Pathogenic Germline Variants in Multiple Myeloma

Abstract BACKGROUND: There is growing evidence supporting inherited predisposition to multiple myeloma (MM). Epidemiologic studies have shown that 1st-degree relatives of MM patients (pts) have a 2-4 fold increase in risk of developing MGUS or MM. Genome-wide association studies (GWAS) have identified common SNPs as well as rare high-penetrance variants that collectively explain ~16% of the estimated heritability of multiple myeloma (PMID 30213928). Pathogenic/likely-pathogenic germline variants (PGV) in hereditary cancer genes (HCG) are common in adult cancer patients (~8%, PMID 29625052), but prevalence in MM is not known. The aim of our study is to investigate the occurrence of PGV in newly-diagnosed MM (NDMM), and to describe clinical characteristics & outcomes of carriers. METHODS: We analyzed MMRF CoMMpass data (version IA16) and identified 895 NDMM pts for whom whole-exome sequencing of germline DNA was available. We used the clinical annotation pipeline from Sema4, a CLIA/CAP certified genetic testing laboratory, to identify pts with PGV according to ACMG variant classification guidelines. We compared clinical characteristics & disease phenotypes of PGV carriers vs non-carriers. We used Chi-Square and Fisher's Exact tests to assess statistical significance, which we defined as a two-sided p value < 0.05. Logistic regression models were used for multivariate analyses. Kaplan-Meier method and Cox proportional-hazards models were used for uni- and multivariate survival analysis, respectively. Bonferroni method was used to account for multiple testing. RESULTS: We identified 83 PGV in 31 distinct HCG in 79 (8.8%) of 895 NDMM pts (83% European ancestry) [Figure 1A]. Most PGV involved DNA damage repair (DDR) genes (78%), and homologous recombination (HR) genes were the most commonly mutated (34%). PGV in CHEK2 were the most common (n=10, 1.1% of all MM pts). 2 pts carried PGV in TP53 and reported extensive family history of Li-Fraumeni-associated cancers (breast, sarcoma, gastric & melanoma). 6 pts had germline mismatch repair (MMR) gene defects (1:149, considerably higher than the estimated prevalence of Lynch syndrome in Western populations). 4 pts carried PGV in BRCA2 (previously identified in a family study as a potential MM predisposition gene, PMID 11904319). MM pts with a family history of hematologic malignancy (leukemia, lymphoma or MM) in a 1st or 2nd-degree relative were significantly more likely to carry PGV (22 vs 7.6%, OR=3.3, p<0.001), an association that remained significant in MVA (OR=4.1, p<0.001). CHEK2 variants emerged as leading drivers of this correlation (OR 18.2, 95% CI 4.1-75, adjusted p<0.01), & especially protein-truncating founder variant c.1100delC. Likelihood of being diagnosed w/ MM before age 40 was significantly higher in PGV carriers (6.3 vs 1.8%, OR=3.7, p=0.025). 25% of those younger than 40 y/o carried PGV, but none of these were in DDR-HR genes, a notable difference with other age groups (0 vs 41%, p=0.02). 2/6 MMR PGV were detected in pts diagnosed before age 40. In univariate survival analysis, DDR-PGV carriers had a significant PFS1 advantage over non-carriers (median 52 vs 35 months, p=0.008), as well as a non-significant OS advantage (p=0.08). PFS1 difference remained significant in MVA after adjusting for age, ISS stage, high-risk cytogenetics, treatment type & transplant status (OR 0.65, 95% CI 0.44-0.97, p=0.03) [Figure 1B]. CONCLUSIONS: PGV in HCG were common (8.8%) in this large cohort of NDMM pts of predominantly European ancestry, especially in those with a family history of hematologic malignancy (1:4, with high prevalence of CHEK2 variants & particularly protein-truncating founder variant c.1100delC), and in those diagnosed before age 40 (1:4). Routine screening in high-prevalence subgroups might be warranted, as carriers may benefit from counseling and enrollment in early cancer detection programs. We observed a clinically and statistically significant PFS1 advantage in carriers of PGV in DDR genes, possibly due to increased sensitivity to MM therapies, a well-described phenomenon in other cancer types (PMID 33158305). Prospective validation of these findings is needed to better understand prognostic & therapeutic implications of PGV in MM. Figure 1 Figure 1. Disclosures Chari: Karyopharm: Consultancy; Takeda Pharmaceutical Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen Pharmaceuticals: Consultancy, Research Funding; Sanofi Genzyme: Consultancy; Oncopeptides: Consultancy; Antegene: Consultancy; Glaxosmithkline: Consultancy; Secura Bio: Consultancy. Richard: Karyopharm, Janssen: Honoraria. Richter: Sanofi: Consultancy; Antengene: Consultancy; Karyopharm: Consultancy; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Adaptive Biotechnologies: Speakers Bureau; Celgene: Speakers Bureau; Janssen: Speakers Bureau; X4 Pharmaceuticals: Consultancy; Oncopeptides: Consultancy; Adaptive Biotechnologies: Consultancy; Secura Bio: Consultancy; Astra Zeneca: Consultancy. Parekh: Foundation Medicine Inc: Consultancy; Amgen: Research Funding; PFIZER: Research Funding; CELGENE: Research Funding; Karyopharm Inv: Research Funding.

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Differences in the Distribution of Cytogenetic Subtypes Between Multiple Myeloma Patients with and without a History of Familial MGUS and Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4000.4000 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4000-4000

Author(s):

Alexandra Greenberg ◽

Margot Cousin ◽

Celine M Vachon ◽

Dirk Larson ◽

Colin L. Colby ◽

...

Keyword(s):

Multiple Myeloma ◽

Family History ◽

Research Funding ◽

Plasma Cells ◽

Statistical Significance ◽

Degree Relative ◽

First Degree Relatives ◽

Familial Tendency ◽

Increased Risk ◽

History Of

Abstract Abstract 4000 Background: We have previously reported that there is an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first-degree relatives of patients with multiple myeloma (Vachon CM. Blood 2009 114: 785–790). There are several cytogenetic subtypes of myeloma, and there are no data on whether certain cytogenetic subtypes of myeloma are more frequently associated with familial MGUS. Methods: We studied patients with myeloma who participated in the familial MGUS study in whom presence or absence of MGUS in the first-degree relatives had been ascertained (Vachon CM. Blood 2009 114: 785–790). Probands were seen at the Mayo Clinic Hematology/Oncology practice (Rochester, MN, USA) between February 2006 and September 2007. Cytogenetic data was acquired via electronic medical record abstraction of fluorescence in-situ hybridization (FISH) lab reports, and used to categorize patients into one of nine cytogenetic subgroups: trisomy(ies), t(6;14), t(11;14), t(4;14), t(14;16), t(14;20), Mixed (those with trisomy(ies) and an IgH translocation), other cytogenetic abnormalities (in the absence of trisomy(ies) or IgH translocation), and normal (Kumar S. Blood 2012;119:2100–2105). We examined whether a difference in the distribution of the six primary cytogenetic categories of myeloma existed between probands with a family history of MGUS and/or myeloma and those without. Results and Conclusions: Of the 248 patients invited to participate, FISH data (with sufficient plasma cells) was available on 119 participants to establish the primary molecular cytogenetic classification of myeloma. All had available information regarding family history of MGUS and multiple myeloma. 27 had an affected first-degree relative with MGUS, and 92 did not. Distributions of cytogenetic subtypes in the two groups are shown in Table 1. IgH translocated MM was more common in myeloma patients who lacked an affected first-degree relative compared to those with familial MGUS (19% vs 30%, P=0.32) Interestingly, the t(11;14) subtype was more common in myeloma patients without familial MGUS compared to those with an first-degree relative with MGUS (19.6% vs 7.4%, P=0.24). The differences in Table 1 did not reach statistical significance, possibly due to the small numbers of individuals with a family history in this sample. However, the distribution (Table 1) suggests that the distribution of cytogenetic subtypes may be different in myeloma that is not associated with familial MGUS compared with myeloma in which a familial tendency is detected. IgH translocated MM appears to have a lower risk of familial tendency. Further investigation is needed to estimate the risk of familial MGUS within each cytogenetic subtype. Disclosures: Kumar: Merck: Consultancy, Honoraria; Millennium: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Research Funding.

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Clinical Characteristics and Prognosis of Thirty-Three Patients with Myeloid Neoplasms and DDX41 Mutation: Mayo Clinic Experience

Blood ◽

10.1182/blood-2021-144400 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3691-3691

Author(s):

Ahmad Nanaa ◽

Aref Al-Kali ◽

David S. Viswanatha ◽

James M. Foran ◽

Talha Badar ◽

...

Keyword(s):

Family History ◽

Board Of Directors ◽

Solid Tumors ◽

Mayo Clinic ◽

Research Funding ◽

Clinical Characteristics ◽

Advisory Committees ◽

Dead Box ◽

History Of ◽

Normal Cytogenetics

Abstract Background: The DEAD-box helicase 41 (DDX41), an RNA helicase, have been described as a component of the RNA spliceosome (Cheah et al. International Journal of Hematology 2017). Although DDX41 mutations predispose to late-onset higher grade myeloid neoplasms (MN), these patients may have a trend toward favorable prognosis and outcomes. In this work, we describe the clinical characteristics and survival outcomes of isolated and co-mutated DDX41 patients (pts). Methods: We retrospectively analyzed 4,524 consecutive pts who underwent next-generation sequencing (NGS) (OncoHeme 42 genes panel, Mayo Clinic) testing and included 32 pts harboring pathogenic DDX41 mutation and one pt with proven DDX41 germline variant of unknown significance (VUS). Chart review of DDX41-mutated (m) cases between 2009 and 2021 was conducted after IRB approval. We compared overall survival (OS) of unmatched 27 t(8;21)AML and 40 inv(16) AML pts with 10 m DDX41-AML pts. JMP® Pro 14.1.0 Software was used for statistical analysis. Results: DDX41 mutations characteristics: Our cohort included 19 (58%) myelodysplastic syndromes (MDS), 10 (30%) acute myelogenous leukemia (AML), 2 (6%) myeloproliferative neoplasms (MPN), one clonal cytopenia of undetermined significance (CCUS) (3%) and one (3%) germline carrier. Germline testing was carried out in 10 pts, 9 of whom (90%) were confirmed to be germline). The start-loss variant (p.M1I) was the most common mutation type (N=10, 31%). Other types were frameshift (N=9, 28%), missense mutation (N=8, 25%), nonsense (N=3, 9%), and splice site mutation (N=2, 2%). Twenty-one (65.6%) DDX41 mutations clustered in the N-terminus (NT), 7 (22%) in the helicase-C domain (HCD), and 4 (12.5%) in the DEAD-box domain. Compared to NT mutations, patients with HCD mutation had no family history of solid tumors and were more likely to have an accompanying additional DDX41-VUS (0% vs 70%; p=.001) and (N=6, 86% vs. N=2,10%; p=.0001); respectively. I solated vs. co-mutated DDX41: Twenty (60%) pts were isolated-DDX41 and 13 (40%) were co-mutated. The median DDX41-VAF was 48% vs. 45% (p= .2) in the isolated compared to the co-mutated cases, respectively. The median number of co-mutations in the 13 co-mutated cases was 1 (range,1-3) with DNMT3A (38%), ASXL1 (30%), JAK2 (N=3, 23%), and EZH2 (N=2, 15%) were the most common co-mutations detected. Isolated DDX41 had more males (85% vs. 54%, p=.05), the p.M1I variant (47% vs. 8%, p=.02), normal cytogenetics (100% vs. 91%, p= .02), and less family history of solid tumors (77% vs. 33%, p= .02) compared to their co-mutated counterparts. However, there was no difference in OS (p=.99). Comparison of clinical characteristics and hematological features of isolated and co-mutated DDX41 pts are reported in (Table 1). Treatment and survival outcomes in DDX41-MDS/AML : Twenty-three (80%) patients were treated, MDS pts received hypomethylating agents (HMA) (N=10, 71%), HMA plus Venetoclax (HMA+VEN) (N=1, 7%), erythropoiesis-stimulating agents (N=2, 14%) and lenalidomide (N=1 ,7%). AML pts were treated with induction chemotherapy (N=6, 67%) and HMA+VEN (N=3, 33%). Overall response rate of MDS/AML patients was 77% and 100% of AML pts achieved complete remission (CR) when treated with induction chemotherapy or HMA+VEN regimen. There was no significant difference in OS between responders vs. non-responders 2-yr-OS (90% vs. 50%; p=.38) and treated vs. untreated 2-yr-OS (83% vs. 100%; p=.52). Comparing m DDX41-AML vs. core binding factor-AML: After a median follow-up of 33.3 months, all m DDX41-AML patients were alive. There was a significantly better OS in mDDX41-AML patients compared to pts with t(8;21) AML with 2-yr-OS (100% vs. 51%; p=.024) and a trend of better survival when compared to inv(16) AML 2-yr-OS (100% vs. 84%; p=.2). Conclusion We describe the characteristics and outcomes of m DDX41 patients. We demonstrated that isolated and co-mutated m DDX41 patients have different features. Isolated DDX41 patients had male predominance, more p.M1I variant, normal cytogenetics and less family history of solid tumors. In this study we found that m DDX41 AML has high response to treatment and has comparable (if not possibly better) OS compared to other "favorable risk" AML. This study, although limited by the small number of patients, supports the universal testing for DDX41 mutation in adults with MN diagnosis. Figure 1 Figure 1. Disclosures Al-Kali: Astex: Other: Research support to institution; Novartis: Research Funding. Foran: abbvie: Research Funding; OncLive: Honoraria; boehringer ingelheim: Research Funding; trillium: Research Funding; pfizer: Honoraria; takeda: Research Funding; revolution medicine: Honoraria; bms: Honoraria; gamida: Honoraria; actinium: Research Funding; aptose: Research Funding; novartis: Honoraria; servier: Honoraria; taiho: Honoraria; syros: Honoraria; sanofi aventis: Honoraria; certara: Honoraria; kura: Research Funding; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Badar: Pfizer Hematology-Oncology: Membership on an entity's Board of Directors or advisory committees. Salama: Mayo Clinic: Current Employment, Other: Mayo Clinic had the contractual work for the central pathology review for this study and I was one of the reviewing pathologists; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Litzow: Astellas: Research Funding; Biosight: Other: Data monitoring committee; Amgen: Research Funding; AbbVie: Research Funding; Actinium: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board. Patnaik: Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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Patterns of Family History of Cancer in Adults with Hematologic Malignancies

Blood ◽

10.1182/blood-2021-147900 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4378-4378

Author(s):

Karen Seiter ◽

Kyaw Swa ◽

Kyaw Htun ◽

Paul Baskind ◽

Delong Liu

Keyword(s):

Family History ◽

Family Member ◽

Research Funding ◽

Germ Line ◽

Hematologic Malignancy ◽

Family Members ◽

Hematologic Malignancies ◽

Median Number ◽

History Of

Abstract Hematologic malignancies have generally been considered to be sporadic diseases. More recently several germ line mutations that lead to hereditary hematologic malignancies have been discovered, even in adults. We sought to evaluate the frequency of a family history of hematologic or other malignancy in pts admitted to the hospital for treatment of a hematologic malignancy. We also studied exposure history including use of cigarettes. All pts signed informed consent. Pts were entered prospectively and interviewed with a standard questionnaire. 702 pts (median age 61.9: range 16.3-91.3 years) were enrolled. Diagnoses were AML: 396 pts, aplastic anemia: 5 pts, ALL: 96 pts, CLL: 24 pts, CML 42 pts, CMML 10 pts, MDS 30 pts, MM 19 pts, MPD 10 pts, and NHL 70 pts. 473 pts (67.4%) had a family member with cancer. There was a total of 1037 cancers in these family members. The median number of family members with cancer was 1 (range 0-10). The frequency of each type of family member cancer is displayed in the table. 19.7% of pts had a family member with leukemia or other hematologic malignancy (leukemia: 12.0%, other hematologic: 7.7%). Compared to pts with a hematologic malignancy other than AML, pts with AML were more likely to have a family member with any type of cancer (72.4% vs 60.7%, p=0.001). Pts with AML were also more likely to have a family member with a history of any type of hematologic malignancy (22.4% vs 16.0%, p=0.03), but not specifically a history of leukemia (13.4% vs 10.1%, p=0.11). Compared to pts with hematologic malignancies other than AML, pts with AML were also more likely to have a family member with prostate cancer (16.2% vs 9.5%, p=0.01), or breast cancer (29.5% vs 21.9%, p=0.02). 51.4% of pts had a history of smoking (either current or prior). Pts with AML were more likely to be current or former smokers compared to pts with other hematologic malignancies (55.8% vs 45.8%, p=0.008). These data support the role of genetics and exposure in adults with AML. Figure 1 Figure 1. Disclosures Seiter: Delta FLY: Research Funding; Novartis: Honoraria; Rafael: Research Funding; Sun Pharma: Research Funding; Jazz: Honoraria, Research Funding; Glycomimetics: Research Funding; Incyte: Honoraria; Forma: Research Funding; Celgene (BMS): Honoraria, Research Funding. Liu: Beigene: Honoraria, Speakers Bureau; Pfizer: Research Funding; Astellas: Honoraria, Speakers Bureau; Pharmacyclics: Honoraria, Speakers Bureau; Incyte: Honoraria; Celgene: Research Funding.

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Clinical characteristics and sociodemographic features of psychotic major depression

Annals of General Psychiatry ◽

10.1186/s12991-021-00341-7 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Meng-qi Wang ◽

Ran-ran Wang ◽

Yu Hao ◽

Wei-feng Xiong ◽

Ling Han ◽

...

Keyword(s):

Family History ◽

Major Depression ◽

Clinical Characteristics ◽

Missing Values ◽

Psychotic Disorders ◽

Mental Health Center ◽

Psychiatric Diseases ◽

First Onset ◽

History Of ◽

Psychotic Major Depression

Abstract Background Psychotic major depression (PMD) is a subtype of depression with a poor prognosis. Previous studies have failed to find many differences between patients with PMD and those with non-psychotic major depression (NMD) or schizophrenia (SZ). We compared sociodemographic factors (including season of conception) and clinical characteristics between patients with PMD, NMD, and schizophrenia. Our aim was to provide data to help inform clinical diagnoses and future etiology research. Methods This study used data of all patients admitted to Shandong Mental Health Center from June 1, 2016 to December 31, 2017. We analyzed cases who had experienced an episode of PMD (International Classification of Diseases, Tenth Revision codes F32.3, F33.3), NMD (F32.0–2/9, F33.0–2/9), and SZ (F20–20.9). Data on sex, main discharge diagnosis, date of birth, ethnicity, family history of psychiatric diseases, marital status, age at first onset, education, allergy history, and presence of trigger events were collected. Odds ratios (OR) were calculated using logistic regression analyses. Missing values were filled using the k-nearest neighbor method. Results PMD patients were more likely to have a family history of psychiatric diseases in their first-, second-, and third-degree relatives ([OR] 1.701, 95% confidence interval [CI] 1.019–2.804) and to have obtained a higher level of education (OR 1.451, 95% CI 1.168–1.808) compared with depression patients without psychotic features. Compared to PMD patients, schizophrenia patients had lower education (OR 0.604, 95% CI 0.492–0.741), were more often divorced (OR 3.087, 95% CI 1.168–10.096), had a younger age of onset (OR 0.934, 95% CI 0.914–0.954), less likely to have a history of allergies (OR 0.604, 95% CI 0.492–0.741), and less likely to have experienced a trigger event 1 year before first onset (OR 0.420, 95% CI 0.267–0.661). Season of conception, ethnicity, and sex did not differ significantly between PMD and NMD or schizophrenia and PMD. Conclusions PMD patients have more similarities with NMD patients than SZ patients in terms of demographic and clinical characteristics. The differences found between PMD and SZ, and PMD and NMD correlated with specificity of the diseases. Furthermore, allergy history should be considered in future epidemiological studies of psychotic disorders.

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Season of birth interacts with measures of inbreeding in multiplex schizophrenia pedigrees: evidence from genetic isolates in Daghestan

Open Medicine ◽

10.2478/s11536-006-0041-8 ◽

2006 ◽

Vol 1 (4) ◽

pp. 392-398

Author(s):

Kazima Bulayeva ◽

John McGrath

Keyword(s):

Genetic Diversity ◽

Family History ◽

Age Of Onset ◽

Population Genetic Study ◽

Season Of Birth ◽

High Genetic Diversity ◽

Low Genetic Diversity ◽

High Prevalence ◽

History Of ◽

Genetic Isolates

AbstractWhile the season-of-birth effect is one of the most consistent epidemiological features of schizophrenia, there is a lack of consistency with respect to the interaction between season of birth and family history of schizophrenia. Apart from family history, measures related to consanguinity can be used as proxy markers of genomic heterogeneity. Thus, these measures may provide an alternate, indirect index of genetic susceptibility. We had the opportunity to explore the interaction between season of birth and measure of consanguinity in well-described genetic isolates in Daghestan, some of which are known for their relatively high prevalence of schizophrenia. Our previous population-genetic study showed Daghestan has an extremely high genetic diversity between the ethnic populations and a low genetic diversity within them. The isolates selected for this study include some with more than 200 and some with less than 100 generations of demographical history since their founding. Based on pedigrees of multiply-affected families, we found that among individuals with schizophrenia, the measure of consanguinity was significantly higher in the parents of those born in winter/spring compared to those born in summer/autumn. Furthermore, compared to summer/autumn born, winter/spring born individuals with schizophrenia had an earlier age-of-onset, and more prominent auditory hallucinations. Our results suggest that the offspring of consanguineous marriages, and thus those with reduced allelic heterogeneity, may be more susceptible to the environmental factor(s) underpinning the season-of-the effect in schizophrenia.

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Comparative survival analysis using the International Stratification Score (ISS) in newly-diagnosed multiple myeloma in the Uruguayan population

Medicine and Pharmacy Reports ◽

10.15386/mpr-1750 ◽

2021 ◽

Author(s):

David Israel Garrido ◽

Virginia Bove ◽

Victoria Matosas ◽

Eloisa Riva

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Latin America ◽

Survival Analysis ◽

Hematologic Malignancy ◽

Staging System ◽

Newly Diagnosed ◽

Hematopoietic Stem ◽

Survival Estimation ◽

Real Practice

Background and aims. Multiple myeloma is a frequent hematologic malignancy, in which the International Stratification Score (ISS) is widely used to estimate the overall survival. However, there are no studies in Latin America evaluating its performance. This study aims to describe the ISS performance in the overall survival estimation for newly diagnosed multiple myeloma patients in Uruguay. Methods. This is a retrospective registry‐based survival analysis through the Grupo Uruguayo de Mieloma Múltiple (GUMMA) database, including newly diagnosed multiple myeloma patients from January 2001 until May 2019. Results. 249 patients were included, 51.81% males and an average age of 63.49 years. According to ISS and Durie-Salmon score (DSS), 47.79% and 82.3% were ISS III and DSS III, respectively. Also, 32.3% were DSS B. Auto hematopoietic stem cell transplantation was performed in 31.73% of patients, and bortezomib was used in 44.18% as frontline therapy. The overall survival was 80% for ISS1, 64.9% ISS2, and 48.6% ISS3 (Log-Rank; p <0.01). The average overall survival was 116.5 months for ISS 1, 77.6 months for ISS 2, and 57.8 months for ISS 3. The hazard ratio between ISS II and ISS I was 2.42 (95% CI 1.10-5.33; p<0.05), and 3.94 (95% CI 1.88-8.26; p<0.05) between ISS III and ISS II. Conclusion. The ISS staging system allows an adequate stratification of patients according to overall survival in the real-practice setting. However, considering the relevance of the new cytogenetic advances, it is necessary to increase the availability and quality of iFISH in Latin America.

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Incidence, Management and Outcomes of Arterial and Venous Thromboembolism after Chimeric Antigen Receptor Modified T Cells for B-Cell Lymphoma and Multiple Myeloma

Blood ◽

10.1182/blood-2020-136782 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 7-7

Author(s):

Anna L. Parks ◽

Swetha Kambhampati ◽

Bita Fakhri ◽

Charalambos Andreadis ◽

Lissa Gray ◽

...

Keyword(s):

Risk Factors ◽

Multiple Myeloma ◽

T Cells ◽

Venous Thromboembolism ◽

B Cell ◽

Research Funding ◽

Vte Prophylaxis ◽

Therapeutic Anticoagulation ◽

Car T ◽

History Of

Introduction: Chimeric antigen receptor modified T Cell (CAR-T) therapy is a rapidly developing treatment for patients with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). Although this population is at high risk for thrombosis, there are few data about rates of venous thromboembolism (VTE) and arterial thromboembolism (ATE) with CAR-T. Additionally, treatment with anticoagulation is complicated because of the prevalence of thrombocytopenia following CAR-T. Our goal was to determine the incidence, associated risk factors, management and outcomes of VTE and ATE in the 60 days following CAR-T therapy. Methods: We performed a single-center, retrospective cohort study of all patients who received inpatient CAR-T cells at UCSF Medical Center between January 2018 and May 2020 for R/R NHL or MM as standard-of-care or on a clinical trial. The outcomes of incident VTE and ATE were identified by ICD-10 codes and medical record review. Patient characteristics, pre-existing thrombosis risk factors, laboratory results, medications, and major or clinically relevant non-major bleeding or recurrent thrombotic complications were obtained through chart review. We used descriptive statistics to delineate risk factors, incidence, management and outcomes of thrombotic events. Results: Ninety-one patients who underwent CAR-T therapy were included in the analysis, 37 with NHL and 54 with MM. For NHL, mean age was 63 (range 38-82), and 41% were women. For MM, mean age was 62 (range 33-77), and 50% were women. Patients with NHL were treated with either investigational or Federal Drug Administration-approved CD19-directed therapies, and patients with MM were treated with a variety of investigational B-cell maturation antigen-directed (BCMA) therapies. For thrombotic risk factors, 13% of patients with NHL had a history of VTE, 3% had a history of ATE, 27% had a BMI ≥30, 59% had a recent procedure including central venous catheter (CVC) placement, 14% had an intensive care unit (ICU) stay, and 22% had an infectious complication in the 30 days pre- or post-CAR-T. Forty-one percent of patients with NHL had neurotoxicity of any grade, and 59% had CRS of any grade. At 30 days, 57% had a complete response, 41% had a partial response, 3% had stable disease. For MM, 6% of patients had a pre-existing history of VTE, 2% had a history of ATE, 19% had a BMI ≥30, 96% had a recent procedure, 11% had an ICU stay and 19% had an infection. Seventeen percent had neurotoxicity, and 85% had CRS. Thirty-two percent of patients with NHL and 48% with MM received pharmacologic VTE prophylaxis while undergoing CAR-T. For those who did not receive VTE prophylaxis, thrombocytopenia was the reason for holding prophylaxis, which occurred in 51% and 50% of NHL and MM patients, respectively. In the 60 days post-CAR-T, 4 (11%) patients with NHL were diagnosed with VTE-3 pulmonary embolism (PE) and 1 lower extremity deep vein thrombosis (DVT) associated with a previously placed inferior vena cava filter. Four (7%) patients with MM were diagnosed with VTE-1 PE and 3 upper extremity DVTs associated with CVCs. Five out of these 8 (63%) patients had symptomatic VTE, while the remainder were incidental on PETCT. Mean time from CAR-T infusion to VTE diagnosis was 20 days (range 6-39 days). There were no documented ATEs. Six out of 8 (75%) were treated with therapeutic anticoagulation. Of those who were anticoagulated, 4 patients received direct oral anticoagulants and 2 received low-molecular-weight-heparin. Duration was 3 months in 3 patients, 11 days in 1, 150 days in 1, and indefinitely in 1 with atrial fibrillation. Among all 8 patients with VTE, there were no bleeding events or recurrent thromboses regardless of whether or not they received anticoagulation. Discussion: In this cohort of patients with R/R NHL or MM who received either CD19- or BCMA-directed therapies, almost 1 in 10 developed VTE in the 60 days post-CAR-T. This occurred in the context of a high prevalence of risk factors for thrombosis and low rates of pharmacologic prophylaxis. Among those who developed VTE, the majority were treated with therapeutic anticoagulation for at least 3 months, without documented bleeding or recurrent VTE. Our findings provide crucial information on a common complication that can inform patients, clinicians and researchers and should be expanded upon in larger, prospective studies to identify optimal preventive and therapeutic strategies. Disclosures Fakhri: University of California San Francisco: Current Employment. Andreadis:Jazz Pharmaceuticals: Honoraria; Karyopharm: Honoraria; Incyte: Consultancy; Merck: Research Funding; Gilead/Kite: Consultancy; Novartis: Research Funding; BMS/Celgene/Juno: Honoraria, Research Funding; Genentech: Consultancy, Current equity holder in publicly-traded company. Wong:Janssen: Research Funding; Amgen: Consultancy; Roche: Research Funding; Fortis: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Research Funding; GSK: Research Funding. Shah:BMS, Janssen, Bluebird Bio, Sutro Biopharma, Teneobio, Poseida, Nektar: Research Funding; GSK, Amgen, Indapta Therapeutics, Sanofi, BMS, CareDx, Kite, Karyopharm: Consultancy.

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Patients with History of Myocardial Infarction and Acute Cerebrovascular Accidentin Clinical Practice: Demographic, Clinical Characteristics, Drug Treatment and Outcomes (Data of Outpatient and Hospital Registry REGION)

Rational Pharmacotherapy in Cardiology ◽

10.20996/1819-6446-2019-15-5-656-662 ◽

2019 ◽

Vol 15 (5) ◽

pp. 656-662 ◽

Cited By ~ 1

Author(s):

E. Yu. Okshina ◽

M. M. Loukianov ◽

S. Yu. Martsevich ◽

S. S. Yakushin ◽

N. P. Kutishenko ◽

...

Keyword(s):

Myocardial Infarction ◽

Clinical Practice ◽

Family History ◽

Drug Treatment ◽

Clinical Characteristics ◽

Beta Blockers ◽

All Cause Mortality ◽

History Of ◽

Hospital Registry

Aim. To assess the demographic and clinical characteristics, drug treatment and outcomes in patients with a history of acute cerebrovascular accident (ACVA) and with concomitant history of myocardial infarction (MI) in clinical practice based on outpatient and hospital parts of REGION registry.Material and methods. The total 1886 patients with a history of ACVA (aged of 70.6±12.5 years, 41.9% men) were enrolled into the outpatient registry REGION (Ryazan) and the hospital registry REGION (Moscow). 356 patients had ACVA and a history of MI (group “ACVA+MI” and 1530 patients had ACVA without history of MI (group “ACVA without MI”). The incidence of cardiovascular diseases (CVD), non-CVD comorbidities, drug therapy and outcomes were analyzed.Results. In the group ACVA+MI compared with group ACVA without MI the significantly higher proportions of patients with the following conditions (diagnosis) were revealed: arterial hypertension (AH) – 99.1% and 94.2%; coronary heart disease (CHD) – 100% and 57%; chronic heart failure (CHF) – 61.5% and 41.8%; atrial fibrillation (AF) – 42.7% and 23.8%; repeated ACVA – 32.9% and 18.9%, respectively, p<0.0001 for all. In ACVA+MI and ACVA without MI groups the respective proportions of patients were smokers – 16.2% and 23.7% (p=0.10), had a family history of premature CVD – 3.2% and 1.2% (p=0.01), and had a hypercholesterolemia – 47% and 59.7% (p<0.001). The incidence of drug administration with proved positive prognostic effect was insufficient in both groups, but higher in the ACVA+MI group compared with ACVA without MI group (on average 47.1% and 40%, respectively), including: anticoagulants in AF – 19.1% and 21.4% (p=0.55); antiplatelets in CHD without AF – 69.4% and 42% (p<0.001); statins in CHD – 26.4% and 17.2% (p<0.001); beta-blockers in CHF – 39% and 23.8% (p=0.002), respectively. During 4- year follow-up in the group ACVA+MI compared with group ACVA without MI there were significantly higher all-cause mortality – 44.9% and 26.8% (p<0.001), nonfatal recurrent ACVA – 13.7% and 5.6% (p=0.0001), and nonfatal MI – 6.9% and 1.0% (p<0.0001), respectively.Conclusion. The proportion of patients with a history of MI was 18.9% among the patients with a history of ACVA. In patients of ACVA+MI group, compared with patients of ACVA without MI group a higher incidence of the following characteristics was revealed: a presence of AH, CHD, CHF, AF, repeated ACVA and a family history of premature CVD. The incidence of taking drug with proved positive effect on prognosis in patients of the compared groups was insufficient, especially of statins and anticoagulants in AF. During the follow-up period ACVA+MI group was characterized by a higher all-cause mortality and higher incidence of nonfatal ACVA and MI. In these patients the improvement of the quality of pharmacotherapy and of the secondary prevention effectiveness are the measures of especial importance.

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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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Lenalidomide (Revlimid), Bortezomib (Velcade) and Dexamethasone (RVD) for Heavily Pretreated Relapsed or Refractory Multiple Myeloma

Blood ◽

10.1182/blood.v118.21.2936.2936 ◽

2011 ◽

Vol 118 (21) ◽

pp. 2936-2936

Author(s):

Victor H Jimenez-Zepeda ◽

Donna E. Reece ◽

Suzanne Trudel ◽

Christine Chen ◽

Vishal Kukreti

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Research Funding ◽

Clinical Characteristics ◽

Phase 1 ◽

Prior Exposure ◽

Rank Test ◽

Continuous Variables ◽

Previously Treated ◽

Grade 3

Abstract Abstract 2936 Almost all patients (pts) with multiple myeloma eventually relapse and remission duration decreases with each regimen. The median Progression Free Survival (PFS) and Overall Survival (OS) in pts with relapsed myeloma refractory to lenalidomide (len) and bortezomib (btz) is poor at 5 and 9 months respectively. A phase 1 study of len plus btz in pts with relapsed or relapsed, refractory MM (RRMM) demonstrated favorable toxicity and promising response and survival further confirmed in a phase 2 study with len, btz and dexamethasone (dex) [RVD]. In this retrospective study, we assessed the efficacy and toxicity profile of RVD therapy for pts with advanced RRMM. We retrospectively reviewed the records of all pts with RRMM treated with RVD at Princess Margaret Hospital between 03/09 and 05/11. Relapse was defined according to the Uniform International Criteria. Pts were given RVD therapy as previous described by Anderson et al and must have completed at least one cycle of RVD therapy. Primary endpoints were response rate (RR), PFS, OS, and toxicity. Pts discontinued therapy if they experienced PD, no additional benefit or unacceptable toxicity. Definitions of response and progression were used according to the EBMT modified criteria with a category of very good partial response (VGPR). To examine variables independently prognostic for PFS and OS, multivariate Cox analysis was performed. Differences in continuous variables between groups were compared using Mann-Whitney or Kruskal-Wallis tests. Survival curves were constructed according to the Kaplan-Meier method and compared using the log rank test. Thirty pts with RRMM received RVD therapy. Clinical characteristics are seen in Table 1. Median age at RVD initiation was 57 yrs (37–76 yrs), and 46.7% were male. Pts received a median of 3 prior therapies (1–6). In many instances, pts previously treated with len had len added to btz + dex at progression (n=6), or pts previously treated with btz had btz added to len + dex, at progression (n=5). Thalidomide (thal), len and btz containing regimens were previously used in 60%, 73.3% and 80% of pts respectively. PR or better was observed in 46.6%. After a median of 4.6 cycles (1–14), VGPR was seen in 4.8%, PR in 33% and SD in 14%. Pts who achieved PR or better experienced a significant improvement in PFS. There was no difference in terms of RR between those pts according to prior exposure to either btz or len (p=0.7 and 0.9 respectively). Eight pts experienced non-hematological grade 3/4 adverse events (26%), including muscle weakness, sepsis and pneumonia but there was no worsening of peripheral neuropathy. Grade 3–4 neutropenia and/or thrombocytopenia were commonly seen in 70% of pts (n=21). Disease progression was seen in 19 pts at a median of 3.9 months. Median PFS for pts previously exposed to len was 2.3 months vs 2.9 months for those with no prior exposure (p=0.75). On the other hand, median PFS for pts previously exposed to btz was 2.1 months vs 3.4 months for those with no prior exposure (p=0.9) In addition, median PFS for pts who achieved at least PR was significantly better at 5.9 vs 2.0 months for those who did not (p<0.005). (Figure 1) FISH cytogenetics studies were available in 19 out of 30 patients at relapse: 5 -normal, 4–13q deletion, 3-p53 deletion and 2 - t(4, 14). High-risk MM pts had a median PFS significantly lower of 0.6 months (CI 95%, 0–1.99) vs 4.7 months for those without high-risk features (CI 2.5–7.0) (p=0.008) (Figure 2) At the time of submission, 13 pts are alive (43.3%) and 7 pts (23%) continue on RVD therapy.Table 1.Clinical characteristics of patients with RRMM treated with RVDClinical characteristic N=30MedianRange%Age5737-76Male46.7%Female53.3%Hemoglobin (g/L)10571-155Creatinine (mmol/L)99.936-383Beta-2 microglobulin (mmol/L)280119-1440Lactate dehydrogenase (U/L)18189-255IgG56.6% (17)IgA23.3% (7)IgM3.3% (1)Light Chain16.6% (5)Kappa (mg/L)4005.3-346063.3% (19)Lambda (mg/L)5145.1-530036.7% (11)KappaLambda*BMPC57%6-95%M-spike serum (g/L)300-77M-spike urine (g/d)0.890-7.9Prior therapies31-6ASCT83.3% (25)Thal60% (18)Len73.3% (22)Btz80% (24)*BMPC, Bone marrow plasma cells In conclusion, RVD is active and well tolerated in pts with RRMM, including pts who have received prior len, btz, thal and ASCT but PFS is short at 3.9 months in this highly advanced disease group of patients. We question whether response is dependent on recognized risk factors such as adverse cytogenetics. Disclosures: Jimenez-Zepeda: J & J: Honoraria. Reece:Bristol, Meyers, Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Johnson&Johnson: Research Funding; Merck: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Millennium: Research Funding; Amgen: Honoraria. Kukreti:Celgene: Honoraria.

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