Comparison of Cytogenetics Between Asian and Caucasian Myeloma Reveal Higher Frequency of Abnormalities Associated with Poor Prognosis in Asian Patients

Abstract Abstract 5060 Introduction In multiple myeloma, cytogenetics is informative in only about a third of patients. Despite this limitation, it remains a commonly available laboratory investigation that has prognostic utility and allows detection of global changes including ploidy. While cytogenetics abnormalities in myeloma have been well documented, a direct comparison between Western and Asian patients has not been performed. Methods Retrospective analysis of 190 newly diagnosed multiple myeloma patients presenting to the National University Hospital Singapore (NUH) between 2000–2009, and 494 newly diagnosed multiple myeloma patients from the Mayo Clinic myeloma database from 2000 to 2005 were analyzed. All abnormalities were logged onto an excel spreadsheet where all cytobands were represented. Gains, losses and structural abnormalities including specific translocations were documented separately. Abnormalities present in 5% or more samples with cytogenetic abnormalities were further analysed and compared between the 2 cohorts using chi-square test. Bonferroni correction is used when multiple comparisons were made. Results 80/190 (42%) of NUH patients had an abnormal karyotype compared with 180/494 (36%) in the Mayo clinic cohort (not statistically significant p=0.17). Distribution of ploidy status was very similar between the NUH and Mayo cohort with 35% and 27% being hyperdiploid in the NUH and Mayo cohort respectively (p=0.57). In both cohorts, the most common gains are whole chromosome gains involving chromosomes that are commonly trisomic in hyperdiploid myeloma. However, the pattern of trisomies is different between the NUH and Mayo cohort, with trisomies of chromosome 5, 7, and 19 more common in NUH (p-values <0.0001 for all three comparisons). Loss of 1p21was more common in NUH compared with Mayo (9% vs 2%, p=0.01) although loss of chromosome 7 was more common in Mayo compared to NUH (15% vs 0%, p=0.0002). t(11;14) is the most common translocations for both cohorts. Translocations involving chromosome 1 with different partners are also common in both cohorts. However, there are also interesting differences. Rearrangements involving the IgH (14q32) [10% NUH vs 4% in Mayo] and MYC (8q24) [6% in NUH vs 1% in mayo] loci are more common in the NUH cohort. In fact, when MYC translocations with IgH or IgL are included, 9 (11%) cases in the NUH cohort were affected versus 4 (in the Mayo Clinic cohort (p=0.0002). Recurrent rearrangement of 3q27 was observed in 5% of the NUH cohort while no cases were noted in the Mayo cohort. A search of the Mitelman Database of Chromosome Aberrations and Gene Fusion in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman) showed that only 4 out of 1643 Caucasian myeloma karyotype recorded had this abnormality (p<0.0001). 1q21 deletion and MYC rearrangements are associated with poorer prognosis. Conclusion From this comparison, the general patterns of cytogenetic abnormalities are similar between Asian and Western patients. The most important difference between Asian patients and western patients was the higher incidence of poor prognostic cytogenetic abnormalities in Asian patients including 1p21 deletion and gene rearrangements involving the MYC gene locus. 3q27 was predominantly seen in the Asian patient cohort and rarely in western patients. This could be a unique feature of Asian myeloma patients and more studies will have to be done to confirm this. These differences may have important implication on outcome of patients in Asian and Western Countries, and also unique biology that could potentially be exploited therapeutically. Disclosures: Fonseca: Consulting:Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.

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Clinical Impact of 18f-FDG PET/CT As a Valuable Prognostic Tool for the Newly Diagnosed Multiple Myeloma with Extramedullary Disease

Blood ◽

10.1182/blood-2019-129831 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3142-3142

Author(s):

Dong Won Baek ◽

Hee Jeong Cho ◽

Sang Kyun Sohn ◽

Sung-Hoon Jung ◽

Hong chae Moon ◽

...

Keyword(s):

Multiple Myeloma ◽

Fdg Pet ◽

Survival Outcomes ◽

Newly Diagnosed ◽

Prognostic Tool ◽

Pet Ct ◽

National University ◽

18F Fdg ◽

Fdg Pet Ct

Purpose 18F-FDG PET/CT (PET/CT) could be a valuable tool to predict long-term survival outcomes in patients with newly diagnosed multiple myeloma (MM). It has ability to distinguish metabolically active sites such as extramedullary disease (EMD) as well as bone damage with relatively high sensitivity and specificity. In this study, we attempted to evaluate the role of PET-CT as a novel prognostic tool for patients with newly diagnosed MM who have EMD. Patients and Methods This study included 211 patients who were newly diagnosed with multiple myeloma from Kyunpook National University Hospital and Chonnam National University Hwasun Hospital. We retrospectively analyzed the medical records of enrolled patients. PET/CT was performed at the diagnosis and EMD was identified in 36 patients (17.1%). Results With a median follow-up duration of 21.5 months (range 1.4-67.7), the estimated 2-year PFS and OS rates were 46.1% and 79.6%, respectively. The presence of PET/CT positive EMD and high maximum standardized uptake value (SUVmax) on baseline PET/CT were significantly associated with inferior long-term survivals in terms of PFS (p=0.013, p=0.007) and OS (p=0.002, p=0.004). In addition, patients who underwent autologous stem cell transplantation (auto-SCT) showed superior PFS (p=0.005) and OS (p=0.022) in PET/CT positive EMD group. Meanwhile, Revised-International Staging System (R-ISS) successfully predicted the prognosis in this study. When we modified R-ISS with the presence of EMD, survival outcomes of the R-ISS stage III patients who didn't have EMD were similar to R-ISS II, while patients with PET/CT positive EMD showed even worse prognosis than the R-ISS stage III group. In the multivariate survival analysis, the presence of EMD (hazard ratio (HR), 2.397; 95% confidence internal (CI), 1.281-4.483; p=0.006) and auto-SCT (HR, 0.326; 95% CI, 0.194-0.549; p<0.001) were related to PFS, while LDH (HR, 2.56; 95% CI, 1.221-5.366; p=0.013) level and auto-SCT (HR, 0.398; 95% CI, 0.167-0.953; p=0.039) were independent prognostic factors of OS. Conclusion In conclusion, PET/CT positive EMD was a poor prognostic factor in patients with newly diagnosed MM. In addition, PET/CT could be a valuable tool to make better risk-adapted treatment strategies with R-ISS in EMD positive MM patients. Above all, patients with PET/CT positive EMD should be considered auto-SCT to improve long-term survivals. Figure Disclosures No relevant conflicts of interest to declare.

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

JOURNAL FOR CLINICAL AND DIAGNOSTIC RESEARCH ◽

10.7860/jcdr/2021/46545.14741 ◽

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.

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Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-122291 ◽

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.

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Patients with newly diagnosed multiple myeloma and chromosome 1 amplification have poor outcomes despite the use of novel triplet regimens

American Journal of Hematology ◽

10.1002/ajh.23705 ◽

2014 ◽

Vol 89 (6) ◽

pp. 616-620 ◽

Cited By ~ 12

Author(s):

Noa Biran ◽

Jyoti Malhotra ◽

Emilia Bagiella ◽

Hearn Jay Cho ◽

Sundar Jagannath ◽

...

Keyword(s):

Multiple Myeloma ◽

Chromosome 1 ◽

Newly Diagnosed ◽

Poor Outcomes

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Asian Subgroup Analysis - Denosumab Vs Zoledronic Acid in Bone Disease Treatment of Newly Diagnosed Multiple Myeloma: An International, Double-Blind, Double-Dummy, Randomized Controlled Phase 3 Study

Blood ◽

10.1182/blood-2018-99-113132 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 3251-3251

Author(s):

Chang-Ki Min ◽

Sung-Soo Yoon ◽

Wee Joo Chng ◽

Shang-Yi Huang ◽

Cheng-Shyong Chang ◽

...

Keyword(s):

Multiple Myeloma ◽

Zoledronic Acid ◽

Research Funding ◽

Acid Group ◽

Newly Diagnosed ◽

Primary Analysis ◽

Employment Equity ◽

Double Blind ◽

Asian Patients ◽

Equity Ownership

Abstract Introduction: Denosumab is a monoclonal antibody targeting receptor activator of nuclear factor-kappa B ligand (RANKL) that has been shown to reduce skeletal-related events (SREs) associated with bone lesions in patients with multiple myeloma. Results from the full primary analysis of an international, double-blind, double-dummy, randomized controlled phase 3 (20090482) study that assessed the efficacy and safety of denosumab vs zoledronic acid for preventing SREs in patients with multiple myeloma (MM) indicated that denosumab was non-inferior to zoledronic acid for time to SREs. Here we present a sub-analysis to evaluate efficacy and safety outcomes in a subgroup of Asian patients enrolled in the 20090482 study. Methods: Adult patients from Asian countries with newly diagnosed MM and ≥1 documented lytic bone lesion were included in this analysis. Patients received subcutaneous denosumab (120 mg) plus intravenous placebo or intravenous zoledronic acid (4 mg) plus subcutaneous placebo in 4-week cycles. The primary endpoint was time to first on-study SRE; the incidence of adverse events (AEs) by preferred term was also examined. Results: Overall, 196 Asian patients (denosumab, n=103; zoledronic acid, n=93) were included in this analysis. Patient demographics were generally well balanced between groups. Median (interquartile range [IQR]) number of months on study was 17.5 (9.8-30.2) for the denosumab group and 20.2 (13.1-29.2) for the zoledronic acid group. Median (IQR) cumulative drug exposure was 15.9 (8.5-24.0) months for denosumab and 17.4 (9.1-26.7) months for zoledronic acid. Fewer patients in the denosumab group developed first on-study SRE compared with the zoledronic acid group; the crude incidence of SREs at the primary analysis cutoff was 38.8% in the denosumab group and 50.5% in the zoledronic acid group. Median (95% CI) time in months to first on-study SRE was not reached (11.2-not reached) for the denosumab group and 12.3 (3.1-not reached) for the zoledronic acid group (hazard ratio [HR], 0.77; 95% CI, 0.48-1.26; Figure 1). Overall, all patients (100%) experienced ≥1 treatment-emergent AE; the AEs reported in ≥20% of patients in either treatment arm are presented in Table 1. The most common AEs reported in either subgroup (denosumab, zoledronic acid) were diarrhea (51.0%, 51.1%), nausea (42.2%, 46.7%), pyrexia (38.2%, 41.3%), upper respiratory tract infection (37.3%, 40.2%), and constipation (33.3%, 31.5%). Renal toxicity (preferred terms of blood creatinine increased, renal failure, urine output decreased, acute kidney injury, renal impairment, and blood urea decreased) occurred in 9 of 102 (8.8%) patients in the denosumab group and 20 of 92 (21.7%) patients in the zoledronic acid group. Adjudicated osteonecrosis of the jaw was reported in 7 (6.9%) patients in the denosumab group and 5 (5.4%) patients in the zoledronic acid group. Hypocalcemia was reported in 19 (18.6%) patients in the denosumab group and 17 (18.5%) patients in the zoledronic acid group. Conclusion: Results from this Asian subgroup analysis were comparable to those of the full analysis set. In addition, in this analysis there were numerically fewer patients in the denosumab arm that developed a first on-study SRE compared with those in the zoledronic acid arm, and the time to first on-study SRE had a trend favoring the denosumab-treated patients. The AE profiles for denosumab and zoledronic acid in the Asian subgroup were comparable to those observed in the full primary analysis, with renal toxicity similarly reported to be higher in the zoledronic acid group. Overall, this analysis supports that denosumab may be an additional treatment option for the standard of care for Asian patients with newly diagnosed MM with bone disease. Disclosures Chng: Merck: Research Funding; Aslan: Research Funding; Celgene: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, accommodation, expenses; Amgen: Consultancy, Honoraria, Other: Travel, accommodation, expenses. Chang:BMS: Consultancy, Speakers Bureau; AbbVie: Consultancy; Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy; Takeda: Consultancy; Roche: Consultancy, Speakers Bureau; Novarits: Consultancy, Speakers Bureau. Wong:Amgen: Consultancy, Research Funding, Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Archigen: Research Funding; Baxalta: Research Funding; Pfizer: Research Funding; Apellis: Research Funding; Roche: Research Funding; Boehringer: Research Funding; Ingelheim: Research Funding; AbbVie: Research Funding; Alexion: Consultancy; Astellas: Speakers Bureau. Shimizu:Amgen Inc.: Other: Non-remunerative Position of Influence, Denosumab 20090482 Global Steering Committee Member; Fujimoto Pharmacuetical Corp: Consultancy; Daiichi-Sankyo, Co., Ltd: Consultancy. Gao:Amgen Asia Holding Limited: Employment, Equity Ownership. Glennane:Amgen: Employment, Equity Ownership. Guan:Amgen: Employment, Equity Ownership.

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Effectiveness of antipsychotic drugs in schizophrenia: a 10-year retrospective study in a Korean tertiary hospital

npj Schizophrenia ◽

10.1038/s41537-020-00122-3 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Sanghoon Oh ◽

Tae Young Lee ◽

Minah Kim ◽

Se Hyun Kim ◽

Suehyun Lee ◽

...

Keyword(s):

Antipsychotic Drugs ◽

Tertiary Hospital ◽

University Hospital ◽

Antipsychotic Medications ◽

Asian Patients ◽

Kaplan Meier ◽

Number Of Patients ◽

National University ◽

Seoul National University ◽

Effectiveness Studies

AbstractExtensive research has been carried out on the comparative effectiveness of antipsychotic medications. Most studies, however, have been performed in Western countries. The purpose of this study was to compare the effectiveness, indicated by time to any-cause discontinuation, of antipsychotic drugs in a large number of patients with schizophrenia in South Korea. We identified 1458 patients with schizophrenia or schizophreniform disorder who were treated with antipsychotic medications using a clinical data warehouse at the Seoul National University Hospital between March 2005 and February 2014. Kaplan–Meier survival analyses were used to estimate the time to discontinuation of antipsychotic drugs. We compared the survival curves of different antipsychotics using log-rank tests. Overall, the median time to discontinuation for any cause was 133 days (95% CI, 126–147). The longest time to discontinuation was observed for clozapine, followed by aripiprazole, paliperidone, olanzapine, amisulpride, risperidone, quetiapine, ziprasidone, and haloperidol. Specifically, clozapine was significantly different from all other antipsychotic drugs (all p < 0.001). Aripiprazole also had a significantly longer time to discontinuation than amisulpride (p = 0.001), risperidone (p < 0.001), quetiapine (p < 0.001), ziprasidone (p < 0.001), and haloperidol (p < 0.001). In Asian patients with schizophrenia, clozapine was the most effective antipsychotic in terms of time to discontinuation, followed by aripiprazole. This study extends the findings of previous effectiveness studies from Western populations and suggests the need to develop guidelines for the pharmacotherapy of schizophrenia tailored to Asian individuals.

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Metaphase cytogenetics and plasma cell proliferation index for risk stratification in newly diagnosed multiple myeloma

Blood Advances ◽

10.1182/bloodadvances.2019001275 ◽

2020 ◽

Vol 4 (10) ◽

pp. 2236-2244

Author(s):

Patrick W. Mellors ◽

Moritz Binder ◽

Rhett P. Ketterling ◽

Patricia T. Greipp ◽

Linda B. Baughn ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Proliferation ◽

Risk Stratification ◽

Proliferation Index ◽

Newly Diagnosed ◽

Cytogenetic Abnormalities ◽

Improve Risk Stratification ◽

Risk Scoring ◽

Risk Scoring System ◽

Cell Proliferation Index

Abstract Metaphase cytogenetic abnormalities, plasma cell proliferation index (PCPro), and gain 1q by fluorescence in situ hybridization (FISH) are associated with inferior survival in newly diagnosed multiple myeloma (MM) treated with novel agents; however, their role in risk stratification is unclear in the era of the revised International Staging System (R-ISS). The objective of this study was to determine if these predictors improve risk stratification in newly diagnosed MM when accounting for R-ISS and age. We studied a retrospective cohort of 483 patients with newly diagnosed MM treated with proteasome inhibitors and/or immunomodulators. On multivariable analysis, R-ISS, age, metaphase cytogenetic abnormalities (both in aggregate and for specific abnormalities), PCPro, and FISH gain 1q were associated with inferior progression-free (PFS) and overall survival (OS). We devised a risk scoring system based on hazard ratios from multivariable analyses and assigned patients to low-, intermediate-, and high-risk groups based on their cumulative scores. The addition of metaphase cytogenetic abnormalities, PCPro, and FISH gain 1q to a risk scoring system accounting for R-ISS and age did not improve risk discrimination of Kaplan-Meier estimates for PFS or OS. Moreover, they did not improve prognostic performance when evaluated by Uno’s censoring-adjusted C-statistic. Lastly, we performed a paired analysis of metaphase cytogenetic and interphase FISH abnormalities, which revealed the former to be insensitive for the detection of prognostic chromosomal abnormalities. Ultimately, metaphase cytogenetics lack sensitivity for important chromosomal aberrations and, along with PCPro and FISH gain 1q, do not improve risk stratification in MM when accounting for R-ISS and age.

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Total Therapy 2 (TT 2) for Newly Diagnosed Patients with Multiple Myeloma (MM): Examination of Dose Effect of Thalidomide (T) among Those Randomized to T.

Blood ◽

10.1182/blood.v104.11.934.934 ◽

2004 ◽

Vol 104 (11) ◽

pp. 934-934

Author(s):

Raymond Thertulien ◽

Bart Barlogie ◽

Maurizio Zangari ◽

Athanasios Fassas ◽

Julie Stover ◽

...

Keyword(s):

Multiple Myeloma ◽

Dose Distribution ◽

Dose Effect ◽

Consolidation Therapy ◽

Newly Diagnosed ◽

Consolidation Chemotherapy ◽

Cytogenetic Abnormalities ◽

Dose Effects ◽

Total Therapy ◽

Observation Times

Abstract TT 2 has completed accrual of 668 patients as of February 2004, of whom 323 were randomized to T. All patients received intensive reduction with VAD, DCEP, CAD, DCEP, melphalan-based tandem autotransplants; consolidation chemotherapy with DPACE; and interferon maintenance. T randomization data still blinded. We report, however, on the effect of total cumulative T dosing through induction (n=185; median T dose 26g, range 0 to 100 g), tandem transplants (n=141; median T dose 33 g, range 0 to 160 g) and consolidation therapy (n=69, median T dose 74 g, range 5 to 250 g). No significant differences in T dose distribution according to quartiles at the 3 observation points existed when examined according to age, gender and prognostically potentially relevant features such as cytogenetic abnormalities, CRP, B2M, LDH and albumin. EFS and OS were then compared, according to T dosing quartiles, from first transplant, consolidation and maintenance initiation. T dose effects were not observed for the first two observation times. When considered from initiation of maintenance, there was one event among 31 patients in the 2 upper quartiles of the cumulative T dose compared to 7 of 35 for the 2 lower quartiles (p=.02). We conclude that, among patients randomized to the T arm of TT 2, cumulative dosing does not reveal an effect until after consolidation therapy, probably attesting to the marked efficacy of the cytotoxic components of TT 2. Figure Figure

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Chromosomal Translocation (14;16)-Positive Multiple Myeloma Shows Negativity for CD56 Expression and Unfavorable Outcome Even in the Era of Novel Drugs

Blood ◽

10.1182/blood.v124.21.3349.3349 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3349-3349

Author(s):

Tomoko Narita ◽

Atsushi Inagaki ◽

Tsutomu Kobayashi ◽

Yoshiaki Kuroda ◽

Toshihiro Fukushima ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Features ◽

Plasma Cells ◽

Conflicts Of Interest ◽

Flow Cytometric Analysis ◽

Unfavorable Outcome ◽

University Hospital ◽

Fish Analysis ◽

Newly Diagnosed ◽

Novel Drugs

Abstract Introduction Multiple myeloma (MM) is an incurable plasma cell neoplasm developing through long-term multistep genetic events. Biological and clinical features of the MM are known to be associated in part with relatively early genetic aberrations such as chromosomal translocations involving IGH. The t(14;16)(q32;q23) involving c-MAF oncogene locus is an important chromosomal aberration observed in approximately 5 percent of newly diagnosed MM. Various studies have suggested that MM carrying t(14;16) is associated with specific clinical characteristics. However, these studies were not definitive, since the number of the patients analyzed was relatively small. The aim of this study is to clarify the clinical features of patients with newly diagnosed MM harboring t(14;16) detected by double-color fluorescence in situ hybridization (FISH) in Japan. Methods Clinical and laboratory features of t(14;16)-positive MM diagnosed between 2002 and 2013 were collected retrospectively as a nationwide study in Japan after approval by each institutional ethical committee. The t(14;16) translocation was detected by FISH analysis using bone marrow or peripheral blood samples from all patients. Expression of surface antigens such as CD56 and CD20 was detected by flow cytometric analysis (FCM) and defined as positive when more than 20% of the CD38-positive plasma cells were positive. To compare t(14;16)-positive and t(14;16)-negative MM, we also assessed 132 patients with newly diagnosed symptomatic MM and without c-MAF mRNA expression, as confirmed by global RQ/RT-PCR using purified plasma cells (Tajima E, et al.:Haematologica 2005; 90: 559, Inagaki A et al.: Leuk Res 2013; 37: 1648) at Nagoya City University Hospital. Results In total, 37 patients carrying t(14;16)-positive MM were enrolled from 19 institutions. Median ages of the MM patients with or without t(14;16) at diagnosis were 62 and 68, respectively. Regarding the cell surface phenotype, none of the t(14;16)-positive MM cells was positive for CD56 (Fig. 1), whereas 82 of 118 (69%) t(14;16)-negative ones were positive. Positivity for CD20 antigen was more common in t(14;16)-positive MM cells (11/23, 48%) than in t(14;16)-negative ones (16/115, 14%)(p= 0.001). The proportion of patients with additional chromosome aberrations other than t(14;16), determined by G-banded karyotyping, was higher in patients with t(14;16) (16/30, 53%) than in those without (19/131 cases, 15%) (p< 0.001). Moreover, MM patients with t(14;16) showed higher frequencies of IgG subtype M protein, leukocytosis (p= 0.001), thrombocytopenia (p< 0.001) and hyperproteinemia (p= 0.001), and a lower frequency of hypercalcemia (p= 0.001), compared to those without t(14;16). Overall survival (OS) of the patients with t(14;16) was significantly shorter than that of those without t(14;16) even though the patients received one or more lines of treatment containing novel drugs such as bortezomib, thalidomide and lenalidomide (p= 0.014) (Fig. 2). Poor PS (PS ≥ 2-4), low PLT count (<100x103/ƒÊL), or high LDH levels (>1.0N) were significantly unfavorable prognostic factors for OS in patients with t(14;16)-positive MM, whereas they were not in those without t(14;16). Progression-free survival (PFS) of the patients with t(14;16) was also significantly shorter than those without t(14;16) (p= 0.002) Conclusion The t(14;16)-positive MM comprises a specific category in MM, which is featured by negativity for CD56, higher positivity for CD20 and unfavorable outcome, even in the novel drug era. Unraveling biological characteristics of this specific disease category will lead us to establish novel treatment strategies. Disclosures No relevant conflicts of interest to declare.

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Multiple Myeloma in the Afro-Caribbean Inner City Population: Conventional Cytogenetics and Survival

Blood ◽

10.1182/blood.v124.21.5710.5710 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5710-5710

Author(s):

Dhvani Thakker ◽

Charles Yun ◽

Adam Goldrich ◽

Helzner Elizabeth ◽

Daniel Fein ◽

...

Keyword(s):

Multiple Myeloma ◽

Logistic Regression ◽

Survival Data ◽

Poor Prognosis ◽

Regression Models ◽

Chromosome Banding ◽

Newly Diagnosed ◽

Cytogenetic Abnormalities ◽

Logistic Regression Models ◽

Adjusted Logistic Regression

Abstract Background: Multiple Myeloma (MM) is the second most common hematologic malignancy in the United States. African Americans have among the highest risks of MM and MGUS with several distinct features compared to existing literature. Furthermore, the prevalence of MM is even higher in the Afro-Caribbean population. Cytogenetic and molecular genetic abnormalities predict outcome in patients with MM. Hyperdiploid MM (H-MM) generally has a better prognosis than nonhyperdiploid MM (NH-MM). In addition, patients with additional chromosome 1 abnormalities, loss of chromosome 13, translocation t(14;16) and t(4;14) tend to have a worse survival while patients with translocations t(11;14) are associated with improved survival. In our patient population, the most common cytogenetic abnormalities and their effect on survival remain unknown. Objective: This study was performed to establish a profile of Afro-Caribbean patients with newly diagnosed Multiple Myeloma in order to gain further insight into unique cytogenetic abnormalities and their effects on survival. Methods: Patients with Multiple Myeloma at Kings County Hospital Center and University Hospital at Brooklyn from 2000-2013 were identified by our tumor registries (n=311). We included all the newly diagnosed patients from 2000-2013 who underwent a bone marrow biopsy and conventional cytogenetic by chromosome banding and FISH (n= 173). Patients who did not have a cytogenetic analysis were excluded. Data was collected at the time of initial presentation to include demographics and cytogenetic abnormalities. Survival data was obtained from Social Security Death Index. Differences in frequency of each cytogenetic abnormality by mortality status were examined using Chi-Square or Fisher’s Exact Tests. Two sets of age-adjusted logistic regression models were used to examine potential cytogenetic correlates of both poor (less than two years) and good (4 years or more) survival. Data analysis was performed using SPSS Advanced Statistics. Results: The median age at the time of diagnosis was 65 (Range 36-90). Chromosome banding and FISH showed abnormal cytogenetics in 46% of our patients (n=79). These patients were also found to have multiple abnormal clones. NH-MM was found in 24% (n=19) and H-MM was found in 39% (n=31) of the 79 patients. The most commonly affected abnormalities were trisomiesof odd-numbered chromosomes; +1 (47%), +3 (19%), +5 (21%), +7 (24%), +9 (47%), +11 (42%), +15 (44%), +17 (9%) and +19 (29%). Thirty five percent of 173 patients have expired (n=60). The median survival in the deceased patients was 6.2 years (Range 0.34-12.9). When we examined all patients who lived greater than four years post-diagnosis (n=152), we found significant abnormalities including +5 (p=0.052), NH-MM (p=0.009) and t(11;14) (p=0.03) (See Table 1). Indicators of poor prognosis including 1q gain (p=0.13), loss of chromosome 13 (p=0.21) and del17 (p=0.08) were not significant. In patients who are living, 19% (n=29) have not yet reached the four-year post-diagnosis survival. Less than ten percent underwent autologous stem cell transplantation. Excludes patients who lived less than 3 months post diagnosis August 5 2014 Table 1: Age-Adjusted Logistic Regression Models Predicting Good Survival (lived 4 years or more post-diagnosis) Chromosome abnormality ( + gain, - loss) Age-Adjusted Odds Ratio (95% CI) N=152 P-value 1+ 0.77 (0.26, 2.29) 0.63 1- 2.91 (0.58, 14.57) 0.19 3+ 1.05 (0.35, 3.17) 0.93 5+ 0.47 (0.22, 1.00) 0.052 7+ 0.39 (0.14, 1.10) 0.08 11+ 0.80 (0.36, 1.75) 0.57 14+ 2.07 (0.62, 6.91) 0.24 15+ 0.74 (0.34,1.60) 0.44 19+ 1.20 (0.46, 3.13) 0.71 X- 0.42 (0.11, 1.50) 0.18 Y- 0.40 (0.13, 1.26) 0.12 Hyperdiploidy 0.88 (0.39, 2.00) 0.88 Nonhyperdiplody 0.24 (0.08, 0.70) 0.009 t(4;14) 0.76 (0.27, 2.15) 0.60 t(11;14) 0.18 (0.04, 0.86) 0.03 Conclusion: In this group of Afro-Caribbean patients, median survival (6 years) was higher than Surveillance, Epidemiology, and End Results (SEER) data and more recent review of literature. Gain of chromosome 5 and t(11;14) are consistent with existing data for good prognosis. However, NH-MM which is usually an indicator of poor prognosis was also highly significant in the four-year post-diagnosis survival. This further supports the notion that prognostic value of cytogenetic analysis in this population requires further exploration. Disclosures No relevant conflicts of interest to declare.

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