Dispenzieri, Angela

Abstract Multiple myeloma (MM) is a heterogeneous disease that may be evaluated by a broad array of imaging and laboratory techniques to measure disease activity and predict prognosis. Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scanning has been shown to be predictive of patient outcomes throughout the disease course. We sought to corroborate these findings by examining the prognostic impact of PET/CT scanning in the posttransplant setting. We retrospectively analyzed PET/CT scans in 229 MM patients receiving an autologous stem cell transplant (ASCT) near day 100, and correlated these findings with time to progression(TTP) and overall survival (OS) to assess the impact of day 100 PET/CT scan findings as an independent prognostic factor. The median OS for the entire cohort was 61.5 months (95% confidence interval [CI], 49-75) and the median TTP was 18.5 months (95% CI, 15.4-21.8). Among patients with abnormal day 100 PET findings (PET+), median TTP was 12.4 months vs 24 months among those with normal PET findings (PET−) (P < .0001). The median OS in the PET+ group was 46 months compared with 99 months in the PET− group (P < .0001). We conclude that an abnormal PET/CT scan near day 100 post-ASCT is predictive of shorter TTP and OS, with prognostic significance retained after adjusting for disease response and other prognostic variables in MM.

Introduction: Diastolic dysfunction has been characterized in relation to the relaxation and compliance properties of the left ventricle; limited information exists regarding its relationship to systolic function as assessed by deformation imaging. Objectives: To determine if there is left ventricular systolic dysfunction detected by global longitudinal strain (GLS) measured by two dimensional speckle tracking echocardiography in patients with immunoglobulin light chain (AL) amyloidosis with different degrees of diastolic dysfunction and normal ejection fraction (EF). Methods: Consecutive biopsy-proven AL patients with preserved EF (≥ 55%) who had a comprehensive echocardiogram performed and strain analysis were included. Cohort was divided into 5 groups according to the different grades of diastolic dysfunction: Group 0: normal filling pressures; Group 1: abnormal relaxation; Group 2: pseudo-normal pattern; Group 3: reversible restrictive; Group 4: fixed restrictive. Images were acquired and performed on a Vivid 9 from the 3 apical views, and analyzed on vendor-specific software (Echo-PAC, GE). GLS was averaged from the 16 segments, and their means compared by ANOVA and each pair with Student’s t test. Results: A total of 858 patients were included, mean age was 63.7 years ± 10.1, and 61.5% were male. From those, 205 (24%) were in group 0; 299 (35%) in group 1; 255 (30%) in group 2; 65 (7%) in group 3; and 34 in group 4 (4%). GLS means measurements were -18.95 ± 2.4, -16.86 ± 3.4, -15.60 ± 3.9, -12.31 ± 3.0, and -10.48 ± 3.3, respectively (P<0.0001). All individual GLS values were significantly different statistically when compared between each group (P<0.01 for all pairs; figure). Conclusions: Longitudinal systolic mechanical function is progressively impaired in AL amyloid patients as diastolic dysfunction progresses, despite normal EF. This systolic dysfunction provides insights into the intrinsic relationship between the components of the cardiac cycle.

Introduction: The T peak - T end interval (Tpe) is a measure of transmural dispersion of repolarisation with prolongation of this interval linked to an increased risk of ventricular arrhythmias and sudden death. Patients with cardiac amyloid experience a high rate of sudden cardiac death. Objective: To determine the prognostic utility of the Tpeak-Tend interval in patients with transthyretin (TTR) cardiac amyloidosis. Methods: Of the 240 patients who underwent evaluation for TTR amyloidosis at our tertiary referral center from 1966 to 2010, 39 met inclusion criteria (65 excluded for AF, 66 BBB/Paced Rhythm, 25 CAD, 21 other). Inclusion criteria were presence of histological diagnosis of TTR amyloid and confirmed cardiac involvement by echocardiogram or biopsy and absence of atrial fibrillation (AF) or bundle branch block/paced rhythm on the index surface ECG, or history of coronary heart disease (CAD). Tpe was measured in leads V3 and V5. Cox proportional hazards model were used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Kaplan-Meier curves were used to estimate overall survival and differences between curves were estimated using log rank. Primary endpoints were death or heart transplantation. Results: Of the 39 patients, 85% were male, and 69% were mTTR. Mean age 66.4 ± 13.9 years. Mean follow up period of 4.2 ± 3.2 years, 25 died and 5 received heart transplants. Median survival was 3.8 years, with 5 year survival 34%. On univariate analysis, Tpe in lead V3 was predictive of adverse outcome, HR per 10msec, 1.195 (1.051-1.370). Further multivariate analysis, in a model accounting for age, gender, Lead V3 Tpe was independently associated with survival, HR per 10msec, 1.207, (1.094-1.411, p=0.009). Conclusions: The Tpe interval in Lead V3 at diagnosis is a novel, noninvasive independent predictor of survival in transthyretin cardiac amyloidosis patients in sinus rhythm.

Objective: Recent MRI studies have demonstrated the common occurrence of late gadolinium enhancement (LGE) in cardiac amyloidosis (CA). However, the association of LGE presence and pattern with other clinical, morphological, functional, and biochemical parameters has not yet been demonstrated. It is important to define this association, since many of these parameters (NYHA class, ventricular thickness, cardiac biomarkers) have prognostic implications. Methods: Of 151 patients with confirmed systemic amyloidosis who underwent LGE cardiac MRI between January 2006 and December 2007 to evaluate for possible CA, 120 (AL 100, senile 9, and familial 11) were included after meeting of inclusion and exclusion criteria. Cine MRI images were analyzed for morphologic and functional data. LGE images were analyzed for presence and pattern of LGE. Clinical data including ECG’s and cardiac biomarkers was obtained. Results: LGE evidence of CA was present in 95 patients and absent in 25 patients. Three main patterns of LGE were observed. These were global diffuse transmural (homogenous or heterogenous) or subendocardial, suboptimally nulled myocardium without clear hyperenhancement, and focal patchy LGE. Symptoms, morphologic/functional variables, ECG voltages, and cardiac biomarker levels were worst in patients with global diffuse LGE, followed by suboptimally nulled myocardium, focal patchy LGE, and absent LGE groups (Table 1 ). Conclusions: The presence of LGE in amyloidosis patients is associated with worse clinical, morphologic, functional, and biochemical parameters. Amongst patients with abnormal LGE, global diffuse (transmural or subendocardial) LGE is associated with the worst profile. This provides initial evidence that the presence and pattern of LGE in CA is associated with other markers of prognosis.

Objective: In AL amyloidosis, early detection of cardiac involvement is desirable because of prognostic and therapeutic implications. Recent pilot MRI studies have demonstrated that late gadolinium enhancement (LGE) is a common finding in cardiac amyloidosis (CA) and reflects interstitial expansion due to amyloid infiltration. However it is not known whether evaluation of the myocardial substrate via LGE MRI may allow for earlier detection of CA compared with morphological assessment on the basis of increased left ventricular thickness (LVT). Methods: Between January 2006 and December 2007, 100 patients with confirmed AL amyloidosis underwent LGE MRI at our institution to evaluate for CA. Morphological evidence of CA was considered to be present when LVT was increased (mean of septum and inferolateral wall > 12 mm). LGE images were analyzed for presence and pattern of LGE. Clinical data was also reviewed. Results: Increased LVT was present in 69 patients. Abnormal LGE images were present in 76 patients (global diffuse transmural or subendocardial LGE in 43, suboptimally nulled myocardium in 18, and focal patchy LGE in 15 patients). LGE was present in 21 of 22 patients with a diagnosis of CA on cardiac biopsy. Seven patients (10%) with increased LVT did not have LGE. Conversely of 31 pts with normal LVT, 14 (45%) had abnormal LGE on MRI (usually suboptimally nulled myocardium or focal patchy LGE) and also had significantly higher incidence of low voltage ECG (50% vs. 0%), lower absolute limb lead voltage (6.5±3 vs. 9.7±2.6 mm), increased RV thickness (4.9±1.1 vs. 4.1±1) and higher BNP (316±376 vs. 107±103) compared to 17 patients without LGE (Table 1 ). Conclusions: MRI LGE is common in patients with CA and evaluation of the myocardial substrate using this technique may allow for earlier detection of cardiac involvement in AL amyloidosis compared with morphological assessment on the basis of increased LVT.

Introduction: Intrinsic wave propagation is a novel approach to measure myocardial stiffness (MS) as validated in animal studies. Aims and Hypothesis: 1) To compare MS measured by the wave method with chamber stiffness (CS) derived from noninvasively estimated end-diastolic pressure-volume relationship (EDPVR) in patients; 2) To test the hypothesis that MS is superior to CS for predicting outcomes in patients with cardiac amyloidosis (CA). Methods: Prospective study in 56 patients with amyloidosis (CA: 38, noncardiac amyloidosis, NCA: 18; 90% AL-type; age 63 ± 10 yrs; ejection fraction 57 ± 11%) and 36 normal subjects (age 49 ± 13 years). Intrinsic velocity propagation of myocardial stretch (iVP), a measure of MS, was measured by ultra-high frame rate (250-465Hz) tissue Doppler imaging. Left ventricular (LV) EDPVR were reconstructed using the noninvasive single-beat method (Fig.A). Stiffness coefficients (α, β, load-independent) and CS (dP/dV) were calculated. End-diastolic pressure (EDP) was estimated from E/e’. Adverse events at follow-up (death, heart failure, stroke, significant arrhythmia) were recorded. Results: iVP was higher in CA compared to NCA and controls, indicating higher MS (Fig. B). This was confirmed by EDPVR, which were steeper and shifted leftward (Fig. A). The slope (β) of EDPVR and CS (dP/dV) were higher and LV capacitance (V 30 , volume at 30 mmHg) was lower in CA (Fig. A) and correlated with iVP (β: r = 0.59; CS dP/dV, r = 0.43; EDP, r = 0.61; all p<0.0001). Patients with higher LV thickness (r = 0.66), lower LV longitudinal strain (r = -0.57) and elevated NT-proBNP (r = 0.69) had higher iVP. At follow-up (median 2.5 years), after adjusting for relevant confounders, an iVP >2.7 m/s was strongly associated with excess events (p<0.0001; Fig. C) and was superior to measures of CS (dP/dV: p = 0.28; β >6.5: p = 0.03; Fig. D). Conclusions: Myocardial stiffness by intrinsic wave method shows similar findings to chamber stiffness by EDVPR, but is more strongly related to outcomes in patients with amyloidosis.

AbstractMultiple myeloma (MM) remains an incurable disease despite incorporation of novel agents. Venetoclax, a B‐cell lymphoma 2 (BCL‐2) inhibitor is approved for some hematologic malignancies but not yet for MM, although clinical trials have shown efficacy in patients with MM, particularly those harboring t(11;14). We reviewed the medical records of relapsed and/or refractory MM patients to study the efficacy and safety of venetoclax used outside of clinical trials at Mayo Clinic between December, 2016 and March, 2019. The data cut‐off date was August 06, 2020. We identified 56 patients of whom 42 (75%) harbored t(11;14). The median number of prior therapies was six (range 1–15) and 14% of patients had received ≥10 prior lines of therapy. Fifty‐three (95%) patients were refractory to an immunomodulatory drug and proteasome inhibitor. Venetoclax was used as monotherapy or doublet, in combination with dexamethasone in 55% (n = 31) and a triplet or quadruplet in 45% of patients. No patient experienced tumor lysis syndrome. Overall response rate in 52 evaluable patients was 44%. The median time to best response was 2 months and median duration of response was 13.6 months. The median PFS for the entire cohort was 5.8 (95% CI 4.9–10.3) months and median OS was 28.4 (95% CI 14.6‐not reached) months. The presence of t(11;14) was associated with improved PFS (median 9.7 months vs. 4.2 months, p = 0.019) and OS (median not reached vs. 10.8 9 months, p = 0.015). Venetoclax demonstrates encouraging activity in heavily‐treated patients with relapsed/refractory MM, particularly the t(11;14) patient‐population.