MicroRNAs Are Differentially Expressed Among Cytogenetic Subgroups in Multiple Myeloma.

Abstract Abstract 2833 Poster Board II-809 Micro-RNAs (miRNAs) are a class of small non-coding single stranded RNAs of 20-22 nucleotides in length. MiRNAs regulate gene expression by binding to the 3' UTR of target mRNAs, which leads to either mRNA degradation or translational inhibition of this target mRNA. MiRNAs play a critical role in cell growth, survival and differentiation and have been suggested to function as tumor suppressor and oncogenes, and/or play a critical role in the pathogenesis of Multiple Myeloma (MM). We investigated miRNA expression in 41 newly diagnosed patients with MM who were included in a clinical trial. MiRNA expression profiling was performed in BM derived CD138 selected plasma cells (PC) obtained from newly diagnosed MM patients with a minimum monoclonal PC purity of > 80%. A quantitative PCR-method (TaqMan low density arrays-microRNA assay', Applied Biosystems) was used for miRNA quantification. The relative expression levels of miRNAs were calculated using the 2-DDCt method and the data was normalized using the endogenous control RNU48. 176/365 miRNAs (48.2%) were expressed in these MM patients. Unsupervised hierarchical clustering based on the average-linkage method and principal component analysis (PCA) was performed in Partek software (Partek Genomics Suite), showing a differential hierarchy for the chromosomal translocation or gain subgroups. When patients with or without chromosome 13 deletions were compared, no correlation was found between expression levels of miRNAs located on chromosome 13 and the deletion status of this chromosome as determined by FISH. Three miRNAs, i.e. miRNA-126, miRNA-145 and miR-517c were identified that were different between MM patients with or without chromosome 13 deletion. These miRNAs were not located on chromosome 13. Likewise, when comparing the miRNA expression in MM patients with or without chromosome 1q gain, the three most differentially expressed miRNAs were miRNA-23a, miRNA-200a# and miRNA-145, which are not on chromosome 1. In addition, miR-18a, located on chromosome 1 was upregulated in MM patients with 1q gain. MM patients with t(4;14) showed differential expression of miRNA-520g, miRNA-28 and miRNA-502. Currently we evaluate potential association of microRNA expression with the clinical response of MM patients to Bortezomib. In conclusion, our data indicate that miRNAs are differentially expressed in subgroups of MM patients characterized by common cytogenetic abnormalities. Disclosures: Goldschmidt: Johnson and Johnson: Research Funding, Speakers Bureau. Sonneveld:Johnson and Johnson: Research Funding, Speakers Bureau.

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A Novel Approach to Risk Stratification in Multiple Myeloma Using ISS Stage and FISH

Blood ◽

10.1182/blood-2019-130639 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1800-1800 ◽

Cited By ~ 1

Author(s):

Shaji K. Kumar ◽

Patricia Greipp ◽

Morie A Gertz ◽

Angela Dispenzieri ◽

Linda B Baughn ◽

...

Keyword(s):

Risk Assessment ◽

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Final Model ◽

Survival Table ◽

The Impact ◽

1Q Gain

Background: A variety of risk factors have been described in multiple myeloma and current risk assessment incorporates ISS stage with specific FISH results and serum LDH (R-ISS). However, this model does not include all the current abnormalities described as prognostic for survival in multiple myeloma. Importantly, the impact of many of these high-risk abnormalities are not uniform. We examined if we can better integrate FISH results into a risk assessment tool to better predict the outcomes of newly diagnosed MM. Patients and methods: We studied a cohort of 1316 patients with FISH done within 6 months of diagnosis of MM, in whom results for commonly observed abnormalities were available. We specifically examined the individual impact of common translocations involving chromosome 14, MYC rearrangements, chromosome 1q gain (single or multiple duplication) and del13q/monosomy 13. A risk assessment system was developed, weighting each abnormality according to their Risk Ratio and integrating ISS stage and serum LDH into the final model construction. Overall survival was calculated from diagnosis, with those alive at last follow up being censored. Results: We first examined the impact of each of the above FISH abnormalities: 1) high risk translocations [t(4;14), t(14;16), or t(14,20)], 2) trisomies, 3) t(11;14), 4) MYCrearrangements, 5) del13q/monosomy 13, and 6) 1q gain . Each of the abnormalities, except for t(11;14), was prognostic for survival (Table 1 with the risk ratios). For 1q gain, the median OS was NR, 105 mos and 79 mos respectively for no abnormality, duplication of 1 copy and duplication of multiple copies, (p<0.001). On multivariate analysis, t(11;14) and trisomies were no longer prognostic for overall survival (Table 1). The cumulative impact of abnormalities demonstrated worsening survival in the presence of increasing numbers of abnormalities (Figure 1). Including ISS stage 3 and LDH > ULN as additional variables for prognostication indicated both were individually prognostic for OS. In a multivariate analysis, including these two and FISH abnormalities, 1q gain and LDH were not independently prognostic. The final model consisted of HR translocations, MYCrearrangements, del17p/monosomy 17, del13q/monosomy 13, and ISS stage 3. Each of these variables was weighted using their risk ratio and a composite score was developed using 998 patients for whom all variables were available (range: 0-7.9; median 1.8). Three patient groups were characterized: group 1 (0; 32%), group 2 (1-4; 58%) and group 3 (>4; 10%) with a median OS of 53 mos, 106 mos, and NR, respectively, p <0.001 (Figure 2). Conclusion: Using the most relevant FISH and laboratory factors, in a large cohort of patients, we refined the current system to develop a risk stratification system that predicts survival in patients with newly diagnosed MM treated with contemporary treatment regimens. This needs validation in future studies. Disclosures Kumar: Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. Gertz:International Waldenstrom Foundation: Research Funding; Annexon: Consultancy; Medscape: Consultancy, Speakers Bureau; Amyloidosis Foundation: Research Funding; Abbvie: Other: personal fees for Data Safety Monitoring board; i3Health: Other: Development of educational programs and materials; Springer Publishing: Patents & Royalties; Physicians Education Resource: Consultancy; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Ionis/Akcea: Consultancy; Alnylam: Consultancy; Prothena Biosciences Inc: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Appellis: Consultancy; Research to Practice: Consultancy; Teva: Speakers Bureau; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Amgen: Consultancy. Dispenzieri:Akcea: Consultancy; Janssen: Consultancy; Intellia: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Lacy:Celgene: Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Kapoor:Celgene: Honoraria; Janssen: Research Funding; Sanofi: Consultancy, Research Funding; Glaxo Smith Kline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Cellectar: Consultancy. 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. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy.

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A Multi-Center Epidemiological and Prognostic Analysis of Cytogenetic Abnormalities in a Cohort of 1015 Chinese Patients with Newly-Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-132076 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3094-3094

Author(s):

Fengyan Jin ◽

Guangxun Gao ◽

Yujun Dong ◽

Chunrui Li ◽

Wenrong Huang ◽

...

Keyword(s):

Multiple Myeloma ◽

Risk Stratification ◽

Research Funding ◽

Asian Population ◽

Response To Therapy ◽

Chinese Patients ◽

Newly Diagnosed ◽

Cytogenetic Abnormalities ◽

Western Countries ◽

1Q Gain

Introduction: Emerging evidence supports that cytogenetic abnormalities (CAs) drive myelomagenesis and heterogeneity (e.g., clinical presentation, response to therapy, and prognosis) of multiple myeloma (MM). Diversity of CAs, including primary (IgH translocations and trisomies) and secondary CAs (copy number abnormalities) argues that MM is not a "single disease". Thus, identification of CAs at diagnosis is essential for risk stratification, guiding treatment, and prognostic estimation in daily practice. However, although frequency, configuration, and significance of CAs have been well documented in the Western countries, this information is lacking in the Asian population. To this end, a multi-center retrospective analysis was carried out to examine epidemiology and prognostic significance of CAs alone or in combination in a cohort of Chinese patients with newly-diagnosed MM (NDMM). Materials and Methods: A total of 1015 NDMM patients who had the baseline information of CAs detected by FISH at four institutes nationwide were included. According to the IMWG consensus updated in 2016, 1q gain, del(17p), t[4;14], and t[14;16] were defined as high-risk CAs (HRCAs), while another HRCA t[14;20] was not tested routinely in a majority of these patients. In addition, del(1p) and del(13q14) were considered as an adverse CA. According to the mSMART3.0 proposed by Mayo Clinic in 2018, double-hit (DHMM) and triple-hit MM (THMM) were defined as co-occurrence of 2 or >= 3 HRCAs, respectively. The Kaplan-Meier approach was used to estimate progression-free survival (PFS) and overall survival (OS). Results: In this cohort, the median age of 1015 patients was 61 years; 63.5% were male. The type of IgG, light chain, IgA, IgD, non/oligosecretory, IgM, or IgE accounted for 42.9%, 26.2%, 24.5%, 3.4%, 2.5%, 0.4%, and 0.1%, respectively. Del(13q) (46.4%) and 1q gain (46.1%; 3 copies = 73.8%, >= 4 copies = 26.2%) represented the most common CAs, followed by t(4;14) (14.0%), t(11;14) (11.8%), del(1p) (11.5%), del(17p) (9.9%; 20-50% cells = 35.6%, > 50% cells = 64.4%), and t(14;16) (5.1%). While none of these CAs was detected in 23.8% of cases, the frequency of patients who carried 1 - 5 CAs was 31.9%, 28.0%, 13.4%, 2.0%, and 0.9%, respectively. In the 1q+ cases, 36.4% patients carried second CA(s), including del(13q) (61.1%), t(4;14) (20.3%), del(1p) (14.8%), del(17p) (10.7%), t(11;14) (10.4%), and t(14;16) (8.1%). In the del(17p) cases, 57.5% patients had additional CA(s), including del(13q) (75.2%), 1q gain (49.5%), del(1p) (21.6%), t(4;14) (19.6%), t(14;16) (8.7%), and t(11;14) (2.2%). In the cases bearing IgH translocations, 26.0% patients also carried other CA(s), including del(13q) and 1q gain (61.9% for each), and del(17p) (9.3%). In the cases harboring HRCAs, the percentage of patients who carried 1 - 4 HRCAs was 70.2%, 24.8%, 3.7%, and 1.1%, respectively. Overall, 14.3% and 2.9% patients had DHMM or THMM, of whom 65.0%, 18.0%, 12.0%, and 5.0% had 2 - 5 HRCAs, respectively. While there was no significant difference in PFS between the cases carrying 1 and 2 CAs (P = 0.209), the patients who had 3 or more CAs displayed a sharp reduction in median PFS (P = 0.022 and P = 0.003 for 3 vs 1 or 2 CAs). Although multiple CAs was associated with shorter median OS, no statistical significance was observed for each comparison (P > 0.05). However, patients who carried >= 2 HRCAs had significantly shorter median PFS (12.1 months; P = 0.0004) and OS (29.3 months; P = 0.027) than those who had one single HRCA (32.2 and 65.6 months for median PFS and OS). Conclusion: In comparison with the Western countries, the incidence of secondary HRCAs (e.g., 1q gain and del(17p)) is relatively higher in Chinese patients at diagnosis, while the standard-risk CA such as t(11;14) is clearly less frequent. The proportion of Chinese patients who carry multiple CAs (up to 5) or HRCAs appear to be greater as well. In this context, patients carrying two or more HRCAs, so called DHMM or THMM, exhibit significantly worse outcome than those carrying only one HRCA. Together, this study builds up an up-to-date profile of CAs for Chinese patients, which might lay a foundation for revising the criteria for risk stratification and the guideline for treatment that is more feasible and practicable in China. It also provides the information about frequency and configuration of MM-driven CAs, which might be more relevant to the Asian population. Disclosures Kumar: Takeda: Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding.

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MiR-15a, Mir-16-1 and Mir-17-92 Cluster Expression Are Linked to Poor Prognosis in Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.5000.5000 ◽

2012 ◽

Vol 120 (21) ◽

pp. 5000-5000

Author(s):

Chen Lijuan ◽

Xiao Gao ◽

Zhang Run ◽

Qu Xiaoyan ◽

Zhang Sensen

Keyword(s):

Multiple Myeloma ◽

Cell Proliferation ◽

Mirna Expression ◽

Poor Prognosis ◽

Conflicts Of Interest ◽

Progression Free Survival ◽

Newly Diagnosed ◽

Quantitative Real Time Pcr ◽

Free Survival ◽

Chromosome 13

Abstract Abstract 5000 Multiple myeloma (MM) is characterized by a profound genomic instability of potential prognostic relevance. Loss of chromosome 13, observed in almost half of patients, negatively affects prognosis. MiR-15a, miR16-1 and miR-17-92 cluster, located on 13q, play important roles in the regulation of cell proliferation, differentiation and apoptosis. Therefore, we investigated a possible correlation of miRNA expression with chromosome 13 deletions (del(13)) and prognosis. We measured the expression of miR-15a, miR16-1 in 70 newly diagnosed MM patients and miR-17-92 cluster in 85 newly diagnosed MM patients by quantitative real-time PCR analyses. MiR-15a, miR-16-1 and miR-17 -92 cluster expression levels are independent of the del(13). High levels of miR-15a, miR-16-1, miR-17, miR-20a and miR-92-1 are associated with shorter progression-free survival (PFS), suggesting poor prognosis. Our data suggest that the expression of specific miRNAs may be contributed to MM prognosis. Disclosures: No relevant conflicts of interest to declare.

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Utilization of Autologous Stem Cell Transplantation in Older Patients with Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2019-130689 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5701-5701

Author(s):

Justin King ◽

Mark A. Fiala ◽

Scott R. Goldsmith ◽

Keith E. Stockerl-Goldstein ◽

Mark A. Schroeder ◽

...

Keyword(s):

Multiple Myeloma ◽

Stem Cell ◽

Older Patients ◽

Research Funding ◽

Small Sample ◽

Poor Performance Status ◽

High Dose ◽

Cell Transplant ◽

Newly Diagnosed ◽

Equity Ownership

Historically, high-dose therapy in combination with autologous stem cell transplants (ASCT) for multiple myeloma (MM) was reserved for younger patients. In more recent years, the use of ASCT has expanded in the older population. However, there is still limited data on the utilization and efficacy of ASCT in older patients, particularly those over the age of 75. To further evaluate this issue, we retrospectively analyzed all patients with newly diagnosed MM between the ages of 75-78, the institutional cutoff for ASCT eligibility, that were referred to the stem cell transplant unit at our institution for consultation from the years 2012-2018. Baseline characteristics, anti-myeloma treatments, and patient outcomes were abstracted through chart review. Seventy-five patients were referred to our institution. 71% were male, 29% female. 39% patients were considered ineligible for ASCT by the consulting transplant physician. Most patients were considered transplant ineligible due to comorbidities or poor performance status. Of the 46 patients eligible for ASCT, 52% underwent the procedure during their first-line therapy. The majority of those patients received reduced intensity melphalan (140 mg/m2) while 2 patients received conventional dosing (200 mg/m2). The other 22 patients eligible for ASCT declined or elected to defer the procedure and to be treated with conventional therapy. The characteristics of these three groups were similar and are detailed in Table 1. After a median follow-up of 30 months, 25% of the patients had expired. Estimated median overall survival (OS) was 71.3 months (unable to quantitate 95% CI) for all patients. Compared to transplant eligible patients, regardless of transplant receipt, those who were transplant ineligible had a 186% increase risk for death (HR 2.86; 95% CI 1.12-7.35; p = 0.029). There was also a notable trend for longer OS in those who underwent ASCT compared to those who were eligible but declined the procedure, but it was not statistically significant (HR 0.36; 95% CI 0.10-1.28; p = 0.114). At a transplant center, two-thirds of patients referred for newly diagnosed MM between the ages 75-78 were considered eligible for ASCT and one-third underwent the procedure. Outcomes were better for patients eligible for ASCT, regardless of whether they underwent the procedure. There was also a trend for better OS in patients who underwent the procedure compared to those who declined. While small sample sizes and the retrospective nature of the study limit our ability to draw conclusions, it appears that ASCT has an OS benefit among patients age 75-78. Disclosures Fiala: Incyte: Research Funding. Stockerl-Goldstein:AbbVie: Equity Ownership; Abbott: Equity Ownership. Vij:Genentech: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Sanofi: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wildes:Janssen: Research Funding; Carevive: Consultancy.

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VTE Rates and Safety Analysis of Newly Diagnosed Multiple Myeloma Patients Receiving Carfilzomib-Lenalidomide-Dexamethasone (KRD) with or without Rivaroxaban Prophylaxis

Blood ◽

10.1182/blood-2019-124403 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1835-1835 ◽

Cited By ~ 4

Author(s):

Katrina M Piedra ◽

Hani Hassoun ◽

Larry W. Buie ◽

Sean M. Devlin ◽

Jessica Flynn ◽

...

Keyword(s):

Multiple Myeloma ◽

Venous Thromboembolism ◽

Board Of Directors ◽

Research Funding ◽

High Dose ◽

Newly Diagnosed ◽

Advisory Committees ◽

Cancer Trial ◽

Oncology Research ◽

Increased Risk

Introduction Immunomodulatory agents (IMiD's) are associated with an increased risk of venous thromboembolism (VTE), particularly when combined with high dose steroids. Studies evaluating the use of lenalidomide-bortezomib-dexamethasone (RVD) and carfilzomib-lenalidomide-dexamethasone (KRD) in the frontline setting for multiple myeloma (MM) have reported a 6% and 24% incidence of thrombosis, respectively, despite primary thrombotic prophylaxis with aspirin (ASA) (Richardson, et al. Blood. 2010; Korde, et al. JAMA Oncol 2015). Recent data, including the Hokusai VTE Cancer Trial, have suggested that safety and efficacy of direct oral anticoagulants (DOACs) are preserved in the setting of treatment of solid malignancy-associated thrombosis (Raskob, et al. N Engl J Med. 2018; Mantha, et al. J Thromb Thrombolysis. 2017). Despite this data, there is limited experience and use of DOACs in prevention of thromboses in the setting of hematologic malignancies, specifically MM. After careful review of literature, since early 2018, we changed our clinical practice and routinely placed newly diagnosed MM (NDMM) patients receiving KRD at Memorial Sloan Kettering Cancer Center (MSKCC) on concomitant rivaroxaban 10 mg once daily, regardless of VTE risk stratification. In the following abstract, we present VTE rates and safety data for newly diagnosed MM patients receiving RVD with ASA vs. KRD with ASA vs. KRD with rivaroxaban prophylaxis. Methods This was an IRB-approved, single-center, retrospective chart review study. All untreated patients with newly diagnosed MM, receiving at least one cycle of RVD or KRD between January 2015 and October 2018 were included. The period of observation included the time between the first day of therapy until 90 days after completion of induction therapy. Patients were identified by querying the pharmacy database for carfilzomib or bortezomib administration and outpatient medication review of thromboprophylaxis with rivaroxaban or ASA. VTE diagnoses were confirmed by ICD-10 codes and appropriate imaging studies (computed tomography and ultrasound). Descriptive statistics were performed. Results During the observation period, 241 patients were identified to have received RVD or KRD in the frontline (99 RVD with ASA; 97 KRD with ASA; 45 KRD with rivaroxaban). Baseline characteristics were well distributed among the three arms, with a median age of 60 (30-94) in the RVD ASA arm, 62 (33-77) in the KRD ASA arm, and 60 (24-79) in the KRD rivaroxaban arm. Patients had International Staging System (ISS) stage 3 disease in 13% (N=13), 9.3% (N=9), and 11% (N=5) of the RVD ASA, KRD ASA, and KRD rivaroxaban arms, respectively. Median weekly doses of dexamethasone were higher in both KRD arms, 40 mg (20-40) vs. 20 mg (10-40) in the RVD ASA arm. The average initial doses of lenalidomide were 22 mg in the RVD ASA arm compared to 25 mg in both the KRD ASA and KRD rivaroxaban arms. After querying the pharmacy database, no patients were identified to have a history or concomitant use of erythropoietin stimulating agent (ESA) use. Treatment-related VTE's occurred in 4 patients (4.0%) in the RVD ASA arm, 16 patients (16.5%) in the KRD ASA arm, and in 1 patient (2.2%) in the KRD rivaroxaban arm. Average time to VTE was 6.15 months (Range 5.42, 9.73) after treatment initiation in the RVD ASA group, while it was 2.61 months (Range 0.43, 5.06) in the KRD ASA group and 1.35 months in the KRD rivaroxaban group. Minor, grade 1 bleeding events per the Common Terminology Criteria for Adverse Events (CTCAE) were identified in 1 (1.1%) patient in the RVD ASA arm, 5 (5.2%) patients in the KRD ASA arm, and 1 (2.2%) patient in the KRD rivaroxaban arm. Conclusion More efficacious MM combination therapies have been found to increase the risk of VTE when using ASA prophylaxis, indicating better thromboprophylaxis is needed. We found patients receiving ASA prophylaxis with KRD were more likely to experience a VTE and these events occurred earlier compared to patients receiving ASA prophylaxis with RVD. Importantly, the rate of VTE was reduced to the same level as ASA prophylaxis with RVD when low-dose rivaroxaban 10 mg daily was used with KRD, and without necessarily increasing bleeding risk. Our retrospective data support the development of prospective clinical trials further investigating DOAC use in thromboprophylaxis for NDMM patients receiving carfilzomib-based treatments. Figure Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Lesokhin:BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Genentech: Research Funding; Juno: Consultancy, Honoraria. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landgren:Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Sanofi: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Off-label use of rivaroxaban for outpatient prophylaxis of venous thromboembolism (VTE) will be explicitly disclosed to the audience.

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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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Potential Relationship between Clinical Significance and Serum Exosomal miRNAs in Patients with Multiple Myeloma

BioMed Research International ◽

10.1155/2019/1575468 ◽

2019 ◽

Vol 2019 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Zhi-yao Zhang ◽

Yan-chen Li ◽

Chuan-ying Geng ◽

Hui-juan Wang ◽

Wen-ming Chen

Keyword(s):

Multiple Myeloma ◽

Clinical Characteristics ◽

Clinical Symptoms ◽

Clinical Feature ◽

Newly Diagnosed ◽

Related Factors ◽

Expression Levels ◽

Potential Relationship ◽

Exosomal Mirnas ◽

Exosomal Mirna

This study evaluated the potential relationship between exosomal miRNAs and clinical symptoms in patients with multiple myeloma (MM). Forty-eight newly diagnosed myeloma patients and sixteen normal donors were enrolled in the study. The results showed that the relative expression levels of let-7c-5p, let-7d-5p, miR-140-3p, miR-185-5p, and miR-425-5p in the exosomes of MM patients were significantly lower than those of healthy controls. Furthermore, there were significant differences in the clinical characteristics of myeloma, such as kidney damage, while the expression levels of the same miRNA in exosomes and serum are not correlated. The expression of exosomal miRNA is related to the expression levels of clinical feature-related factors, such as creatinine, β2-microglobulin, β-CTX, and IL-6 in serum. Establishing this relationship could contribute to understanding the pathogenesis of MM.

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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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Chromosome 1q Amplification Is Associated with a History of Prior Malignancies Among Patients Newly Diagnosed with Multiple Myeloma

Blood ◽

10.1182/blood-2019-125407 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2193-2193

Author(s):

Elizabeth B Lamont ◽

Andrew J. Yee ◽

Stuart L. Goldberg ◽

Andrew D Norden

Keyword(s):

Prostate Cancer ◽

Multiple Myeloma ◽

Clinical Trials ◽

Usual Care ◽

Real World ◽

Research Funding ◽

Newly Diagnosed ◽

History Of ◽

Equity Ownership ◽

Prior Malignancy

Background: Over the past 20 years, observational data from usual care clinical oncology settings has been leveraged to inform estimates of cancer treatment-associated benefits and risks among patients not treated on clinical trials. Increasing genomic testing to inform treatment decisions in usual care settings now meaningfully augments traditional observational data, positioning it to provide insights beyond clinical care into tumor biology. We studied patients with newly diagnosed multiple myeloma (MM), comparing cytogenetic test patterns according to history of prior malignancy. Methods: In this retrospective cohort study, we identified 2,380 patients from the COTA real-world database (RWD) who were newly diagnosed with MM in the years 2010-2018. The COTA RWD is a de-identified composite of both abstracted electronic health record and administrative data pertaining to patients receiving their cancer care at one of COTA's clinical oncology practice partners. Among these patients, 1769 (74%) had evidence of MM-associated cytogenetic testing with fluorescent in-situ hybridization (FISH) within the 120 days surrounding their date of diagnosis. The 1,769 patients form the analytic cohort. We compared patients' FISH results for t(4;14), deletion(17p), t(14;16), deletion(13), t(14;20), t(6;14), t(11;14), deletion (1p), and amplification(1q) according to their history of prior malignancy. Results: Within the cohort, 263 prior malignancies were identified in 241 patients (14%, 241/1,769). Two-hundred and twenty-one patients (92%) had one prior malignancy, 28 (7.9%) had two prior malignancies, and one (<1%) had four prior malignancies. The most common prior malignancies were prostate (n=50), breast (n=19), melanoma (n=14), skin (n=13), and cervix (n=6). Amplification of the long arm of chromosome one (amp(1q)) was noted in 31% of patients (75/241) with a prior malignancy vs. 24% of patients (370/1,528) without (chi2 test p=0.02). Overall 25% of patients had amp(1q). No other translocations, amplifications, deletions were associated with prior cancers. A non-parametric test for trend revealed a strong positive association between patients' malignancy count (range 0-4) and amp1q (p<0.01). MM patients with prior lymphomas and prior melanomas also had high rates of amp(1q), though these were not significantly different from patients without these prior malignancies. In a multivariable logistic regression model that adjusted for patient demographic attributes, other known potentially collinear MM poor prognostic factors (i.e., revised ISS stage, IgA sub-type, lambda light chains) and adjusted standard errors for clustering of patients within treatment settings, a history of prostate cancer remained clinically and statistically significantly positively associated with amp(1q) (OR 2.1, 95% CI: 1.9-2.2) as did history of two or more prior malignancies (OR 2.8, 95% CI: 2.3-3.3). Of note, amp(1q) was positively associated with IgA subtype (OR 1.5, 95% CI: 1.3-1.6) and the presence of lambda subtype (OR 1.3, 95%CI: 1.3-1.4). Conclusions: Using RWD, we found that newly diagnosed MM patients with histories of prostate cancer and those with two or more prior malignancies were more likely to have amp(1q), a poor prognostic marker in MM. Gains in 1q have previously been identified among patients with prostate and lymphoid cancers, but to our knowledge this is the first study to identify an association with a prior history of cancer, especially prostate cancer, and amp(1q) in MM. This relationship is worth further exploration of whether there is a common pathway associated with for example risk of prostate cancer and amp(1q) in MM. Clinical trials are less likely to answer this question as patients with prior malignancies are often excluded from enrollment. Overall, the results reported suggest that RWD is an efficient and comparatively inexpensive tool to support research in cancer biology through hypothesis generating and testing analyses of linked real-world phenotypic and genotypic data. Disclosures Lamont: COTA: Employment. Yee:Celgene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Adaptive: Consultancy; Amgen: Consultancy, Honoraria. Goldberg:Cancer Outcomes Tracking and Analysis (COTA) Inc.: Equity Ownership; COTA: Equity Ownership; Bristol-Myers Squibb: Consultancy. Norden:COTA: Employment, Equity Ownership.

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Status of Chromosome 13 in Multiple Myeloma: Integrated Approach Using SNP Mapping Array and Gene Expression Array.

Blood ◽

10.1182/blood.v106.11.1563.1563 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1563-1563

Author(s):

Paola E. Leone ◽

Brian A. Walker ◽

David Gonzalez ◽

Matthew Jenner ◽

Fiona M. Ross ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Multiple Myeloma ◽

Snp Array ◽

Regulatory Genes ◽

Expression Array ◽

Array Data ◽

Chromosome 13 ◽

Expression Levels ◽

Cell Cycle Regulatory Genes

Abstract Deletions on chromosome 13 are thought to be one of the most important prognostic features in Multiple Myeloma (MM). The biology underlying this is, however, uncertain. Chromosome 13 abnormalities have been evaluated conventionally by FISH using probes for 13q14, covering the retinoblastoma gene (RB1) region. Typically, for recurrent regions of loss of heterozygosity (LOH) it is possible to map a minimally deleted region within which an important gene may be located. This should be the case with 13q−, or alternatively there may be linkage with another genetic lesion, which could be contributing to the poor prognosis. Following the implementation of high-density single-nucleotide polymorphism (SNP) array, it is now possible to genotype the whole human genome with a mapping resolution of less than 50 Kb. Thus, the SNP array approach offers an opportunity to analyze both copy number abnormalities and LOH simultaneously. The aim of this study was to determine the numerical alterations, LOH and changes in the gene expression profile of the chromosome 13 in MM, and its possible association with other genetic events. For this purpose, we analyzed 17 patients included on the Myeloma IX trial with deletion of 13q14 compared with 22 samples without deletion, using Affymetrix 50K SNP arrays and Affymetrix U133 Plus 2 expression array. IGH translocations and 13q deletion were determined by FISH. dChipSNP and WGSA programs were used to analyze the data. With respect to 13q14, there was 100% correlation between FISH and SNP array results. 16 out of 17 cases with deletion of the RB1 gene by FISH analysis showed loss of 13q arm by SNP array, demonstrating that loss of the whole chromosome 13 is responsible for 13q deletions found in MM in >90% of cases, with only one case showing a defined region of deletion of chromosome 13 (13q14.11–13q21.2). Using gene expression arrays we could not define a specific pattern characteristic of expression loss in genes at 13q. Lower RB1 expression levels were not only restricted to cases with del(13). However, samples containing IGH translocations (t(11;14) and t(4;14)) without del(13) showed up to 4 times more RB1 expression, suggesting that MM evolution in cases containing IGH translocations is independent of RB1 expression. Interestingly, the hyperdiploid cases with and without del(13) expressed similar level of RB1. We also investigated whether other key cell cycle regulatory genes were associated with del(13); in particular, 4 cases showed 9p21 LOH by SNP array and no different gene expression levels, which suggest that LOH does not seem to be a mechanism of lost of expression of CDKN2A, CDKN2B and p14/ARF. We could not find any significant correlation with del(13) and expression of cell cycle regulatory genes, apart from 8/17 samples with del(13) that had low expression of p53 gene, including 6 t(4;14) cases and 2 t(11;14) cases. Also, 2 cases without monosomy 13 (1 with t(4;14) and 1 with t(11;14)), showed low p53 expression levels. However, SNP array data did not show any deletion at 17p in 38 cases, with the exception of a case with monosomy 13 and t(11;14) in which SNP array data showed loss at 17pter-17q21.2 and FISH detected p53 deletion. Further investigation between the association of p53 and del(13) are ongoing and maybe useful in defining the biology of this poor subgroup of patients.

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