Genetic Abnormalities in Multiple Myeloma: Prognostic and Therapeutic Implications

Some genetic abnormalities of multiple myeloma (MM) detected more than two decades ago remain major prognostic factors. In recent years, the introduction of cutting-edge genomic methodologies has enabled the extensive deciphering of genomic events in MM. Although none of the alterations newly discovered have significantly improved the stratification of the outcome of patients with MM, some of them, point mutations in particular, are promising targets for the development of personalized medicine. This review summarizes the main genetic abnormalities described in MM together with their prognostic impact, and the therapeutic approaches potentially aimed at abrogating the undesirable pathogenic effect of each alteration.

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Outcome and Prognostic Factors of 17p Deleted Multiple Myeloma Patients

Blood ◽

10.1182/blood.v124.21.3994.3994 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3994-3994

Author(s):

Miriam Kull ◽

Veronica Teleanu ◽

Daniela Hayde ◽

Katrin Wildbihler ◽

Stephanie Harsdorf ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factors ◽

Univariate Analysis ◽

Autologous Transplantation ◽

Novel Agents ◽

Treatment Modalities ◽

Prognostic Impact ◽

The Novel ◽

Clone Size ◽

Genetic Abnormalities

Abstract Introduction: During the last decade, the outcome of patients (pts) with symptomatic multiple myeloma (MM) has markedly improved. However, there is still a significant proportion of pts who do not achieve a longtime control of their disease. In particular, pts presenting with a deletion 17p (del17p) still have dismal prognosis. In order to better stratify this important group of MM pts we sought to investigate the prognostic impact of the following parameters in a larger cohort of del17p pts: del17p clone size, concomitant genetic abnormalities, treatment modalities and the incorporation of the novel agents lenalidomide and bortezomib. Methods: We identified 54 MM pts diagnosed between 1998 – 2012 who had a del17p at diagnosis and were treated at the University Hospital of Ulm. The patients were screened for additional chromosomal aberrations by fluorescence in situ hybridization (FISH) performed on purified bone marrow plasma cells. Results: The median age at MM diagnosis was 59 years and the proportion of male pts was 52%. At presentation the median del17p clone size was 83% (range: 28%-98%). In the vast majority of cases (83%) the presence of a del17p was associated with the presence of a del13q14. Other concomitant genetic abnormalities detected by FISH were t(4;14) in 17%, t(11;14) in 30% and gain at 1q21 (+1q21) in 31% of cases (figure 1). The median overall survival (OS) was poor (18.9 months) and did not change substantially over time (similar median survival in pts diagnosed before 2006 versus pts diagnosed thereafter). The del17p clone size had no impact on OS, neither the presence of a t(4;14) or a t(11;14). In patients with an additional +1q21 OS was significantly shorter (15.2 versus (v) 32.4 months; p=0,032). The incorporation of one of the novel agents into first-line treatment did not change the outcome significantly. In contrast, pts receiving at least one autologous transplantation showed a significantly longer OS (33.1 v 12.7 months; figure 2). On univariate analysis there was an improved median OS for pts undergoing an allogeneic transplantation (n=15; 32.4 v 14.4 months; p=0.025). In multivariate analysis ISS stage and the implementation of an autologous transplantation remained significant prognostic factors for OS. Conclusions: The outcome of MM pts with a del17p remains poor, even after the introduction of lenalidomide and bortezomib into clinical practice. The development of novel therapeutic strategies therefore is urgently warranted. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Significance of Modified Risk Stratification Msmart 3.0 and Autologous Stem Cell Transplantation for Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-130092 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5593-5593

Author(s):

Andrey Garifullin ◽

Sergei Voloshin ◽

Vasily Shuvaev ◽

Irina Martynkevich ◽

Elizaveta Kleina ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Risk Stratification ◽

Risk Group ◽

High Risk Group ◽

Prognostic Impact ◽

Newly Diagnosed ◽

Genetic Abnormalities ◽

Standard Risk

Background The risk-stratification systems are repeatedly updated in accordance with the emergence of new information about the prognostic impact of anomalies and other factors. The most extensive and modern system in this time is mSMART risk stratification involving many parameters such as genetic anomalies, albumin, beta-2-microglobulin, LDH, Plasma Cell S-phase and GEP levels. It is possible to use risk-adapted treatment programs with or without ASCT. Nevertheless, the role of complex karyotype, combination of genetic abnormalities and ASCT remains unclear. Aims To estimate the genetic abnormalities in patients with newly diagnosed multiple myeloma and define the role of risk-stratification and ASCT in prognosis of disease. Methods The study included 159 patients (median age 63 years, range 28 - 83; male: female ratio - 1:1.37) with NDMM. Metaphase cytogenetics on bone marrow samples was done by standard GTG-method. FISH analyses were performed according to the manufacturer's protocol for detection primary IgH translocations, 13q (13q14/13q34) deletion, 1p32/1q21 amplification/deletion, P53/cen 17 deletion (MetaSystems DNA probes). We additional searched the t(4;14), t(6;14), t(11;14), t(14;16) and t(14;20) in patients with IgH translocation. All patient was treated by bortezomib-based programs (VD, CVD, VMP, PAD). ASCT was performed at 42% patients. Results The frequency of genetic abnormalities in NDMM patients was 49% (78/159). IgH translocation was detected in 26.4% (42/159) patients: t(11;14) - 16.3% (26/159), t(4;14) - 5.0% (8/159); TP53/del17p - 5.6% (9/159); 1p32/1q21 amp/del - 12% (19/159); hypodiploidy - 3.1% (5/159); hyperdiploidy - 1.25% (2/159); del5q - 0,6% (1/159); other - not found. Combination two aberrations was discovered in 11.9% (19/159) patients, complex abnormalities (>3 aberrations) - in 4.4% (7/159) patients. The median OS in "two aberration" and "complex abnormalities" groups were lower than in standard-risk mSMART 3.0 (normal, t(11;14), hypodiploidy, hyperdiploidy and other): 49 months, 26 months and was not reached, respectively (p=.00015). The median PFS for these groups was 12 months, 11 months and 30 months, respectively (p=.011). Differences between "two aberration" and "complex abnormalities" groups were not find (p> .05). We modified high-risk (gain 1q, p53 mutation, del 17p deletion, t(4;14), t(14;16), t(14;20), R-ISS stage III, double and triple hit myeloma) mSMART 3.0 by adding "two aberration" and "complex abnormalities" groups on based the OS and PFS results. The final analysis was based on the results of the complex examination of 87 patients: 53 patients in standard-risk group and 34 patients in high-risk group. The median OS in standard-risk mSMART 3.0 was not reached, in high-risk mSMART 3.0mod - 48 months; 5-years OS was 62% and 38%, respectively (p=0.0073). The median PFS was 43 and 29 months, respectively (p=.09). The best results of OS and PFS were reach in both groups of patient who performed ASCT. The median OS in standard-risk mSMART 3.0 with ASCT (n=37) was not reached, in high-risk mSMART 3.0mod with ASCT - 48 months (n=20); standard-risk mSMART 3.0 without ASCT - 40 months (n=16); in high-risk mSMART 3.0mod without ASCT - 22 months (n=14); 5-years OS was 81%, 60%, 33% and 28%, respectively (p=0.0015). The median PFS was not reached, 46, 22 and 19 months, respectively (p=.017). Conclusions The combination of two aberrations and complex abnormalities is unfavorable prognostic markers. The median OS and PFS was higher in standard-risk than high-risk group according mSMART 3.0mod. The ASCT can improve treatment's outcomes and life expectancy especially in patients with high-risk. It can be useful for update risk stratification in a future. Disclosures Shuvaev: Novartis: Consultancy; Pfize: Honoraria; Fusion Pharma: Consultancy; BMS: Consultancy.

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Prognostic Impact of Clinico-Pathological Parameters on the Outcome of Multiple Myeloma Patients: A Single-Center Analysis on 143 Consecutive Patients Treated with Standard Versus Intensive Chemotherapy.

Blood ◽

10.1182/blood.v108.11.5436.5436 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5436-5436

Author(s):

Truc Ngo ◽

Martina Kleber ◽

Barbara Deschler ◽

Gabriele Ihorst ◽

Monika Engelhardt

Keyword(s):

Multiple Myeloma ◽

Prognostic Factors ◽

Statistical Significance ◽

Performance Status ◽

Stage Ii ◽

Treatment Modalities ◽

High Dose ◽

Prognostic Impact ◽

Group A ◽

Group B

Abstract Multiple myeloma (MM) remains an incurable disease, with significant variation in the response and survival even with current treatment modalities, such as high-dose chemotherapy (CTx) and autologous stem cell transplantation (auto-SCT), novel drugs and intensive supportives. Hence, prognostic parameters that help to predict the benefit of different therapeutics are of utmost importance to be defined further. The objective of this analysis was to determine whether treatment selection and response are markedly influenced by specific clinico-pathological parameters and how these effect overall survival (OS). Of 143 consecutive MM patients (pts) receiving either standard therapy (Std-CTx, group A, n=79) or auto-SCT (group B, n=64) at our center between 1997–2003, gender, age, MM-type, -stage, number of CTx lines, LDH,β 2-MG and bone marrow (BM) infiltration were evaluated on response and survival in uni- and multivariate analyses and hazard ratios (HR) were determined. To further pay tribute to pts’ average age, as MM is primarily a disease of the elderly, special attention was paid to the influence of the performance status (Karnofsky Index=KI) and number of concurrent diagnoses (CD). Pts in groups A and B were comparable in terms of gender distribution, MM type, CD and LDH-level. However, group A as compared to B pts were older (65 vs. 56 yrs), had received more radiation (26 vs. 19%) and showed higher β2-MG (5 vs. 2.3g/L; respectively). Moreover, pts in group B as compared to A had more advanced disease (Durie and Salmon [D&S] stage II/III: 92 vs. 65%), a higher BM-infiltration (40 vs. 30%), and were treated later in their disease course. In group A pts, HR were increased for β2-MG>3, D&S stage II/III, stage B disease, CD>1, LDH>200U/L and age >60y, and HR decreased for females and KI>80%, reaching significance for β2-MG, D&S stage II/III, stage B disease, CD and KI. Although these HR were also observed for group B pts, none of these prognostic factors reached statistical significance. Multivariate analysis on all pts identified β2-MG >3mg/L and age >60y as independent prognostic factors, with HRs of 3.6 (95% CI 1.6–8.1) and 2.1 (CI 0.9–5.0), respectively. Of note, current CR/PR rates for group A and B pts are 4 vs. 20%, and at last follow-up (6/2006) median OS from treatment initiation is 49.5% vs. 61.4%, respectively. Our data show that an elevated β2-MG, D&S stage II/III, stage B disease, more than 1 CD and reduced performance status before therapy, negatively influence response and OS in Std-group pts, whereas these do not significantly impact HR in auto-SCT pts. We conclude that MM pts benefit from auto-SCT independently of prognostic factors which, however, do impact outcome with Std-CTx alone. Since randomized trials have repetitively shown response and survival with auto-SCT to be superior to Std-CTx, we propose that pts with the above prognostic factors should be carefully evaluated for intensive therapies, as this analysis accentuates that auto-SCT is the treatment of choice for eligible MM pts.

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Prognostic Relevance of Genomic Aberrations In Light Chain Only Multiple Myeloma

Blood ◽

10.1182/blood.v116.21.4036.4036 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4036-4036

Author(s):

Nan Jiang ◽

Connie Qi ◽

Young Trieu ◽

Donna E. Reece ◽

Hong Chang

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

Prognostic Factor ◽

Genetic Risk ◽

Plasma Cells ◽

Chromosome 1 ◽

Prognostic Impact ◽

Cell Transplant ◽

Genetic Abnormalities ◽

Genomic Aberrations

Abstract Abstract 4036 Background: Multiple myeloma (MM) is characterized by an expansion of clonal plasma cells with production of monoclonal immunoglobulin. The majority of MM patients produce an intact immunoglobulin, but in a subset of patients (≂f15%), the tumor produces monoclonal light chains only (LCO). Although specific genomic aberrations have emerged as a major prognostic factor in MM, the genomic changes and their prognostic impact on LCO myeloma patients are not clear. Methods: A total of 86 patients with LCO MM identified by urine and serum immunoelectrophoresis were included in this study. They were all uniformly treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT). The genomic risk factors including del(13q), del(17p), t(4;14), 1q21 gain and 1p loss– were evaluated by cytoplasmic fluorescence in situ hybridization (cIg-FISH) in clonal plasma cells and correlated with patients clinical outcomes. Results: cIg-FISH detected del(13q) in 41%, t(4;14) in 12%, del(17p) in18%, 1q21 gain in 25%, and 1p loss in 19% of the evaluable cases. In our entire cohort, the median post-transplant follow-up was 36.5 months with a median progression free survival (PFS) of 24.8 months [95% confidence interval (CI): 18.4–31.3] and overall survival (OS) of 68.8 months (95% CI: 50.2–87.5). Patients with del(13q) and 1q21 gains had a significantly shorter PFS (median 15.8 vs. 33.4 months, p=0.002; median 19.1 vs. 33.4 months, p=0.011, respectively), and shorter OS (median 56.2 vs. 80.4 months, p=0.021; median 26.9 vs. 77.9 months, p=0.006, respectively), than those without such genetic abnormalities. In addition, 1p loss was associated with a significantly shorter PFS (median 18.2 vs. 37.9 months, p=0.001). However, there was no significant difference in PFS or OS in patients with or without the high-risk genetic factors t(4;14) or del(17p). On multivariate analysis adjusting for all 5 genetic risk factors, del(13q) was an independent prognostic factor for PFS (p=0.011) and OS (p=0.045). Conclusion: Although LCO MM had a similar incidence of genetic abnormalities to common MM, only del(13q) and chromosome 1 abnormalities appear to adversely affect the survival in our cohort. Further larger, prospective studies are warranted to verify the role of these genomic aberrations in the genetic risk stratification of LCO MM. Disclosures: Reece: Celgene: Honoraria, Research Funding.

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Impact of Genetic Abnormalities After Allogeneic Stem Cell Transplantation in Multiple Myeloma: Report of the Societe Francaise De Greffe De Moelle Et De Therapie Cellulaire.

Blood ◽

10.1182/blood.v114.22.1187.1187 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1187-1187

Author(s):

Damien Roos-Weil ◽

Philippe Moreau ◽

Herve Avet Loiseau ◽

Mathieu Kuentz ◽

Noel-Jean Milpied ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Partial Response ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

High Dose ◽

Fish Analysis ◽

Prognostic Impact ◽

Younger Age ◽

Genetic Abnormalities

Abstract Abstract 1187 Poster Board I-209 Background and aim: Del (13q), t (4;14) and del (17p) are well-recognized poor prognostic genetic abnormalities in multiple myeloma after standard chemotherapy and autologous stem cell transplantation (SCT). We investigated the prognostic impact of these genetic abnormalities, detected by fluorescence in situ hybridization (FISH), on the outcome in patients who underwent allogeneic SCT. Patients and methods: This is a retrospective study performed in 20 centres for a total of 175 patients, using the database register of the SFGM-TC and the cytogenetic files of the IFM and MAG groups. The median age of the population at diagnosis was 51 years (range, 28-62 years). FISH analysis was performed either at diagnosis or at relapse before allograft. Chromosomal abnormalities were found in 127 of 175 patients (73%), distributed as follows (in percent of patients evaluable for each abnormality): 59% for del (13q), 26% for t (4;14), 25% for del (17p), 24% for t (11;14) and 4% for t (14;16). Béta2microglobuline was superior to 4 mg/L in 51% and more than 92% had received at least one prior high-dose therapy followed by autologous SCT. Forty percent of patients were transplanted in the first course of the disease. Most patients (79%) received two or less lines of treatments before transplantation. Prior treatments included thalidomide and bortezomib in, respectively, 25% and 27% of cases. At transplant, 12% of patients were in complete response (CR), 6% in very good partial response (VGPR), 66% in partial response (PR), 8% in stable disease (SD) and 8% in progressive disease (PD). The median time from diagnosis to transplant was 15 months (range, 4-175 months). Seventy seven percent of patients received reduced conditioning regimen, including antithymoglobulin (ATG) in 52% of cases. Peripheral blood and bone marrow were used as the source of cells in 78% and 19%, respectively. Most donors (69%) were match related donors. Results: Best response to transplant was CR, VGPR, PR, SD and PD in, respectively, 38%, 12%, 33%, 7% and 10% (among 130 patients with available data). With a median follow-up of 36 months, the 3-year progression free survival (PFS) and overall survival (OS) were 34% and 52%, respectively. Three-year post-transplant progression occurred in 53%. One-year transplant-related mortality (TRM) was 21%. Grade II to IV acute graft-versus-host disease (GvHD) was present in 33%. Limited and extensive chronic GvHD occurred respectively in 16% and 23% of evaluable patients. In univariate analysis, del (13q), t (4;14) and del (17p) had no impact on the PFS, OS and progression. Three-year PFS and OS were, respectively, 39% and 53% for del (13q), 29% and 38% for del (17p), 26% and 38% for t (4;14), 25% and 43% for t (11;14), 31% and 45% for the group of patients without any of these cytogenetic abnormalities. Patients transplanted in the first course of the disease with t (4;14) (n=14) and with del (17p) (n=6) had a 3-year PFS of 36% and 44%, respectively. In multivariate analysis, better PFS was significantly associated with younger age (P= 0.02, HR=1.1), sensitive disease status at transplant (P=0.04, HR=0.55) and two or less prior lines of treatments (P<0.001, HR=0.3); better OS was associated with younger age and two or less prior lines of treatments (respectively, P=0.01, HR=1.1; and P=0.02, HR=0.5). Conclusion: These data suggest no impact of genetic abnormalities after allogeneic SCT for multiple myeloma and did not confirm the encouraging results of allogeneic SCT for t (4;14) myeloma (Schilling et al., Leukemia, 2008). More studies are warranted to better define the possible role of early allograft in poor prognostic myeloma and to further develop risk-adapted strategy based on cytogenetics. Disclosures: No relevant conflicts of interest to declare.

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Prognostic Impact Of Comorbidity In Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.5340.5340 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5340-5340 ◽

Cited By ~ 1

Author(s):

Rafael Ríos Tamayo ◽

Joaquín Martínez López ◽

Manuel Jurado ◽

María Esther Clavero Sánchez ◽

Fátima López Jiménez ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factors ◽

Liver Disease ◽

Plasma Cell ◽

Cox Regression ◽

Conflicts Of Interest ◽

Statistical Significance ◽

Univariate Analysis ◽

Prognostic Impact ◽

Alcoholic Fatty Liver

Abstract Multiple myeloma (MM) is a heterogeneous disease. Evaluation of prognostic factors and risk stratification at diagnosis is necessary to compare outcome. Attempts have been made to apply a comorbidity score in the clinical sitting, but a standardized general approach is still lacking. We hypothesized that a comprehensive examination of every associated disease in a large cohort of patients could better highlight the prognostic impact of comorbidity in MM. All consecutive patients diagnosed in our institution, from 1993 to 2013, with symptomatic MM according to IMWG criteria were included in our population-based MM registry. Patients with plasma cell leukemia or with palliative management were excluded. Clinical variables analyzed were: age, sex, Durie-Salmon, International Scoring System (ISS), percentage of plasma cell in bone marrow by morphology (PC), serum creatinine (Cr) and estimated glomerular filtration rate according with Modification of Diet in Renal Disease (eGFR-MDRD). The following comorbodities were analysed: hypertension (HTA), diabetes (DM), obesity (OB) (body mass index > 30 Kg/m2), hyperlipaemia (HL), prior malignancy (PM), hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), peptic ulcer (PU), thromboembolism (TE), renal transplant (RT), splenectomy (S), cutaneous disease (CD), amyloidosis (AM), heart disease (HD) (arrhythmia, congestive heart failure, coronary artery disease, other), lung disease (LD) (chronic obstructive pulmonary disease, asthma, other), liver disease (HE) (cirrhosis, non-alcoholic fatty liver disease, other), neurological disorder (ND), psychiatric disorder (PD) and rheumatologic disorder (RD). Kaplan-Meier method was used to estimate OS curves. Cox regression was used to determine the prognostic impact of each comorbidity in a univariate and multivariate model. 311 patients were eligible. Median age was 66 years (12-91), 148 men (47.6 %) and 163 women. Percentage of comorbidities was: HTA 45; OB 32.5; DM 20.4; HD 20.4; LD 15.2; PU 10; HL 9.7; ND 8; PM 7.8; PD 6.5; HBV 3.9; HE 3.9; TE 3.6; RD 3,5; AM 2.3; HCV 1.9; CD 1.6; S 1; RT 0.6; HIV 0.3. 63 patients (20.4 %) showed no comorbidities. Univariate analysis (table 1) demonstrated that AM (P=0.022), HCV (0.038), HIV (0.022), PD (0.015) and ND (0.05) were significantly associated with shorter OS. The variables associated with mortality in the multivariate analysis were age (p=0.002), ISS (III vs I: p=0.01), PC (p=0.05) and Cr (p=0.02). Results will be validated in another MM series and presented during the meeting. The overall prognosis of MM depends on a variety of host and disease-related characteristics. We confirm age, ISS, PC and Cr as robust and independent prognostic factors. Adjusting for these factors, no isolated comorbidity reach statistical significance; however, comorbidity seems to have a role in MM prognosis. More studies are warranted to define the prognostic impact of comorbidities in MM. Disclosures: No relevant conflicts of interest to declare.

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Neural Stem Cell Marker Nestin As a Novel Unfavorable Prognostic Biomarker for Multiple Myeloma

Blood ◽

10.1182/blood.v128.22.5608.5608 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5608-5608

Author(s):

Hana Svachova ◽

Lucie Rihova ◽

Lenka Besse ◽

Fedor Kryukov ◽

Lenka Zahradova ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Prognostic Factors ◽

Solid Tumors ◽

Research Funding ◽

Roc Analysis ◽

Stem Cell Marker ◽

Prognostic Impact ◽

Cell Marker ◽

Mesenchymal Transition

Abstract Background:Neural stem cell marker nestin is a suitable diagnostic and prognostic indicator of malignancy and potential cancer stem cells marker in solid tumors. Currently, nestin has been demonstrated as an epithelial-to-mesenchymal transition related protein associated with tumor metastasis, chemoresistance, and metabolic changes through altering mitochondrial dynamics in solid tumors. However its role in hematological malignancies remains unknown. Our recent work confirmed nestin protein as a tumor-specific marker for CD138+38+ plasma cells (PC) of multiple myeloma (MM) and potential predictor of worse response to conventional and novel therapy but prognostic potential of nestin has never been studied in MM so far. Aim:The aim of this study was to evaluate whether pretreatment levels of nestin can predict overall (OS) and progression-free (PFS) survival of MM patients. Methods: Nestin was detected in CD138+38+PC of 84 newly diagnosed MM patients (36M/48F; median age 70 years) by flow cytometry. Nestin was assessed as the percentage of nestin-positive PC (Nes+PC) and ratio of median fluorescence intensity of nestin (MFI ratio) and isotypic control. Survival cut-off points were established based on time-dependent ROC analysis. P-values below 0.05 were considered as statistically significant in all analyses. Cox proportional hazards models were used to assess the association of prognostic factors with OS and PFS. The independence of the marker was assessed by multivariate Cox regression model. Survival rates were estimated using the Kaplan-Meier method. Differences in survival among subgroups of patients were compared using the log-rank test. Results: ROC analysis divided patients into 2 groups: high (>50) and low (≤50) %Nes+PC subgroup and high (>4) and low (≤4) MFI subgroup. High %Nes+PC subgroup were associated with shorter OS (p=0.042) and PFS (p=0.003). High MFI ratio subgroup (>4.4) were significantly associated with shorter OS (p=0.005); and PFS (p=0.025) (Fig.1). Univariate hazard ratios (HR) showed prognostic impact of %Nes+PC (p=0.003) and of MFI ratio (p=0.017) for OS; %Nes+PC (p=0.005) and of MFI ratio (p=0.028) for PFS (Tab.1). 5 parameters: ISS: stage 3 vs. stage 1, del p53, age (at diagnosis), M protein type: IgG vs. other, LDH (µkat/l) and Beta2 microglobulin (mg/l) were significantly associated with OS after adjustment by nestin. However %Nes+PC or MFI ratio did not achieve independent prognostic status in multivariable model (p=0.223 and p=0.989). Conclusion: These data demonstrate for the first time that nestin protein might have prognostic implication for MM. However, it does not appear to be independently associated with MM outcome when considering standard prognostic factors. The growing importance of nestin in key cell processes responsible for tumorigenesis and metastasis emphasizes the need for further investigation in MM. This pilot study requires to be further validated on a larger cohort of patients. Supported by NT14575, RVO-FNOs/2014/17P, IRP201550, SGS03/LF/2015-2016. Disclosures Besse: Mundipharma-EDO: Other: travel support. Hájek:Takeda: Consultancy; BMS: Honoraria; Janssen: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Research Funding.

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The miRNA 196a2 rs11614913 variant has prognostic impact on Turkish patients with multiple myeloma

BMC Research Notes ◽

10.1186/s13104-020-05392-9 ◽

2020 ◽

Vol 13 (1) ◽

Author(s):

Melya Pelin Kirik ◽

Mustafa Pehlivan ◽

Ayse Feyda Nursal ◽

Yasemin Oyaci ◽

Sacide Pehlivan ◽

...

Keyword(s):

Multiple Myeloma ◽

Plasma Cells ◽

Univariate Analysis ◽

Clinical Findings ◽

Rank Test ◽

Prognostic Impact ◽

Genetic Abnormalities ◽

Single Clone ◽

Turkish Patients ◽

The Impact

Abstract Objective Multiple myeloma (MM) arises from malignant plasma cells as a single clone in the bone marrow. Accumulating evidences have reported that there is an association between miR-196a2 (rs11614913) variant and various cancers while there were unverified and inconsistent results in MM. The goal of this study is to investigate the impact of the miR-196a2 variant on clinical findings and susceptibility in MM. Two hundred MM patients (156 patients under transplantation of autologous stem cell) and 200 healthy controls included in this study. Results The statistical analysis showed no significant relationship for allele and frequencies of miR-196a2 genotype between patients and controls (p > 0.05). Log-rank test showed that gender has highly significant impact on both OS and PFS (p = 0.027, p = 0.045). In the univariate analysis, TT genotype (p = 0.022), and CT/TT (p = 0.008) had better OS. In the multivariate analysis, CC/CT-TT were associated with positively OS (p = 0.041). Currently, the most valuable prognostic markers in MM that has clinical implication are genetic abnormalities. It can be concluded from the results that miR-1962a variant is effective in prognosis of the MM. It is believed that these findings will help us understand the molecular basis of disease.

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Revisiting the Impact of Immunoglobulin Isotypes in Multiple Myeloma

Blood ◽

10.1182/blood-2020-138903 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 19-19

Author(s):

Susan Bal ◽

Smith Giri ◽

Kelly N. Godby ◽

Luciano J. Costa

Keyword(s):

Multiple Myeloma ◽

Renal Function ◽

Prognostic Factors ◽

Renal Dysfunction ◽

Research Funding ◽

Performance Status ◽

Prognostic Impact ◽

Ecog Performance Status ◽

Immunoglobulin Isotypes ◽

Race Ethnicity

Background Multiple Myeloma (MM) is a malignancy of terminally differentiated B lymphocytes (plasma cells, PCs) characterized by secretion of immunoglobulins and/or light chains (LCs). Association of immunoglobulin isotypes with survival in the context of contemporary therapies and accounting for modern prognostic factors has not been determined. Methods We utilized the Flatiron Health Electronic Health Record (EHR)-derived de-identified database to source patients (pts) with newly diagnosed MM from 01/2011 to 02/2020 with documented isotype data as part of the initial diagnostic work up. This nationwide database comprises de-identified, longitudinal patient-level demographic, clinical, and outcomes data curated via technology enabled abstraction. We used self-reported race and ethnicity and constructed a composite race/ethnicity variable as used by the National Cancer Institute. Similarly, we defined baseline labs (hemoglobin, serum creatinine, calcium, LDH) as those available within 90 days of diagnosis. We compared baseline characteristics using appropriate bivariate methods. Finally, we used Kaplan-Meier methods and Cox proportional hazard regression models to compare overall survival (OS), from the date of diagnosis, among the different isotypes (IgA, IgD, IgM, Light Chain (LC), others) with IgG MM after adjusting for known prognostic variables such as FISH abnormalities, ISS, renal function, age, sex, race/ethnicity, LDH, ECOG performance status, and treatment. Results We identified 8468 patients in the database who met the inclusion criteria. Patient with IgA MM (N=1688) were more likely to have ISS-III (IgA 21% vs. IgG 16%, p<0.001), anemia (IgA 41% vs. IgG 35%, p<0.001) and t(4;14) (IgA 8% vs. IgG 4%, p<0.001) than patients with IgG MM (N=4858). LC MM (N=1748) have more renal dysfunction (LC 21% vs. IgG 11%, p<0.001) and t(11;14) (LC 17% vs. IgG 8%, p<0.001). Patients with IgD MM (N=44) were younger, more likely to be male and non-Hispanic White, have ISS-III, high LDH, anemia and renal dysfunction and t(11;14). Patients with IgM MM (N=84) had higher incidence of hypercalcemia and lower proportion of patients with high LDH (Table). Across all groups 3106 (36.7%) patients received therapy containing a proteasome inhibitor (PI) and an immunomodulatory agent based triplet (IMiD), while 1458 (17.2%) received IMiD-based doublet, 2284 (27.0%) PI-based doublet, and 2109 (24.9%) received hematopoietic cell transplantation. Patients with IgA (mOS 4.7 vs 5.6 years, p<0.001) and LC MM (4.8 vs. IgG 5.6 years, p<0.001) patients have inferior OS (Figure). The adverse prognostic impact of IgA (HR 1.2, 95% CI 1.1-1.3, p<0.001) and LC isotypes (HR 1.2, 95% CI 1.1-1.3, p<0.001) on OS persisted even after adjustment for FISH abnormalities, ISS stage, renal function, age, sex, race/ethnicity, ECOG performance status, LDH, and treatment. Conclusion Using a contemporary "real world" dataset, we illustrate the distinct clinical features of MM with different immunoglobulin isotypes. Our findings suggest that IgA and LC MM are associated with poor survival suggestive of their unique biology beyond presence of high-risk FISH abnormalities and other adverse prognostic factors. Figure Disclosures Costa: Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy; Genentech: Consultancy; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

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Role of melatonin in regulating neurogenesis: Implications for the neurodegenerative pathology and analogous therapeutics for Alzheimer’s disease

Melatonin Research ◽

10.32794/mr11250059 ◽

2020 ◽

Vol 3 (2) ◽

pp. 216-242 ◽

Cited By ~ 1

Author(s):

Mayuri Shukla ◽

Areechun Sotthibundhu ◽

Piyarat Govitrapong

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adult Neurogenesis ◽

Adult Brain ◽

Therapeutic Approaches ◽

Therapeutic Implications ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Progenitor Cell Proliferation

The revelation of adult brain exhibiting neurogenesis has established that the brain possesses great plasticity and that neurons could be spawned in the neurogenic zones where hippocampal adult neurogenesis attributes to learning and memory processes. With strong implications in brain functional homeostasis, aging and cognition, various aspects of adult neurogenesis reveal exuberant mechanistic associations thereby further aiding in facilitating the therapeutic approaches regarding the development of neurodegenerative processes in Alzheimer’s Disease (AD). Impaired neurogenesis has been significantly evident in AD with compromised hippocampal function and cognitive deficits. Melatonin the pineal indolamine augments neurogenesis and has been linked to AD development as its levels are compromised with disease progression. Here, in this review, we discuss and appraise the mechanisms via which melatonin regulates neurogenesis in pathophysiological conditions which would unravel the molecular basis in such conditions and its role in endogenous brain repair. Also, its components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain would aid in accentuating the therapeutic implications of this indoleamine in line of prevention and treatment of AD.

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