Low serum total cholesterol levels predict inferior prognosis of patients with POEMS syndrome.

Low serum cholesterol levels are associated with increased tumor morbidity and mortality. However, the relationship between serum lipid profile and POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) is still unclear. The aim of our study was to clarify the importance of the serum lipid profile in predicting the severity and prognosis of patients with POEMS syndrome. Forty-three patients with newly diagnosed POEMS syndrome admitted to the Department of Hematology of Jiangsu Provincial People's Hospital between August 2013 and February 2023 were selected. They had explicit serum lipid profiles. There were 27 males and 16 females with a median age of 54 years (range, 28-77 years). Survival curves were plotted using the Kaplan-Meier method, and comparisons between the two groups were performed using the log-rank test. The Cox proportional-hazards model examined risk factors associated with the prognosis of POEMS syndrome. Receiver-operator characteristic (ROC) curves assessed the predictive accuracy. 23 (53.5%) patients had low total cholesterol (TC) levels. Low levels of TC were concerned with unfavorable progression-free survival (PFS) (p = 0.007) and overall survival (OS) (p = 0.004), and at the same time, the low circulating TC concentration was an independent risk factor for PFS (p = 0.020) and OS (p = 0.011). Low TC values could improve the risk stratification, especially in high-risk patients. In conclusion, low serum TC levels may predict inferior prognosis in patients with POEMS syndrome; in future clinical application, low TC may be a reliable indicator of prognosis.

Survival trends and prognostic factors of patients with newly diagnosed multiple myeloma accompanied with extramedullary disease.

Background: Extramedullary disease (EMD) is an unusual event in patients with MM. This study aimed to assess the prognostic impact of EMD and develop an EMD-based risk model to estimate the survival of patients with newly diagnosed multiple myeloma (NDMM).Methods: A total of 518 patients were enrolled in this study, of which 121 presented with EMD at the initial diagnosis. Patients were divided into non-EMD, extramedullary-bone-related (EM-B) and extramedullary-extraosseous (EM-E) groups. Clinical characteristics were compared using the chi-squared test or Fisher's exact test. Survival curves were plotted using the Kaplan-Meier method, and a nomogram was constructed based on the Cox proportional hazards model.Results: Compared to patients without EMDs, patients with EM-E were younger (p = 0.028), and those with EM-B had less renal damage (p < 0.001). The EM-E group had the worst progression-free survival (PFS) and overall survival (OS). In addition, patients with multiple sites of EMD invasion or high Ki67 expression had poor OS. Lenalidomide-based treatment showed the worst outcome, and autologous stem cell transplantation (ASCT) remarkably improved the survival of patients with EMD. A prognostic model (MM prognostic index, MM-PI) comprising lactate dehydrogenase (LDH), circulating plasma cells (CPC), del(17p), and type of extramedullary involvement was developed, and a 4-factor nomogram.Conclusions: We established a risk model incorporating extramedullary disease that provides accurate and individualized survival estimates for patients with NDMM.

Single-cell transcriptomic atlas throughout anti-BCMA CAR-T therapy in patients with multiple myeloma.

Introduction: The emergence of chimeric antigen receptor (CAR)-T therapy targeting B cell maturation antigen (BCMA) has improved the prognosis of patients with multiple myeloma (MM); however, the majority of patients eventually experience relapse. Methods: In this study, employing the latest single-cell RNA sequencing technology, we examined 24 bone marrow or peripheral blood samples collected throughout the course of anti-BCMA CAR-T therapy, analyzing a total of 59,725 bone marrow cells and 72,479 peripheral blood cells. Results: Our findings reveal that tumor cells in relapsed patient exhibit higher expression levels of HSP90B1 and HSPA5, and demonstrate significantly enriched pathways regarding endoplasmic reticulum stress and unfolded protein response. In the analysis of T cells, we observed that patient with impaired effector function and increased expression of immune checkpoints in endogenous T cell are more susceptible to relapse. Notably, T cells from both the bone marrow microenvironment and peripheral blood share highly similar biological characteristics. Discussion: Overall, this study provides a comprehensive atlas of endogenous immune cells, particularly in the relatively long term, after CAR-T therapy. It offers clinical evidence for a deeper understanding of the internal environment post CAR-T treatment and for identifying mechanisms underlying relapse.

Survival trends and prognostic factors for patients with extramedullary plasmacytoma: A population-based study.

Background: Extramedullary plasmacytoma (EMP) is a localized plasma cell neoplasm that originates from tissues other than bone. The survival trends and prognostic factors of patients with EMP in recent years remain unreported. Methods: We used the SEER databases to extract the data. Survival curves were calculated using the Kaplan-Meier method and a nomogram was created based on the Cox's proportional hazards model. Results: A total of 1676 cases of EMP were identified. Patients in period-2 (2008-2016) show similar survival (p=0.8624) to those in period-1(1975-2007). Age, gender, race, and sites were prognostic of patient outcomes. And the use of surgery was associated with improved survival. The patients were randomly assigned to the training cohort and the validation cohort in a ratio of 2:1. Four factors including age, gender, race, and sites were identified to be independently predictive of the overall survival of patients with EMP. A prognostic model (EMP prognostic index, EMP-PI) comprising these four factors was constructed. Within the training cohort, three risk groups displayed significantly different 10-year survival rates: low-risk (73.0%, [95%CI 66.9-78.2]), intermediate-risk (39.3%, [95%CI 34.3-44.3]), and high-risk (22.6%, [95%CI 15.3-30.9]) (p<0.0001). Three risk groups were confirmed in the internal validation cohort. We also constructed a 5-factor nomogram based on multivariate logistic analyses. Conclusion: The survival of patients with EMP did not improve in recent years. The EMP-PI will facilitate the risk stratification and guide the risk-adapted therapy in patients with EMP.

LncRNA MEG3 promotes the sensitivity of bortezomib by inhibiting autophagy in multiple myeloma.

BACKGROUND: Bortezomib resistance hampers the long-term survival of multiple myeloma (MM) patients. Our previous study has proved that downregulated lncRNA MEG3 is associated with the poor clinical outcome in MM. However, the effect of MEG3 on the sensitivity of bortezomib in MM and its possible molecular mechanism remains muddled. METHODS: In this study, CCK8 and flow cytometry techniques were used to assess cell viability in MEG3 overexpressed MM cells after bortezomib treatment. The expression of autophagy-related protein LC3 and p62 were distinguished by Western blot, and the mCherry-GFP-LC3 puncta reflecting autophagy level was observed under fluorescence microscope. RNA immunoprecipitation (RIP) technology was used to detect the binding relationship of MEG3 and ATG2B to PTBP1. RESULTS: Increased toxicity of bortezomib and diminished autophagy level were found in MEG3 overexpressed MM cells. Mechanistically, we discovered that RNA-binding protein PTBP1 could bind to MEG3 and ATG2B by RIP assay. Upregulation of MEG3 promoted PTBP1 expression and inhibited the expression level of ATG2B, suggesting that MEG3 recruited PTBP1 and then decayed ATG2B expression. CONCLUSION: In summary, our study illustrated that MEG3 increased bortezomib sensitivity by hindering autophagy through the PTBP1/ATG2B axis, providing a new therapeutic target for bortezomib-resistant MM patients.

Identification of clinical implications and potential prognostic models of chromatin regulator mutations in multiple myeloma.

BACKGROUND: With the rapid development of next-generation sequencing (NGS) technologies, researchers are making efforts to reveal the genomic landscape of multiple myeloma (MM). However, the clinical significance of many mutations remains poorly defined due to the genetic heterogeneity of MM. To systematically explore the clinical implications of gene mutations and build practical prognostic models, we performed DNA sequencing in newly diagnosed MM patients. METHODS: MM cells were purified from bone marrow aspirates using CD138 microbeads and subjected to sequencing with a 387-gene Panel. Nomogram was developed using Cox's proportional hazards model, and candidate variables were screened by stepwise regression. Internal validation was carried out by the bootstrap method. RESULTS: Between July 2016 and December 2020, a total of 147 patients were included in our study. We found patients with a higher mutational load had a significantly shorter progress-free survival (PFS) (19.0 vs. 32.0 months, P = 0.0098) and overall survival (OS) (3-year OS rates were 66.1% and 80.0%, P = 0.0290). Mutations in chromatin regulators (CRs) including KMT2C (14.3%), KMT2D (14.3%), EP300 (11.6%) and ARID gene family (31.3%) were highly frequent in newly diagnosed MM patients. Interestingly, proteins encoded by these genes could form a complex called KMT2C/D COMPASS (KCDCOMs). Patients with mutations of ARID gene family had a significantly shorter PFS (15.5 vs. 34.0 months, P = 0.0003) and OS (3-year OS rates were 64.9% and 81.0%, P = 0.0351) than patients without ARID gene mutations. Incorporating ARID gene mutations into the current staging system could successfully improve their prognostic performance. The PFS and OS nomogram models (including 1q21 copies, ARID gene mutations, extramedullary disease, mutational load and TP53 mutations) showed good predicting performance in both training and validation sets. CONCLUSION: Our findings emphasized the importance of CRs mutations in newly diagnosed MM patients and indicated the mutations affecting KCDCOMs might promote the development of MM. High mutational load and harboring mutations in the ARID gene family were novel predictors of adverse prognosis in MM. Prognostic models based on gene mutations were commendably prognostic evaluation methods that could provide a reference for clinical practices.

Baohuoside I Inhibits Tumor Angiogenesis in Multiple Myeloma via the Peroxisome Proliferator-Activated Receptor γ/Vascular Endothelial Growth Factor Signaling Pathway.

Angiogenesis plays an important role in the development of multiple myeloma (MM). Baohuoside I (BI) is a core flavonoid monomer with anticancer property. However, the mechanism of BI on MM-stimulated angiogenesis has not been revealed. In this study, we demonstrated that BI inhibits MM-induced angiogenesis in vitro and angiogenesis in a xenograft mouse model in vivo. We further showed that peroxisome proliferator-activated receptor γ (PPARγ) transcriptional activity was mediated by a direct physical association between BI and PPARγ. Meanwhile, inhibition of PPARγ using lentivirus transfection of shRNA in human myeloma cell lines showed that the facilitation of PPARγ blocked angiogenesis and PPARγ repressed vascular endothelial growth factor (VEGF) transcription. Furthermore, BI treatment decreased VEGF expression, whereas VEGF expression remained unchanged after PPARγ knockdown when exposed to BI. Overall, our study is the first to reveal that BI inhibits MM angiogenesis by the PPARγ-VEGF signaling axis.

Comprehensive meta-analysis of anti-BCMA chimeric antigen receptor T-cell therapy in relapsed or refractory multiple myeloma.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy shows impressive results in clinical trials. We conducted a meta-analysis based on the most recent data to systematically describe the efficacy and safety of anti-BCMA CAR T therapy for patients with relapsed or refractory multiple myeloma (R/R MM). METHODS: PubMed, Embase, Web of Science, Cochrane library, ClinicalTrials.gov, China Biology Medicine disc (CBM disc) and Wanfang Data were searched on 8 November 2020. Registration number of PROSPERO was CRD42020219127. RESULTS: From 763 articles, we identified 22 appropriate studies with 681 patients. The pooled overall response rate (ORR) was 85.2% (95%CI 0.797-0.910), complete response rate (CRR) was 47.0% (95%CI 0.378-0.583), and minimal residual disease (MRD) negativity rate was 97.8% (95%CI 0.935-1.022). The pooled incidence of grade 3-4 cytokine release syndrome was 6.6% (95%CI 0.036-0.096) and neurotoxicity was 2.2% (95%CI 0.006-0.038). The median progression-free survival (PFS) was 14.0 months and median overall survival (OS) was 24.0 months. Subgroup analysis showed dual epitope-binding CAR T cells achieved the best therapy outcomes and humanized CAR T cells had the best safety profile. Patients who were older, heavily pre-treated or received lower dose of CAR T cells had worse ORR. There was no significant difference in ORR, CRR and PFS between patients with and without high-risk cytogenetic features. The PFS and CRR of non-extramedullary disease (EMD) group was superior to those of EMD group. CONCLUSION: Anti-BCMA CAR T therapy is effective and safe for patients with R/R MM. It can improve the prognosis of patients with high-risk cytogenetic features while the prognosis of patients with EMD remains poor. Moreover, patients are likely to benefit from an earlier use of CAR T therapy and human-derived CAR T cells have obvious advantages based on the existing data.

Anti-tumor activity of a novel proteasome inhibitor D395 against multiple myeloma and its lower cardiotoxicity compared with carfilzomib.

Carfilzomib, a second-generation proteasome inhibitor, has significantly improved the survival rate of multiple myeloma (MM) patients, but its clinical application is still restricted by drug resistance and cardiotoxicity. Here, we identified a novel proteasome inhibitor, D395, and assessed its efficacy in treating MM as well as its cardiotoxicity at the preclinical level. The activities of purified and intracellular proteasomes were measured to determine the effect of D395 on the proteasome. CCK-8 and flow cytometry experiments were designed to evaluate the effects of D395 on cell growth and apoptosis. The effects of D395 and carfilzomib on serum enzyme activity, echocardiography features, cardiomyocyte morphology, and hERG channels were also compared. In our study, D395 was highly cytotoxic to MM cell lines and primary MM cells but not normal cells, and it was well tolerated in vivo. Similar to carfilzomib, D395 inhibited osteoclast differentiation in a dose-dependent manner. In particular, D395 exhibited lower cardiotoxicity than carfilzomib in all experiments. In conclusion, D395 is a novel irreversible proteasome inhibitor that has remarkable anti-MM activity and mild cardiotoxicity in vitro and in vivo.

Survival trends and prognostic factors in patients with solitary plasmacytoma of bone: A population-based study.

Solitary plasmacytoma of bone (SPB) is a single, isolated plasmacytoma originated from the bone. The survival trends of patients with SPB in recent years remain unknown. And the prognostic system of SPB may also need to be refined. The 18 Surveillance, Epidemiology, and End Results (SEER) databases of the National Cancer Institute in the United States were used to extract data for this study. The third edition of the International Classification of Disease for Oncology (ICD-O-3) code 9731 was used to identify cases of SPB. For each case, factors including age at the time of diagnosis, sex, race, marital status, insurance status, primary sites of tumors, and the use of surgery were collected. The outcomes of patients with SPB were compared between two groups. And the prognostic impacts of baseline characteristics and use of surgery was studied. A total of 4103 (from 1976 to 2016) cases of SPB were identified. The median age was 65 years old. Patients in time period-2 (2008-2016) show better survival as compared to those in time period-1(1976-2007) (median overall survival: 88 months vs. 73 months, p = 0.0332). Age ≤ 65 years and being male were associated with better outcomes. The widowed individuals had significantly inferior survival and myeloma-specific survival than the single, married, or divorced individuals (p values all <0.0001). Patients with lesions in bones of skull and face and associated joints had longer survival as compared with those with bone lesions in other sites (median overall survival: 107 months vs. 79 months, p = 0.0694). The use of surgery was significantly associated with improved survival (median survival: surgery performed 98 months vs. not performed 73 months, hazards ratio [HR]: 0.7623, 95% CI: 0.7009-0.8472; p < 0.0001) and myeloma-specific survival (median myeloma-specific survival: surgery 160.0 months vs. no surgery 143.0 months, HR: 0.8469, 95% CI: 0.7493-0.9572; p = 0.0078). Multivariable analysis revealed that surgery, marital status, and age were independent prognostic factors for overall survival in patients with SPB. The improvement in the survival of patients with SPB has been observed in recent years. And several potential prognostic factors were identified. Future prospective studies are warranted to explore the roles of novel agents, surgery, and systemic chemotherapy in the treatment of SPB.

Promoter hypermethylation influences the suppressive role of long non-coding RNA MEG3 in the development of multiple myeloma.

Methylation is a fundamental regulator of gene transcription. Long non-coding RNA maternally expressed 3 (MEG3) inhibits cell proliferation in various types of cancer. However, the molecular mechanisms of MEG3 methylation in the regulation of multiple myeloma (MM) are unknown. In the present study, MEG3 upregulation was negatively associated with the International Staging System (ISS) status of the bone marrow samples of 39 patients with MM. MEG3 overexpression in an MM cell line resulted in elevated p53 expression. Furthermore, the results of methylation-specific PCR revealed that the abnormal methylation status of the MEG3 promoter region was present in eight of the 39 bone marrow samples collected. Treatment of the MM cell line with the DNA methylation inhibitor 5-Aza-2'-deoxycytidine (5-Aza-CdR) resulted in tumor cell proliferation inhibition, apoptosis induction and G0/G1 cell cycle arrest. Furthermore, 5-Aza-CdR decreased aberrant hypermethylation of the MEG3 promoter and increased the expression of MEG3. However, 5-Aza-CdR exerted no effect on p53 expression. To the best of our knowledge, the present study is the first to report that the demethylation reagent 5-Aza-CdR may serve as a therapeutic agent in MM by upregulating MEG3 expression. However, the mechanism of action was independent of p53 expression.

TRPV2-induced Ca2+-calcineurin-NFAT signaling regulates differentiation of osteoclast in multiple myeloma.

BACKGROUND: Myeloma bone disease (MBD) can cause bone destruction and increase the level of Ca2+ concentration in the bone marrow microenvironment by stimulating osteoclastic differentiation. Nevertheless, the relationships between MBD and highly efficient stimuli of Ca2+ in multiple myeloma (MM) progression, and possible regulatory mechanisms are poorly defined. Here, we reported that the nonselective cation channel transient receptor potential vanilloid 2 (TRPV2) plays a functional role in Ca2+ oscillations and osteoclastogenesis. METHODS: To investigate the expression of TRPV2 in MM, we analyzed publicly available MM data sets and performed immunohistochemistry in MM patients. The correlations between TRPV2 expression levels and osteoclast-related cytokines were analyzed. Fluo-4 staining and ELISA assays were used to assess the regulated function of TRPV2 in intracellular Ca2+ and cytokines. Western blotting and Chromatin immunoprecipitation (ChIP) assays were performed to explore the signaling pathway of TRPV2-induced osteoclastic differentiation. Real-time PCR, Western blotting, ELISA and tartrate-resistant acid phosphatase (TRAP) staining were performed to detect the biological effects of TRPV2 inhibitor on osteoclastogenesis. RESULTS: The functional expression of TRPV2, involved in the osteolysis through gating the calcium influx, was changed in the MM cells cultured in a high Ca2+ environment. Mechanistically, TRPV2 modulates nuclear factor-κB ligand (RANKL)-dependent osteoclastic differentiation through the Ca2+-calcineurin-NFAT signaling pathway. Of clinical relevance, systemic administration with SKF96365 could attenuate the MM-induced osteoclast formation in vitro. CONCLUSIONS: Our study uncovers the possible roles of TRPV2, which enhances MBD, suggesting that targeting osteocyte-MM cells interactions through blockade of TRPV2 channel may provide a promising treatment strategy in MM.

Long Non-Coding RNA MEG3 Functions as a Competing Endogenous RNA to Regulate HOXA11 Expression by Sponging miR-181a in Multiple Myeloma.

BACKGROUND/AIMS: Long non-coding RNA maternally expressed gene 3 (MEG3) has been reported to play an essential role in cancer progression and metastasis. However, the overall biological role and regulatory mechanism of MEG3 in multiple myeloma (MM) development and progression remains largely ill-defined. METHODS: MEG3 and miR-181a expression of MM patients were analyzed by publicly available MM data sets. Cell counting kit-8 and flow cytometry analysis were used to identify the function of MEG3 on MM in vitro. Additionally, we conducted tumor formation experiments in mice models to explain the role of MEG3 on MM in vivo. Then, several mechanism experiments, including dual-luciferase reporter assay and RNA immunoprecipitation were performed to evaluate the emulative relationship between MEG3 and miR-181a. RESULTS: In this research, we found that MEG3 was downregulated in MM patients, which was linked with tumor progression. In addition, we demonstrated that miR-181a was overexpressed in MM patients in consistent with its cancer-promoting function. Importantly, several mechanism experiments revealed that MEG3, acting as an endogenous competitive RNA, could contend with miR-181a to inhibit tumor progression. Furthermore, as the target mRNA of miR-181a, homeobox gene A11(HOXA11) could be positively regulated by MEG3 through sponging miR-181a competitively in vitro. CONCLUSION: Our present work supplies the first discovery of a MEG3/miR-181a/HOXA11 regulatory network in MM and highlights that MEG3 may serve as a promising target for MM therapy in the future.