Citations

Introduction: Transthyretin cardiac amyloidosis (TTR-CA) can cause heart failure with preserved EF (HFpEF). We previously reported a clinical/echo-based score (TCAS) and defined a cut-off that predicted risk of TTR-CA in HFpEF. Herein, we assess the comparative performance of an artificial-intelligence ECG-based screening tool (AI-ECG). Hypothesis: AI-ECG successfully identifies TTR-CA in HFpEF cohorts across a range of TTR-CA prevalence Methods: Referral HFpEF cohort was constructed from a referral population of HFpEF patients (EF ≥ 40%) undergoing 99m Tc-pyrophosphate scintigraphy (PYP) at Mayo Clinic (2013-2020, n=484, 38% with TTR-CA). Community HFpEF cohort was prospectively screened with PYP (n=275; age ≥ 60, LV wall thickness (WT) ≥ 12 mm, 4% with TTR-CA). TCAS was built using a multivariable logistic regression model and converted to a simple point score comprised of age (60-69, 70-79, ≥ 80: +2, +3, +4 points respectively), male sex (+2), relative WT > 0.57 (+2), posterior WT ≥ 12 mm (+1), EF < 60% (+1), and hypertension diagnosis (-1). TCAS was validated in the community cohort. A deep neural network trained to predict cardiac amyloidosis from a single 12-lead ECG, was applied to both referral and community cohorts. Patients were excluded if ECG was not available ≤ 12 months before PYP or if used in development of the AI-ECG. Standard ROC methods were applied. Youden’s index was used to define optimal cut-off. Results: Predictive characteristics of AI-ECG were strong and compared favorably with TCAS across a range of true TTR-CA prevalence (Table). Conclusions: Using a single ECG, AI-ECG effectively predicts TTR-CA with an excellent negative predictive value to rule out TTR-CA and a positive predictive value sufficient to warrant specific TTR-CA testing. This was particularly evident in the community. AI-ECG holds promise for simple, cost-effective global screening of at-risk populations, especially those with limited access to advanced cardiac imaging.

Abstract Almost all patients with multiple myeloma (MM) eventually relapse, either asymptomatically or with end-organ damage. However, it remains unclear whether initiating therapy at the time of biochemical progression (BP) improves the outcomes compared with initiating therapy at the clinical progression (CP) stage. Here, we retrospectively assessed 1347 patients with relapsed MM. Most progressions were BP (60.4%); 39.6% had CP. The most prevalent symptoms at relapse were new or evolving bone disease (80.9%), anemia (38.0%), and renal failure (12.7%). Patients with BP had longer median time from second-line treatment to the next treatment compared with patients who had CP (17.0 vs 9.6 months; P &lt; .001) as well as longer median overall survival from first relapse (59.4 vs 26.2 months; P &lt; .001). Male sex (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.02-2.18; P = .04), plasma cell labeling index ≥2% (OR, 1.58; 95% CI, 1.02-2.45; P = .04), and extramedullary disease at diagnosis (OR, 1.84; 95% CI, 1.08-3.13; P = .03) were associated with higher risk of CP, whereas very good partial remission or better had decreased risk of CP (OR, 0.62; 95% CI, 0.43-0.91; P = .02). To conclude, patients with CP have inferior postprogression outcomes compared with patients who have BP. Patients with deeper response to first-line therapy are less likely to develop CP. The presence of a specific CRAB (C, hypercalcemia; R, renal failure; A, anemia; B, bone disease) symptom at diagnosis predicts for the development of similar CRAB symptoms at relapse.

Abstract Introduction: There is evidence that lack of a social network is a link to inferior outcomes in cancer patients. Mayo clinic performs all its stem cell transplants for multiple myeloma patients as an outpatient. This requires a full-time chaperone or caregiver for the duration of the transplant. Patients who do not have a caregiver are hospitalized for the duration of the transplant. In this study we compared outcomes between patients hospitalized for the entire transplant and those who have a caregiver and are initially managed as an outpatient.Materials and methods: All patients with multiple myeloma transplanted at the Mayo Clinic in Rochester Minnesota between 1/1/2000 and 12/31/2019 were included for analysis. Patient had to have been transplanted within 12 months of the original diagnosis. The definition of inpatient transplantation was hospitalization prior to day 0 of transplantation for conditioning and continued hospitalization until evidence of neutrophil engraftment occurred.Results: There were 41 patients who were considered inpatient transplants and 2103 that were outpatient transplants. The patients were well balanced for age, sex, serum creatinine, and international stage at diagnosis. For inpatient transplants the median days in the hospital was 21 (interquartile range 18 to 28). For outpatient transplants the median number of days in the hospital was 0 (interquartile range 0 to 6). Relapse free survival was not significantly different between the 2 groups, but overall survival was 95 versus 58 months favoring those that had transplantation as an outpatient (p=.0008). Conclusion: There appears to be in association between myeloma patients that lack a caregiver and require inpatient stem cell transplantation and overall survival.

Abstract Mass-spectrometry (MS) assays detect lower levels of monoclonal proteins and result in earlier detection of monoclonal gammopathy of undetermined significance (MGUS). We examined heavy chain MGUS prevalence using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS among 3 risk groups, ages 50 or older: 327 African Americans (AA) and 1223 European Americans (EA) from a clinical biobank and 1093 unaffected first-degree relatives (FDR) of patients with hematologic disorders. Age- and sex-adjusted prevalence rates were directly standardized to 2010 United States population. Prevalence ratios were estimated for comparisons of AA and FDR to the EA group using the Poisson distribution. Results were also compared with population-based prevalence using conventional gel-based methods. Risk groups had similar sex and age distributions. MALDI-TOF MGUS prevalence was higher in the AA (16.5% [95% confidence interval (CI), 12.2%, 20.8%]) and FDR (18.3% [95% CI, 16.6%, 21.6%]) than in EA (10.8% [95% CI, 8.8%, 12.7%]), translating to prevalence ratios of 1.73 (95% CI, 1.31, 2.29) and 1.90 (95% CI, 1.55, 2.34), respectively. MALDI-TOF EA prevalence was over threefold higher than conventional estimates but showed similar age trends. Thus, the MALDI-TOF assay found greater numbers with MGUS but similar relative differences by race, family history, and age as prior studies.

Background: Cardiac amyloidosis (CA) results from extracellular deposition of insoluble amyloid fibrils in the myocardium, leading to myocardial stiffening, restrictive cardiomyopathy and poor prognosis. Thus, measurements of myocardial stiffness might help with identification of patients with cardiac amyloid deposition. The speed of wave transmission of myocardial stretch (Vm) is a novel measure of myocardial elasticity. Our aim was to investigate the behavior of Vm in the left ventricular (LV) myocardium of patients with CA. We hypothesized this wave speed will be increased in these patients and will partly explain the reduction in systolic myocardial function. Methods: We prospectively studied 23 consecutive patients with systemic amyloidosis, of whom 17 (age 59±13 years) had confirmed cardiac involvement (15 AL, 2 TTR), and compared to 18 control subjects (age 47±13 years) with normal LV function. Comprehensive transthoracic echocardiography was performed. Tissue Doppler cineloops (350-450 frames/s) were acquired from 6 LV walls from 3 standard apical views. Regional and global Vm were measured as the wave speed of the onset of myocardial stretch from LV base to apex (late diastole). Results: Subjects with CA (n=17) had higher Vm compared to normal subjects (2.5±0.8 vs 1.5±0.2 m/s; P<0.001, respectively). They also had lower LV ejection fraction (56±11 vs 65±4%; P=0.02), global longitudinal strain (GLS -14±5 vs -20±2%, P<0.001), and myocardial relaxation (mitral annulus septal e’ velocity 4.7±1.9 vs 9.2±2.4 cm/s; P<0.001) and higher LV mass (150±54 vs 87±18 g/m2; P<0.001), left atrial volume (44±7 vs 27±6 mL/m2; P<0.001), and estimated LV filling pressure (E/e’ 20±9 vs 8±3; P<0.001). There was a strong positive association between Vm and LV wall thickness (R=0.62; P<0.001), GLS (R=0.45; P=0.01) and septal E/e’ (R=0.42; P=0.02) and an inverse correlation between Vm and septal e’ (R=-0.39; P=0.03), but not with ejection fraction (P=0.37). Conclusion: This pilot study indicates that Vm is elevated in patients with CA compared to normal subjects, commensurate with the effects of amyloid deposition on LV structure and function. This novel measurement shows promise for noninvasive assessment of diastolic myocardial stiffness in patients with CA.

Abstract Multiple myeloma (MM) is a plasma cell malignancy that is characterized by diverse clinical presentations. Although biochemical assessment of disease activity is commonly used to monitor treatment response, findings on magnetic resonance imaging and positron emission tomography (PET)/computed tomography (CT), among other imaging modalities, have proven to harbor prognostic value. We sought to corroborate these findings by examining the prognostic significance of fluorodeoxyglucose PET/CT scanning in the setting of newly diagnosed MM. We retrospectively analyzed 195 patients with a PET/CT available at diagnosis and at 6 months posttreatment to examine their value as an adjuvant metric to conventional hematologic responses in terms of time to next treatment (TTNT) and overall survival (OS). The median TTNT and OS for the entire cohort were 24.6 months (95% confidence interval [CI], 20.4-29.1) and 79 months (95% CI, 63.1-119.1), respectively. When comparing PET/CT negative (−) with PET/CT positive (+) patients, we found significantly prolonged median TTNT (55.2 vs 17.8 months, P &lt; .0001) and OS (unreached vs 60.8 months, P &lt; .0001) in the former group. We then examined the additive value of PET/CT on the hematologic response achieved at 6 months and found that PET/CT (−) is associated with significantly increased median TTNT and OS for the very good partial response (VGPR) group and the less than VGPR group. Importantly, PET/CT retained prognostic significance after adjusting for multiple other predictive variables. We conclude that a PET/CT (−) at 6 months confers a significant prognostic advantage for patients with newly diagnosed MM and adds significant value to the hematologic response assessment.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).

AbstractCastleman disease (CD) is a rare lymphoproliferative disease characterized by diverse clinical and pathologic features. Due to its rarity, there are limited studies comparing currently available therapies. The role of autologous stem cell transplantation (ASCT) in CD has not yet been established. In this paper, we describe the clinical characteristics, treatment choices, and outcomes in 34 Mayo Clinic patients diagnosed with multicentric CD from July 1, 2003 to April 30, 2018. Eighteen patients (53%) also met the criteria for POEMS, including 14 with the osteosclerotic variant. The first‐line treatments included: steroid monotherapy (4), cytotoxic chemotherapy (6), rituximab alone (8) or with chemotherapy (2), anti‐IL6 treatment (3), and ASCT (10). The median follow‐up was 4.8 (range: 0.1–15.2) years. The 5‐ and 10‐year overall survival rates were 84% and 71%, respectively. Sixteen patients received high‐dose chemotherapy followed by ASCT during their disease course. Among those, 14 had multicentric CD associated with POEMS. There were no transplant‐related deaths. All patients had at least a partial response to ASCT, most of whom achieved a complete response. The favorable outcomes seen with ASCT in this cohort suggest that transplantation may have a role in multicentric CD, particularly for patients with multicentric CD associated with POEMS.