Influencing Factors of Non-Genetic Factors Influencing the Overall Survival of Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 15-15
Author(s):  
Lin Gui ◽  
Fei Wang ◽  
Jinning Shi ◽  
Baoan Chen

Objective: To explore the non-genetic prognostic factors in patients with multiple myeloma (MM). Methods: Kaplan-Meier survival curve, Log-rank test and Cox regression model were used to carry out univariate and multivariate analysis on clinical and laboratory parameters of 51 MM patients who were newly diagnosed with MM and had complete follow-up data in the Department of Hematology, Jiangning Hospital Affiliated to Nanjing Medical University, Nanjing From November 2011 to October 2012. Results: Of the 51 patients, 29 were male and 22 were female. Followed up to December 2019, 21 died and 30 survived. The univariate analysis showed the prognosis was influenced by factors including age, disease stage, standard treatment, new drugs, maintenance treatment, hypercalcemia, globulin, albumin, hemoglobin. Patients aged <65 years, with ISS stage I and II, with standardized treatment, with new drugs, with normal or below normal blood calcium, with normal or below normal globulin, with albumin ≥ 35g/L or patients with hemoglobin ≥100g/L have longer survival time. The multivariate analysis showed that maintenance treatment, hypercalcemia and hemoglobin were independent risk factors influencing the prognosis of MM patients. Conclusion: Patients with blood calcium ≥ 2.6mmol/L, hemoglobin <100g/L and those who do not undergo regular maintenance therapy have a poor prognosis. Key words multiple myeloma; overall survival; non-genetic; prognostic factors Disclosures No relevant conflicts of interest to declare.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1670-1670
Author(s):  
Paul Mehan ◽  
Giridharan Ramsingh ◽  
Jingqin Luo ◽  
Daniel Morgansztern ◽  
Ravi Vij

Abstract Solitary plasmacytoma (PCM) is a focal, neoplastic, plasma cell disorder without evidence of systemic disease. While PCM is a clinically distinct entity, survival can be limited by progression to multiple myeloma. Prior studies have attempted to identify factors influencing survival in PCM but have been limited by small patient cohorts. This study identified 1472 patients with PCM using the SEER database between 1988 and 2004. The median age of the patients was 64 years (range 12–97), 65.4% male, 34.6% female, 83% Caucasians, 10.7% African Americans and 6.3% other races. 63.8% had medullary PCM and 36.2% extramedullary PCM. 84% of medullary PCM occurred in axial skeleton and the rest in appendicular skeleton. Extramedullary PCM most frequently occurred in the head and neck region (51.4%) followed by skin/subcutaneous tissue (16.2%), GI tract 6% and other sites (26.4%). 55.2% were treated with radiation therapy alone, 29.5% with radiation therapy and surgery and 15.3% with surgery alone. 558 died during this period and the mean overall survival was 6.83 years (range, 0–16.9). The cause of death was multiple myeloma in 49.6%, other cancers 20.9% and cardiovascular diseases 12.9%. In all patients, survival probability at one year was 87.6% (95% CI, 85–89%), at five years was 58.9% (95% CI, 56–62%), and at 10 years was 40.0% (95% CI, 36–44%). The five year overall survival in the ≤40yo cohort was 83.5% as compared to 76.7% and 44.8% in the 40–60yo and >60yo groups, respectively (p<0.0001). The five year disease specific survival probability in the ≤40yo cohort was 94.5% as compared to 86.0% and 66.2% in the 40–60yo group and >60yo group, respectively (p<0.0001) (figure 1)). Overall survival in the extramedullary PCM was 65.9% at five years as compared to 54.6% in the medullary PCM (p<0.0001) and the disease specific survival in the extramedullary PCM was 86.2% compared to 70.1% in the medullary PCM (p<0.0001) (figure 1). Multivariate analysis of disease specific survival revealed that younger age, male gender, extramedullary type, and race other than African American or Caucasian were favorable prognostic factors (Table 1). Younger age, extramedullary site, treatment with XRT + surgery, and race other than African Americans were associated with improved overall survival by multivariate analysis (Table 1). To our knowledge, this is the largest published review of survival in PCM. This study identifies several prognostic risk factors influencing survival in PCM. These risk factors can be used to identify patients at high risk for progression to multiple myeloma. Those at highest risk could be considered for future trials comparing adjuvant systemic therapy compared to local therapy alone. Table 1. Multivariate Analysis of Prognostic Factors Disease Specific Survival Overall Survival Variable Category HR 95% CI P HR 95%CI P Abbreviations: HR, Hazard Ratio; Q, Confidence Inverval Sex Female --- -- --- -- --- --- Male 0.74 0.58~ 0.94 0.01 0.95 0.80~1.13 0.57 Age <40yo --- --- --- --- --- --- 40–60yo 2.68 115~ 6.2 0.02 1.74 1.04~2.91 0.03 >60yo 6.94 3.06~ 15.73 <0.01 5.55 3.40~9.06 <0.01 Race Black --- --- --- --- --- --- White 0.74 0.52~ 1.06 0.1 0.72 0.56~0.92 0.01 Others 0.31 0.13~ 0.75 <0.01 0.48 0.29~0.79 <0.01 Primary Site Extramedullary --- --- --- --- --- --- Medullary 2.35 1.74~.3.18 <0.01 1.37 1.13~1.65 <0.01 Treatment Surgery Only --- --- --- --- --- --- XRT Only 0.90 0.62~ 1.31 0.59 0.82 0.64~1.04 0.10 XRT + Surgery 0.84 0.55~1.26 0.39 0.68 0.52~0.89 <0.01 Period 1988–1993 --- --- --- --- --- --- 1994–1999 0.96 0.72~1.30 0.8 0.96 0.78~1.19 0.74 2000–2004 0.94 0.68~1.30 0.7 0.94 0.75~1.18 0.6 Figure 1: Figure 1:.


2022 ◽  
Author(s):  
Bo-Wen Zheng ◽  
Bo-Yv Zheng ◽  
Hua-Qing Niu ◽  
Xiao-Bin Wang ◽  
Guo-Hua Lv ◽  
...  

Abstract Background The clinical characteristics and prognostic factors of axial chondroblastoma (ACB) are still poorly understood. Purpose To characterize clinicopathological characteristics in a large ACB cohort and investigate their correlation with survival. We also sought to compare these results with extra-axial CB (EACB). Methods Our institution's local database was retrospectively reviewed and included a total of 132 CB patients, including 61 ACB patients and 71 EACB patients. Immunohistochemistry was used to assess the expression levels of Vimentin (Vim), S100, and cytokeratin (CK) on tumor cells in 132 tissue specimens. Results Overall, ACB and EACB had similar characteristics, except for older age and tumor size, as well as higher Vim expression, incidence of surrounding tissue invasion and postoperative sensory or motor dysfunction. Whereas wide resection and absence of invasion of surrounding tissues were consistently associated with favorable survival in the ACB and EACB cohorts in univariate analysis, most parameters showed differential prognostic significance between the 2 groups. Significant prognostic factors for local recurrence-free survival in multivariate analysis included the type of resection and chicken-wire calcification in the ACB cohort. Multivariate analysis of overall survival demonstrated that the type of resection was a significant predictor in the ACB cohort, whereas the type of resection and postoperative sensory or motor dysfunction were predictive of overall survival in the EACB group. Conclusion These data suggest that there may be distinct biological behaviors between ACB and EACB and may provide useful information to better understand the prognostic characteristics of patients with ACB and to improve outcome prediction in patients with ACB.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 17557-17557
Author(s):  
J. Xiao ◽  
T. Lin ◽  
Y. Cao ◽  
X. Fu ◽  
C. Guo ◽  
...  

17557 Background: Natural Killer (NK) cell lymphoma is a group of increasingly recognized but poorly defined disease entities. This study investigated its clinical features and prognostic factors for southern China population. Methods: Patients with pathologically confirmed NK cell lymphoma in one center since 1999 to 2004 were included. Central histological and immunohistochemical review was undertaken to every case. The major study endpoint was overall survival. Survival curves were estimated by the Kaplan-Meier method. Detailed clinical, pathological and laboratory data were included in univariate analysis and statistically significant factors in univariate analysis were then included in multivariate analysis. Results: Totally 64 eligible patients were identified. Of these, 59 patients were extranodal NK cell lymphoma nasal type, 3 patients were aggressive NK cell lymphoma and 2 patients were blastic NK cell lymphoma. From the basic analysis, 47% of the patients had stage I disease, 42% were stage II, 11% were stage III or IV. B-symptoms were present in 39%. 73% of these patients had International Prognostic Index (IPI) 0 or 1. Before treatment, 25% complicated with anemia. As to the therapy, 38% received chemotherapy alone, 3% received radiotherapy alone and 59% received a multidisciplinary therapy. After initial therapy, 59% achieved CR, 22% achieved PR and 19% were refractory disease. With a median follow-up duration of 20 months, the median overall survival was 28 months (95% CI: 10, 45). Hb lower than 110 g/l before treatment was statistically significant in multivariate analysis (p = 0.031). Presenting B-symptoms and ECOG PS score higher than 1 were also independent prognostic factors (P = 0.001 and 0.006 respectively). Conclusions: The outcome of patients with NK cell lymphoma was poor even for Stage I or II cases. Our data suggested Hemoglobin < 110 g/l had more prognostic value than IPI and Ann Arbor staging system for NK cell lymphoma in southern China, but it needs further confirmation. No significant financial relationships to disclose.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15797-e15797
Author(s):  
Brandon M Huffman ◽  
Zhaohui Jin ◽  
Cristobal T. Sanhueza ◽  
Mindy L. Hartgers ◽  
Benny Johnson ◽  
...  

e15797 Background: Duodenal adenocarcinoma is a rare tumor representing approximately 0.3% of all gastrointestinal tract cancers. Prognostic factors in relation to survival outcomes for these patients are sporadically reported in the medical literature. We aimed to evaluate outcomes of patients with duodenal adenocarcinoma who underwent pancreaticojejunostomy treated at Mayo Clinic Rochester from January 1, 2006 to December 31, 2016. Methods: Clinicopathological data of 52 duodenal cancer patients were collected. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of < 0.05 was considered significant. Results: The median age at diagnosis was 65.9 years (range 39-81). The median overall survival was 51 months (95% CI 31.3-105.4) and the median progression free survival was 30.4 months with median follow up of 73.4 months. There were 3, 9, 21, and 19 patients with stage I, II, III, and IV disease, respectively. Depth of tumor invasion (p = 0.0156) and lymph node metastasis (p = 0.0441) were associated with overall survival on multivariate analysis. Advanced clinical staging influenced overall survival in univariate analysis, but lost prognostic significance in multivariate analysis. Age, gender, surgical technique, presence of metastases, tumor size, number of lymph nodes removed, location of duodenal segment involvement, and adjuvant treatment had no significant impact on overall survival. Laparoscopic approach did not influence survival but was associated with less hospital days (p = 0.0437). Conclusions: Depth of tumor invasion and lymph node status were associated with improved overall survival in patients with duodenal adenocarcinoma. Laparoscopic procedure decreased the hospital stay without affecting outcomes.


2020 ◽  
Author(s):  
Yuki Mukai ◽  
Yuichiro Hayashi ◽  
Izumi Koike ◽  
Toshiyuki Koizumi ◽  
Madoka Sugiura ◽  
...  

Abstract Background: We compared outcomes and toxicity between radiation therapy (RT) with concurrent retrograde super-selective intra-arterial chemotherapy (IACRT) and RT with concurrent systemic chemoradiotherapy (SCRT), for gingival carcinoma (GC). Methods: We included 84 consecutive patients who were treated for GC ≥ stage III, from 2006 to 2018, in this retrospective analysis (IACRT group: n=66; SCRT group: n=18).Results: Median follow-up time was 24 (range: 1–124) months. The median prescribed dose was 60 (6–70.2) Gy (IACRT group: 60 Gy; SCRT group:69 Gy). At 3 years, the two groups significantly differed in overall survival (OS; IACRT: 78.75%, 95% confidence interval [CI]: 66.00–87.62; SCRT: 50.37%, 95% CI: 27.58–73.0; P = 0.039), progression-free survival (PFS; IACRT: 75.64%, 95% CI: 62.69–85.17; SCRT: 41.96%, 95% CI: 17.65–70.90; P = 0.028) and local control (LC; IACRT: 77.17%, 95% CI: 64.23–86.41; SCRT: 41.96%, 95% CI: 17.65–70.90; P = 0.015). In univariate analysis, age ≥ 65, decreased performance status (PS) and SCRT were significantly associated with worse outcomes (P < 0.05). In multivariate analysis, age ≥ 65 years, clinical stage IV, and SCRT were significantly correlated with poor OS (P < 0.05). Patients with poorer PS had significantly worse PFS.Conclusions: This is the first report to compare outcomes from IACRT and SCRT among patients with GC. IACRT is an effective and organ-preserving treatment for GC.Trial registration: retrospectively registered


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4622-4622
Author(s):  
Michael Axelson ◽  
Shirisha Reddy ◽  
Crystal Lumby ◽  
Sue Sivess-Franks ◽  
Jonathan Dowell ◽  
...  

Abstract Background: Myelodyplastic syndrome (MDS) is the disease of the elderly and increasingly common in the veteran population. Here we report a single institution experience with MDS at the Dallas VA Medical Center. Patients and Method: From a period of 1998–2007, eighty three pts were identified out of which 54 pts had bone marrow (BM) biopsy proven diagnosis of MDS. Overall survival (OS) analysis with dependent variables (Age at diagnosis, IPSS Score, WHO morphologic diagnosis, number of blood and platelet transfusions required, Hb level, ANC, cytogenetics, blast percentage, BM cellularity at diagnosis) were conducted by selection method “foreward” and only these significant variables were used in the Cox regression for multivariate analysis. Methods of Kaplan and Meier were used to generate OS curves. Results: The median age of diagnosis was 74 yrs with a median follow up time of 12.5 months. The WHO morphologic subtype was RA/RARS (n=13), Del5q (n=1), RCMD/RCMDRS (n=34), RAEB1 (n=3), RAEB2 (n=1), missing (n=2). The distribution of IPSS score was 0 (n=25); 0.5 (n=15); 1.0 (n=8), 1.5 (n=4), missing (n=2). Five pts had treatment related MDS and 3 pts transformed to AML. One patient had concurrent MGUS and one patient developed multiple myeloma. At diagnosis, 23 pts had a hemoglobin (Hb) value of less than 10g/dl. Only 4 pts had ANC less than 500; sixteen pts had ANC 500–1800 and 34 pts had normal counts. A majority of pts had normal cytogenetics (n=37), 5 pts had good risk, 5 pts had intermediate risk and 7 pts had poor risk cytogenetics. Six pts had hypocellular (<30%) BM at diagnosis whereas 16 pts had a hypercellular marrow (> 50%). Only 4 pts had more than 5% blast in the BM. Twenty nine pts eventually became blood transfusion dependent and 12 pts needed platelet transfusion at some point. Thirty six pts were treated with erythropoietin (with or without neupogen) and 13 pts received some type of disease modifying therapy (5-azacytidine/lenalidomide/ATG/clinical trial). The mean survival time was 106 months. Median survival was not reached at the time of analysis. In the univariate analysis, IPSS score (p=0.003), No. of blood transfusions (p=0.028), cytogenetics (p=0.0001) and blast percentage (p=0.0015), were statistically significant. BM cellularity (p=0.06) and Hb level (p=0.09) showed a trend towards significance. On multivariate analysis, Hb greater than 10 (HR 0.08; p=0.011), abnormal cytogenetics (HR 4.2; p=0.001), BM Blast > 5% (p=0.026) and BM cellularity < 30% (HR 4.6; p=0.033) emerged as the significant predictors of overall survival. IPSS score or Blood transfusion requirement did not pan out to be significant. Conclusion: MDS in the veteran population may be different from general population and may have unique predictors of survival. A larger number of patients and longer duration of follow up is required to further evaluate these prognostic factors.


2008 ◽  
Vol 123 (1) ◽  
pp. 114-120 ◽  
Author(s):  
M S Mosleh-Shirazi ◽  
M Mohammadianpanah ◽  
M A Mosleh-Shirazi

AbstractAim:To report the characteristics, prognostic factors and treatment outcomes of 102 patients with squamous cell carcinoma of the oral tongue treated and followed up at a single institution over a 25-year period.Patients and methods:This retrospective study was carried out by auditing the medical records of 102 patients diagnosed with squamous cell carcinoma of the oral tongue and treated at our institution between 1982 and 2007. Patient follow up ranged from nine to 310 months (median 35 months). Fifty per cent of the patients were treated with surgery followed by a combination of chemotherapy and radiotherapy (43.1 per cent received concurrent chemoradiation and 6.9 per cent received sequential chemotherapy and radiotherapy), whereas 29.4 per cent received surgery followed by adjuvant radiotherapy alone. The remaining patients (20.6 per cent) did not undergo surgery and were treated with definitive radiotherapy with or without chemotherapy.Results:There were 48 men and 54 women. The age at presentation was 19–85 years (median 57 years). The peak incidence was observed between 60 and 70 years. Resection margins were clear in 75 per cent of patients and involved in 25 per cent. Stage I disease was found in 11.8 per cent of patients, stage II in 34.3 per cent, stage III in 22.5 per cent and stage IV in 31.4 per cent. The five-year disease-free survival and overall survival were 65.7 and 72.5 per cent, respectively. Thirty-five patients suffered recurrence after treatment, 74.0 per cent of them at the site of initial cervical nodal involvement. Univariate analysis for overall survival revealed the following as prognostic factors: treatment schedule (surgical vs non-surgical; p < 0.001); age (<60 years vs ≥60 years; p = 0.038); extent of cervical lymph node involvement (p = 0.015); primary tumour stage (p < 0.001); node stage (p = 0.034); and disease stage (p = 0.013). However, on multivariate analysis, only non-surgical treatment (p = 0.001) and advanced disease stage (p = 0.05) were found to have a negative influence on survival.Conclusions:Our limited data suggest that, in Iran, squamous cell carcinoma of the oral tongue tends to present at a locally advanced stage, with a high frequency of locoregional failure and a poor outcome. Combined modality therapy should be considered for the majority of patients with squamous cell carcinoma of the tongue.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3989-3989
Author(s):  
Corrado Tarella ◽  
Angela Gueli ◽  
Federica Delaini ◽  
Anna Maria Barbui ◽  
Riccardo Bruna ◽  
...  

Abstract BACKGROUND Follicular lymphoma (FL) is the most common indolent form of non-Hodgkin's lymphoma. However, FL is a heterogeneous disorder and in a proportion of patients, the disease is very resistant to standard frontline therapies. In the current analysis clinical features and outcome to primary treatment were evaluated in a large series of FL patients who were consecutively treated at the Hematology Centers of Bergamo and Torino, Italy between 1976 and 2012. The aim of the study was to define the rate of refractory disease and the long term survival of patients according to response to their primary treatment. METHODS Medical records of 597 FL patients were reviewed. In front line therapy, rituximab was employed in 330 patients (55%), front-line high dose therapy with autograft (HDS) was administered in 58 patients (9.7%). Primary refractory disease was defined as full refractoriness (stable or progressive disease) or progressive disease within six months after initial response. Univariate analysis was done for prognostic factors including gender, age at diagnosis (age≤60 and >60 years), histological grade, IPI score (low=0-2 versus high=3-5), bone marrow (BM) involvement, rituximab administration in 1st line treatment, lymphocyte to monocyte ratio at diagnosis (>2.6 vs ≤2.6), presence of primary refractory disease, and the administration of front-line HDS. Cox model was also used for multivariate analysis. RESULTS: A total of 375 patients (63%) were older than 60 years (range: 18-88) and 49% were males. There were 476 patients (79.7%) with stage III-IV, 286 patients (48%) with BM involvement, 185 (31%) had a high IPI score and 28 patients (5%) presented with high histological grade. Eighty-seven patients (13%) displayed primary refractory disease. At a median follow-up of 8 years, median overall survival (OS) was 25 years for all patients, 32.6 years for responsive patients compared to 5 years for primary refractory patients (p=<0.0001). Among primary refractory patients, those with fully refractory disease had a shorter survival (median OS: 2.7 years) compared to patients with early progressive disease (median OS: 5 years). The strikingly different outcome of primary refractory vs. responsive patients is shown in the Figure 1. A significant prolonged survival was observed in patients who were treated with rituximab in primary therapy. The median OS is not reached for rituximab treated patients compared to 19 years for those who did not receive rituximab. Median OS was 25 years for patients with low IPI and 14.6 years for the high risk group. By univariate analysis, age and BM involvement were also significant prognostic factors for OS. Median OS for patients 60 years old or younger compared to older patients were 32.6 versus 13 years, respectively. The median survival was not reached for patients without BM involvement vs 19 years for patients with BM involvement (p=0.001). By multivariate analysis high IPI, refractory disease and not receiving rituximab in first line regimens were independent negative prognostic factors for OS, as detailed in Table 1. CONCLUSION: FL patients who display responsive disease to their primary treatment have a very long life expectancy with median survival of 32.6 yrs. Similarly to the aggressive lymphoma subtypes, primary refractory disease is of major concern also for FL. Research studies should be focused on the early identification of primary refractory patients to promptly institute adapted therapy for this unfavorable subgroup, and possibly optimize treatment strategies for patients with high-risk FL. Table 1. Multivariate analysis for overall survival Parameter Hazard Ratio (95% Confidence interval) p-value Age (yrs): >60 vs. ≤ 60 1.54 (1.5-2.3) .03 Histologic grade: 1-2 vs 3 2.25 (0.5-9.1) .3 IPI *Score: low (0-2) vs high(3-5) 0.59 (0.4-0.9) .009 Primary Refractory: yes vs no 4.40 (3.0-6.5) < .0001 Rituximab 1st line: yes vs no 0.56 (0.4-0.8) .005 BM# involvement: yes vs no 1.44 (1.0-2.1) .06 *International prognostic index was used to have a uniform prognostic factors scoring system for patients treated over the three decades of the survey. # Bone marrow Figure 1. Overall Survival in 597 follicular lymphoma patients according to response to primary treatment Figure 1. Overall Survival in 597 follicular lymphoma patients according to response to primary treatment Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4434-4434
Author(s):  
Wenzhuo Zhuang ◽  
Sha Song ◽  
Huiying Han ◽  
Gao Fan ◽  
Nengjun Yi ◽  
...  

Abstract PIs resistance is a major challenge for multiple myeloma (MM). The bone marrow microenvironment facilitates crucial interactions between the myeloma cells and mesenchymal stem cells (MSCs) that permit MM to survive and proliferate progression. Exosomes are involved in intercellular communication, and in this study we investigated how the transfer of exosomic PMSA3 (encodes proteasome subunit α7) and lncPSMA3-AS1 from MSCs to MM cells affected proteasome inhibitors resistance (Figure 1). We firstly underscored that exosomes derived from r-MSCs (MSCs derived from bortezomib-resistant patients), but not from s-MSCs (MSCs derived from bortezomib-resistant patients) reduced the proteasome inhibitors sensitivity in MM cells (Figure 2). To further elucidate mechanisms of Proteasome inhibitors (PIs) resistance, we retrieved a database containing gene expression profile of 169 myeloma cases with clinical response and disease prognosis (GSE9782). The analysis of this dataset showed that the mRNA levels of PSMA3 and PSMA3-AS1 in CD138+ cells are upregulated in bortezomib-resistant patients (Figure 3A-3D). Moreover, Kaplan-Meier analysis showed that high PSMA3 levels in CD138+ MM cells were correlated with reduced progression-free survival (PFS) (p = 0.0307) and overall survival (OS) (p = 0.0328) (Figure 3E). Cox proportional hazards regression analysis further demonstrated that high PSMA3 was an independent prognostic factor for MM patients with bortezomib therapy in a multivariate analysis (p = 0.0013, HR = 1.3104, 95%CI = 1.1113-1.545). Further analysis of Oncomine data showed that the PSMA3 levels appeared a progressive increase in MGUS, SM, MM and PCL (Figure 3F-3H). Similarly, our PIs resistant models (U266BR, U266CR, U266IR, MM.1SBR, MM.1SCR, MM.1SIR) consistently displayed up-regulation of PSMA3 and PSMA3-AS1 expression (Figure 3J). Consistent with this previously published study, our clinical data showed that the mRNA levels of PSMA3 and PSMA3-AS1 are upregulated in CD138+ MM cells derived from bortezomib resistant patients relative to those from bortezomib sensitive patients (Figure 3I). In addition, r-MSCs had increased expression of PSMA3 and PSMA3-AS1 compared to s-MSCs (Figure 3K). Moreover, the expression of PSMA3 and PSMA3-AS1 in MSCs were positively correlated with that in CD138+ myeloma cells (Figure 3L). These data suggested that high levels of PSMA3 and PSMA3-AS1 were correlated with proteasome inhibitors resistance in MM. We further identified that PSMA3 and PSMA3-AS1 in MSCs could be incorporated into exosomes and transmitted to myeloma cells, thus promoting PIs resistance (Figure not shown). PSMA3-AS1 was capable of forming an RNA duplex with PSMA3 pre-mRNA at overlapping regions and this duplex transcriptionally promoted PSMA3 expression by increasing its stability, conferring bortezomib resistance to myeloma cells (Figure not shown). To evaluate the therapeutic potential of PSMA3-AS1 in MM in vivo, bioluminescent MM models (U266-luc), which recapitulates the clinical sequelae, anatomic distribution of MM lesions, and hallmark bone pathophysiology observed in MM patients were established. Intravenously administered siPSMA3-AS1 was found to be effective in increasing bortezomib sensitive (Figure 4). Moreover, circulating exosomal PSMA3 and PSMA3-AS1 derived from the plasma of MM patients were significantly associated with both progression-free survival (PFS) and overall survival (OS) in the univariate analysis, and were still statistically significant after adjusting for the international staging system (ISS) and several other clinical variables in the multivariate analysis (Figure not shown). In summary, our results indicated a unique role of exosomic lncPSMA3-AS1 in transferring proteasome inhibitors resistance from MSCs to MM cells, through a novel exosomic lncPSMA3-AS1/PSMA3 signaling pathway. Exosomic PSMA3 and PSMA3-AS1 may serve as a potential therapeutic target for proteasome inhibitors resistance and a prognostic predictor for clinical response. Disclosures No relevant conflicts of interest to declare.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5111-5111
Author(s):  
Shaji Kumar ◽  
Jessica L. Haug ◽  
Linda Wellik ◽  
Thomas E. Witzig ◽  
John A. Lust ◽  
...  

Abstract Background: Abnormally increased tumor associated neovasculature plays an important role in tumor progression in solid tumors and hematological malignancies. In multiple myeloma (MM) bone marrow angiogenesis, measured in terms of microvessel density (MVD), has prognostic value, and appear to increase with disease progression from monoclonal gammopathy of undetermined significance to relapsed MM. We have shown that MVD has prognostic value in patients with newly diagnosed MM including patients undergoing upfront high dose therapy and stem cell transplantation, but comparison with other known prognostic factors has been limited by sample size. It is also not known whether the MVD adds prognostic value once the recently described International Staging System (ISS) is applied. The goal of this study was to determine the prognostic effect of bone marrow MVD in newly diagnosed MM relative to the ISS and other known prognostic factors. Methods: We studied 400 patients with newly diagnosed MM seen at the Mayo Clinic between March of 1988 and December 2001. Sections from bone marrow biopsy blocks from the time of initial diagnosis were studied by immunohistochemistry using antibodies against CD34 antigen to high light the endothelial cells. Under low power (100X); three areas with maximum number of microvessels (hotspots) were identified. Each of these areas was further studied at 400X magnification and the number of microvessels per high power field counted. The average of the three readings was taken as the MVD for the sample. In addition, the samples were graded as low, intermediate or high by using a visual estimate as previously described. Additional clinical data was extracted from medical records. Some of the patients have been included in previous studies related to angiogenesis. Results: A total of 400 patients in whom a bone marrow biopsy from within 30 days of diagnosis was available were studied. The pts were followed for a median of 37 months (Range: 1 month to 16.5 years) and 318 pts (80%) had died at the time of this analysis. The median MVD for the entire group was 14.7 (Range 0–168). The median overall survival for the three groups according to the MVD grade was lower for the high grade group (31.9 months) compared to the intermediate grade group (37.2 months) and the low grade group (not reached); P &lt;0.029, log rank test. We examined this group of patients for other factors prognostic for overall survival. Factors significant on univariate analysis included ISS stage, platelet count (&lt;150 vs. &gt;= 150 X 106/L), and plasma cell labeling index (&lt;1 vs &gt;=1). In a multivariate analysis using these variables and MVD as a continuous variable, high MVD and the ISS staging system were significantly associated with poorer survival (Table). Conclusion: In this large group of pts with newly diagnosed MM, we confirm the prognostic value of increased bone marrow angiogenesis. We examined the MVD as a continuous variable in the multivariate analysis for a closer evaluation of this measure in this comparison. More importantly, the prognostic value appears to be independent of the ISS and other major prognostic factors. The resultsof this study reinforces the biological relevance of this finding in MM. HR 95% CI P value MVD 1.006 (1.001, 1.011) 0.0279 ISS Stage I 0.37 (0.25, 0.56) &lt;0.001 ISS Stage II 0.58 (0.41, 0.83) 0.0025


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