Abstract B41: Distribution of cytogenetic abnormalities in African American multiple myeloma patients may be unique for different geographic regions

2016 ◽  
Author(s):  
Preeya Patel ◽  
Manisha Bhutani ◽  
Kyle Madden ◽  
Myra R. Robinson ◽  
Rupali Bose ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African American ◽  
Cytogenetic Abnormalities ◽  
Geographic Regions

Distribution of Cytogenetic Abnormalities in African American Multiple Myeloma Patients May be Unique for Different Geographic Regions

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5337-5337
Author(s):  
Manisha Bhutani ◽  
Preeya Patel ◽  
Myra M Robinson ◽  
Rupali Bose ◽  
Kyle Madden ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African American ◽  
Racial Differences ◽  
Lower Incidence ◽  
Research Funding ◽  
Cook County ◽  
Cook County Hospital ◽  
Cytogenetic Abnormalities ◽  
Significant Difference ◽  
Similar Incidence

Abstract BACKGROUND: Multiple myeloma (MM) is the most common hematologic malignancy in the African American population, with an incidence more than 2 times higher than Caucasian population [Landgren O et al Blood 2006]. Historically, the African American MM patients have had better outcomes compared with other races [Ailawadhi S et al Br J Haematol 2012], but no biologic explanations exist for this observation. Greenberg et al [Blood Cancer J 2015] have recently reported on differences in commonly observed baseline cytogenetic abnormalities (CA) between African American and Caucasian MM patients seen at Mayo Clinic (Rochester, MN), Cook County Hospital (Chicago, IL) and University of Maryland (Baltimore, MD). We examined the MM cohort at our referral center to validate these observations. PATIENTS & METHODS: The Levine Cancer Institute MM database was interrogated for all patients presenting with MM between January 2012 and April 2015. Baseline clinical and pathology variables were compared between the African American and Caucasian cohorts. Continuous variables were compared using nonparametric rank tests, while incidences and proportions (e.g. CAs including t(11;14), t(4;14), monosomy13/del13q and del17p) were compared using Fisher's exact tests. RESULTS: A total of 662 patients were identified; excluding those with MGUS classification, 368 patients were included in the analysis (African Americans n = 130, Caucasian n = 238). The median age of African American MM patients was significantly younger than Caucasian MM patients (median age 60 years vs. 65 years, p=0.010), with similar gender distribution. There was a numerically larger proportion of African American patients with anemia (40.8% vs 30.8%, p =0.166), however, there was no significant difference in degree of BM plasmacytosis amongst the two groups. The overall distribution of MM patients by IMWG risk stratification (Chng et al, Leukemia 2013) was also similar between the two groups. The African American MM patients had a numerically higher incidence of a metaphase abnormality on conventional cytogenetics (21.7% vs. 13.9%, p =0.154). They had a significantly lower incidence of t(11;14) [7.7% vs. 16%, p=0.024], a numerically higher incidence of t(4;14) [6.2% vs. 3.8%, p=0.309], and similar incidence of deletion 13/del13q [22.3% vs. 18.9%, p=NS ] and del17p [7.7% vs. 7.6%, p=NS ]. CONCLUSIONS: The present dataset is the largest single institution report on CA racial differences in MM patients. We found that unlike previous reports of lower incidence of t(4;14) or del17 p in African American MM patients by Greenberg et al, we have observed a higher incidence of t(4;14) and similar incidence of del17p in our experience compared to Caucasian MM patients. The different pattern of CA distribution compared to published literature may represent geographic heterogeneity and potentially influence survival outcomes. Disclosures Cogdill: Celgene: Speakers Bureau; Onyx: Speakers Bureau; Millennium: Speakers Bureau; Novartis: Speakers Bureau. Usmani:Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Research Funding, Speakers Bureau; Janssen Oncology: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pharmacyclics: Research Funding; Millennium: Honoraria, Speakers Bureau; Array BioPharma: Honoraria, Research Funding.

scholarly journals Analysis of Racial Differences in the Incidence of a Targetable Biomarker, t(11;14), in Patients with Multiple Myeloma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Fang Liu ◽  
Jeries Kort ◽  
Shashirekha Shetty ◽  
Ravikumar Kyasaram ◽  
John Shanahan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
African American ◽  
Racial Differences ◽  
Racial Disparity ◽  
Categorical Variables ◽  
Female Ratio ◽  
Cytogenetic Abnormalities ◽  
Blood Cancer ◽  
Chromosome 13 ◽  
Monoclonal Gammopathies

Introduction Compared with Caucasian Americans (CA), African Americans (AA) have an increased incidence of multiple myeloma (MM), earlier age at diagnosis, and overall better prognosis [1]. The molecular mechanisms underlying such racial disparity are not well understood. Using targeted next generation sequencing assay or traditional fluorescence in situ hybridization (FISH) methods, previous studies reported that t(11;14) is more common in AA compared with CA with MM and monoclonal gammopathies [2,3]. However, the number of AA cases studied were small and conflicting data exists. Clinical trials in relapsed or refractory MM indicate that t(11;14) is a biomarker which may be used to predict response to a therapeutic agent (venetoclax) which targets BCL-2 [4,5]. Identifying racial differences in molecular biomarkers would be helpful in our understanding of the known racial disparities of incidence in MM and in the development of therapeutic trials. Methods 737 patients with newly diagnosed MM or smoldering myeloma (SM) at University Hospitals Seidman Cancer Center between 2009 and 2020 were identified. All had myeloma FISH panel sent at diagnosis, which included trisomy of chromosomes 3, 7, or 11, deletion 13q14.3 or loss of chromosome 13, deletion 17p13.1, 1q21 (CKS1B) amplification, and 14q32.3 rearrangements. IGH/CCND1 [t(11;14)(q13;q32)] dual fusion probe was used prior to 2018. Extra signal would trigger reflex test for IGH/FGFR3 [t(4;14)(p16.3;q32)] and IGH/MAF [t(14;16)(q32;q23)]. IGH break apart probe was used since 2018. IGH rearrangement would trigger reflex testing for translocation partners as listed above. Between-group differences were assessed with T-test for continuous variables, and Chi-square / Fisher's exact test for categorical variables. Results Of the 737 patients (661 MM, 76 SM), 502 (68.1%) were self-reported as CA, 213 (28.9%) were AA, and 22 (3.0%) were of other races or listed as unknown. Median age was 71 among CA and 70 among AA (p=0.67). The male-female ratio was 291/211 (58% male) among CA and 101/112 (47% male) among AA (p=0.0095). Overall t(11;14) was detected in 4.5% of cases, 5.2% CA and 2.8% AA (p=0.165); among 661 MM, t(11;14) was tested positive in 30/656 (4.57%), including 23 (5.1%) CAs, 6 (3.1%) AAs, and 1 others (p= 0.80); among 76 SM, t(11;14) was tested positive in 3/76 (3.95%), all were CAs. The percentages of patients who tested positive for other cytogenetic abnormalities were as follows: trisomy 3,7, or 11 was detected in 35.6% CA and 32.4% AA (p=0.42); 1q21 amplification was detected in 25.5% CA and 23.9% AA (p=0.72); deletion 13q14.3 or loss of chromosome 13 was detected in 16.5% CA and 10.7% AA (p=0.08); deletion 17p13.1 was detected in 6.4% CA and 5.2% AA (p=0.54); t(4;14) was detected in 2.8% CA and 1.4% AA (p=0.27); t(14;16) was detected in 0.4% CA and 0.5% AA (p=0.89) Conclusions This retrospective series of 737 MM and SM patients did not find an increased incidence of the targetable biomarker t(11;14) in AA patients. The overall percentage of t(11;14) cases was lower than expected. The lack of our finding a racial difference differs from some other reports, perhaps due to a fairly enriched AA population. There were also no significant racial differences found in other cytogenetic abnormalities. Further investigation at the molecular level should be performed to elucidate the mechanisms of racial disparity in MM. References [1]. Landgren O, Devesa S, Mink P, et al. African-American multiple myeloma patients have a better survival than Caucasian patients: a population-based study including 28,636 patients. Blood. 2009;114:1832. [2]. Kzandjian D, Hill E, Hultcrantz M, et al. Molecular underpinnings of clinical disparity patterns in African American vs. Caucasian American multiple myeloma patients. Blood Cancer J. 2019;9(2):15. [3]. Baughn LB, Pearce K, Larson D, et al. Differences in genomic abnormalities among African individuals with monoclonal gammopathies using calculated ancestry. Blood Cancer J. 2018;8(10):96. [4]. Kortüm KM, Einsele H. First targeted therapy in multiple myeloma. Blood. 2017;130(22):2359-2360. [5]. Kumar S, Harrison S, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. EHA Library. Abstract LB2601. Disclosures No relevant conflicts of interest to declare.

Language and Literacy Predictors of Dialect Density Among School-Age African American Children From Two Geographic Regions

2020 ◽  
Vol 51 (3) ◽  
pp. 807-820
Author(s):  
Lena G. Caesar ◽  
Marie Kerins
Keyword(s):  
African American ◽  
Multiple Regression ◽  
Oral Language ◽  
East Coast ◽  
Geographic Region ◽  
Literacy Skills ◽  
School Age ◽  
Regression Analyses ◽  
Geographic Regions ◽  
American Children

Purpose The purpose of this study was to investigate the relationship between oral language, literacy skills, age, and dialect density (DD) of African American children residing in two different geographical regions of the United States (East Coast and Midwest). Method Data were obtained from 64 African American school-age children between the ages of 7 and 12 years from two geographic regions. Children were assessed using a combination of standardized tests and narrative samples elicited from wordless picture books. Bivariate correlation and multiple regression analyses were used to determine relationships to and relative contributions of oral language, literacy, age, and geographic region to DD. Results Results of correlation analyses demonstrated a negative relationship between DD measures and children's literacy skills. Age-related findings between geographic regions indicated that the younger sample from the Midwest outscored the East Coast sample in reading comprehension and sentence complexity. Multiple regression analyses identified five variables (i.e., geographic region, age, mean length of utterance in morphemes, reading fluency, and phonological awareness) that accounted for 31% of the variance of children's DD—with geographic region emerging as the strongest predictor. Conclusions As in previous studies, the current study found an inverse relationship between DD and several literacy measures. Importantly, geographic region emerged as a strong predictor of DD. This finding highlights the need for a further study that goes beyond the mere description of relationships to comparing geographic regions and specifically focusing on racial composition, poverty, and school success measures through direct data collection.

Cytogenetic Abnormalities of Undetermined Clinical Sinigicance Correlate with Poor Prognosic Factors in Multiple Myeloma

2015 ◽  
Vol 15 ◽  
pp. e106
Author(s):  
Y.K. Lee ◽  
M. Kim ◽  
E.J. Lee ◽  
H.J. Kang ◽  
H.-S. Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Cytogenetic Abnormalities

scholarly journals Development and Analysis of a Weighed Prognostic Model in Newly Diagnosed Multiple Myeloma Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 47-48
Author(s):  
Xue-Han Mao ◽  
Yan Xu ◽  
Yuting Yan ◽  
Jiahui Liu ◽  
Huishou Fan ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Prognostic Factor ◽  
Prognostic Model ◽  
Cytogenetic Abnormalities ◽  
Total Score Range ◽  
Prognosis Model

Background and Objective: Multiple myeloma (MM) is characterized with significant cytogenetic changes and complex tumor microenvironment, thus patient survival is extremely heterogeneous. Various disease-related or patient-related factors affect the prognosis of patients. This study tried to analyze the prognostic indicators of patients with newly-treated MM, especially explored the prognosis of multiple cytogenetic abnormalities and the ratio of lymphocytes to monocytes (LMR). Additionally, we established a comprehensive prognostic model to help determine the patient prognosis. Methods: After screening, 603 patients of untreated MM from January 2008 to June 2017, with complete baseline indicators were enrolled into the study. By univariate and multivariate Cox analysis, risk factors related to the prognosis of patients were evaluated, and a weighted prognosis model was established to compare the survival differences of patients in each risk stratification. Result: Optimal thresholds of ALC, LWR, NLR and LMR were determined by ROC curve and Youdex index: ALC = 1.415, LWR = 0.325, NLR = 1.935, LMR = 2.95. Survival analysis showed that patients with LMR ≤ 2.95, ALC ≥ 1.415 and LWR ≥ 0.325 had significantly better survival compared with their respective control groups. Cox multivariate analysis showed that among the four indicators, only LMR≤2.95 was an independent adverse prognostic factor for overall survival (OS)(Figure 1A). 17p deletion, 1q21 amplification, t (4; 14) / t (14; 16) were define as high-risk cytogenetic abnormalities (HRA). Of the 603 patients, about 60% were associated with at least one high-risk cytogenetic event. Among them, the occurrence of cumulative 0, 1, 2, and 3 HRA were 39.6% (239/603), 42.5% (256/603), 16.6% (100/603), and 1.3% (8/603), respectively. There was no significant difference in survival among patients with same number of HRAs. The median OS of patients with 0, 1 and ≥ 2 HRA were not reached, 62.1 months (95% CI, 49.3-74.9) and 30.4 months (95% CI, 24.5-36.3), respectively (p <0.001)(Figure 1B).Final Cox regression model showed that age 65 ~ 74 (HR=1.77, 95%CI, 1.24-2.51, p=0.001), age ≥75 (HR=2.46, 95%CI, 1.69-3.58, p < 0.001), LDH≥247 U/L (HR =1.65, 95%CI, 1.07-2.51, p=0.023), ISS stage III (HR=1.76, 95%CI, 1.24-2.50, p=0.002), LMR≤2.95 (HR=1.53, 95%CI, 1.08-2.18, p=0.017), 1 HRA (HR=1.87, 95%CI, 1.27-2.75, p=0.002) and ≥2 HRA (HR=3.48, 95%CI, 2.22-5.45, p<0.001) are independent adverse prognostic factors for OS. Then weighted risk factors were summed to establish a comprehensive prognosis model, with a total score range of 0-6 points. Accordingly, the whole cohort was divided into low risk (0-1 points, 45.4%), intermediate risk (2 points, 27.9%), high risk (3 points, 19.2%) and ultra-high risk (4-6 points, 7.5 %) groups. The median OS of the four risk groups were 85.8 months (67.1-104.5), 49.0 months (44.7-53.3), 35.4 months (31.3-39.5), and 23.2 months (18.8-27.6), respectively (p<0.001). The C-statistics of this prognostic model is 0.68 (95% CI, 0.64-0.71), which is significantly better than the D-S stage (C-statistics = 0.52, 95% CI, 0.50-0.55, p <0.001), ISS (C-statistics = 0.60, 95% CI, 0.57-0.64, p <0.001) and R-ISS stage (C-statistics = 0.60, 95% CI, 0.57-0.63, p <0.001). Bootstrap resampling and calibration curve showed that the model has an accurate predictive effect on both short-term and long-term prognosis of patients(Figure 1C). Conclusion: In our analysis, ALC, LWR, LMR were associated with poor prognosis in NDMM patients, while NLR had no significant prognostic significance. Among the four indicators, LMR≤2.95 was the only independent prognostic factor. In NDMM patients, survival of patients with the same number of high-risk cytogenetic abnormalities were comparable with each other, regardless of whichever combination of HRA. Higher number of high-risk cytogenetic abnormalities were associated with worse prognosis. Cox multivariate analysis showed that, old age (65-74 years old, ≥75 years old), increased LDH (≥247 U/L), decreased LMR (≤2.95), ISS III, 1 HRA and ≥ 2 HRA were independent adverse prognostic factors that affect the OS of MM patients. 4. A comprehensive weighted prognostic model was established with the above factors, which was proved to effectively distinguish different prognosis of patients. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Relationship of Bone Marrow Plasma Cell Morphology with Cytogenetic Abnormalities in Patients with Multiple Myeloma

2021 ◽  
Author(s):  
Vikram Narang ◽  
Maneet Luthra ◽  
Avantika Garg ◽  
Amit Dhiman ◽  
Neena Sood
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Descriptive Analysis ◽  
Cross Sectional Study ◽  
Chi Square ◽  
Morphological Pattern ◽  
Cross Sectional ◽  
Cytogenetic Abnormalities ◽  
Cytogenetic Studies ◽  
Chi Square Test

Introduction: Cytogenetics has become an integral part of Multiple Myeloma (MM) diagnosis and prognostication. A combination of conventional cytogenetics and interphase Fluorescence In Situ Hybridization (FISH) is currently used to stratify tumours into high, intermediate and standard risk disease. Aim: To compare the morphological details of plasma cells with cytogenetic abnormalities. Materials and Methods: The present retrospective cross sectional study was conducted at Department of Pathology Dayanand Medical College and Hospital, Ludhiana in three and a half year duration (1st January 2014 to 30th June 2017). All the diagnosed MM patients in whom cytogenetic was available were included and descriptive analysis was done using Chi-Square test and relevant statistical analysis using SPSS 21 version. Correlation was done with various morphological pattern (plasmacytic, plasma blastic). Results: Cytogenetic studies were performed on 42 cases using FISH technique (n=31, 81.6%) and GTG (Giemsa) banding (n=4, 10.5%). Three (7.9%) patients were tested with both methods. In the present study, all the patients (n=2,100%) with plasmablastic morphology who got tested with cytogenetics had del13q14.3 and none of the patients with normal genome (n=22) had plasmablastic morphology. Conclusion: Morphologic patterns of plasma cells and cytogenetic studies correlate well and can together help in better prognostication of MM patients.

scholarly journals Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4396-4396
Author(s):  
Patrick Mellors ◽  
Moritz Binder ◽  
Rhett P. Ketterling ◽  
Patricia Griepp ◽  
Linda B Baughn ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Risk Stratification ◽  
Board Of Directors ◽  
Research Funding ◽  
Multivariable Analysis ◽  
Risk Modeling ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities ◽  
Improve Risk Stratification

Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p < 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p < 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p < 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p < 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Continuous absence of metaphase-defined cytogenetic abnormalities, especially of chromosome 13 and hypodiploidy, ensures long-term survival in multiple myeloma treated with Total Therapy I: interpretation in the context of global gene expression

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 3849-3856 ◽  
Author(s):  
John Shaughnessy ◽  
Joth Jacobson ◽  
Jeff Sawyer ◽  
Jason McCoy ◽  
Athanasios Fassas ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Multiple Myeloma ◽  
Global Gene Expression ◽  
Cell Cycle Gene ◽  
Term Survival ◽  
Cytogenetic Abnormalities ◽  
Chromosome 13 ◽  
Prognostic Implications ◽  
Total Therapy

Abstract Metaphase cytogenetic abnormalities (CAs), especially of chromosome 13 (CA 13), confer a grave prognosis in multiple myeloma even with tandem autotransplantations as applied in Total Therapy I, which enrolled 231 patients between 1989 and 1994. With a median follow-up of almost 9 years, the prognostic implications of all individual CAs, detected prior to treatment and at relapse, were investigated. Among all CAs and standard prognostic factors examined prior to therapy, only hypodiploidy and CA 13 (hypo–13 CA), alone or in combination, were associated with shortest event-free survival and overall survival (OS). The shortest postrelapse OS was observed with hypo–13 CA, which was newly detected in 18 of all 28 patients presenting with this abnormality at relapse. Superior prognosis was associated with the absence of any CA at both diagnosis and relapse (10-year OS, 40%). The lack of independent prognostic implications of other CAs points to a uniquely aggressive behavior of hypo–13 CA (present in 16% of patients at diagnosis). With the use of microarray data in 146 patients enrolled in Total Therapy II, overexpression of cell cycle genes distinguished CA from no CA, especially in cases of del(13) detected by interphase fluorescence in situ hybridization (FISH). FISH 13, resulting in a haploinsufficiency of RB1 and other genes mapping to chromosome 13, as well as activation of IGF1R, appears to have an amplifying effect on cell cycle gene expression, thus providing a molecular explanation for the dire outcome of patients with CA 13 compared with those with other CAs.

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