Citations

e19503 Background: The risk of venous thromboembolic events (VTE) despite mandatory thromboprophylaxis (TPx) in patients with multiple myeloma (MM) receiving contemporary lenalidomide (Len)-based regimens is not well-defined. Methods: Medline, Embase, and CENTRAL databases were queried to identify phase 1-3 clinical trials of Len-based regimens with mandatory TPx published until April 2018. Random effects meta-analysis was performed using CMAv3 software to obtain crude, and per 100 patient-cycle incidence rate (IR). Prespecified subgroup analyses were performed to obtain IR for VTE by (1) line of treatment (newly diagnosed [ND], relapsed/refractory [RR] and maintenance [Mx] phase) and (2) different Len-based regimens. Results: We screened 1069 citations and analyzed data from 43 trials with 8696 patients, including 17 in ND, 23 in RR and 3 in Mx phase. 12 out of 43 were Phase 3 randomized controlled trials. The overall incidence of VTE in 8696 patients was 4.6% (95% CI, 3.7-5.8%), with 1.0 event (95% CI, 0.7-1.4%) per 100 patient cycles. In patients with NDMM (n = 3295), 193 (5.9%) experienced VTE with a pooled IR of 0.9 (95% CI, 0.3-2.3) per 100 patient-cycle. Among RRMM patients (n = 3981), 251 (6.3%) experienced VTE with a pooled IR of 1.0 (95% CI, 0.4-2.3) per 100 patient-cycle. The incidence of VTE was highest with the following triplet regimens: Rd + Proteasome inhibitor (PIs) and Rd + Anthracycline (Ac) [+/- Vincristine], with the latter having a high risk of VTE regardless of the treatment phase (table). With Len Mx (n = 1420), 38 (2.7%) patients had VTE, with a pooled IR of 0.2 (95% CI, 0-2.1) per 100 patient-cycle. Conclusions: Patients with MM undergoing treatment with Len-based regimens remain at risk of VTE despite current TPx strategies. The estimates of VTE IR provided by this analysis can guide clinicians in assessing treatment-related risk of VTE in this setting. [Table: see text]

Background Thromboprophylaxis is routinely used with lenalidomide‐based regimens in multiple myeloma because of a substantial risk of venous thromboembolism (VTE). However, little is known about the incidence of VTE with contemporary lenalidomide‐based regimens. The objective of the current study was to estimate the incidence of VTE despite thromboprophylaxis with currently used lenalidomide‐based regimens in patients with myeloma. Methods The Ovid MEDLINE, Embase, and Cochrane databases were queried from study inception to January 2019 for keywords to cover the following concepts: “lenalidomide,” “venous thromboembolism,” and “multiple myeloma.” Phase 1, 2, and 3 clinical trials evaluating lenalidomide‐based regimens with thromboprophylaxis were included. The pooled incidence rate of VTE was estimated using a random‐effects model. Results The search generated 1372 citations, with 51 clinical trials and 9069 patients included for analysis. The most common thromboprophylaxis agents were aspirin, low‐molecular‐weight heparin or warfarin, administered either per risk‐stratification or at investigators' discretion. The pooled incidence of VTE in trials of patients who had newly diagnosed and relapsed/refractory myeloma was 6.2% (95% CI, 5.4%‐7.1%) over median treatment durations ranging from 2 to 34 cycles, which translated into 1.2 VTE events per 100 patient‐cycles (95% CI, 0.9‐1.7 VTE events per 100 patient‐cycles). Among contemporary regimens, the risk of VTE was low with combined lenalidomide and low‐dose dexamethasone (0.2 [95% CI, 0.1‐0.6] events/100 patient‐cycles) and lenalidomide maintenance (0.0 [95% CI, 0.0‐0.7] events per 100 patient‐cycles). VTE risk was higher with combined lenalidomide and low‐dose dexamethasone plus proteasome inhibitors (1.3 [95% CI, 0.7‐2.3] events per 100 patient‐cycles). Conclusions Despite adequate thromboprophylaxis, lenalidomide‐based regimens have a substantial risk of VTE in controlled clinical trial settings. Further studies are needed on new thromboprophylaxis strategies with regimens that have a high VTE risk.

Background: Efficacy of an intervention is commonly evaluated using P values, in addition to effect size measures such as absolute risk reduction, relative risk reduction, and numbers needed to treat. However, these measures are not always intuitive to clinicians. The fragility index (FI) is a more intuitive number that can facilitate interpretation but can only be used with binary outcomes. FI is the minimum number of patients who must be moved from the nonevent group to the event group to turn a significant result nonsignificant. In this retrospective analysis, we assessed the robustness of cardiovascular randomized controlled trials (RCTs), which report a positive (statistically significant) primary outcome by using the FI. Methods and Results: We searched Medline from 2007 to 2017 to identify cardiovascular RCTs published in 6 high impact journals ( The Lancet , New England Journal of Medicine , Journal of the American Medical Association , Circulation , Journal of the American College of Cardiology and European Heart Journal ). Only RCTs with sample sizes >500 and a 2-by-2 factorial design or dichotomous primary outcomes were selected. FI was calculated using a defined approach. Among the cohort of 123 RCTs that met inclusion criteria, median FI was 13 (interquartile range, 5–26). In 28 trials (22.8%), FI ranged between 1 and 4. In 37 trials (30.1%), number of patients lost to follow-up was higher than the FI. Pharmaceutical interventions had higher FI compared with other interventions, FI=19 (7–52; P =0.002). Median FI varied according to subspecialty (electrophysiology=2; heart failure=11; interventional cardiology=8; P =0.020) and multiregional RCTs had higher FI=22 (12–53.25; P =0.023). FI did not differ based on risk of bias indicators, funding, or publication year. Conclusions: Considerable variations in FI were observed among cardiovascular trials, suggesting the need for careful interpretation of results, particularly when number of patients lost to follow-up exceeds FI.

Background: Primary cutaneous diffuse large B cell lymphoma-leg type (DLBCL-LT) is relatively uncommon lymphoma accounting for about 1 to 3 % of all cutaneous lymphoma and about 10-20% of primary cutaneous B cell lymphomas. There is data for survival outcomes in primary cutaneous B cell lymphoma in general population after introduction of rituximab but little is known about outcomes in DLBCL-LT patients in general population. The available data on survival in DLBCL-LT are from small case series and single institution studies. We conducted this study to evaluate the survival outcome in patients with PCDLBCL-LT after introduction of rituximab. Methods: We utilized SEER 18 database to select adult (18+ years) patients diagnosed from 2004 to 2014 with ICD-3-0 code of 9680/3 (diffuse large B cell lymphoma, not otherwise specified)with localized stage by summary stage 2000 with skin as the primary site of disease to identify patient with DLBCL-LT. Patients were divided into various cohorts based on age (<65 versus 65+ years), sex, race (Caucasians, African American and Others) and median household income of county of residence (< $50,00 versus ≥ $50,000). We utilized SEER*stat to calculate age adjusted incidence rate using 2000 US standard population. Kaplan Meyer curve was utilized to calculate 5-year overall survival. Cox proportional hazard model was used for multivariate analysis of factor associated with survival. Result: A total of 485 patients were identified with DLBCL-LT as the only or first primary cancer case. The median age at diagnosis was 70 years. Its incidence was found to be about 0.09 case per 100,000 population with incidence in males being about 1.6 times that of females. Majority of patient included in our study were males (52 %), older (59.4%), and Caucasians (85.6%). 5-year overall survival was found to be 59%. Older patients were found to have significantly worse 5-year overall survival compared to younger patients with HR of 7.9 with 95% CI of 4.9 to 12.7. There was no disparity in cancer outcome based on race, sex or median income of the county of residence. When we compared the outcome of patients diagnosed in earlier 5 years to later 6 years of the study period, the survival curves almost overlapped suggesting that there has been little if any improvement in outcome in recent years. Conclusion: Our study showed that about 60% of patients with DLBCL-LT live for 5 years in real world setting which is comparable to the outcome reported by other studies on outcome in primary cutaneous B cell lymphoma. Even though this is disease of elderly, as the median age at diagnosis is 70 years, the outcome in older population was found to be significantly worse compared to younger patients. Given this is relatively uncommon disease, we recommend large registry-based studies to try to improve outcome in these patient population. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, systemic, progressive, and fatal condition in which misfolded proteins, mainly produced in the liver, deposit in muscle and organ tissues leading to symptoms of peripheral neuropathy, and possible cardiomyopathy and autonomic neuropathy. The Norfolk Quality of Life (QOL)-Diabetic Neuropathy (DN) Questionnaire is a patient-reported measure that has been validated for capturing neuropathic-specific QOL in patients with hATTR amyloidosis. Examination of patients' responses to the items of the Norfolk-QOL-DN can provide important insights into the impact of hATTR amyloidosis, and its treatment, on concrete aspects of patients' daily activities and physical functioning. Objective: To provide a descriptive analysis of item-level responses to the Norfolk-QOL-DN by patients with hATTR amyloidosis with polyneuropathy, who participated in the NEURO-TTR trial, in order to identify the impact of treatment with inotersen versus placebo on concrete aspects of patients' functioning and daily activities. Methods: Data come from the NEURO-TTR trial, a multicenter, multinational, double-blind trial (NCT01737398) of 172 adults with hATTR amyloidosis with polyneuropathy who received 65 weeks of either treatment with the investigational drug inotersen, an antisense oligonucleotide, or a matching placebo. The Norfolk QOL-DN was administered to patients at baseline, week 35, and week 66. The Norfolk QOL-DN is a 35-item measure which captures neuropathic-related QOL. Nineteen items from the scale were determined to elicit concrete information about functioning and daily activities. Each of these 19 items used five response choices: "no problems", "very mild problems", "mild problems", "moderate problems", and "severe problems". Response options were dichotomized such that the latter two options were coded as indicating substantial impairment in functioning or activities. Descriptive analyses compared, for each item, the proportion of patients in the inotersen and placebo arms at baseline and week 66 (and change from baseline to week 66) who indicated substantial impairment. Results: At baseline, there were no differences for any Norfolk QOL-DN items in the proportions of patients who indicated substantial impairment. However, at week 66, patients receiving inotersen were less likely than those receiving placebo to indicate that they had a substantial impairment on several aspects of functioning and daily activities. Patients in the inotersen arm were half as likely as those receiving placebo to indicate a problem of pain keeping them awake at night (15% vs. 37%) and being moderately or severely bothered by the touch of bedsheets (12% vs. 27%). A noticeably smaller percentage of patients receiving inotersen than placebo reported problems with their symptoms affecting their usual activities (37% vs. 50%); having difficulty moving their fingers (47% vs 64%); feeling unsteady on their feet (49% vs 67%); having difficulty getting out of a chair (51% vs. 62%) or walking down stairs (42% vs. 58%); and having difficulty bathing (24% vs. 35%), dressing (21% vs 35%), walking (41% vs 60%), getting on/off the toilet (22% vs. 37%), and utensil use (19% vs. 31%). Percentages of change in patients from baseline to week 66 show larger increases in having substantial impairment in these functions and activities for patients receiving placebo than inotersen, with those receiving inotersen generally showing small increases, and even decreases in substantial impairment over the course of treatment. Conclusion: Following 66 weeks of treatment, hATTR amyloidosis patients receiving inotersen were less likely than those receiving placebo to report substantial impairment in many aspects of functioning and activities of daily living, including moving fingers, balance while standing, getting out of a chair, walking down stairs, bathing, dressing, walking, getting on/off the toilet, and using utensils. Ability to engage in these functions and activities was better preserved in patients treated with inotersen than placebo. These findings present a context for understanding the concrete impact of inotersen treatment on the day-to-day lives of patients with hATTR amyloidosis with polyneuropathy. Disclosures Yarlas: Optum: Employment; Akcea: Research Funding. Merlini:Millenium: Consultancy; Pfizer: Consultancy; Janssen: Consultancy; Prothena: Consultancy; Ionis: Consultancy; Akcea: Consultancy. White:Optum: Employment; Akcea: Research Funding. Sikora Kessler:Optum: Employment; Akcea: Research Funding. Lovley:Optum: Employment; Akcea: Research Funding. Guthrie:Akcea: Employment, Other: Stock Ownership. Pollock:Akcea: Employment. Gertz:Apellis: Consultancy; Amgen: Consultancy; janssen: Consultancy; Alnylam: Honoraria; Prothena: Honoraria; annexon: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Ionis: Honoraria; Medscape: Consultancy; Physicians Education Resource: Consultancy; Research to Practice: Consultancy; celgene: Consultancy.

Abstract Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, progressive, and fatal disease caused by the buildup of transthyretin-derived amyloid protein in major organs, predominantly affecting the peripheral nerves and heart. Inotersen, a second-generation antisense oligonucleotide targeting TTR mRNA, has shown efficacy and safety in patients with hATTR in a randomized, double-blind, placebo-controlled, phase 3 study, NEURO-TTR (ClinicalTrials.gov, NCT01737398; Benson NEJM 2018). Patients with hATTR amyloidosis who completed the NEURO-TTR study were eligible to receive inotersen for up to 5 years in a phase 3 open-label extension study (ClinicalTrials.gov, NCT02175004). Methods: In NEURO-TTR, patients were randomized 2:1 to receive inotersen (300-mg weekly subcutaneous doses) or placebo. In the open-label extension, patients continued inotersen (inotersen-inotersen) or switched from placebo to inotersen (placebo-inotersen). Evaluations included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7; higher scores indicate worse neuropathy), Norfolk Quality of Life-Diabetic Neuropathy questionnaire total score (Norfolk QoL-DN; higher scores indicate worse QoL), and adverse events (AEs). Cardiomyopathy (CM) was defined by a diagnosis of hATTR-CM at trial entry or by an interventricular wall thickness of 13 mm or more on transthoracic echocardiography at baseline, as ascertained by a central reader, or no known history of persistent hypertension (systolic blood pressure, ≥150 mm Hg) within 12 months before screening. Results : In the placebo-controlled, double-blind, phase 3 NEURO-TTR study, 112/172 patients were randomized and received inotersen. At baseline, patients were predominantly white (91.9%) males (68.6%) with a mean age of 59.2 years. A total of 67.4% had stage I (ambulatory) and 32.6% had stage II (ambulatory with assistance) disease. Inotersen-treated patients who had stage II disease had a longer duration of disease from diagnosis (40.9 vs 24.8 months, respectively) and from onset (72.6 vs 63.2 months, respectively) of hATTR polyneuropathy symptoms compared with placebo-treated patients who had stage II disease, indicating more advanced disease. A higher proportion of inotersen-treated patients had CM at baseline (67% vs 55%, respectively), and more severe CM, measured by higher NT-proBNP levels and longer duration of disease from hATTR-CM symptom onset, compared with placebo-treated patients. In the phase 3 open-label extension study as of Sept 15, 2017, 134 of 135 patients enrolled received ≥1 dose of inotersen. The mean age was 60.4 years and most patients were male (69.4%). Extended dosing with inotersen up to 27 months continued to improve mNIS+7 and Norfolk QoL-DN in the open-label extension compared to placebo-treated patients at week 66 in the double-blind NEURO-TTR study; mean changes from open-label extension baseline to open-label extension week 52 in the inotersen-inotersen group were 5.1 points for mNIS+7 (vs 25.5 for placebo-treated patients in the double-blind NEURO-TTR study) and 3.9 points for Norfolk QoL-DN (vs 10.7 for placebo-treated patients in the double-blind NEURO-TTR study). Initiation of inotersen in placebo-treated patients (placebo-inotersen) resulted in improvement in mNIS+7 and Norfolk QoL-DN by week 26. Few patients discontinued treatment because of AEs (inotersen-inotersen, 9%; placebo-inotersen, 4%). The rate of treatment-related serious AEs was low in both treatment groups (2% each). There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of exposure. We will present 2-year follow-up results from the open-label extension study. Conclusions: Results of the open-label extension show continued benefit, measured by mNIS+7 and Norfolk QoL-DN, and confirmed that earlier initiation of treatment is important for optimal clinical outcomes. No new safety concerns were identified. Results from the longer-term follow-up for the open-label extension will further elucidate how inotersen may benefit patients with hATTR amyloidosis. Disclosures Brannagan: Alnylam: Honoraria, Other: Investigator, Speakers Bureau; Ionis: Other: Investigator. Wang:Ionis: Other: Investigator, Speakers Bureau. Coelho:Prothena: Consultancy, Honoraria; Ionis: Consultancy, Other: Investigator; Alnylam: Consultancy, Honoraria, Other: Investigator; Pfizer: Consultancy, Honoraria, Other: Investigator. Waddington Cruz:Ionis: Honoraria; Genzyme/Sanofi: Honoraria; Pfizer: Honoraria. Polydefkis:Pfizer: Honoraria; Alnylam: Honoraria. Dyck:Ionis: Consultancy; Alnylam: Consultancy. Plante-Bordeneuve:Alnylam: Consultancy; Pfizer: Consultancy, Other: reimbursement for travel and meeting; Ionis: Other: reimbursement for travel and meeting. Berk:Ionis: Honoraria, Other: Investigator; Alnylam: Honoraria, Other: Investigator; Pfizer: Other: Investigator. Barroso:Pfizer: Consultancy, Honoraria, Other: Thaos registry, Speakers Bureau; Alnylam: Honoraria, Other: Investigator. Conceição:Alnylam: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Hughes:Ionis: Employment. Kwoh:Ionis: Employment. Jung:Ionis: Employment. Guthrie:Akcea: Employment. Pollock:Akcea: Employment. Benson:Ionis: Other: Investigator, Research Funding. Gertz:janssen: Consultancy; Teva: Consultancy; spectrum: Consultancy, Honoraria; Alnylam: Honoraria; Ionis: Honoraria; Amgen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; celgene: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; Physicians Education Resource: Consultancy.

Abstract Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, systemic, progressive, and fatal condition in which misfolded proteins, mainly produced in the liver, deposit in muscle and organ tissues leading to symptoms of peripheral neuropathy, and possible cardiomyopathy and autonomic neuropathy. Primary results from the NEUTO-TTR trial indicated that patients with hATTR amyloidosis who received 65 weeks of treatment with inotersen had better preservation of quality of life (QOL), as measured by the Norfolk QOL-Diabetic Neuropathy (DN) Questionnaire total score and the physical component summary score of the SF-36v2® Health Survey (SF-36v2), than did patients who received placebo. Whether the benefits of inotersen on domains of QOL differ across subgroups of patients has not been previously addressed. Objective: To examine the efficacy of inotersen for preserving QOL in subgroups of patients with hATTR amyloidosis, defined by time of disease onset (early or late) and ambulatory stage (Stage 1 or Stage 2). Methods: Data come from the NEURO-TTR trial, a multicenter, multinational, double-blind trial (NCT01737398) of 172 adults with hATTR amyloidosis with polyneuropathy who received 65 weeks of treatment with either the investigational drug inotersen, which is an antisense oligonucleotide, or matching placebo. The Norfolk QOL-DN and SF-36v2 were administered to patients at baseline, week 35, and week 66. The Norfolk QOL-DN is a 35-item measure which captures neuropathic-related QOL, representing five domains: activities of daily living, autonomic neuropathy, large fiber neuropathy/physical functioning, small fiber neuropathy, and neuropathic symptoms. The SF-36v2 is a 36-item measure which captures generic health-related QOL, representing eight domains: physical functioning, role limitations due to physical health (role-physical), bodily pain, general health, vitality, social functioning, role limitations due to emotional health (role-emotional), and mental health. Patient subgroups were defined by: (1) patients' time of symptom onset: whether symptoms first occurred early (at or before age 50) or late (after age 50) in life; and (2) patients' disease severity, as defined by ambulatory disability - Stage 1 (walking without assistance) or Stage 2 (walking with assistance, such as a cane or walker). Mixed-effects repeated-measures models tested treatment differences (inotersen vs. placebo) in changes of mean Norfolk QOL-DN and SF-36v2 domain scores from baseline to week 66 for each patient subgroup. Results: Inotersen was more effective than placebo for preserving QOL in patients with early onset of symptoms: treatment differences in scores were statistically significant (p<0.05) for four of the five Norfolk QOL-DN domains (all except small fiber neuropathy) and for all eight SF-36v2 domains. In patients with late onset of symptoms: statistically significant treatment differences in scores were observed for no Norfolk QOL-DN domains and only one of eight SF-36v2 domains (physical functioning). Inotersen was more effective than placebo for preserving QOL in patients with Stage 1 severity, treatment differences were statistically significant for three of the five Norfolk QOL-DN domains (all except autonomic neuropathy and small fiber neuropathy) and for five of eight SF-36v2 domains (all except general health, vitality, and mental health). In patients with Stage 2 severity, significant treatment differences in scores were observed for only one Norfolk QOL-DN domain (activities of daily living) and no SF-36v2 domains. Conclusion: Following 66 weeks of treatment, inotersen was more effective than placebo for preserving QOL in patients with hATTR amyloidosis who had early onset of symptoms or who were in Stage 1 of disease severity. Preserving QOL in patients with early onset is critical, as many of these patients are likely to be in the work force, raising children, and leading active lives. The benefits seen for patients in Stage 1 disease severity point to the crucial importance of early diagnosis and treatment, as there may be a window in which treatment can preserve QOL in patients with hATTR amyloidosis prior to the late progressive stages. Disclosures Yarlas: Optum: Employment; Akcea: Research Funding. Merlini:Pfizer: Consultancy; Millenium: Consultancy; Akcea: Consultancy; Prothena: Consultancy; Janssen: Consultancy; Ionis: Consultancy. White:Optum: Employment; Akcea: Research Funding. Sikora Kessler:Optum: Employment; Akcea: Research Funding. Lovley:Optum: Employment; Akcea: Research Funding. Guthrie:Akcea: Employment, Other: Stock Ownership. Pollock:Akcea: Employment. Gertz:Apellis: Consultancy; Research to Practice: Consultancy; Teva: Consultancy; celgene: Consultancy; Amgen: Consultancy; Physicians Education Resource: Consultancy; Ionis: Honoraria; annexon: Consultancy; Alnylam: Honoraria; Medscape: Consultancy; Prothena: Honoraria; janssen: Consultancy; Abbvie: Consultancy; spectrum: Consultancy, Honoraria.

Abstract Introduction: Systemic amyloidoses are a group of rare disorders characterized by the accumulation of misfolded proteins in tissue, resulting in the dysfunction of vital organs (eg, heart and kidneys). In amyloid light chain (AL) amyloidosis, the most common form of systemic amyloidosis, the amyloidogenic protein is a misfolded light chain (LC) or a fragment of an LC produced by clonal plasma cells. Current therapies used to treat AL amyloidosis limit LC production but do not directly target deposits underlying multiorgan failure. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits. In an interim analysis of a phase 1/2 dose-escalation study in 27 patients with AL amyloidosis and persistent organ dysfunction (NCT01707264; EudraCT2012-002683-27), monthly infusions of NEOD001 were safe, well tolerated, and associated with renal and cardiac responses.1 Here we report updated results from the escalation phase and new results from the expansion phase of this study. Patients and Methods: Inclusion criteria for this trial were that patients complete ≥1 PCD treatment before enrollment, attain partial hematologic response (HR) or better to any previous therapy, and have persistent organ dysfunction. NEOD001 was administered intravenously every 28 days. During the dose-escalation phase, 27 patients received NEOD001 at 0.5, 1, 2, 4, 8, 16, or 24 mg/kg in a 3+3 study design. An additional 42 patients with renal, cardiac, or peripheral nerve involvement were enrolled and treated (24 mg/kg) in the expansion phase. We assessed safety/tolerability, pharmacokinetics, immunogenicity, cardiac and renal responses based on consensus criteria, and neuropathy responses using the Neuropathy Impairment Score-Lower Limb (NIS-LL). Results: The 42 additional patients enrolled in the expansion study included cohorts with renal (16 patients), cardiac (15 patients), and peripheral nerve (11 patients) involvement. In the overall population (n = 69), the median age was 60 years, and 61% of patients were men. Median (range) time since diagnosis was 2.8 (0.4-12.8) years, and 45% of patients underwent ≥3 previous plasma cell-directed regimens. The total number of infusions administered was 913 over a mean of 13.2 (range, 3-35) months. NEOD001 treatment was not associated with dose-limiting toxicities or discontinuations; patients did not develop antidrug antibodies or treatment-related serious adverse events. The most frequent treatment-emergent adverse events, regardless of relationship to study drug, were fatigue, upper respiratory tract infection, nausea, and diarrhea. In a best response analysis, 53% of cardiac-evaluable patients (N = 36) and 63% of renal-evaluable patients (N = 35) met respective criteria for organ response; no patients experienced disease progression. The median time to initial response was 2 months (cardiac) and 4 months (renal). After 9 months of treatment, 82% of patients with measurable peripheral neuropathy at baseline (N = 11) achieved a peripheral neuropathy response based on the NIS-LL score. Conclusions: Our interim results demonstrated that monthly NEOD001 infusions were safe and well tolerated and that organ response rates compared favorably with traditional chemotherapy. These updated results from the escalation phase and these new results from the expansion phase, including results from patients with peripheral nerve involvement, support the design of ongoing late-stage clinical studies. Antibody therapy may allow for effective treatment of patients with AL amyloidosis. Reference: 1. Gertz MA, Landau H, Comenzo RL, et al. First-in-human phase 1/2 study of NEOD001 in patients with light chain amyloidosis and persistent organ dysfunction. J Clin Oncol. 2016;34(10):1097-1103. Disclosures Gertz: Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria; Ionis: Research Funding; Annexon Biosciences: Research Funding. Comenzo:Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding. Sanchorawala:Celgene: Research Funding; Takeda: Research Funding; Prothena: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; GlaxoSmithKline: Consultancy; Millennium: Consultancy, Other: Travel, accommodations; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:BMS: Consultancy; Celgene: Consultancy, Research Funding; Prothena: Consultancy; Array Biopharma: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy. Walling:Stealth: Consultancy; BioMarin: Equity Ownership; Apex: Consultancy; Pharm-Olam: Consultancy; NuMedii: Consultancy; Amgen: Equity Ownership, Patents & Royalties; Crown Bioscience: Consultancy; KaloBios: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Corcept: Consultancy; Prothena: Consultancy; Aduro: Consultancy; Codexis: Consultancy; Upsher Smith: Consultancy, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Schenk:Prothena: Employment, Equity Ownership, Other: Leadership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Liu:Prothena: Employment, Equity Ownership; Weston Brain Institute: Honoraria. Liedtke:Prothena: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Gilead: Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding.

Abstract Introduction:In amyloid light chain (AL) amyloidosis, the most common form of systemic amyloidosis, misfolded light chain (LC) or a fragment of an LC produced by clonal plasma cells accumulates in tissue, resulting in the dysfunction of vital organs and systems (eg, heart, kidneys, nervous system). Current therapies used to treat AL amyloidosis limit LC production but do not directly target deposits underlying multiorgan failure. Approximately 75% of patients do not achieve organ responses and have persistent organ dysfunction. Amyloid-directed therapies may stabilize and potentially reverse organ damage by specifically targeting existing LC aggregates. NEOD001, a monoclonal antibody, targets misfolded LC and is thought to neutralize circulating LC aggregates and to clear insoluble deposits. We have previously reported that monthly infusions of NEOD001 were safe and well tolerated. In addition, NEOD001 was associated with renal and cardiac responses. Here we analyzed the association between organ response and depth and time since last plasma cell-directed (PCD) treatment in the entire cohort of 69 patients enrolled in both the dose-escalation and the expansion phases of the phase 1/2 study. Methods: Inclusion criteria for this trial were that patients complete ≥1 PCD treatment before enrollment, attain partial hematologic response (HR) or better to any previous therapy, and have persistent organ dysfunction. NEOD001 was administered intravenously every 28 days. During the dose-escalation phase, 27 patients received NEOD001 at 0.5, 1, 2, 4, 8, 16, or 24 mg/kg in a 3+3 study design. An additional 42 patients with renal, cardiac, or nerve involvement were enrolled and treated (24 mg/kg) in the expansion phase. We assessed cardiac and renal responses based on consensus criteria and neuropathy responses using the Neuropathy Impairment Score-Lower Limb (NIS-LL). For this analysis, we focused on the relationship between organ response after treatment with NEOD001 to the time since last or best HR and the depth of best and last HR. Results: A total of 69 patients were enrolled, 27 in the dose-escalation and 42 in the expansion cohorts. The entire population included 36 cardiac-evaluable patients, 35 renal-evaluable patients, and 11 patients evaluated for peripheral neuropathy; 39% were women, and the median age was 60 years. Time since diagnosis was 2.8 (0.4-12.8; median, range) years, and 45% of patients had undergone ≥3 previous PCD regimens. Of the patients evaluable for organ response, best response rates indicating organ response were observed in 53% of cardiac-evaluable patients (n = 19/36) and 63% of renal-evaluable patients (n = 22/35). NIS-LL scores indicated that 82% (n = 9/11) of patients met criteria for a peripheral neuropathy response to NEOD001. Cardiac and renal response rates for NEOD001-treated patients could not be attributed to previous PCD treatment regimens. For example, 37% of the NEOD001 cardiac responders and 35% of nonresponders received cyclophosphamide-bortezomib-dexamethasone. Similarly, for NEOD001 renal responders vs nonresponders, 27% vs 25% were treated with autologous stem cell transplantation and 27% vs 31% were treated with bortezomib-dexamethasone. There was no relationship between NEOD001 cardiac, renal, or peripheral nerve organ response and time since last chemotherapy, time since last or best HR, or depth of last or best HR. Finally, an equivalent percentage of evaluable patients experienced renal or cardiac response regardless of whether they had received their most recent PCD treatment ≤6 months or >6 months before NEOD001 initiation. The median time since last PCD treatment to the start of NEOD001 intervention for all patients was 6.5 (range, 0.6-85.8) months and the median time to first cardiac response after NEOD001 treatment for all cardiac responders was 2 months. NEOD001 treatment was safe and well tolerated. Conclusions: Patients treated with monthly NEOD001 infusions had high organ response rates that were independent of time since previous chemotherapy, depth of hematologic response, or predominant type of PCD treatment. Ongoing studies of NEOD001 include VITAL (phase 3 in patients with newly diagnosed AL amyloidosis) and PRONTO (phase 2b in previously treated AL amyloidosis patients with persistent cardiac dysfunction). Disclosures Liedtke: Gilead: Research Funding; Prothena: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Research Funding. Comenzo:Takeda: Consultancy, Research Funding; Karyopharm: Research Funding; Janssen: Consultancy, Research Funding; Prothena: Consultancy, Research Funding. Landau:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx/Amgen: Research Funding; Spectrum Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy. Sanchorawala:Prothena: Research Funding; Takeda: Research Funding; Celgene: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; GlaxoSmithKline: Consultancy; Millennium: Consultancy, Other: Travel, accommodations; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Novartis: Consultancy. Zonder:Prothena: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Seattle Genetics: Consultancy; Array Biopharma: Consultancy. Walling:Corcept: Consultancy; Stealth: Consultancy; Codexis: Consultancy; Exelixis: Consultancy; Newgen: Consultancy; Mateon (was Oxigene): Consultancy; Apex: Consultancy; Aduro: Consultancy; Prothena: Consultancy; Upsher Smith: Consultancy, Patents & Royalties; KaloBios: Consultancy; NuMedii: Consultancy; Pharm-Olam: Consultancy; Crown Bioscience: Consultancy; BioMarin: Equity Ownership; Amgen: Equity Ownership, Patents & Royalties. Kinney:Prothena: Employment, Equity Ownership, Other: Leadership. Koller:Prothena: Employment, Equity Ownership, Other: Travel, accommodations. Schenk:Prothena: Employment, Equity Ownership, Other: Leadership. Guthrie:Prothena: Employment, Equity Ownership, Other: Leadership. Liu:Prothena: Employment, Equity Ownership; Weston Brain Institute: Honoraria. Gertz:Annexon Biosciences: Research Funding; Ionis: Research Funding; Prothena Therapeutics: Research Funding; Novartis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Research to Practice: Honoraria, Speakers Bureau; Med Learning Group: Honoraria, Speakers Bureau; Celgene: Honoraria; NCI Frederick: Honoraria; Sandoz Inc: Honoraria; GSK: Honoraria.