognosis of MM patients in primary EMD group and recurrent EMD group were analyzed. The classified baseline data were expressed by the number of cases (percentage), the χ2 test was used to compare the two classification data groups. The OS and PFS curves were drawn by multiplication positive limit method (Kaplan-Meier). Log-rank test was used for the univariate analysis of prognosis, and COX proportional risk regression model was used for the multiple factors of prognosis. β 2 microglobulin≥2.7 g/L, lactic dehydrogenase≥250 U/L, serum calcium≥2.75 mmol/L, plasma cells in bone marrow≥60% were the poor prognostic factors for PFS. Serum calcium≥2.75 mmol/L and the plasma cells in bone marrow≥60% were the poor prognostic factors for OS. Multivariate regression analysis enroling the statistically significant factors in univariate analysis baseline date in factors in showed that plasma cell level≥60% in bone marrow was independent poor prognostic factors for PFS, and serum calcium≥2.75 mmol/L was an independent poor prognostic factor for OS. The IgG type is the most common type of MM complicated by EMD. The remission depth of primary EMD group≥VGPR was lower than that of recurrent EMD group, and there was significant difference between the two groups (P<0.05), and the median OS time of patients with primary EMD group was shorter than that of patients with recurrent EMD group, the difference was statistically significant (P<0.05). The 3-year survival rates of primary EMD group and recurrent EMD group were 10.0% and 34%, respectively, there was no significant difference between the two groups (P>0.05). The 5-year survival rate was 0 and 20%, respectively, there was significant difference between the two groups (P<0.05). The remission depth of primary EMD group≥VGPR is lower than that of recurrent EMD group，and the OS time of patients in primary EMD group is shorter than that in recurrent EMD group. Bortezomib-based chemotherapy could not improve the prognosis of patients with primary EMD and recurrent EMD, and the prognosis of patients with primary EMD is even worse.

Exosomal mRNAs and lncRNAs involved in multiple myeloma resistance to bortezomib.

The bone marrow microenvironment plays an essential role in multiple myeloma (MM) progression. We aimed to explore the alterations of levels of long noncoding RNAs and messenger RNAs (mRNAs), derived from exosomes in peripheral blood, in resistance to bortezomib (Btz) of MM patients. Peripheral blood samples were collected from five Btz‐resistant and five Btz‐sensitive MM patients. Exosomes in patients' peripheral blood were enriched, and the profiles of long noncoding RNAs (lncRNAs) and mRNAs in exosomes were determined using deep sequencing. Bioinformatics analysis was performed to explore biological function. MTS was employed to determine the viability of Roswell Park Memorial Institute (RPMI) 8226 and LP‐1 cells incubated with exosomes derived from Btz‐resistant patients. Quantitative polymerase chain reaction (qPCR) was used to evaluate the levels of exosomal FFAR1, SP9, HIST1H2BG, and ITIH2. Incubation with Btz‐resistant patient‐derived exosomes significantly increased the viability of Btz‐treated RPMI 8226 and LP‐1 cells in a dose‐dependent manner. We identified 482 lncRNAs and 2099 mRNAs deregulated in exosomes of the Btz‐resistance group; and 78 mRNAs were enriched in DR‐related pathways, including mammalian target of rapamycin, platinum drug resistance, and the cAMP and phosphoinositide 3‐kinase–Akt signaling pathways. qPCR results verified the increases in FFAR1 and SP9 and decreases in HIST1H2BG and ITIH2 in Btz‐resistant patient‐derived exosomes. Moreover, exosomal FFAR1 and SP9 exhibited potential as independent prognostic indicators of survival of MM patients. Our study reveals significant dysregulation of exosomal RNA components in the Btz‐resistant group of MM patients as well as several mRNAs that may be used as biomarkers of prognosis of MM patients that are resistant to Btz.

Activation of Serum/Glucocorticoid Regulated Kinase 1/Nuclear Factor-κB Pathway Are Correlated with Low Sensitivity to Bortezomib and Ixazomib in Resistant Multiple Myeloma Cells

Multiple myeloma (MM) is an incurable malignancy often associated with primary and acquired resistance to therapeutic agents, such as proteasome inhibitors. However, the mechanisms underlying the proteasome inhibitor resistance are poorly understood. Here, we elucidate the mechanism of primary resistance to bortezomib and ixazomib in the MM cell lines, KMS-20, KMS-26, and KMS-28BM. We find that low bortezomib and ixazomib concentrations induce cell death in KMS-26 and KMS-28BM cells. However, high bortezomib and ixazomib concentrations induce cell death only in KMS-20 cells. During Gene Expression Omnibus analysis, KMS-20 cells exhibit high levels of expression of various genes, including anti-phospho-fibroblast growth factor receptor 1 (FGFR1), chemokine receptor type (CCR2), and serum and glucocorticoid regulated kinase (SGK)1. The SGK1 inhibitor enhances the cytotoxic effects of bortezomib and ixazomib; however, FGFR1 and CCR2 inhibitors do not show such effect in KMS-20 cells. Moreover, SGK1 activation induces the phosphorylation of NF-κB p65, and an NF-κB inhibitor enhances the sensitivity of KMS-20 cells to bortezomib and ixazomib. Additionally, high levels of expression of SGK1 and NF-κB p65 is associated with a low sensitivity to bortezomib and a poor prognosis in MM patients. These results indicate that the activation of the SGK1/NF-κB pathway correlates with a low sensitivity to bortezomib and ixazomib, and a combination of bortezomib and ixazomib with an SGK1 or NF-κB inhibitor may be involved in the treatment of MM via activation of the SGK1/NF-κB pathway.