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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, This study used SEER databases to analyze the prognostic system of solitary plasmacytoma of bone. The results showed that age ≤65 years and being male were associated with better outcomes. The widowed individuals had significantly inferior survival than the others. In addition, the use of surgery was significantly associated with improved survival.

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.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.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.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.

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

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.

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.

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 G(0)/G(1) 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.

Bone destruction is a major complication of multiple myeloma (MM). Healthy bone is constantly remodeled through bone resorption by osteoclasts and bone formation by osteoblasts. New bone formation in MM is virtually non-existent, because differentiation of osteoblasts is inhibited by DKK1, a Wnt-β-catenin signaling inhibitor secreted by MM cells, reported by our group in NEJM, 2003. MM in its early stages is totally dependent on its microenvironment and for the hyperdiploid type MM this dependence is perpetual. Based on concordant gene expression signatures, predominantly driven by recurrent translocations and hyperdiploidy, we have classified MM into 7 distinct molecular entities. One subgroup, with significantly less bone disease and superior event-free and overall survival following high-dose therapy and stem cell transplantation than the other subgroups, defined as the Low Bone (LB) disease subgroup. Consistent with the LB phenotype, we have observed a strong inverse correlation between DKK1 and CST6 expression and by analyzing gene expression profiling (GEP) and RNA-sequencing data of more than 1,000 myeloma patients, we identified CST6 as the most upregulated gene in the LB subgroup. The aim of the present study was to determine the role of Cystatin E/M (CST6) in MM biology and to apply this knowledge to prevent both bone disease and MM cell growth. CST6, a 14-17 kD secretory protein, is a lysosomal protease inhibitor and suggested tumor suppressor gene. We showed that overexpression of CST6 in human MM cell lines prevents MM cell growth in vitro and in vivo. Also, purified CST6 protein from conditioned media of CST6-overexpressing MM cells significantly inhibits MM cell growth (p Disclosures van Rhee: CDCN: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy; Adaptive Biotech: Consultancy; EUSA: Consultancy.

Background Iron is an essential element for cell growth, including cancer cells, and is present in the microenvironment. We have shown that multiple myeloma (MM) cells have abnormal iron metabolism and harbor increased intracellular iron. However, the mechanism by which MM cells retain iron has remained largely elusive. Methods Expression and clinical relevance of the transferrin receptor in MM samples were analyzed in publicly available microarray and RNA-sequencing databases. Macrophages were isolated from C57BL/6J mice and were induced to specific subtypes by cytokines or culturing with MM cells. The 5TGM1-KaLwRij MM mice were used to confirm whether MM cells induce macrophage polarization in vivo. Specific subtypes of macrophage and transferrin receptor expression in MM cells were assessed by flow cytometry. Expression of ferroportin (FPN1) and ferritin in MM cells and/or macrophages were analyzed by Western blots. Single-cell RNA-sequencing (scRNA-seq), RNA-seq, and gene expression profiles (GEPs) were employed to identify ferroportin-signaling pathways in both tumor cells and macrophages of primary human MM samples. Results MM cells induced polarization with a significant increase of CD38+CD206- M1 macrophages both in vitro and in vivo. We also confirmed that the tumor associated macrophages (TAMs) were increased in the 5TGM1-KaLwRij MM mice. MM cells upregulated ferroportin expression in macrophages to provide iron to MM cells in co-culture studies and in vivo models. The transferrin receptor antibody treatment prevented MM cells from taking up iron from macrophages. scRNA-seq identified a subset of FPN1+ TAMs in human bone marrow aspirates, which are assumed to provide iron to MM cells. Using RNA-seq and GEPs analyses in primary human samples, multiple signaling pathways were differentially modulated in FPN1+ versus FPN1- TAMs, including those related to inflammation and apoptosis Conclusions Increased expression of the transferrin receptor in MM cells strongly suggests that tumor cells take up iron from its environment. MM cells promote intracellular iron mobilization in macrophages, which provide iron to MM cells in a transferrin-dependent manner. Blockade of iron trafficking between MM cells and macrophages might be a promising approach to MM therapy. Disclosures van Rhee: EUSA: Consultancy; CDCN: Consultancy; Karyopharm: Consultancy; Adaptive Biotech: Consultancy; Takeda: Consultancy.

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. Electronic supplementary material The online version of this article (10.1186/s12964-018-0280-8) contains supplementary material, which is available to authorized users.

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.

Table1. Correlations of clinical parameters with serum calcium in 90 MM patients. (DOCX 17 kb)

Cereblon (CRBN), Ikaros (IKZF1), Aialos (IKZF3) and multiple myeloma oncogene 1 (MUM1) are important component of CRBN signaling pathway when treat MM cells with IMiDs. CRBN interacts with the DNA damage-binding protein-1 (DDB1), Cullin 4 (Cul4A or Cul4B) and regulator of Cullins 1 (ROC1) to form the functional E3 ubiquitin ligase complex (E3ULC). CRBN increases the interaction between E3ULC and IKZF1/3, leading to increased ubiquitination degradation of IKZF1/3, and then induce cytotoxicity in myeloma cells. Subsequently, degradation of IKZF1/3 induce depression of multiple myeloma oncogene 1 (MUM1), which is also called interferon regulatory factors (IRF4) and proved to be involved in the anti-MM activity of IMIDs in previous studies. Immunohistochemical (IHC) staining may be a convenient approach for researchers to differentiate the myeloma cells and non-myeloma cells in BM samples. In this study, we evaluated CRBN, IKZF1/3 and MUM1 expression level in bone marrow (BM) by immunohistochemical (IHC) staining and investigated the relationship between expression level and treatment outcome after IMiDs-based or bortezomib-based therapy in 123 newly diagnosed multiple myeloma (NDMM) patients. H-score method was applied according to both intensity and extent of staining. The intensity was graded from 0 to 3("0"for absent staining, "1" for weak expression, "2" for intermediate expression, and "3" for strong expression of the protein). The extent was graded from "0" to "100" to represent the percentage of MM cells with positive staining of any intensity. H-score was obtained by multiplying the intensity and extent score, ranging from 0 to 300, which reflected protein expression level in MM cells. The median H-score of CRBN, IKZF1, IKZF3 and MUM1 were 200, 0, 180 and 180, respectively. According to the median H-score, we classified the patients into high or low expression group. One hundred and twenty-three NDMM patients were enrolled in this study, including 64 males (52.0%) and 59 females (48.0%). The median age was 60 years (range 34-84). Fifty-one patients (41.5%) received IMiDs-containing regimen as the first-line therapy. The median follow-up time was 24.0 months (range, 10-76 months). After treated with IMiDs, patients with high level of CRBN and MUM1 achieved better overall response rate (ORR) than those expressed low level (CRBN, 88.0% vs. 42.3%, P=0.001; MUM1, 83.3% vs. 48.1%, P=0.009). Besides, patients with CRBN and MUM1 overexpression also had better overall survival (median OS, CRBN, not reached vs. 21.0 months, P=0.004; MUM1, not reached vs. not reached, P=0.021) and progression free survival (median PFS, CRBN, 28.0 vs. 12.0 months, P=0.002; MUM1, 32.0 vs. 12.0 months, P Disclosures No relevant conflicts of interest to declare.