Gertz, Morie A.

AbstractGain of 1q22 at diagnosis portends poorer outcomes in multiple myeloma (MM), but the prognostic significance of acquired 1q22 gain is unknown. We identified 63 MM patients seen at Mayo Clinic from 1/2004 to 12/2019 without 1q22 gain at diagnosis who acquired it during follow up and compared them to 63 control patients who did not acquire 1q22 gain with similar follow up. We also compared outcomes in the acquired 1q22 gain group with outcomes in 126 patients with 1q22 gain present at diagnosis. The incidence of acquired 1q22 gain was 6.1% (median follow‐up 6.8 years); median time to acquisition was 5.0 years (range: 0.7–11.5 years). Abnormalities on baseline fluorescence in situ hybridization (FISH) included trisomies (54%) and monosomy 13 (39%); 16 (25%) had high‐risk (HR) translocations or del(17p). Median progression‐free survival with front line therapy was 29.5 months in patients with acquired 1q22 gain, versus 31.4 months in control patients (p = .34) and 31.2 months in patients with de novo 1q22 gain (p = .04). Median overall survival (OS) from diagnosis was 10.9 years in patients with acquired 1q22 gain, versus 13.0 years in control patients (p = .03) and 6.3 years in patients with de novo 1q22 gain (p = .01). Presence of HR FISH at baseline increased risk of 1q22 gain acquisition. We demonstrate that acquisition of 1q22 gain is a significant molecular event in MM, associated with reduced OS. Among HR patients for whom this clonal evolution is determined, a risk‐adapted approach and/or clinical trial should be considered.

Abstract Background/Introduction Cardiomyopathy (CM) with associated heart failure and polyneuropathy (PN) are common manifestations of hereditary transthyretin amyloidosis (ATTRv), a progressive, debilitating, and fatal disease that results from the deposition of misfolded transthyretin (TTR) protein throughout the body. NEURO-TTR (NCT01737398) showed that inotersen, an antisense oligonucleotide inhibitor of TTR protein production, slowed the progression of PN and maintained quality of life in patients with ATTRv. Purpose To report efficacy and safety from the open-label extension (OLE) of the NEURO-TTR study in patients with ATTRv PN overall and in CM subgroups. Methods Patients who completed NEURO-TTR, enrolled in the OLE (NCT02175004), and either switched from placebo in NEURO-TTR to inotersen in the OLE (placebo-inotersen) or received inotersen in NEURO-TTR and remained on inotersen in the OLE (inotersen-inotersen) were included. Assessments included the modified Neuropathy Impairment Score +7 composite score (mNIS+7 [range –22.3 to 346.3], a measure of neuropathy with higher scores indicative of poorer function), TTR levels, and safety monitoring. Utilizing patients from Europe and North America (EU+NA) as of 28 July 2020, this post hoc analysis examined two subgroups: CM ECHO and severe CM ECHO. CM was defined as a diagnosis of ATTRv CM at study entry or all of the following criteria: a left ventricular wall thickness of ≥1.3 cm on transthoracic echocardiography at baseline, no known history of persistent hypertension (systolic blood pressure ≥150 mm Hg) within 12 months before study screening, and evaluable baseline ECHO obtained by central assessment. Severe CM was defined as an interventricular septum thickness ≥1.5 cm at baseline. Descriptive statistics are reported. Results In the overall population and both CM subgroups, the placebo-inotersen group demonstrated slowing of neurological disease progression compared with natural history based on NEURO-TTR placebo projection (estimated natural history will be presented). Furthermore, in the overall population and both CM subgroups, the inotersen-inotersen group demonstrated sustained benefit compared with the placebo-inotersen group (Table). Change in serum TTR levels will be presented. There have been no reports of grade 4 thrombocytopenia or acute glomerulonephritis under enhanced monitoring in patients in the EU+NA despite the increased duration of exposure. No new safety concerns were identified. Conclusions Inotersen treatment for >3 years slowed the progression of PN associated with ATTRv in patients with CM, including severe CM. In both subgroups, greater neurological preservation was observed in those who initiated inotersen earlier (inotersen-inotersen group), underscoring the benefits of early treatment. No new safety signals were detected in this OLE analysis; enhanced monitoring is successful in managing the risk for thrombocytopenia and acute glomerulonephritis. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was sponsored by Akcea Therapeutics, an affiliate of Ionis Pharmaceuticals, Inc.

SummaryPatients with asymptomatic/smouldering Waldenström macroglobulinaemia (SWM) have a variable risk of progression to active WM. Our study evaluated 143 patients with SWM consecutively seen between January 1996 and December 2013. With a median [95% confidence interval (CI)] follow‐up of 9·5 [8·1–11·5] years, the cumulative rate of progression was 11% at 1 year, 38% at 3 years and 55% at 5 years. On multivariate analysis, haemoglobin (Hb) ≤123 g/l [risk ratio (RR) 2·08; P = 0·009] and β2‐microglobulin (β2M) ≥2·7 µg/ml (RR 2·0; P = 0·01) were independent predictors of a shorter time‐to‐progression (TTP) to active WM. Patients with myeloid differentiation factor 88 wild type (MYD88WT) genotype (n = 11) demonstrated a trend toward shorter TTP [median (95% CI) 1·7 (0·7–8·7) vs. 4·7 (2·4–7·7) years for the MYD88L265P cohort, n = 42; P = 0·11]. The presence of C‐X‐C chemokine receptor type 4 (CXCR4) mutation (n = 29) did not impact the TTP (median: 3 years for CXCR4WT vs. 5·6 years for CXCR4MUT, P = 0·34). The overall survival (OS) for patients with SWM (median: 18·1 years) was comparable to an age‐, sex‐ and calendar year‐matched USA population (median: 20·3 years, P = 0·502). In conclusion, Hb and β2M at diagnosis represent independent predictors of progression to active WM. Comparable survival of SWM and a matched USA population argues against pre‐emptive intervention in this patient population.

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.

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.

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.