Advanced International Staging System Research Articles

Prognostic Implications of Circulating Plasma Cell Percentage in Multiple Myeloma and Primary Plasma Cell Leukemia Defined by New Criteria.

The definition of primary plasma cell leukemia (pPCL) has been revised from ≥20% to ≥5% circulating plasma cells (CPC). However, the precise prognosis associated with CPC remains controversial. This study aimed to investigate prognostic biomarkers for myeloma patients based on CPC presence. A comprehensive analysis was conducted on 309 consecutive patients diagnosed with either multiple myeloma or pPCL, utilizing peripheral blood smears stained with Wright-Giemsa. Patients were grouped by CPC percentage: 0% (221, 71.5%), 1-4% (49, 15.9%), 5-19% (16, 5.2%), ≥20% (23, 7.4%). CPC >5% correlated with unfavorable characteristics, including anemia, renal dysfunction, and advanced International Staging System. Common cytogenetic abnormalities such as 1q21 amplification, 17p deletion, and Myc rearrangement were prevalent among CPC-positive patients. Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with CPC ≥5% (29.47 vs. 10.03 months; 64.10 vs. 12.30 months). Additionally, PFS and OS were shorter in CPC-positive patients without autologous hematopoietic stem cell transplantation (ASCT) and those with response < partial remission to the first-line regimen. Furthermore, an association emerged between soft tissue-related extramedullary disease and inferior PFS, while Myc rearrangement correlated with abbreviated OS. Biological characteristics displayed greater aggressiveness in patients with positive CPC, leading to significantly shorter PFS and OS. The presence of CPC, ASCT, and overall response rate were independent prognostic factors. While no new threshold for pPCL with CPCs is proposed, Myc rearrangements and CPC positivity could serve as ultra-high-risk factors for multiple myeloma.

In the era of Bortezomib-based Induction, intensification of Melphalan-based conditioning with Bortezomib does not improve Survival Outcomes in newly diagnosed Multiple Myeloma: a study from the Chronic Malignancies Working Party of the EBMT

Bortezomib (Vel)- Melphalan 200 mg/m2 (Mel200) (Vel-Mel) has been utilised to intensify conditioning in autologous hematopoietic stem cell transplantation (AHCT) for multiple myeloma (MM). This EBMT registry-based study compared Vel-Mel with Mel200 during upfront AHCT. Between 2010 and 2017, MM patients who received Vel-Mel (n = 292) conditioning were compared with 4,096 Mel200 patients in the same 58 centres. Pre-AHCT, compared to Mel200 patients, Vel-Mel patients had similar International Staging System (ISS) scores and cytogenetic risk profiles; a similar proportion had received bortezomib-based induction (85% and 87.3%, respectively) though they were younger with a better performance status. Vel-Mel patients were more likely to achieve CR post-induction (40.6% vs 20.3%, p < 0.001) and by day 100 of AHCT (CR/VGPR: 70.2 % vs. 57.2%, p < 0.001). There was no difference in 3-year PFS (49% vs 46%, p = 0.06) or early post-AHCT mortality. In multivariable analysis, Vel-Mel associated with inferior PFS (HR: 1.69 (1.27–2.25, p < 0.001) and OS (HR:1.46 (1.14–1.86,p = 0.002), similar to negative effects on PFS of advanced ISS (HR:1.56 (1.33–1.83, p < 0.001), high-risk cytogenetics (HR:1.43(1.18–1.74, p < 0.001) and poor post-induction response(<=PR)(HR: 1.43(1.25–1.62, p < 0.001) Overall, despite superior pre- and post-AHCT responses, there was no improvement in PFS or OS following Vel-Mel. This data supports the findings of the smaller prospective IFM study.

1q21+ is associated with poor prognosis in newly diagnosed multiple myeloma patients with extramedullary disease: a retrospective study.

1q21+ is a common cytogenetic abnormality in multiple myeloma (MM) and is considered an independent predictor of poor prognosis; however, its impact on extramedullary disease (EMD) remains unknown. Our study reviewed the clinical relevance and prognostic value of 1q21+ status in 92 patients with NDMM and EMD. 1q21+ was detected in 23.9% (22/92) of patients. Patients with 1q21+ presented with advanced International Staging System stages (P = 0.006), lower level of hemoglobin (P = 0.004), higher percentage of plasma cells in the bone marrow (P < 0.001), higher level of serum β2-microglobulin (7.24g/L vs. 3.85g/L, P = 0.003), and higher levels of lactic dehydrogenase (LDH) (206.5 U/L vs. 177 U/L, P = 0.019). The prevalence of soft tissue-related EMD (EMD-S) (54.5% vs. 18.6%, P < 0.001), renal dysfunction (50.5% vs. 17.7%, P = 0.002), and hypercalcemia (27.3% vs. 7.1%, P = 0.011) was also higher. 1q21+ was strongly associated with other high-risk cytogenetic abnormalities, including IgH/FGFR3 (22.7% vs. 4.3%, P = 0.007) and IgH/MAF translocations (22.7% vs. 1.4%, P < 0.001). 1q21+ patients had significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: 24months vs. 47months, P = 0.002; PFS: 14months vs. 38months, P < 0.001); the poor survival outcomes could not be reversed by autologous hematopoietic stem cell transplantation. Multivariate analysis suggested that 1q21+ , EMD-S, elevated lactate dehydrogenase (LDH) levels, and P53 deletion were independent risk factors for poor prognosis in patients with EMD. In patients with 1q21+ EMD, hypercalcemia, elevated LDH levels, and P53 deletion were independent adverse risk prognostic factors.

1q21+ Is Associated with Poor Prognosis in Newly Diagnosed Multiple Myeloma Patients with Extramedullary Disease: A Retrospective Study

Abstract: Background: 1q21+ is a common cytogenetic abnormality in multiple myeloma (MM) and is considered as an independent factor for poor prognosis, but its impact on extramedullary disease (EMD) remains unknown. Method: In our retrospective analysis, patients who met the diagnostic criteria of IMWG and first diagnosed with EMD from January 2011 to May 2022 were enrolled in the study. EMD patients were divided into 2 subgroups: 1q21+ and 1q21- according to the FISH analysis. 1q21+ abnormality was regarded as gain of 1q21 (gain [1q21], 3 copies) and amplification of 1q21 (amp [1q21], ≥4 copies). Continuous variables were analyzed by independent-sample t test or Mann-Whitney U test and categorical variables were compared using chi-square test or Fisher's exact test. Kaplan-Meier method was applied for PFS and OS curve made and differences were evaluated by Log-rank test. Cox proportional hazard models were constructed for prognostic factors analyze. Result: Patients with 1q21+ presented with advanced International Staging System stages (stage III percentage: 68.2% vs. 30.0%, P=0.006), lower level of hemoglobin (91g/dL vs. 113.5g/dL, P=0.004), higher tumor burden (BMPC infiltration≥50% : 45.0% vs. 11.9%, P＜0.001), higher level of serum β2-microglobulin (7.24 g/L vs. 3.85 g/L, P=0.003) and lactic dehydrogenase (LDH) (206.5 U/L vs. 177 U/L, P=0.019). Higher incidence of soft tissue related EMD (54.5% vs. 18.6%, P＜0.001), renal dysfunction (50.5% vs. 17.7%, P=0.002) and hypercalcemia (27.3% vs. 7.1%, P=0.011) was also observed in 1q21+ subgroup. 1q21+ was found to be strongly associated with other high risk cytogenetic abnormalities including IgH/FGFR3 translocation (22.7% vs. 4.3%, P=0.007) and IgH/MAF translocation (22.7% vs. 1.4%, P＜0.001). Patients with 1q21+ had a significantly shorter overall survival (OS) and progression-free survival (PFS) (OS: 24 months vs. 47 months, P=0.002; PFS: 14months vs. 38months, P＜0.001), and the poor survival outcome couldn't be reversed by autologous hematopoietic stem cell transplantation (auto-HSCT). Further investigation estimated the impact of cooccurrence of 1q21+ and del17p on survival outcome. For median OS, 1q21- patients without del17p was 47 months, 1q21+ patients without del17p were 28 months, 1q21- patients with del17p was 22 months, and patients presented with both 1q21+ and del17p was 18 months (p=0.02). The median PFS for 1q21- without del17p, 1q21+ without del17p, 1q21+ with del17p was 38 months, 20 months and 6.5 months respectively, while not reached for 1q21- patients (P＜0.001). Multivariate analysis suggested 1q21+ along with EMD-S, elevated LDH level and P53 deletion were independent risk factors for poor prognosis in EMD patients. For 1q21+ EMD patients, hypercalcemia, elevated LDH level and P53 deletion were defined as independent adverse risk prognostic factors. Conclusion: Taken together, our findings emphasized that 1q21+ increased the possibility of disease progression and predicted poor survival in EMD patients. 1q21+ EMD tends to be associated with other high risk disease factors. ASCT may not overcome the adverse effect of 1q21+ in EMD patients. We suggested 1q21+ should be considered as a high-risk factor and added into routine assessment of risk stratification in EMD patients.

A Brazilian Real-Life Experience of Multiple Myeloma Patients: Final Results from the Mmybrave Multi-Center Study

Background: Despite incremental therapeutic improvements for patients (pt) with multiple myeloma (MM) over the past two decades, large discrepancies still exist worldwide in outcomes and in terms of access to novel agents and stem-cell transplantation (SCT). Moreover, the real-world effectiveness of novel therapies may not reflect pt profiles and outcomes from clinical trials. Management of MM in Brazil is subject to constraints that may impact clinical outcomes, and continual assessment of trends in treatment patterns and results in real life is warranted. Methods: The objective of MMyBRAve (NCT03506386) was to investigate the demographic and clinical characteristics, as well as the patterns of care and treatment results, for patients with MM treated at selected experienced hematology/oncology centers in Brazil. Eligible pts were aged ≥18 years and had been diagnosed with MM using contemporaneous IMWG criteria between 01/2008 and 12/2016. Demographic and clinical data were collected from institutional charts retrospectively between 06/2018 and 08/2019 using a dedicated electronic case report form. Treatment and patient evaluation were left to local standards of care. Baseline pt and disease characteristics, as well as treatment patterns, were analyzed descriptively. The overall survival (OS) was analyzed using the Kaplan-Meier method, and predictors of OS were explored using Cox proportional-hazards model. The OS was compared between subgroups defined according to selected baseline characteristics, eligibility to transplantation (Tx) at baseline, and type of institution (public vs private). Results: 17 institutions (Inst) contributed data from 943 pts, who had a mean age of 68.4 years (range, 29 to 103). Females comprised 46.3% of the pts, and 61.1% were reportedly White. Considering the 792 pts with information on immunoglobulin (Ig) isotype, 57.7% had IgG, 21.2% IgA, 16.9% light-chain only, non-secretory in 3.5%, and IgD, IgE or IgM in 0.6%. International Staging System (ISS) stage at diagnosis was I in 19.3%, II in 21.3%, III in 26.6%, and unknown in 32.8%. 491 (52.1%, 95% confidence interval [CI], 48.9% to 55.3%) pts were considered Tx-ineligible at baseline. 452 (47.9%, 95% CI, 44.7% to 51.1%) pts were considered Tx-eligible, and 250 (55.3% of 452; 95% CI, 50.6% to 60.0%) underwent Tx as part of frontline therapy. Overall, after a median follow-up of 63 months, the median OS was 70 months, with OS probabilities of 87% at 12 months, 78% at 24, 70% at 36, 62% at 48, and 55% at 60 months. Tx-ineligible pts were significantly older and had significantly higher levels of creatinine and lactic dehydrogenase (LDH), and more advanced ISS than Tx-eligible pts. Median OS times were 49 and 93 months for Tx-ineligible and Tx-eligible patients, with a hazard ratio (HR) of 0.52 favoring Tx-eligible (95% CI, 0.43 to 0.63; P<0.001). 519 pts came from public Inst, and 424 from private. The former had significantly lower levels of hemoglobin and significantly higher levels of creatinine, calcium and LDH, and more advanced ISS than pts from private Inst. Median OS in these two groups were 61 and 74 months, with a HR of 0.78 favoring pts from private Inst (95% CI, 0.64 to 0.94; P=0.010). Pts from public Inst were more likely to receive melphalan- or thalidomide-based frontline regimens, whereas those from private Inst were more likely to receive bortezomib in frontline. Other univariable baseline factors associated with OS were age, hemoglobin, creatinine, calcium, and Durie-Salmon stage. In multivariable analysis for factors associated with OS, all these remained significant, and so was Inst (HR=0.61, P=0.002). Although there was no significant difference in Tx eligibility between public and private Inst (46.1% vs 50.2%; P=0.224) or in the percentage of patients undergoing Tx (24.5% vs 29.0%; P=0.134), adding this variable to the multivariable model for OS suggested that it confounds the association between type of Inst and OS, since Tx eligibility became a stronger prognostic factor (HR=0.586, P<0.001) than type of Inst (HR=0.81, P=0.073). Conclusions: Comparing these results with those from previous studies, the OS of pts with MM is improving in Brazil. Discrepancies remain in OS for patients from public and private institutions. Although the reasons for this finding remain to be ascertained, differential access to novel therapies cannot be ruled out as a determining factor.

The utility of serum amylase as a prognostic marker in multiple myeloma.

Ectopic production of amylase by tumor cells is known since 1951. Elevated amylase in multiple myeloma (MM) was first described in 1988. It has been postulated that translocation of chromosome 1, where amylase gene is situated, is responsible for ectopic production from the malignant plasma cells. Anecdotal reports have shown hyperamylasemia in MM to be associated with extensive bone disease, rapid progression, and shorter survival. Serum amylase estimation is a ubiquitous test. This prospective study was conducted to ascertain the degree of elevated amylase, its clinical utility, and implications in MM patients. In an 18-month period, all consenting patients with newly diagnosed or relapsed MM were tested for serum amylase levels. The study excluded patients with elevated lipase, abnormal creatinine clearance, and evidence of intestinal obstruction or perforation. Patients with amylase value >100 U/L were designated to have "elevated amylase level" for the purpose of this study. We enrolled 58 patients with MM, of which 29.3% (n = 17) were found to have elevated serum amylase levels. The median age of patients with elevated amylase was 65 years. The male-to-female ratio was 1.9:1. There was no statistical association between age, gender, type of heavy chain class, light chain, or high-risk cytogenetics. Among patients with the International Staging System (ISS), Stages I, II, and III, 20.8% (n = 5), 31.3% (n = 5), and 41.2% (n = 7) were noted to have elevated amylase levels. A statistically significant association was noted between the presence of extramedullary disease (EMD) and elevated amylase level (P = 0.028). Higher mortality (29.4% versus 17%) and shorter mean survival of (30.2 ± 3.3 months versus 51.7 + 4.9 months) were recorded in patients with elevated amylase levels in comparison to those with normal levels. Elevated serum amylase level in MM is indicative of advanced ISS stage, the presence of EMD, higher risk of mortality, and shorter survival. Serum amylase can be used as a cost-effective tool in myeloma management.

H3K36 Trimethylation Mediated By SETD2 Regulates Cell Proliferation and Cell Cycle By Modulating BCMA-JNK and c-Myc Pathways in Multiple Myeloma

In addition to genetic aberrations, accumulating evidence indicates that deregulation of histone methyltransferases, such as MMSET, EZH2 and KDM6A, plays crucial roles in the oncogenic transformation and development of multiple myeloma (MM). For example, overexpression of MMSET leading to a global increase in H3K36me2, is believed to be the driving force in the pathogenesis of t (4;14) MM. However, as the histone methyltransferase is responsible for H3K36me3, the role of SETD2 is not been known in myeloma.To explore the possible clinical value of SETD2 in MM, we first examined the gene expression profile from GEO database, which indicated that the SETD2 expression was significantly decreased in MM patients when compared with monoclonal gammopathy of undetermined significance and smoldering multiple myeloma patients (GSE6477). Moreover, the expression of SETD2 decreased with the advanced international staging system stage of MM patients (GSE19784). The Kaplan-Meier analysis showed that low expression of SETD2 was significantly associated with a poor overall survival in MM patients (GSE2658, P<0.05; GSE9782, P<0.001). Thus, our analysis suggests that SETD2 might participate in cancer progression and could become a biomarker for the prognosis of patients with MM.We then investigated the biological role and the underlying mechanism of SETD2 in MM. Firstly, we used lentiviral-mediated RNA interference to knockdown SETD2 (SETD2 KD) in MM cell lines (RPMI8226 and MM.1S). CCK8 and colony-forming assays showed that reduced expression of SETD2 significantly promoted MM cell proliferation and colony growth. BrdU incorporation assay revealed increased DNA synthesis in SETD2 KD MM cells. Then, treatment with JIB-04, a small molecule inhibitor targeting H3K36me3 loss in SETD2 KD MM cells showed that H3K36me3 recovery was capable of reversing the tumor-promoting effect due to SETD2 down-regulation of MM cells in vitro. Moreover, the xenograft growth assay revealed that SETD2 down-regulation facilitated tumor growth and JIB-04 treatment exhibited anti-myeloma activity in vivo. Therefore, we conclude that SETD2 plays an important role in MM maintenance, and inhibition of H3K36me3 shows therapeutic efficacy for MM.To further explore the underlying mechanisms, we performed the RNA-Seq analysis and discovered that low H3K36me3 level was associated with reduced expression of CDKN1A and increased expression of TNFRSF17 (BCMA) and c-Myc in MM cells. The Gene Set Enrichment Analysis (GSEA) revealed that MAPK signaling pathway was enriched in SETD2 knockdown and JIB-04 treated MM cells. Subsequent Western blotting analysis further confirmed that SETD2 KD cells had increased JNK activation, while JIB-04 treated group showed decreased level of p-JNK. To investigate whether BCMA was the directly transcriptional target for H3K36me3, we carried out a dual-luciferase reporter assay in both SETD2 KD and JIB-04 treated MM cells, and confirmed that H3K36me3 inhibited the expression of BCMA through physically interacting with motifs in its promoter. Furthermore, down-regulation of BCMA in SETD2 KD MM cells could lead to a reduction of p-JNK and an up-regulation of CDKN1A, and resulting inhibited cell proliferation and cell cycle progression. Furthermore, blockage of the JNK pathway by its inhibitor SP600125 resulted in significant inhibition of MM cell proliferation induced by SETD2 knockdown. Additionally, suppression of c‐Myc using 10058‐F4 inhibited proliferation, and induced cell cycle arrest as well as CDKN1A expression in SETD2 KD MM cells. These results indicate that BCMA/JNK and c-Myc pathways were involved in STED2 and H3K36me3 mediated cell proliferation in MM.Together, our data delineate that SETD2-dependent H3K36me3 modification plays a critical role in regulation cell proliferation and cell cycle by BCMA-JNK and c-Myc pathways in MM cells. Targeting the SETD2-H3K36me3 pathway represents a promising therapy for MM. DisclosuresNo relevant conflicts of interest to declare.

CD44 Expression in Different Plasma Cell Diseases

CD44 expression in different plasma cell diseasesIntroductionMyeloma is a genetically complex disease which develops via a multistep process whereby plasma cells are driven towards malignancy through the accumulation of genetic “hits” over time. This multistep process permits myeloma to have four recognisable clinical stages including monoclonal gammopathy of undetermined significance (MGUS) , smouldering multiple myeloma (SMM) , multiple myeloma (MM) and plasma cell leukemia (PCL). CD44 as a complex adhesion molecule, is highly expressed in a variety of solid tumors and involved in metastasis and chemotherapy resistance . Previous studies had found that CD44 was also highly expressed in MM, and associated with advanced clinical stage, extramedullary myeloma (EM) and poor survival. However the relation of CD44 expression in different plasma cell disease remain unknown.Patients and MethodsNewly diagnosed MGUS (n=12), SMM (n=11), MM (n=133) and PCL (n = 8) patients who were hospitalized in our hospital from December 2017 to December 2020 were enrolled. The diagnosis was based on the criteria of the International Myeloma Working Group. CD44 was detected by flow cytometry as follows: 2 ml of heparin anticoagulated bone marrow was collected from the patients at the time of diagnosis, 1×10 6 cells were detected, and a gate was set for identifying abnormal plasma cells characterized by CD138 and CD38. CD44 positive was defined as more than 20% of the plasma cells expressed CD44.ResultsFrom December 2017 to December 2020, a total of 164 patients diagnosed in our hospital were included in the study, including 12 MGUS patients, 11 SMM patients, 133 MM patients and 8 PCL patients. The expression proportion (7.9%±11.9%, 11.2%±15.5%, 40.2%±37.7%, 81.9%±25.6%, P < 0.001) and expression intensity (the mean fluorescence intensity was 1 742.8±1 023.1, 2 915.7±923.0, 6 692.6±11 275.5, 25 359.6±22 604.5, P=0.001) of CD44 on the monoclonal plasma cells of MGUS, SMM, MM and PCL patients gradually increased. In 133 MM patients, 73 cases were for CD44 positive. CD44 positive patients were more likely to show ＞3 focal bone lesion (75.3% VS 50.0%, P=0.002), and international staging system（ISS）III stage (68.5% VS 51.7%, P=0.048) compared those with CD44 negative. CD44 expression rate was significantly higher in MM patients with extramedullary disease (n=26) than those without (n=107) (56.7%VS 36.2%, P=0.031)Conclusion: Our study showed that from MGUS, SMM, MM to PCL, the CD44 expression on abnormal plasma cells was gradually increased. CD44 overexpression was associated with osteolytic lesions, advanced ISS staging and extramedullary myeloma. The results indicated that CD44 was related to the invasion degree of plasma cell disease, and could be used as a marker for differential diagnosis between different plasma cell disease. DisclosuresNo relevant conflicts of interest to declare.

Long non-coding RNA ANRIL and its target microRNAs (microRNA-34a, microRNA-125a and microRNA-186) relate to risk stratification and prognosis in multiple myeloma

ABSTRACT Objective This study aimed to investigate the correlations of long non-coding RNA ANRIL (lncRNA ANRIL), microRNA (miR)-34a, miR-125a and miR-186 with disease risk, clinical features and prognosis of multiple myeloma (MM). Method Totally, 87 MM patients and 30 controls were recruited. LncRNA ANRIL and its target miRNAs (miR-34a, miR-125a and miR-186) in bone marrow derived plasma cells were detected by RT-qPCR. Treatment response was assessed and survivals were calculated in MM patients. Results LncRNA ANRIL expression was increased, while miR-34a, miR-125a and miR-186 expressions were reduced in MM patients compared with controls. Meanwhile, lncRNA ANRIL negatively correlated with miR-34a and miR-125a but not miR-186 in MM patients, while did not correlate with miR-34a, miR-125a or miR-186 in controls. In MM patients, lncRNA ANRIL high expression associated with higher beta-2-microglobulin (β2-MG) and more advanced international staging system (ISS) stage; miR-125a high expression associated with lower β2-MG, less advanced ISS stage and less t (14; 16) abnormality; miR186 high expression associated with increased albumin; while miR-34a did not associate with any clinical features. Furthermore, lncRNA ANRIL high expression associated with decreased complete response (CR), while miR-34a high and miR-125a high expression associated with increased CR and objective response rate. Additionally, lncRNA ANRIL high expression associated with shorter progression-free survival (PFS), while miR-34a high expression associated with prolonged overall survival (OS), and miR-125a high expression associated with longer PFS and OS. Conclusion LncRNA ANRIL and its target miRNAs might serve as biomarkers for assisting with personalized treatment and prognosis improvement of MM.

LncRNA ANRIL promotes multiple myeloma progression and bortezomib resistance by EZH2-mediated epigenetically silencing of PTEN.

Multiple myeloma (MM) is a plasma cell malignancy of bone marrow. In the present study, we aimed to study the function and potential mechanism of the antisense non-coding RNA in the INK4 Locus (ANRIL) in MM. The expression levels of ANRIL in MM patients and healthy donors were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). The effects and mechanisms of ANRIL in MM were evaluated by cell viability assay, BrdU incorporation assay, tumor xenograft model, flow cytometry, western blot, RNA immunoprecipitation (RIP), transcriptome RNA sequencing, and chromatin immunoprecipitation (ChIP). We found that ANRIL was upregulated in MM patients and cell lines, and associated with advanced international staging system (ISS) stage and poor overall survival. Enforced ANRIL expression promoted proliferation and tumor xenograft growth of MM cells, while knockdown of ANRIL exhibited opposite effects. Moreover, ANRIL overexpression increased the half-maximal inhibitory concentration (IC50) of bortezomib and reduced bortezomib-induced apoptosis in MM cells. ANRIL was found to accumulate in the nuclei of MM cells, and interact with EZH2 by RIP assay. Transcriptome RNA sequencing identified PTEN as a target of ANRIL in MM cells. In the ChIP assay, knockdown of ANRIL reduced EZH2 occupancy and H3K27me3 binding to the promoter region of PTEN. Furthermore, EZH2 knockout or PTEN restoration abrogated the effects caused by ANRIL overexpression in MM cells. Our results indicated that ANRIL exerted oncogenic functions and conferred chemoresistance of MM cells by EZH2-mediated epigenetically silencing of PTEN.

The Prevalence of Euthyroid Hypertriiodothyroninemia in Newly Diagnosed Multiple Myeloma and its Clinical Characteristics

ObjectiveTo evaluate the prevalence of euthyroid hypertriiodothyroninemia and/or hyperthyroxinemia and its clinical characteristics in multiple myeloma (MM) patients. MethodsPreviously untreated, newly diagnosed patients with MM were enrolled at the Beijing Chao-yang Hospital between January 2016 and December 2019. Thyroid function and clinical characteristics were analyzed. ResultsA total of 105 patients were enrolled in this study. Thirteen (12.38%) patients exhibited euthyroid hypertriiodothyroninemia with strikingly elevated total triiodothyronine (TT3) levels (>8 ng/mL). Among these 13 patients, 12 patients were immunoglobulin (Ig) G type (92.31%), and 1 patient was light-chain κ type (7.69%). Compared with other patients with MM, patients with hypertriiodothyroninemia were more likely to be IgG type and had higher serum globulin and lower albumin levels and more advanced International Staging System stage (all P < .05). Among the 13 euthyroid hypertriiodothyroninemia patients, 8 patients have been followed up and checked for thyroid function. The TT3 levels in all 8 patients were normalized to the reference range after antimyeloma chemotherapy. ConclusionAbout 12% of patients with MM had euthyroid hypertriiodothyroninemia. Their strikingly elevated TT3 was normalized after chemotherapy. Clinicians should be aware of the possibility of high TT3 levels in euthyroid patients with MM and the potential risk of MM in patients with strikingly elevated TT3.

Long non-coding RNA T cell factor 7 is associated with increased disease risk and poor prognosis, and promotes cell proliferation, attenuates cell apoptosis and miR-200c expression in multiple myeloma.

The aim of the present study was to investigate the association of long non-coding RNA T cell factor 7 (lncRNA TCF7) with disease risk, prognosis and its cellular function in multiple myeloma (MM). A total of 132 de novo symptomatic patients with MM and 50 controls were enrolled. Plasma cells from patients with MM and controls were separated from bone marrow samples to detect lncRNA TCF7 expression using reverse transcription-quantitative PCR. In addition, treatment responses, event-free survival (EFS) and overall survival (OS) were measured. The effects of lncRNA TCF7 on proliferation, apoptosis and microRNA-200c (miR-200c) expression were assessed by gain- and loss-of-function experiments in RPMI-8226 and U-266 cells. The results demonstrated that lncRNA TCF7 expression was upregulated in patients with MM compared with controls, and the receiver operating characteristic curve revealed that lncRNA TCF7 could distinguish patients with MM from controls with an area under the curve of 0.793 (95% CI, 0.725–0.861). In patients with MM, high lncRNA TCF7 expression was associated with higher β2-microglobulin, more advanced International Staging System stage and increased t (14; 16) mutations. Furthermore, it was demonstrated that lncRNA TCF7 was downregulated in patients with complete response (CR) compared with patients without CR. Furthermore, high lncRNA TCF7 expression predicted worse EFS and OS. lncRNA TCF7 also promoted cell proliferation, whereas it reduced cell apoptosis and miR-200c expression in RPMI-8226 and U-266 cells. In conclusion, the present results suggested that lncRNA TCF7 may be used as a potential biomarker and as a treatment target for MM.

Biochemical phenotyping of multiple myeloma patients at diagnosis reveals a disorder of mitochondrial complexes I and II and a Hartnup-like disturbance as underlying conditions, also influencing different stages of the disease

The aim of this study was to identify novel plasma metabolic signatures with possible relevance during multiple myeloma (MM) development and progression. A biochemical quantitative phenotyping platform based on targeted electrospray ionization tandem mass spectrometry technology was used to aid in the identification of any eventual perturbed biochemical pathway in peripheral blood plasma from 36 MM patients and 73 healthy controls. Our results showed that MM cases present an increase in short and medium/long-chain species of acylcarnitines resembling Multiple AcylCoA Dehydrogenase Deficiency (MADD), particularly, associated with MM advanced International Staging System (ISS). Lipids profile showed lower concentrations of phosphatidylcholine (PC), lysophosphatidylcholine (LPC) and sphingomyelins (SM) in the MM patients and its respective ISS groups. MM cases were accompanied by a drop in the concentration of essential amino acids, especially tryptophan, with a significant inverse correlation between the progressive drop in tryptophan with the elevation of β2-microglobulin, with the increase in systemic methylation levels (Symmetric Arginine Dimethylation, SDMA) and with the accumulation of esterified carnitines in relation to free carnitine (AcylC/C0). Serotonin was significantly elevated in cases of MM, without a clear association with ISS. Kynurenine/tryptophan ratio demonstrates that the activity of dioxigenases is even higher in the cases classified as ISS 3. In conclusion, our study showed that MM patients at diagnosis showed metabolic disorders resembling both mitochondrial complexes I and II and Hartnup-like disturbances as underlying conditions, also influencing different stages of the disease.

HORIZON (OP-106): Melflufen Plus Dexamethasone (dex) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) Exposed to Prior Alkylator Therapy-Subgroup Analysis

HORIZON (OP-106): Melflufen Plus Dexamethasone (dex) in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM) Exposed to Prior Alkylator Therapy-Subgroup Analysis

The international staging system improves the IPI risk stratification in patients with diffuse large B-cell lymphoma treated with R-CHOP

The international staging system (ISS), based on serum beta-2 microglobulin and albumin, is used to predict survival in multiple myeloma, but its prognostic significance in diffuse large B-cell lymphoma (DLBCL) remains unknown. Herein, we retrospectively analyzed 215 de novo DLBCL patients. According to ISS, there were 90 of 215 (41.9%) patients in stage I, 98 of 215 (45.6%) in stage II and 27 of 215 (12.6%) in stage III group. Patients with ISS stage II/III showed shorter overall survival (OS) and event free survival (EFS) than those with stage I treated with R-CHOP (p = 0.012 and p = 0.043, respectively), but not those treated with CHOP regimen (p > 0.05). Multivariable analysis revealed that ISS, independent of IPI, indicated different survival in both OS (HR, 5.690; 95% CI, 1.270–25.495, p = 0.023) and EFS (HR, 2.116; 95% CI, 1.005–4.455, p = 0.049) in DLBCL patients treated with R-CHOP. ISS could identify patients with better outcome in intermediate-high/high IPI risk patients (p < 0.05). Our data suggests that advanced ISS stage is associated with inferior outcome in DLBCL patients treated with R-CHOP. ISS could identify a subgroup of DLBCL patients with superior outcome from high IPI risk patients, which may help to avoid intensive therapy.

Risk factors and characteristics of blood stream infections in patients with newly diagnosed multiple myeloma

BackgroundPatients with multiple myeloma are generally immune-compromised either due to pronounced depression in primary antibody responses or because of anti-myeloma therapy. Infection is a major risk factor for early deaths among these patients. The impact of blood stream infections (BSI) on newly diagnosed myeloma patients has been less studied. We aimed to study the incidence and risk factors of BSI within 3 months after diagnosis of multiple myeloma in a tertiary referral center.MethodsBetween November 2002 and December 2008, consecutive patients with multiple myeloma in Taipei Veterans General Hospital were retrospectively enrolled. Characteristics of patients with or without BSI were collected. Possible factors associated with development of BSI were analyzed by Cox regression.ResultsThere were a total of 222 patients. The incidence of BSI within 3 months after diagnosis is 11.7%. The patients with BSI had poorer survival outcomes than those without (mortality rate: 50% vs. 20.9%, p < 0.001). Moreover, advanced International Staging System stage (stage III vs. I/II: odds ratio [OR] 2.69, p = 0.049) and poor Eastern Cooperative Oncology Group (ECOG) performance status (ECOG > 2 vs. ≤ 2: OR 3.58, p = 0.005) were the independent risk factors of BSI, whereas immunoglobulin deficiency and low absolute lymphocyte count were not associated with risk of BSI development.ConclusionsOur study highlights the characteristic of myeloma patients with BSI and the importance of disease and host factors on risk of BSI. Myeloma patients with risks of BSI should be properly managed to reduce early mortality.

Association between immunophenotypic markers and cytogenetic aberrations in Egyptian patients with plasma cell myeloma

Background Plasma cell myeloma is a devastating disease of clonal plasma cells that show considerable diversity both in their immunophenotypic and in their cytogenetic features. Immunophenotyping has been used widely for diagnostic and prognostic evaluation of malignant plasma cells. Aim The aim of this study was to evaluate the relationship between the immunophenotypic profile and standard prognostic factors, and also to determine the correlation between different antigenic expression and the cytogenetic aberrations as well as clinical stage in patients with plasma cell myeloma. Patients and methods A total of 31 newly diagnosed Egyptian patients with plasma cell myeloma were evaluated by multiparameter flow cytometry. Interphase fluorescence in situ hybridization was performed for detection of the expression of the 14q32 immunoglobulin H rearrangement, t(11;14), t(4;14), 13q del, and 17p del on bone marrow samples collected from the patients at diagnosis. Results Positive expression of CD19, CD20, CD13, and CD33 was detected in 38.7, 51.6, 19.4, and 12.9% of patients, whereas CD56, CD45, CD65, and CD117 were expressed in 41.9, 77.4, 9.7, and 25.8% of patients, respectively. A statistically significant correlation was found between CD13 positivity, CD56 positivity, or CD45 negativity and advanced International Staging System (P=0.011, 0.036, and 0.004, respectively). CD33-negative cases were significantly associated with absence of the 14q32 immunoglobulin H rearrangement (P=0.050) and absence of t(4;14) (P=0.018). CD45 positivity and CD13 negativity were correlated with absence of 13q del (P=0.031 and 0.011, respectively). Conclusion Immunophenotypic antigenic expression profile is associated with advanced clinical stage and absence of some cytogenetic aberrations in plasma cell myeloma.

Distinct Clinical Outcomes between Paramedullary and Extramedullary Lesions in Newly Diagnosed Multiple Myeloma.

This retrospective study aimed to compare the clinical features of paramedullary lesions (PLs) and extramedullary lesions (ELs) of plasmacytomas at diagnosis, using positron emission tomography integrated with computed tomography, using glucose labeled with the positron-emitting radionuclide 18F (18F-FDG-PET/CT) in newly diagnosed multiple myeloma (NDMM), and to address their prognostic impact. Sixty-four patients with NDMM presenting ELs (n=22) and/or PLs (n=42) were included. Patients with ELs at initial presentation had unfavorable laboratory parameters of calcium and lactate dehydrogenase, a higher percentage of bone marrow plasma cells, and showed a trend toward advanced international staging system (ISS), compared to patients with PLs. Using X-ray imaging, high bone disease (HBD) was observed in 50% and 71% of patients with ELs and PLs, respectively. After a median follow-up of 29.2 months (range, 3.4–76.5 months) in survivors, patients with ELs had a significantly lower overall survival (OS) (p=0.033) than patients with PLs did, whereas the progression-free survival (PFS) did not differ significantly (p=0.818). However, the PFS after 1st progression was significantly worse in patients with ELs than in those with PLs (p=0.017). In the multivariate analyses, the negative impact of initial ELs on OS (p=0.033) was sustained. Our results demonstrated the different clinical features and outcomes of ELs and PLs in NDMM. Patients with initial ELs showed a shorter PFS after 1st progression, which translated into poor OS, providing insight into the different biological effect of ELs.

Bortezomib Based Induction Is Superior to Thalidomide Based Induction in Reducing Early Relapses Following Upfront HDM: an Analysis By the Asian Myeloma Working Group

Background: Multiple myeloma is a heterogeneous disease with certain genetic features associated with worse outcomes. The benefit of Bortezomib for high risk genetic patient subgroups remains unclear in an Asian population. We performed a retrospective analysis to compare bortezomib-based induction versus thalidomide-based induction in Asian patients who were treated with upfront autologous transplant.Methods: We retrospectively analyzed outcomes of 240 patients who received autologous transplant in two centers in Singapore (n=167) and one center in Korea (n=73) after bortezomib-based (n=120) versus thalidomide-based induction (n=120) between 2006 and 2014. Patients were staged according to International Staging System (ISS), and responses were defined according to International Myeloma Working Group criteria. Early relapse was defined as relapse within 12 months post-transplant. High risk cytogenetics included the presence of 17p13 deletion, t(14;16), or t(4;14) by FISH.Results: Baseline characteristics (age, gender, ISS, cytogenetics) were not significantly different between groups receiving bortezomib versus thalidomide induction. Bortezomib induction was associated with improved rates of complete response (CR) post-induction (40% vs 25%, p=0.013) and post-transplant (52% vs 48%, p=0.038). Median overall survival (OS) was prolonged with bortezomib (53 months vs 27 months, p=0.027). Multivariate analysis adjusted for baseline characteristics showed bortezomib reduced the risk of early relapse (HR 0.23, 95% CI 0.09-0.57, p=0.001), and improved overall survival (OS) (HR 0.2, 95% CI 041-0.93, p=0.021). Factors independently associated with poorer OS were high risk cytogenetics (HR 1.77, p=0.011), failure to achieve very good partial response (VGPR) or better post-induction (HR 1.70, p=0.005), early relapse (HR 6.20, p<0.001), but not advanced ISS stage or hypodiploidy karyotype. In subgroup analysis, patients with high-risk cytogenetics (n=46) who received bortezomib had improved OS (HR 0.39, CI 0.17 to 0.93, p=0.033), but patients with standard risk cytogenetics did not have significant OS benefit with bortezomib (HR 0.71, p=0.139).Conclusion: Our results suggest that despite upfront autologous stem cell transplantation, patients benefit from bortezomib versus thalidomide induction. Furthermore, bortezomib may be beneficial in overcoming the adverse prognostic effect of high-risk cytogenetics. DisclosuresDurie:Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy.

High Risk of Tumor Lysis Syndrome in Symptomatic Patients with Multiple Myeloma with Renal Dysfunction Treated with Bortezomib.

Tumor lysis syndrome (TLS) is a life-threatening complication associated with cancer chemotherapy. We retrospectively evaluated the risk of developing TLS in patients with symptomatic multiple myeloma undergoing chemotherapy. Sixty-four patients (median age=71 years, range=48-87 years, 35 males/29 females) who were treated at our Institution between April 2006 and December 2015 were evaluated. A total of 124 chemotherapy courses were administered, of which 63 courses were bortezomib-based regimens and 34 courses were immunomodulatory drug (IMiD)-based regimens. TLS occurred in 13 (10.5%) out of 124 chemotherapy courses with five (4.0%) cases of laboratory TLS and eight (6.5%) cases of clinical TLS. The incidences of TLS were 17.5% for bortezomib-containing regimens and 3.2% for non-bortezomib-based regimens. No TLS occurred in the patients treated with IMiD-containing regimens. TLS occurred more frequently in the patients with elevated uric acid, creatinine, or beta-2-microglobulin levels at baseline. The patients with disease classified as advanced International Staging System also developed TLS more frequently. All the patients who developed clinical TLS received bortezomib-containing regimens (8/63, 12.7%). Among them, patients with elevated values of uric acid or creatinine developed clinical TLS more often than those without such elevation. The incidence of clinical TLS was 33.3% if the patients had renal dysfunction at baseline and were subsequently treated with bortezomib-based regimens (8/24 cases). Patients with renal dysfunction or a high uric acid level receiving bortezomib-based chemotherapy have a high risk of developing TLS.