scholarly journals Second allogeneic transplants for multiple myeloma: a report from the EBMT Chronic Malignancies Working Party

2021 ◽  
Author(s):  
Patrick J. Hayden ◽  
Dirk-Jan Eikema ◽  
Liesbeth C. de Wreede ◽  
Linda Koster ◽  
Nicolaus Kröger ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Graft Failure ◽  
Working Party ◽  
Failure Group ◽  
Sibling Donor ◽  
Grade Ii ◽  
Relapse Group ◽  
Relapsed Myeloma

AbstractThe EBMT Chronic Malignancies Working Party performed a retrospective analysis of 215 patients who underwent a second allo-HCT for myeloma between 1994 and 2017, 159 for relapse and 56 for graft failure. In the relapse group, overall survival (OS) was 38% (30–46%) at 2 years and 25% (17–32%) at 5 years. Patients who had a HLA-identical sibling (HLAid-Sib) donor for their first and second transplants had superior OS (5 year OS: HLAid-Sib/HLAid-Sib: 35% (24–46%); Others 9% (0–17%), p < 0.001). There was a significantly higher incidence of acute grade II-IV GvHD in those patients who had also developed GvHD following their initial HLA-identical sibling allo-HCT (HLAid-Sib/HLAid-Sib: 50% (33–67%); Other 22% (8–36%), p = 0.03). More as opposed to fewer than 2 years between transplants was associated with superior 5-yr OS (31% (21–40%) vs. 10% (1–20%), P = 0.005). On multivariate analysis, consecutive HLA-identical sibling donor transplants conferred a significant OS advantage (0.4 (0.24–0.67), p < 0.001). In the graft failure group, OS was 41% at 2 years. In summary, a second allo-HCT using a HLA-identical sibling donor, if available, provides the best transplant outcomes for relapsed myeloma in this setting.

Impact of Nucleated Cell Dose On Engraftment and Survival After Unrelated Cord Blood Transplantation for Severe Aplastic Anemia: A Retrospective Study On Behalf of Eurocord and the EBMT SAA WP.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3201-3201
Author(s):  
Regis Peffault de Latour ◽  
Duncan Purtill ◽  
Annalisa Ruggeri ◽  
Guillermo Sanz ◽  
Gerard Michel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Cord Blood ◽  
Aplastic Anemia ◽  
Graft Failure ◽  
Cord Blood Transplantation ◽  
Severe Aplastic Anemia ◽  
Blood Transplantation ◽  
Cd34 Cells ◽  
Grade Ii

Abstract Abstract 3201 Poster Board III-138 The outcome of patients with severe aplastic anemia (SAA) has greatly improved in recent years, but is still poor for patients who lack a sibling donor and who failed or relapsed after immunosuppressive therapy (IST). Recently, transplantation from unrelated donors has improved significantly. Umbilical cord blood transplantation (UCBT) has extended the availability of HSCT in the absence of a suitable donor but very little data is available in the setting of SAA. We conducted a retrospective analysis on 71 patients (33 male) diagnosed with SAA (9 with PNH) who received a single UCBT (n=57, 79%) or double UCBT (n=14, 19%) from January 1996 to January 2009 in 32 centers (23 EBMT centers). The median age was 13 years (range 2-68 years; 28 adults). Median disease duration before UCBT was 14 months (2-140). Fifty five patients (89%) received immunosuppressive therapy before transplantation and most patients were highly transfused prior to UCBT. Seven percent of cord blood units were identical to recipients (antigen level for HLA-A and B and allelic level for DRB1), 28% of units had 1 HLA mismatch and 65% had 2 or 3 HLA disparities. Median infused cell dose was 4.3 ×107 TNC/Kg (2.1-34.9) and 2.1 ×105 CD34 cells/Kg (0.4-19) for single UCBT and 7.4 ×107 TNC/Kg (5-14.7) and 3.5 ×105 CD34 cells/Kg (1-8.7) for double UCBT. Forty six patients (69%) received a reduced intensity conditioning regimen, most of which were fludarabine-based. Twenty three patients received a total body irradiation (2 Gray, n= 11) and antithymoglobulin was given to 53 patients (79%). Graft-versus host disease (GVHD) prophylaxis consisted mainly of cyclosporin+steroids (70% of patients). Cumulative incidence (CI) of neutrophil recovery (>500mm≥) at day 60 was 51±6% with a median time of 25 days (6-91). In multivariate analysis, the only factor associated with shorter time to engraftment and higher probability of engraftment was pre-freezing TNC dose (>3.9 107/Kg, HR: 1.5, 95%CI: 1-2.2, p=0.05). Chimerism analysis for patients who engrafted (n=37) showed full donor chimerism in 82%. The CI of grade II-IV acute GVHD was 20±5% (10 grade II, 5 grade III, 2 grade IV). Eleven patients of 34 at risk developed chronic GVHD leading to a CI of 18±5% at 3 years. With a median follow-up of 35 months (3 - 83), the estimated probability of 3-years overall survival (OS) was 38±6%. The main cause of death was graft failure associated with infections (n=14, 32%). In multivariate analysis, the only factor associated with survival was pre-freezing TNC dose (>3.9 107/Kg, RR: 0.4, 95%CI: 0.2-0.8, p=0.007). The estimated probability of 3-year overall survival (OS) for patients who received more than 3.9 107/Kg TNC was 45% compared to 18% for those who received less (Figure 1). Other factors such as number of HLA disparities or use of single or double CB unit were not associated with any outcome. However, the 3-year OS after single CBT was 37% and 43% after double CBT. In conclusion, this study highlights the fundamental role of the TNC dose (>3.9 × 107/kg TNC/Kg) on both engraftment and overall survival using cord blood as stem cell source in SAA. It could justify the use of double cord blood transplant if necessary for this indication. Graft failure remains a major issue in this particularly high risk population. Prospective well designed trials are necessary before the inclusion of UCBT in the treatment strategy of advanced severe aplastic anemia. Figure 1: Estimate 3-year overall survival according to the TNC dose Figure 1:. Estimate 3-year overall survival according to the TNC dose Disclosures No relevant conflicts of interest to declare.

Prognostic Factors Influencing Survival in Solitary Plasmacytoma: A SEER Database Analysis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1670-1670
Author(s):  
Paul Mehan ◽  
Giridharan Ramsingh ◽  
Jingqin Luo ◽  
Daniel Morgansztern ◽  
Ravi Vij
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Solitary Plasmacytoma ◽  
Seer Database ◽  
Disease Specific Survival ◽  
Factors Influencing ◽  
Younger Age ◽  
Disease Specific

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 &gt;60yo groups, respectively (p&lt;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 &gt;60yo group, respectively (p&lt;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&lt;0.0001) and the disease specific survival in the extramedullary PCM was 86.2% compared to 70.1% in the medullary PCM (p&lt;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 &lt;40yo --- --- --- --- --- --- 40–60yo 2.68 115~ 6.2 0.02 1.74 1.04~2.91 0.03 &gt;60yo 6.94 3.06~ 15.73 &lt;0.01 5.55 3.40~9.06 &lt;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 &lt;0.01 0.48 0.29~0.79 &lt;0.01 Primary Site Extramedullary --- --- --- --- --- --- Medullary 2.35 1.74~.3.18 &lt;0.01 1.37 1.13~1.65 &lt;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 &lt;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:.

The effect that β-lactam antibiotics have on progression free and overall survival in multiple myeloma patients undergoing autologous stem cell transplantation.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20518-e20518
Author(s):  
Marshall McKenna ◽  
Rena Feinman ◽  
Jaeil Ahn ◽  
Shuqi Wang ◽  
David H. Vesole ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Antibiotic Treatment ◽  
Gut Microbiome ◽  
Cell Transplant ◽  
Cox Regression Analysis ◽  
Antibiotic Effect ◽  
The Impact

e20518 Background: Gut microbiome dysbiosis is correlated with graft-versus-host disease (GVHD) in allogeneic stem cell transplant (allo-SCT) patients. In the allo-SCT population, antibiotics have been associated with increased risk for GVHD mortality and relapse due to loss of gut obligate anaerobes . It has been shown that antibiotics may negatively impact the efficacy of checkpoint inhibitors for patients with solid tumors. Based on these studies, we performed a retrospective analysis to determine if antibiotic treatment affects outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: This is a single institution retrospective study at Hackensack University Medical Center. A list of consecutive MM patients treated from 1/2012 to 12/2015 was obtained and an electronic medical record review of the first 217 who received ASCT was performed. Baseline characteristics, treatment history, transplant course and antibiotic treatment (including β-lactams, fluoroquinolones, macrolides, metronidazole, and vancomycin) were reviewed. Prophylactic antibiotics were excluded. Response was defined using the IMWG criteria. Median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Log rank tests were used to compare the difference in survival between stratified groups. The LASSO cox regression analysis method was used for multivariate analyses of PFS and OS. Results: Of the 217 patients, 205 patients were available for analysis. Median age at ASCT was 61. β-lactams were associated with decreased median PFS (1.95 vs 4.77 years (yrs), p < 0.01) and decreased median OS (7.51 vs 13.45 yrs, p = 0.01). Multivariate analysis adjusting for lasso-selected age, gender, complete remission (CR) after ASCT, and ISS demonstrated independent progression risk associated with β-lactam use (HR = 2.00, 95% CI, 1.28–3.12, p < 0.01). β-lactams were associated with worse OS in multivariate analysis adjusting for lasso-selected age, gender, CR after ASCT and high risk cytogenetics (HR = 1.89, 95% CI, 1.07–3.40, p = 0.03). Conclusions: In this preliminary study, β-lactams predicted for decreased PFS and OS compared to patients who did not receive β-lactams in MM patients undergoing ASCT. The study was limited by its retrospective nature but demonstrates one of the first evaluations of antibiotic effect on the ASCT population in MM. Prospective studies evaluating the impact of antimicrobials on patient outcomes and the gut microbiome are ongoing.

Monoclonal and Oligoclonal Bands After Single Autologous Stem Cell Transplantation in Patients with Multiple Myeloma: Impact On Overall Survival and Progression-Free Survival

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 595-595
Author(s):  
Victor Hugo Jimenez-Zepeda ◽  
Norman Franke ◽  
Andrew Winter ◽  
Suzanne Trudel ◽  
Christine I. Chen ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Stem Cell ◽  
Prognostic Factor ◽  
Light Chain ◽  
Progression Free Survival ◽  
Oligoclonal Bands ◽  
Cell Transplant ◽  
Free Survival

Abstract Abstract 595 Multiple myeloma is a malignancy of terminally differentiated plasma cells in which the malignant plasma cell clone usually produces a single abnormal unique monoclonal antibody with a constant isotype and light chain-restricted paraprotein. Recently, the occurrence of oligoclonal and monoclonal bands (OB/MB) not related to the original clone has been reported in patients with multiple myeloma who undergo autologous stem cell transplant (ASCT) and/or receive treatment with novel agents. Based on this data, the aim of our study was to assess the impact of monoclonal (MB) and oligoclonal bands (OB) occurrence on overall survival (OS) and progression-free survival (PFS) for MM patients undergoing single ASCT at Princess Margaret Hospital (PMH). Patient and Methods: All consecutive patients with documented MM undergoing single ASCT at PMH from 01/00 to 12/07 were evaluated. Oligoclonal banding (OB) was defined as the development of two or more concurrent monoclonal-type bands on the serum electrophoretic pattern, with either a different heavy or light chain component from the original M-protein band at day+100 post-ASCT. A new monoclonal band (MB) was defined as a heavy and/or light chain immunoglobulin distinct from the initially diagnosed MM. All cases with OB/MB in our series fulfilled the criteria of secondary monoclonal gammopathy of undetermined significance (MGUS). Multivariate analysis was performed with the Cox proportional hazard model. All analyses were performed using the SPSS 13.0 software. Results: Between January 2000 and December 2007, 788 patients were identified. Clinical and laboratory characteristics are listed in Table 1 Ninety-six patients (12.1%) developed OB/MB at 3 months from ASCT: 32 patients (33.3%) had OB, and 64 patients (66.7%) had a new MB. The median duration of the OB/MB was 12 months (range 4–52 months). OB and MB emerged after ASCT in 14% (60/409) of patients receiving VAD, 7.0% of patients receiving bortezomib (6/86) and 8.6% of patients receiving thalidomide (6/69) containing regimens as induction therapy. Thirty-seven (38%) patients with subsequent development of an OB/MB had achieved ≥VGPR after induction and this rate improved to 79% (76/96) at day +100 post-ASCT. Patients who did not develop OB/MB had a ≥VGPR rate of 28% and 58% after induction and day+100 post-ASCT, representing a lower rate than patients with OB/MB (p=0.07 and 0.002, respectively). At the time of this analysis, 65 (67.7%) of the cohort patients who developed OB/MB are alive and 68 have already progressed (70.8%). Median overall survival for patients who did not develop OB/MB at day+100 post ASCT was 74.5 months compared to 115.5 months for those who developed OB/MB (p=0.0098). Multivariate analysis shows developing of OB/MB as an independent prognostic factor for OS and PFS (p=0.006 and 0.021, respectively). (Fig1a-b) The duration of the OB/MB did not affect OS and PFS. In conclusion, OB/MB occurrence is an important prognostic factor in MM patients who undergo ASCT, the biological significance and its impact on clinical outcomes should be prospectively validated. Disclosures: Chen: Roche: Honoraria; Johnson & Johnson, Lundbeck, Celgene: Consultancy; Johnson & Johnson, Celgene, GlaxoSmithKline: Research Funding. Tiedemann:Janssen: Honoraria; Celgene: Honoraria. Kukreti:Roche: Honoraria.

Graft-Versus-Host Disease (GVHD) and Survival Outcomes after HLA-Haploidentical (Haplo) Bone Marrow Transplant (BMT) Compare Favorably with Matched Related Donor (MRD), and Matched Unrelated Donor (MUD) BMT Utilizing High-Dose Posttransplantation Cyclophosphamide (PTCy)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 730-730 ◽  
Author(s):  
Shannon R. McCurdy ◽  
Christopher G. Kanakry ◽  
Yvette L. Kasamon ◽  
Javier Bolanos Meade ◽  
Hua-Ling Tsai ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Chronic Gvhd ◽  
Lower Probability ◽  
Survival Outcomes ◽  
High Dose ◽  
Grade Ii ◽  
The Impact ◽  
Grade Iii

Abstract Background: High-dose PTCy has been shown to effectively reduce acute (a) and chronic (c) GVHD after MRD and MUD BMT and to enable the safe implementation of haplo BMT. However, GVHD-related risk factors and survival outcomes, the impact of donor type, and novel composite endpoints, such as cGVHD-free relapse-free survival (cGFRFS), have not been fully characterized in BMT with PTCy. Methods: We retrospectively analyzed 582 consecutive adult pts with advanced or poor-risk hematologic malignancies who received allogeneic BMT with PTCy at Johns Hopkins from 2002-2012. All pts received a T-cell replete bone marrow graft and PTCy (50 mg/kg/d IV) on D+3 and +4. Platforms consisted of: 1) myeloablative conditioning (MAC) with Busulfan/Fludarabine or Busulfan/Cy followed by MRD (n = 193; 33%) or MUD (n=119; 20%) allografting and PTCy as sole GVHD prophylaxis; or 2) nonmyeloablative (NMA) conditioning with Fludarabine/Cy/TBI followed by related haplo (n = 270; 46%) allografting and PTCy, mycophenolate mofetil D5-35, and tacrolimus D5-180. Results: The median follow up was 4 (range 0.3-11.4) years (y). The median pt age at time of BMT was 49 (range 18-66) in the MAC cohort and 54 (range 18-73) in the NMA cohort. On competing risk analysis, the D200 probability of grade II-IV aGVHD was 27% after haplo, 37% after MRD, and 50% after MUD BMT, and grade III-IV aGVHD was 4%, 11%, and 14% respectively. The 3-y probability of cGVHD was 12% after haplo, 8% after MRD, and 19% after MUD BMT. On multivariate analysis adjusted for age and original disease risk index (DRI), MRD and MUD BMT were associated with a statistically significantly higher risk of grade II-IV and grade III-IV aGVHD compared to haplo BMT (each p ≤ 0.001). Compared to haplo BMT, MUD, but not MRD, BMT was also associated with a significantly higher risk of cGVHD (p = 0.009). On multivariate analysis, female into male allografting was independently associated with a higher risk of cGVHD (p = 0.007), whereas age and CMV serostatus of the pt and donor were not statistically significantly associated with risks of acute or chronic GVHD. Pts with grade II-IV aGVHD or cGVHD had a lower probability of relapse, but a higher probability of nonrelapse mortality (NRM) at 3 y compared to pts without GVHD. Among pts with GVHD, an HCT-CI score ≥ 5 was associated with significantly inferior overall survival compared to lower HCT-CI scores. Although MAC matched BMT was associated with less relapse risk than NMA haplo BMT, the 3-y probabilities of NRM, DFS, and overall survival were comparable between the transplant platforms (Table). On multivariate analysis adjusted for pt age and DRI, there were no statistically significant differences in DFS, OS, or cGFRFS in MAC related or unrelated BMT compared to NMA haplo BMT. Conclusions: High-dose PTCy safely modulates acute and chronic GVHD across multiple BMT platforms. The apparently lower risk of aGVHD after NMA haplo BMT with PTCy likely reflects the reduced conditioning intensity and longer duration of immunosuppression utilized. Despite the limitations inherent to a retrospective analysis, these data suggest that key outcomes after BMT with PTCy are comparable across donor types and conditioning intensities. Notably, in all these settings, 3-y estimates of cGFRFS appeared to approach those of DFS. Thus, PTCy may minimize the late morbidity and mortality of cGVHD and allow earlier implementation of novel posttransplantation strategies for relapse prevention. TableOutcomes of BMT with PTCy3-y probabilitiesNMA HaploMAC MRD*MAC MUD*NRM141717DFS384144OS495856cGFRFS313533 * p = NS for all comparisons to haplo BMT on multivariate analysis Disclosures Off Label Use: High-dose posttransplantation cyclophosphamide.

scholarly journals Exosome-Transmitted PSMA3 and PSMA3-AS1 Promotes Proteasome Inhibitors Resistance in Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4434-4434
Author(s):  
Wenzhuo Zhuang ◽  
Sha Song ◽  
Huiying Han ◽  
Gao Fan ◽  
Nengjun Yi ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Clinical Response ◽  
Univariate Analysis ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Mrna Levels ◽  
Free Survival ◽  
Myeloma Cells

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.

scholarly journals Characteristics and Outcome of Multiple Myeloma Patients Presenting with Anemia Only: a Retrospective Multi-Center Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5578-5578
Author(s):  
Tamir Shragai ◽  
Moshe E. Gatt ◽  
Adir Shaulov ◽  
Eirini Katodritou ◽  
Theodora Triantafyllou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
High Risk ◽  
Renal Involvement ◽  
Response To Therapy ◽  
Bone Lesions ◽  
Hematopoietic Stem ◽  
Entire Cohort

Abstract Background: Multiple myeloma (MM) is defined as bone marrow monoclonal plasmocytosis combined with either specific laboratory or imaging findings (SLIM criteria) or one or more of the following myeloma defining events (MDE) including anemia, hypercalcemia, renal failure or lytic bone lesions (CRAB criteria). Patients who presents with anemia but without additional CRAB criteria are scarce, and their clinical course has not yet been characterized in the literature. The current study was designed to evaluate the characteristics, responsiveness to treatment, progression free and overall survival in newly diagnosed MM patients presenting with anemia only. Methods: We retrospectively analyzed the clinical features and outcomes of MM patients that presented with anemia as the only CRAB criteria (i.e. having no evidence of skeletal involvement by PETCT, MRI or total body CT, no renal involvement and no hypercalcemia), that were diagnosed and treated in 9 Israeli and Greek centers between 2010 and 2018. Baseline characteristics at diagnosis, ISS score, treatment regimens, depth and duration of response (by IMWG criteria), hemoglobin (HB) levels during treatment and overall survival (OS) were collected and analyzed. Results: 63 (28 females) patients were included in the analysis. The median age was 72.2 (range 34.4-91.9) years. The median HB level at diagnosis was 9.4 g/l (IQR 6.0-12.0) and median platelets level was 172000 (IQR 59000-454000). The median percent of plasma cells (PCs) in bone marrow at diagnosis was 60% (range 20% to 99%). 11 out of 56 (19%) patients had a high-risk FISH (t 4;14, t 14;16 or del 17p). Bortezomib -based induction was administered in 83%, and upfront autologous hematopoietic stem cell transplantation (autoHCT) was employed in 32%. ORR to 1st line was 87%. 37 (62%) achieved ≥ VGPR, 16 (25%) PR and 7 (13%) SD/PD. Significant predictors for achieving at least VGPR vs. SD or PD were higher albumin level at diagnosis (3.9±0.5 g/l vs. 3.5±0.4g/l, p<0.00), maximal HB level during treatment (13.0±1.0g/l vs. 11.5±1.2 g/l respectively, p<0.00) and maximal improvement in HB level during treatment (median 3.2 [IQR 2.2-4.5]g/l vs 2.2 [IQR 1.1-3.2]g/l, respectively, p<0.00). Median PFS in the entire cohort was 22.1±5.82 months. Predictors for PFS duration on first-line therapy were bone marrow plasmocytosis (HR 1.012 [95% CI 1.001-1.037] p=0.03) and maximal improvement in hemoglobin level (HR 0.71 [95% CI 0.55-0.91] p< 0.00). Multivariate analysis confirmed bone marrow plasmocytosis (HR 1.03 [95% CI 1.01-1.05], p<0.00), higher HB level at diagnosis (HR 0.43 [95% CI 0.27-0.67], p<0.00) and maximal improvement in HB level during therapy (HR 0.37 [95% CI 0.25-0.56] p<0.00) to be associated with longer PFS. In multivariate analysis restricted to non-transplanted patients, factors associated with longer PFS were bone marrow plasmocytosis>60% (HR 4.6 [95% CI 1.5-14.0] p<0.00), HB level at diagnosis (HR 0.32 [95% CI 0.17-0.60], p<0.00), maximal HB improvement (HR 0.23 [95% CI 0.13-0.41] p<0.00) and older age (HR 0.92 [95% CI 0.87-0.97], p<0.00). Within a median follow-up of 34 months, 19 (31%) patients have died; 12 due to PD. The median OS for the entire cohort was 65.93 months and the 3 years mortality rate was 17.5%. Predictors of mortality were high risk cytogenetics (HR 3.01 [95% CI 1.02-8.88] p= 0.04), maximal HB improvement during therapy (HR 0.73, [95% CI 0.54-0.99] p=0.04), and bone marrow plasmocytosis (HR 1.04 [95% CI 1.01 to 1.07] p= 0<.00). Furthermore, median OS for patients <60% plasmocytosis was not reached, compared to 45.3 months for patients with plasmocytosis ≥60% (p=0.048) (figure 1). Only bone marrow plasmocytosis remained as significant factor for mortality in a multivariate analysis (HR 1.04 [95% CI 1.01-1.08], p=0.01). Conclusion: MM patients presenting with anemia only, often have a remarkable bone marrow plasmocytosis Responsiveness to therapy, PFS and OS, depend on the degree of BM plasmocytosis and HB level at diagnosis, both reflecting disease burden. In line with that, response to therapy and long -term PFS can be accurately predicted by the degree of improvement in HB level. In general , patients presenting with anemia only , although they do not have renal impairment or bone disease, seem to have a relatively poor OS of approximately 5 years only , suggesting that these patients may have a relatively "rapidly growing tumor", precluding the development of bone and renal disease. Disclosures No relevant conflicts of interest to declare.

Prognostic Value of Bone Marrow Angiogenesis in Newly Diagnosed Multiple Myeloma: A Comparison with Conventional Prognostic Factors.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5111-5111
Author(s):  
Shaji Kumar ◽  
Jessica L. Haug ◽  
Linda Wellik ◽  
Thomas E. Witzig ◽  
John A. Lust ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Prognostic Value ◽  
Staging System ◽  
Continuous Variable ◽  
Newly Diagnosed ◽  
Grade Group

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

Recombinant Human Erythropoietin May Negatively Influence Survival in Newly Diagnosed Patients with Multiple Myeloma: A Single Center Experience in 246 Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4814-4814
Author(s):  
Eirini Katodritou ◽  
Evgenia Verrou ◽  
Anastasia Banti ◽  
Vassiliki Gastari ◽  
Dimitra Mihou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Serum Creatinine ◽  
Serum Ferritin ◽  
Recombinant Human Erythropoietin ◽  
Newly Diagnosed ◽  
Human Erythropoietin ◽  
The Impact

Abstract Anemia is a common clinical problem in patients with multiple myeloma (MM), which adversely affects their quality of life. The administration of recombinant human erythropoietin (r-HuEPO) improves anemia in about 2/3 of patients. However, it has not been clarified if r-HuEPO has any beneficial or adverse impact on the overall survival, particularly in a clear population of MM patients. The aim of this study was to examine the impact of r-HuEPO administration on the overall survival of newly diagnosed patients with MM. Two hundred forty-six newly diagnosed symptomatic MM patients, 139 males and 107 females, with a median age of 67 years (range 29–90) were studied. R-HuEPO was administered according to standard criteria, when Hb levels were less than 10.5g/dl and it was titrated and discontinued when Hb level reached 13g/dl. The parameters evaluated for predicting survival were: Age, sex, Hb, platelets, bone marrow infiltration, serum creatinine, serum ferritin, ISS score, B2-microglobulin and r-HuEPO administration. Cox regression was used for the univariate and multivariate analysis. One hundred forty-two patients received r-HuEPO and 105 did not. The median duration of r-HuEPO administration was 6 weeks (range 4–10) and the median hemoglobin level of patients who received r-huEPO, was 9.2g/dl (range 7.3–10.5 g/dl). The median follow up was 31 months (range 1–231). The univariate analysis showed that, age, Hb, platelets, serum creatinine, serum ferritin, ISS score, B2-microglobulin and r-HuEPO administration predicted for survival (p<0.05). The multivariate analysis demonstrated that, age, ISS score and r-HuEPO administration were statistically significant for predicting overall survival (p<0.05). The median survival of patients in the r-HuEPO group was 22 months (SD 22.7mo) whereas in the group without r-HuEPO administration it was 40 months (SD 35.8mo) (p=0.02). These results, suggest that r-HuEPO administration may negatively influence overall survival in newly diagnosed patients with MM and therefore, within this context, it should be used with caution. The large number of exclusively MM patients with a long follow up included in this study, highlights the importance of these results.

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