Hodge, David O.

Abstract Background: Outcomes in multiple myeloma (MM) have improved significantly over the years but disparities in outcomes exist among MM patients (pts) belonging to different racial subgroups. Previous studies have explored healthcare access and utilization disparities for pts of different races as potential causes, but genomic differences, which could alter disease biology and clinical behavior, have not been studied. We utilized the MMRF CoMMpass database, which prospectively captures clinical and molecular characteristics of MM patients to explore race-based differences at the genomic level. Methods: The publically available CoMMpass trial database (data release version IA8) was utilized. Pts with race category of White (total n=698) and non-White (total n=223, comprising 129 Blacks, 19 Asians and 45 others) were analyzed for genomics including cytogenetics (fluorescent in situ hybridization; FISH), tumor diploidy (conventional karyotyping), gene expression profiling (GEP), gene copy number variations (CNV), gene single nucleotide variations (SNV) and genomic translocations analysis focused on genes from the FoundationOne Heme panel¨ (402 genes). GEP was considered significantly different between categories for more than or equal to a 2-fold change for a given gene (p<0.05). Categorical variables for FISH probes and diploidy status were compared by Chi-square or Fischer exact test, wherever applicable. Results: GEP clustering analysis uncovered 67 genes differentially expressed between Whites vs. non-Whites (Fig 1A). Baseline cytogenetics aberrations between both race cohorts showed statistically insignificant differences. Multiple cytogenetic abnormalities were seen most commonly in both race groups (~31%) with the distribution of others (in descending order) as such: Del13 > No abnormalities > t(11;14) > 1q amplification > Del17p or p53 > t(4;14) > Del1p > t(14;16) > t(14;20). Aneuploidy status showed insignificant differences between race groups with ~34% of patients from both groups having no aneuploidy. SNV data was present for 90% of Whites and 57% of non-Whites. Overall, 84% of genes had>1 SNV (84%), 2% translocations only and 14% had neither SNVs or translocations. SNVs were classified as Non-specific Non-Synonymous coding (NNSCs), Splice-site (SS) or Tier 1 (T1, codon deletion, insertion, frame-shift, etc.). A total of 880 NNSCs SNVs were observed: 670 in Whites across 227 genes, 210 in non-Whites across 120 genes. In whites, 57% of NNSC SNVs consisted of transition-type mutations and 43% as transversions. In non-Whites, transition mutations comprised 64% of all NNSC SNVs and transversions in the remaining 36%. A total of 38 SS SNVs were observed, 30 in Whites and 8 in non-Whites observed in 25 and 6 genes, respectively. In Whites, 57% of SS SNVs were transition type and remaining 43% were transversion. In non-Whites, an equal % of SS transition and transversion mutations were noted. A total of 240 T1 SNVs were noted; 182 in Whites seen in 82 genes; 58 in non-Whites seen 6 genes. In both Whites and non-Whites, frameshifts (41% in Whites, 47% in non-Whites) and stop-gained (46% in Whites, 45% in non-Whites) SNVs were most common. A total of 17 genes with>10 distinct SNVs were identified in Whites; 5 genes in non-Whites and 4 genes commonly seen in both cohorts (Fig 1B). In Whites, 17 genes were found to have translocations (intrachromosomal TRAF3 and PIK3R2 most common); in non-Whites, 5 genes had translocations (intrachromosomal CIC and EMSY most common). CNV analysis demonstrated 21 genes that were significantly altered with either copy number gain or loss between Whites vs. non-Whites (Fig 1C). Conclusions: We present the first race-based comprehensive genomic analysis utilizing the public interface of the CoMMpass trial. We discovered genomic differences between Whites and non-Whites at several levels including GEP, SNV and CNV, but not at the level of cytogenetics, which are in fact the most commonly performed clinical genomic analysis. Correlation of these variations with MM pt outcomes would be invaluable in understanding disease biology and hopefully mitigating some of the outcome disparities by pt race. As the database grows and becomes more enriched, separate analyses for Blacks, Asians and Hispanics would be attempted. Acknowledgments: We would like to thank the MMRF, Ms. Mary Derome and Dr. Jonathan Keats for providing scientific overview and technical support. Disclosures Fonseca: Millennium, a Takeda Company: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Celgene: Consultancy; BMS: Consultancy; Bayer: Consultancy; Novartis: Consultancy; Sanofi: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Bayer: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Novartis: Consultancy; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms; Sanofi: Consultancy; Janssen: Consultancy; Millennium, a Takeda Company: Consultancy; AMGEN: Consultancy; Patent: Patents & Royalties: Prognostication of MM based on genetic categorization of FISH of the disease; Patent Pending: Patents & Royalties: The use of calcium isotopes as biomarkers for bone metabolisms. Ailawadhi:Takeda Oncology: Consultancy; Amgen Inc: Consultancy; Novartis: Consultancy; Pharmacyclics: Consultancy.

Abstract Background: Cancer diagnosis and treatment are important risk factors for developing clinical depression. Validated tools for screening distress and depression, such as Cancer Distress Thermometer (DT) and PHQ9 (Patient Health Questionnaire), are underutilized, despite endorsement by NCCN and Institute of Medicine. We investigated patient and treatment characteristics as well as patient endorsement of depression or anhedonia to predict those at risk of having depression. Methods: The PHQ9 and/or DT were administered prospectively to patients with hematologic malignancies (HM) before they started antineoplastic therapy at Mayo Clinic in Florida. Patient endorsement of depression or anhedonia was collected from the current visit information survey. Patient demographics, disease and treatment characteristics, chronic medication burden, Charlson comorbidity index, living situation, clinic/hospital visit burden in the month prior to screening and number of psychiatric medications for every patient were recorded. Intergroup comparison of categorical and continuous variables was done by Chi-square and Wilcoxon rank-sum tests, respectively. Linear or logistic regression models were used to compare PHQ9 score with DT (continuous) or endorsing depression or anhedonia (categorical) respectively. Multivariate models were constructed using the stepwise selection technique using all potential variables in the models. All analyses were completed using SAS v9.3. Results: Final analysis included 246 patients with a median age at diagnosis 64.5 (range: 18-94) years, diagnosed between 6/30/93-10/9/14 and screened between 1/13/11-2/13/15. PHQ9 score of ≥9 and DT score ≥5 suggested a high risk of depression and distress, respectively, as per published literature. Patient characteristics at time of survey and analysis are noted in table 1. PHQ9, DT and answers to two questions about depression and anhedonia were available on 129, 129 and 246 patients, respectively. 63% of patients were chemotherapy naïve. In multivariate analysis, PHQ9 score ≥9 was associated with living alone (p=0.003) (Fig.1a) and non-White race (p=0.043) (Fig.1b), while a DT score ≥5 was associated with being currently married (p=0.048) and female gender (p=0.02). The only characteristic significant on univariate but not on multivariate analysis being chemotherapy naive, associated with a DT score ≥5 (p=0.049). Answering "no" to both the questions regarding depression or anhedonia was significantly associated with a low score on PHQ9 (p=0.007). Age at diagnosis, Charlson comorbidity score, chronic medication or visit burden, daily psychiatric medication use or type of malignancy were not associated with scores on any screen. Conclusions: Causes of depression in patients with HM have not been fully explored. We validated previously known risk factors for depression, such as living alone. We also reported for the first time that non-White race independently predicts depression in these patients. Female patients and those currently married are at a higher risk of psychological distress, possibly due to fear of abandoning family. We also found that simply asking a patient two questions about feelings of depression or anhedonia significantly correlates with the well-established PHQ9. Our analysis provides simple tools and reveals at-risk patient subgroups with HM where depression and distress screening should be aggressively instituted for better resource utilization and survivorship. Table 1. Patient Characteristic N % Gender Male Female 146 100 59.4 40.6 Race White Non-White 216 30 87.8 12.2 Marital Status Married Not married* 180 66 73.2 26.8 Living Situation Alone With others 37 209 15 85 Type of Malignancy Aggressive lymphoid Indolent lymphoid Aggressive myeloid Indolent myeloid 124 94 25 3 50.4 38.2 10.2 1.2 Prior Cancer Treatment Yes No 91 155 37 63 Daily Psych Meds Yes No 52 194 21.1 78.9 Patient Status Alive Dead 191 55 77.6 22.4 *Not currently married=single, divorced, widowed or unknown Disclosures No relevant conflicts of interest to declare.

Abstract Background: Outcomes in multiple myeloma (MM) have significantly improved, leading to higher prevalence of this disease. Increasing efforts have been made by various agencies to educate patients (pts), manage quality of life (QoL) and survivorship. A global impact of these efforts including pt awareness, disease knowledge and participation in their care, as well as the physical and emotional impact of MM and its treatments (Rx) has not been assessed. We undertook an international, pt-reported survey to investigate these factors and understand any underlying disparities. Methods: A 61-question patient-reported questionnaire (MM-Q), addressing global aspects of MM pts care (components in Figure 1) was used. MM-Q was administered in collaboration with the International Myeloma Foundation (IMF). To limit responses by MM pt only, “SmartPatient” MM community members and IMF Support Group Leader list were invited to complete the survey. Some of the questions were mandatory, and those with missing responses were withdrawn from the final analysis of that pts MM-Q. Categorical and continuous variables were compared among groups using the Chi-square and Kruskal-Wallis tests, respectively using SAS software (v9.3) with a two-sided significance level of 0.05. Results: Survey responses are available from 894/1240 (72%) individuals thus far. Average survey completion time was 16 minutes. Data from 746 MM-Q was included in this analysis with 466 (62.5%) complete responses. Pts from United States (US) represented 85.7% of the responders (majority from New York State). Ethnicity (n=590) was reported as non-Latino by 97%, race (n=580) was reported as White by 95%, family history of MM was reported by 19 pts and 81 reported prior history of a primary malignancy (most common, 37% non-melanoma skin cancer). Living situation questions (n=538) revealed majority were in a household of 2 (62%), were unemployed/on public assistance (53.5%), travelled alone to medical appointments (74%), with travel times varying from <30 min (55%) to >1 hr (17%). Majority (83%) had no prior knowledge of MM, 63% were patient support group members, and 92% did MM-related research on internet. With respect to MM Rx (n=524), 70% had been on Rx within 3 months and 12% reported non-compliance. Prior Rx included thalidomide (30%), lenalidomide (66%), pomalidomide (11.5%), bortezomib (63.5%), carfilzomib (11%), steroids (100%), and clinical trial participation in 25% pts. Side effects from Rx/QoL in prior 3 months (n=403) are summarized in figure 2. Pts satisfaction with Rx/treating staff (n=378) revealed majority felt their Rx to be effective (92%), right for them (87%) and side effects were as expected (84%). In general, pts acknowledged positive attributes of the Rx staff (worked towards same goal; 91%, participated in decisions; 81%, honesty 89%, confidence; 92%), and their doctor's explanations regarding Rx (benefits; 84%, side effects; 74%, test results; 83%), with the exception of emotional effects of Rx (48%). 94% pts rated their care as good/excellent and 95% were willing to participate in a follow-up survey. Stratification of statistically significant responses by geographical categories, age and time since diagnosis are shown in table 1 and analysis by occupation and educational status is ongoing. Conclusions: We conducted a large patient-reported survey to understand the current state of awareness among MM pts and a global impact of the diagnosis and its Rx on them. We showed that majority of pts who accessed the survey responded (72%), which may be a product of literacy, education and access to technology. Majority of the pts were White and non-Latino, highlighting the possible role of access and awareness in ethnic minorities. We report the large prevalence of psychophysical burden of MM and its Rx in MM pts. In general, MM pts had a high rate of satisfaction related to the Rx and their healthcare providers, but the frequency of discussion regarding emotional effects of Rx between doctors and pts was conspicuously low (48%) and the more recently diagnosed pts were less likely to be satisfied with their treating staff. We also demonstrated significant behavioral pattern differences in geographical, age and time-since-diagnosis subgroups, some of which may be sociocultural, while others may be a result of more patient awareness and understanding of the disease. This knowledge will be very helpful in devising MM survivorship strategies. Disclosures No relevant conflicts of interest to declare.

AbstractIntroductionMyocardial infarction (MI) is associated with an increase in subsequent heart failure (HF), recurrent ischemic events, sudden cardiac arrest, and ventricular arrhythmias (SCA‐VA). The primary objective of the study to determine the role of intercurrent HF and ischemic events on the development of SCA‐VA following first type I MI.Methods and resultsA retrospective cohort study of patients experiencing first type 1 MI in Olmsted County, Minnesota (2002‐2012) was conducted by identifying patients using the medical records linkage system (Rochester epidemiology project). Patients aged ≥18 years were followed from the time of MI till death or 31 July, 2017. Intercurrent HF and ischemic events were the primary exposures following MI and their association with outcome SCA‐VA was assessed. Eight hundred and sixty‐seven patients (mean age was 63 ± 14.5 years; 69% male; 49.8% ST‐elevation myocardial infarction) who had their first type I MI during the study period were included. Majority of acute MI patients were revascularized using percutaneous coronary intervention and bypass surgery (628 [72.43%] and 87 [10.03%] respectively). During a mean follow‐up of 7.69 ± 4.17 years, HF, recurrent ischemic events and SCA‐VA occurred in 155 (17.9%), 245 (28.3%), and 40 (4.61%) patients respectively. Low ejection fraction (adjusted hazard ratio [HR] 0.95; 95% confidence interval [CI], 0.93‐0.98; P < .001), intercurrent HF (adjusted HR 3.11; 95% CI, 1.39‐6.95; P = .006) and recurrent ischemic events (adjusted HR 3.47; 95% CI, 1.68‐7.18; P < .001) were associated with subsequent SCA‐VA.ConclusionSCA‐VA occurred in a small proportion of patients after MI and is associated with intercurrent HF and recurrent ischemic events.

This prospective cohort study aimed to improve hospital outcomes through geographic location of hospitalist patients and conducting daily multidisciplinary team rounds—Goal-directed Achievements through Geographic Location (GAGL). Patients were admitted to a geographic (GAGL) study unit where daily multidisciplinary rounds took place among nursing, case management, a hospitalist, pharmacy, physical and occupational therapy, respiratory therapy, and nutrition services. A total of 985 (56.4%) patients were admitted to the GAGL study unit and 760 patients (43.6%) were admitted to non-GAGL units. Patients admitted to the GAGL study unit had a shorter average length of stay (3.64 days vs 4.35 days, P = .0001) and a lower number of risk events (91 [9.2%] vs 93 [12.2%], P = .038). There was no significant difference in 30-day readmissions, avoidable day events, or code blue team activations. GAGL provides a framework for hospital organizations to improve provider communication, hospital efficiency, and patient safety.

Abstract To provide direct comparison between apixaban and rivaroxaban in patients with acute cancer‐associated venous thromboembolism (Ca‐VTE), consecutive patients treated with apixaban, rivaroxaban, or enoxaparin at Mayo Thrombophilia Clinic (March 1, 2013 to January 31, 2018)) were followed prospectively. The primary effectiveness outcome was venous thromboembolism (VTE) recurrence, and the secondary was mortality. The primary safety outcome was major bleeding, the secondary clinically relevant safety outcome was non‐major bleeding (CRNMB), and the third a composite of major and CRNMB. There were 750 patients treated for acute Ca‐VTE with apixaban (n = 224), rivaroxaban (n = 163), and enoxaparin (n = 363) within 14 days of diagnosis and for at least 3 months, or until study event. Recurrent VTE was diagnosed in 11 receiving apixaban, 7 receiving rivaroxaban (apixaban vs rivaroxaban hazard ratio (HR) 1.31, 95% confidence interval (95% CI) 0.51‐3.36) and 17 in the enoxaparin receiving group (apixaban vs enoxaparin HR 1.14, 95% CI: 0.54, 2.42 and rivaroxaban vs enoxaparin HR 0.85, 95% Cl: 0.36, 2.06). There were 82 deaths in apixaban, 74 rivaroxaban (apixaban vs rivaroxaban HR 1.67, 95% Cl: 1.20, 2.33) and 171 in enoxaparin group (rivaroxaban vs enoxaparin HR 0.73, 95% Cl: 0.56, 0.96). Major bleeding occurred in 11 apixaban, 12 rivaroxaban (apixaban vs rivaroxaban HR 0.73, 95% Cl: 0.32, 1.66) and 21 enoxaparin group (apixaban vs enoxaparin HR 0.89, 95% Cl: 0.43, 1.84 and rivaroxaban vs enoxaparin HR 1.23, 95% Cl: 0.61, 2.50). The CRNMB rate was higher in rivaroxaban compared to apixaban ( P = .03) and LMWH ( P = .01) groups. Recurrence of VTE and major bleeding were similar in apixaban, rivaroxaban, and enoxaparin groups. Rivaroxaban was associated with higher CRNMB but lower mortality compared to apixaban and enoxaparin.

AbstractBackgroundRecipients of implantable cardioverter defibrillator (ICD) generator replacement with multiple medical comorbidities may be at higher risk of adverse outcomes that attenuate the benefit of ICD replacement. The aim of this investigation was to study the association between the Charlson comorbidity index (CCI) and outcomes after ICD generator replacement.MethodsAll patients undergoing first ICD generator replacement at Mayo Clinic, Rochester and Beth Israel Deaconess Medical Center, Boston between 2001 and 2011 were identified. Outcomes included: (a) all‐cause mortality, (b) appropriate ICD therapy, and (c) death prior to appropriate therapy. Multivariable Cox regression analysis was performed to assess association between CCI and outcomes.ResultsWe identified 1421 patients with mean age of 69.6 ± 12.1 years, 81% male and median (range) CCI of 3 (0‐18). During a mean follow‐up of 3.9 ± 3 years, 52% of patients died, 30.6% experienced an appropriate therapy, and 23.6% died without experiencing an appropriate therapy. In multivariable analysis, higher CCI score was associated with increased all‐cause mortality (Hazard ratio, HR 1.10 [1.06‐1.13] per 1 point increase in CCI, P < .001), death without prior appropriate therapy (HR 1.11 [1.07‐1.15], P < .0001), but not associated with appropriate therapy (HR 1.01 [0.97‐1.05], P = .53). Patients with CCI ≥5 had an annual risk of death of 12.2% compared to 8.7% annual rate of appropriate therapy.ConclusionsCCI is predictive of mortality following ICD generator replacement. The benefit of ICD replacement in patients with CCI score ≥5 should be investigated in prospective studies.

Purpose: The relationship between age-related macular degeneration (AMD) and malignancy, especially cutaneous malignancies, is not well studied. We investigated a possible association between AMD and cutaneous malignancies. Methods: A retrospective, consecutive review of all patients who had received at least 1 intravitreal injection for wet AMD between January 1, 2004, and December 31, 2013, was conducted using the Rochester Epidemiology Project in Olmsted County, Minnesota. Age- and sex-matched control groups included 473 pre–anti–vascular endothelial growth factor era wet AMD patients, 504 concurrent time dry AMD patients, and 504 patients with no AMD. The rates of AMD and overall malignancy, cutaneous malignancies, and specific types of cutaneous malignancies were compared between groups of patients. Results: Patients with wet AMD incurred an increased rate of overall malignancies compared to patients with dry AMD {52.8% wet AMD (confidence interval [CI]: 48.3–57.2) vs. 43.7% dry AMD (CI: 39.3–48.1); P= 0.003} or those without AMD (52.8% wet AMD [CI: 48.3–57.2] vs. 35.3% no AMD [CI: 31.1–39.7]; P = <0.001). Patients with dry AMD also had higher rates of malignancy than those without AMD (43.7% dry AMD [CI: 39.3–48.1] vs. 35.3% no AMD [CI: 31.1–39.7]; P = 0.007). Rate of cutaneous malignancies was increased in patients with wet AMD compared to patients with dry AMD (24.4% wet AMD [CI: 20.7–28.4] vs. 14.6% dry AMD [CI: 11.5–17.9]; P = <0.001) and those with no AMD (24.4% wet AMD [CI: 20.7–28.4] vs. 9.7% no AMD [CI: 7.3–12.7]; P = <0.001). Conclusion and Relevance: To the best of our knowledge, this is the first report to establish an association between AMD and cutaneous malignancies, supporting a possible discussion of the association when a patient presents with one of the two conditions.

Background Invasive angiography in the setting of cardiac troponin elevation may reveal non-obstructive coronary arteries leading to uncertainty in diagnosis. Cardiac MR (CMR) may aid in diagnosis, however, the spectrum of diagnostic findings in the patient presenting with symptoms of cardiac ischaemia, elevated cardiac biomarkers and a negative invasive coronary angiogram is yet to be completely described. Methods We queried the Mayo Clinic, Rochester inpatient record from 1 January 2000 to 31 December 2016 to identify patients who: (1) had an elevated troponin T during admission, (2) underwent coronary angiography within 30 days of troponin T elevation which was considered negative for obstructive coronary arterial disease and (3) underwent CMR within 30 days of troponin T elevation. CMR diagnoses were classified as either (1) myocarditis, (2) small area myocardial infarction, (3) stress cardiomyopathy, (4) non-ischaemic cardiomyopathy or (5) normal. Results Of 215 patients, the spectrum of disease seen on CMR was myocarditis (32%), small area infarction (22%), non-ischaemic cardiomyopathy (20%) and stress cardiomyopathy (9.3%). Conclusion In the largest single-centre study assessing the role of CMR in patients admitted with elevated troponin T with a non-obstructive coronary disease on an angiogram, small area infarction was seen in 22% of patients.