Citations

Abstract Introduction: Binary cardiac response assessment using NT-proBNP is prognostic in light chain (AL) amyloidosis. Previous studies suggested that refining the criteria to multi-level cardiac responses improves prognostic prediction. We validate a graded cardiac response assessment tool in AL amyloidosis using NT-proBNP or BNP. Methods: In this retrospective, multicenter study AL amyloidosis patients who were diagnosed between 2010 and 2015, achieving at least a hematological partial response (PR) within 12 months of diagnosis and were evaluable for cardiac response (defined as baseline NT-proBNP >650 pg/mL or BNP >150 pg/mL) were included. The following response criteria were tested: cardiac complete response (carCR, nadir NT-proBNP≤350 pg/mL or BNP≤80 pg/mL); cardiac very good partial response (carVGPR, >60% reduction in NT-proBNP/BNP); Cardiac PR (carPR 31-60% reduction); and cardiac non response (carNR, ≤30% reduction). Response was assessed at fixed time points (6, 12 and 24 months from therapy initiation) and at best response. The primary outcome was overall survival based on depth of cardiac response. Multivariate Cox proportional models were analyzed to determine independent prognostic factors for OS and time to cardiac progression using variables with p-value <0.1 in a univariate analysis. Results: Six hundred and fifty-one patients were included. The median age was 64 years. Mayo 2004 cardiac stage II, IIIA and IIIB was present in 47.5%, 38% and 14.5% of patients, respectively (by definition, patients with Mayo stage I do not have cardiac amyloidosis evaluable for response). Seventy-six percent of patients received only one line of therapy within the initial 12 months of diagnosis. Bortezomib-based therapy was the most common (70.2% of patients) followed by autologous stem cell transplantation (ASCT) in 15.7% of patients. Hematological CR, hematological VGPR and hematological PR as best response was achieved in 38%, 39% and 23% of patients, respectively. Forty-three percent of the patients have died, with 36% of the patients dying within 5-years of diagnosis. The median follow-up of the surviving patients is 70 months (IQR 56-84). Cardiac response was evaluable using NT-proBNP in 494 patients (75.9%), BNP in 109 patients (16.7%) and both NT-proBNP and BNP in 48 patients (7.4%). The latter two were grouped together for further analysis. The median time to best cardiac response among responders was 12 months (IQR 7-21 months; 18 months for carCR, 11.5 months for carVGPR and 9.5 months for carPR). Cardiac response improved over time with a median percentage reduction in NT-proBNP/BNP compared to baseline of 15%, 37% and 54%, at 6, 12 and 24 months respectively. Cardiac responses at 6-, 12- and 24-months are depicted in Figure 1A. At best cardiac response, carCR, carVGPR, carPR and carNR were achieved in 16%, 26%, 23% and 35% of patients, respectively. Patients who achieved a carCR had lower cardiac stage at diagnosis compared to patients who achieved carVGPR or carPR (stage II 65% vs 47% vs 47%, respectively; P<0.001). At least carPR at 6 and 12 months and at least carVGPR at 24-months was associated with better survival compared with a lower depth of response. At best cardiac response, deeper cardiac response was associated with a longer survival (5-year OS 93%, 80%, 62% and 35% for carCR, carVGPR, carPR and carNR, respectively; P<0.001, Figure 1B). A 2-year landmark analysis (excluding early deaths not evaluable for cardiac response depth) confirmed improved survival with a deeper cardiac response (5-year OS 93%, 82%, 70% and 58%, P<0.001; Figure 1C). These cardiac response criteria were independent predictors of survival and time to cardiac progression (>30% rise in NT-proBNP/BNP) in multivariate analysis that included age, type of first line therapy, light chain burden, cardiac stage, and hematological response. Conclusions: We validated the prognostic value of graded cardiac response. These response criteria allow better discrimination of patient populations and assessment of treatment effectiveness in an era of improved therapies for AL amyloidosis. The study emphasizes the importance of early diagnosis which increases the likelihood of deep and durable cardiac responses. Figure 1 Figure 1. Disclosures Dispenzieri: Oncopeptides: Consultancy; Pfizer: Research Funding; Sorrento Therapeutics: Consultancy; Takeda: Research Funding; Alnylam: Research Funding; Janssen: Consultancy, Research Funding. Palladini: Siemens: Honoraria; Pfizer: Honoraria; Janssen Global Services: Honoraria, Other: advisory board fees. Schönland: Janssen: Honoraria, Other: Travel grants, Research Funding; Takeda: Honoraria, Other: Travel grants; Sanofi: Research Funding; Pfizer: Honoraria; Prothena: Honoraria, Other: Travel grants. Hegenbart: Alnylam: Honoraria; Janssen: Consultancy, Research Funding; Prothena: Research Funding; Pfizer: Consultancy, Honoraria; Akcea: Honoraria. Kumar: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Novartis: Research Funding; Merck: Research Funding; Tenebio: Research Funding; Bluebird Bio: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Kastritis: Genesis Pharma: Honoraria; Takeda: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Dimopoulos: Beigene: Honoraria; Takeda: Honoraria; BMS: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Liedtke: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Alnylam: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Other: Clinical Trial Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Kura Oncology: Membership on an entity's Board of Directors or advisory committees. Witteles: Eidos: Research Funding; Alnylam: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Sanchorawala: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Proclara: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Karyopharm: Research Funding; Oncopeptide: Research Funding; Pfizer: Honoraria; Sorrento: Research Funding. Landau: Genzyme: Honoraria; Takeda: Research Funding; Takeda, Janssen, Caelum Biosciences, Celgene, Pfizer, Genzyme: Membership on an entity's Board of Directors or advisory committees. Cibeira: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Akcea: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board; Aurora Biopharma: Other: Stock option.

Abstract Background: Light chain (AL) amyloidosis is a rare, progressive, and typically fatal hematologic disorder caused by plasma cells that produce misfolded AL protein, resulting in deposits of amyloid in tissues and organs that cause organ dysfunction and failure. Birtamimab is an investigational monoclonal antibody designed to neutralize circulating soluble amyloid and deposited insoluble amyloid, thus promoting the phagocytic clearance of amyloid deposits. In 2018, the global phase 3 VITAL study in newly diagnosed, treatment-naïve patients was terminated based on a futility analysis of the composite primary endpoint (time to all-cause mortality [ACM] or time to cardiac hospitalization >90 days after first study drug infusion); the final hazard ratio (HR) numerically favored birtamimab + standard of care (SOC) over placebo + SOC (0.835, 95% CI 0.5799, 1.2011; p=0.330). Post hoc analysis of ACM over 9 months revealed a pronounced survival benefit (HR=0.413, 95% CI 0.191, 0.895; p=0.025; Figure) in a subgroup of patients at high risk for early mortality (Mayo stage IV). At 9 months, the proportions of surviving patients were 74% and 49% in the birtamimab + SOC and placebo + SOC groups, respectively. Post hoc analyses of secondary endpoints in this subgroup also supported clinical and functional benefits of birtamimab + SOC, with clinically meaningful improvements observed in health-related quality of life (assessed with 36-Item Short Form Health Survey version 2; SF-36v2) and 6-minute walk test (6MWT) distance (both nominal p<0.05) at 9 months. Across all birtamimab clinical trials, no drug-related deaths, dose-limiting toxicities, or major risks were identified. Aims: To evaluate the efficacy and safety of birtamimab + SOC versus placebo + SOC in Mayo stage IV patients with AL amyloidosis by assessing time to ACM over 9 months. Methods: The phase 3, double-blind, placebo-controlled AFFIRM-AL study will enroll up to 150 Mayo stage IV patients with newly diagnosed, untreated AL amyloidosis. Patients will receive either 24 mg/kg intravenous birtamimab or placebo every 28 days (both arms will also receive SOC, defined as concomitant chemotherapy with a first-line bortezomib-containing regimen). Patients will be randomly assigned 2:1 to birtamimab or placebo and will be stratified at randomization based on their 6MWT distance (<300 meters vs ≥300 meters). The primary efficacy endpoint of AFFIRM-AL is time to ACM using a log-rank test. Secondary endpoints are change from baseline to month 9 in SF-36v2 and 6MWT distance. Safety endpoints include adverse events, clinical laboratory observations, and immunogenicity analyses. An interim efficacy analysis is planned when ~50% of the events have occurred. Results: Given the >50% relative risk reduction for ACM observed in the post hoc analysis of VITAL for the AL amyloidosis subpopulation of patients with Mayo stage IV disease, the phase 3 AFFIRM-AL study is designed to confirm this effect of birtamimab under a Special Protocol Assessment agreement with the US FDA. Conclusion/Summary: Effective treatments to improve survival in AL amyloidosis are needed, particularly for patients with advanced cardiac involvement, as median overall survival for those with Mayo stage IV disease is approximately 6-9 months. Birtamimab is the only investigational therapeutic in which a survival benefit has been observed, in a post hoc subgroup analysis of VITAL in patients with AL amyloidosis with advanced cardiac involvement. AFFIRM-AL is expected to initiate in mid-2021. (NCT04973137) Figure 1 Figure 1. Disclosures Gertz: Alnylam, Amgen, Annexon, Appellis, Celgene, Ionis/Akcea, Janssen, Medscape, Physicians Education Resource, Prothena, Research to Practice: Other: personal fees; Spectrum: Other: personal fees, Research Funding; AbbVie: Other: personal fees for Data Safety Monitoring board; Teva, Johnson and Johnson, Medscape, DAVA oncology: Other: speaker fees; Pharmacyclics, Proclara: Other: Advisory Board; i3Health: Other: development of educational materials; Springer Publishing: Patents & Royalties. Tripuraneni: Prothena Biosciences Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: related to birtamimab (NEOD001). Kinney: Prothena Biosciences Inc.: Current Employment, Current holder of stock options in a privately-held company, Patents & Royalties: related to birtamimab (NEOD001).

Abstract Background: Systemic light chain (AL) amyloidosis is a plasma cell disorder characterized by multisystem deposition of misfolded immunoglobulin light chains produced by clonal plasma cells. Hematologic and organ responses with treatment have been shown to correlate with survival as early as 3 months from initiation of first-line treatment. Our group recently developed and validated a model integrating organ and hematologic responses for assessment of treatment outcomes at 6 months. Although current organ response criteria do not consider the depth of organ response, this has been shown to have prognostic utility in newly diagnosed patients. So, we designed this study to evaluate a composite hematologic and organ scoring system that also considers the depth of organ response at 1 to 6 months from initiation of first-line treatment. Methods: We included patients with AL amyloidosis who had at least one major organ involvement (cardiac, renal and/or liver involvement) and who had not started a second line treatment by 6 months from the time of initiating first-line treatment. For each patient, we calculated an organ response score and a hematologic response score at 1, 2, 3, 4, 5, and 6 months from initiation of first-line treatment. A score was assigned for each depth of hematologic response as follows: complete response=0, very good partial response=1, partial response=2, and no response/progressive disease=3). To calculate organ response, a score was assigned to each organ based on the depth of organ response (Muchtar et al. 2018): non-evaluable=0, complete response=1, very good partial response=2, partial response=3, and no response=4. The final organ response score was obtained by calculating the average of the individual involved organ scores. We then calculated the composite hematologic and organ response (HOR) score by adding the organ and hematologic responses at each interval and compared overall survival (OS) between patients with HOR score ≤ 5 (group 1) and those with score > 5 (group 2). Results: The cohort included 730 patients diagnosed with AL amyloidosis between February 10 th, 2006 and July 9 th, 2019. Median age was 63 (IQR: 56-69), and 65% were male. The involved light chain was Lambda in 75% of cases. Cardiac, renal, and liver involvement were found in 81%, 61%, and 17% of patients, respectively. Among all patients, 28% underwent autologous stem cell transplantation during their disease course. The median follow up in the entire cohort was 7.0 (95%CI: 6.4-8.0) years and OS was 3.6 (95%CI: 2.6-4.4) years. At 1 to 4 months, we observed a statistically significant difference in OS between patients with HOR score ≤5 vs. >5. However, there was no difference in OS between the 2 groups at 5 and 6 months. These results are presented in Table 1. Conclusion: A composite hematologic and organ response score that takes into consideration the depth of organ response can discriminate 2 groups of patients with distinct survival outcomes as early as 1 month from treatment initiation and maintains its predictive ability for up to 4 months. The lack of predictive ability beyond 4 months in this study may be due to limited sample size especially in group 2 as more patients achieve deeper responses with time. This approach can provide the basis for early changes in treatment but needs validation in future studies. Figure 1 Figure 1. Disclosures Dispenzieri: Janssen: Consultancy, Research Funding; Takeda: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Pfizer: Research Funding; Alnylam: Research Funding. Gertz: Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring. Kapoor: Ichnos Sciences: Research Funding; Karyopharm: Consultancy; Glaxo SmithKline: Research Funding; Pharmacyclics: Consultancy; Amgen: Research Funding; Cellectar: Consultancy; Sanofi: Consultancy; BeiGene: Consultancy; Regeneron Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dingli: GSK: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Novartis: Research Funding; Apellis: Consultancy; Alexion: Consultancy. Kumar: Oncopeptides: Consultancy; Merck: Research Funding; Antengene: Consultancy, Honoraria; Bluebird Bio: Consultancy; Roche-Genentech: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Research Funding; Carsgen: Research Funding; Tenebio: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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.