A Retrospective Database Analysis of Treatment Pathways in US Medicare Patients with Multiple Myeloma and Prior Exposure to Daratumumab, an Immunomodulatory Agent, and a Proteasome Inhibitor

Introduction: Recentreal-world data for multiple myeloma (MM) treatment patterns and outcomes are limited, particularly for patients with refractory or relapsed MM. As the MM treatment landscape evolves, it is important to understand how new treatments are integrated into patient treatment patterns. The aim of this study was to examine patient demographics, clinical characteristics, treatment patterns, and survival among Medicare patients with MM following exposure to daratumumab (DAR), an immunomodulatory agent, and a proteasome inhibitor (PI). Methods: This was a retrospective database analysis utilizing the Centers for Medicare and Medicaid Services claims data during the study period of January 1, 2016, through December 31, 2018. The start of the study period was chosen to align with DAR market entry in the United States (FDA approval November 2015). Medicare patients, diagnosed with MM, and with existing claims for DAR, an immunomodulatory agent, and a PI (tri-exposure) were eligible for inclusion. Index tri-exposure was achieved once a patient had been exposed to all 3 MM treatments, regardless of their sequence. The index date was the first observed claim for any MM regimen (index line of therapy [LOT]) following tri-exposure. Patients were required to have ≥6 months of continuous enrollment prior to the index date (baseline period). Therapies given after the index LOT were defined as post-index therapy. Patient data were assessed until health plan disenrollment, death, or end of study period, whichever occurred first. Results: There were 1336 Medicare patients with MM who met the inclusion criteria. Of these patients, the mean age (standard deviation [SD]) at the index date was 71 (8.5) years and 705 (52.8%) were male. The Southern United States showed the largest representation of patients in this population (n=471, 35.3%). The top baseline comorbidities included respiratory infections (98.3%), osteoarthritis (86.8%), anemia (86.9%), hypertension (78.1%), dyslipidemia (66.5%), chronic pain/fibromyalgia (51.9%), acute or chronic kidney disease (44.5%), cardiac arrhythmia (45.81%), and neutropenia (47.98%). The mean (SD) number of days from the index date until the end of index LOT was 48.7 days (12.0). Among 949 patients (71.0%) who had post-index therapy, the mean (SD) time from the last observed claim for index LOT to the beginning of the post-index therapy and duration of post-index therapy was 51.8 (44.2) days and 57.8 (16.0) days, respectively. The median (range) duration of follow-up time from the index date was 223 (3─886) days. During the study follow-up period, 571 patients (42.7%) died, and the median (range) number of days from the index date until death was 173 (3─873) days. While there was variation in treatment sequencing leading to tri-exposure, the most frequent tri-exposure sequence was an immunomodulatory agent < PI < DAR (33.2% [See Table for overview of treatment sequencing]). Among patients who received index LOT following tri-exposure, 49.4% had triplet therapy and 29.8% had doublet therapy. The most common index LOT regimens were triplet: DAR/pomalidomide/dexamethasone (DEX; 7.6%), elotuzumab/lenalidomide/DEX (5.2%), and DAR/bortezomib/DEX (4.9%). The most common post-index LOT regimens were triplet (39.9%): DAR/pomalidomide (6.1%), carfilzomib/cyclophosphamide/DEX (3.7%), DAR/bortezomib/DEX (3.5%), and DAR/lenalidomide/DEX (3.5%). During follow-up, 52.8% of patients were retreated with DAR, 79% with PI, and 77.3% with immunomodulatory drugs. Conclusions: This study suggests wide variation in treatment sequencing and regimens after tri-exposure to DAR, an immunomodulatory agent, and a PI. Triplet regimens were predominant treatment after the tri-exposure and following the index LOT. Retreatment with the same agents was common. Among those who died, survival was often less than 1 year following tri-exposure. These results highlight the need for new treatment options in triple-class refractory MM settings. Funding: GSK (Study 213462) Figure 1 Figure 1. Disclosures Boytsov: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Cyhaniuk: STATinMED Research: Current Employment. Leung: STATinMED Research: Current Employment. Wang: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Hogea: GlaxoSmithKline, paid employee: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Mudumby: STATinMED Research: Current Employment.

Role of insulin in oleic acid-induced acute lung injury in rat model

Objectives: Acute lung injury (ALI) is an inflammatory condition, therefore, this study was undertaken to determine the effect of insulin (an immunomodulatory agent) in oleic acid (OA)-induced ALI in rat model. Materials and Methods: The experiments were performed on adult male albino rats (total n = 18). The trachea, jugular vein and carotid artery of anaesthetised adult rats were cannulated to keep the respiratory tract patent, deliver saline/drugs and recording of blood pressure, respectively. Animals were divided into three groups. In Group I (control group), normal saline (75 μL) was injected and this group served as control group. In Group II (OA group), OA (75 μL) was administered to induce ALI in rats. In Group III (insulin + OA), OA (75 μL) was injected in insulin pre-treated rats. Respiratory frequency (RF), heart rate (HR) and mean arterial pressure (MAP) were recorded on computerised chart recorder; arterial blood sample was collected to determine PaO2/FiO2. Further, pulmonary water content was determined, and histological examination of the lung was done in all animals. Results: Injection of OA produced ALI indicated by significant increase in RF by 30 min followed by progressive decrease and ultimately death of animal. Significant increase in the pulmonary water content and decrease in PaO2/FiO2 were observed in these animals. Histological examination of lungs showed damage to the lung parenchyma. An immediate decrease in HR and MAP followed by some improvement and then progressive decrease was also observed. Conclusions: Insulin (an immunomodulatory agent) pre-treatment delayed initiation of OA-induced ALI as indicated by protection against OA-induced severe alteration in the RF in the initial stage and less lung injury in histological examination, although; it could not alter the overall course of the disease.

POS0135 REDUCING IMMUNOGENICITY OF PEGLOTICASE (RECIPE) WITH CONCOMITANT USE OF MYCOPHENOLATE MOFETIL IN PATIENTS WITH REFRACTORY GOUT: A PHASE II RANDOMIZED CONTROLLED TRIAL

Background:Pegloticase is a recombinant, pegylated uricase, used for treatment of gout patients who fail oral urate lowering therapy (ULT). Its use has been limited due to immunogenicity leading to infusion reactions.1Objectives:We evaluated if co-administration of an immunomodulatory agent could prolong the efficacy of pegloticase.Methods:Participants were recruited in a Phase II, double-blind, placebo-controlled trial over 18 months and randomized in a 3:1 ratio by site. Inclusion criteria were: a) Age ≥ 18 years who met 2015 ACR/EULAR gout classification criteria and b) chronic refractory gout defined as symptoms inadequately controlled with ULT or contraindications. After a 2-week run-in of mycophenolate mofetil (MMF) 1000 mg twice daily or matching placebo (PBO), they received a combination of pegloticase 8 mg biweekly with MMF or PBO for 12 weeks. Subsequent to this MMF or PBO were discontinued but pegloticase was continued for another 12 weeks. The primary endpoint was proportion of patients who sustained a serum urate (SU) level of ≤ 6 mg/dl at 12 weeks. Secondary endpoints included 24-week durability of SU ≤ 6 mg/dl and rate of adverse events (AEs). Fisher’s exact test and Wilcoxon two-sample test were used for analyses along with Kaplan-Meier estimates and log-rank tests to compare survival curves between groups. Hypothesis tests were two-tailed and p-value (p) < 0.05 indicated statistical significance.Results:Of 42 subjects screened, 35 were randomized, and 32 who received at least one dose of pegloticase were included in modified intention to treat analyses. Subjects were predominantly men (88%), mean age of 55.2 years (SD=9.7). Mean duration of gout was 13.4 years (SD=9.0), mean baseline sUA was 9.2 mg/dL (SD=1.6). Tophi were present in 88% and majority were on optimized ULT - 59% on allopurinol and 16% on febuxostat, with 63% reporting > 1 flare in the past year. At baseline both arms (MMF vs. PBO) had similar comorbidities – (82% vs 70%), diabetes mellitus/metabolic syndrome (14% vs 20%), coronary artery disease/peripheral vascular disease (41% vs.70%), BMI>30 (86% vs. 90%) and renal insufficiency (defined as eGFR < 90 mL/min; 73% vs. 70%). At 12 weeks, 19 of 22 (86%) in the MMF arm achieved SU ≤ 6 mg/dl compared to 4 of 10 (40%) in PBO arm (p-value = 0.01). At 24 weeks, the SU was ≤ 6 mg/dl in 68% of MMF arm vs. 30% in PBO (p-value = 0.06), and rates of AEs per month were similar between groups with the PBO arm having more infusion reactions (30% vs. 0%). The MMF arm had higher AEs compared to placebo: musculoskeletal (41% vs. 10%), gastrointestinal (18% vs. 10%), and infections (9% vs. 0%). Figure 1 shows that the percentage of subjects maintaining a sUA < 6 mg/dL at 12 weeks was significantly higher (p=0.02) in the MMF arm, and a significant difference (p=0.03) at 24 weeks indicates sustained benefit from MMF.Conclusion:To our knowledge this is the first randomized-controlled proof of concept trial to demonstrate the ability of an immunomodulatory agent in prolonging the efficacy of pegloticase. Short-term concomitant use of MMF therapy with pegloticase was well tolerated and showed a clinically meaningful improvement in the targeted SU ≤6 mg/dL at 12 and 24 weeks. This study suggests an innovative approach to utilize pegloticase therapy in patients with chronic gout.References:[1]Sundy et al. Efficacy and tolerability of pegloticase for the treatment of chronic gout in patients refractory to conventional treatment: two randomized controlled trials. JAMA. 2011;306(7):711-20.Figure 1.Proportion of subjects maintaining serum urate (SU) ≤ 6 mg/dL over 24 week study period in mycophenolate mofetil + pegloticase vs. placebo + pegloticaseDisclosure of Interests:Puja Khanna Consultant of: Horizon Pharmaceuticals, Swedish Orphan Biovitrum A, Grant/research support from: Selecta, 2)DYVE, Dinesh Khanna Consultant of: Horizon Pharmaceuticals, Gary Cutter: None declared, Jeff Foster: None declared, Josh Melnick: None declared, Sara Jaafar: None declared, Stephanie Biggers: None declared, Fazlur Rahman: None declared, Hui-Chen Kuo: None declared, Michelle Feese: None declared, Kenneth Saag Consultant of: AbbVie, Inc., Bayer, Daiichi Sankyo Company LTD, Gilead Services, Inc., Horizon Pharma plc, Mallinkrodt, Radius Health, Inc., Roche/Genentech, Shanton Pharma Co., LTD, Teijin, Dyve Bioscience, LG Chem, Regeneron Pharmaceuticals., Swedish Orphan Biovitrum AB, Takeda Pharmaceuticals America, Inc.,

P011 Sharing is caring: a regional service development project exploring secondary immunosuppression in children

Background/Aims The range of approved immunosuppressive and immunomodulatory (IM) agents has grown considerably with an increasing list of indications across paediatric specialties. At present, there is limited evidence supporting best practice for prescribing and monitoring of IM agents in children and young people (CYP). We present a staged service development project exploring cross-specialty prescribing and monitoring of IM agents at a tertiary children’s hospital (Great North Children’s Hospital, GNCH) and data sharing with local hospitals across northeast England. Methods In Phase 1, we searched pharmacy databases and surveyed specialty teams in GNCH to identify clinicians regularly prescribing IM agents to CYP over a twelve-month period. Phase 2 was a cross-specialty retrospective case-notes review of prescribing, monitoring and infection surveillance in a representative sample of CYP on IM agents. Phase 3 explored information sharing with six other hospitals in the region and acute presentations to these sites involving CYP on IM agents. Results Phase 1 identified 9 paediatric and 2 adult specialties prescribing IM agents to 416 CYP. 32 discrete IM therapies were prescribed with significant between-specialty overlap in drugs prescribed but a wide range of prescribing and monitoring practices. Phase 2 assessed 77 CYP on IM agents in detail - 57% were prescribed &gt;1 IM agent, 100% had FBC measured at least once (range once only to weekly), 18% developed lymphopenia at least once and 40% were prescribed prophylactic antibiotics. Previous varicella exposure had been assessed in 70%. Phase 3 data are summarised in Table 1. P011 Table 1:Information sharing and acute presentations to regional hospitals local to immunosuppressed patientsTotal number of patients141Mean age in years (range)11 (2 - 17)NDiagnosisJIA without uveitis108JIA with uveitis9Uveitis alone8Systemic JIA4Period fever4Behçet’s disease2Juvenile dermatomyositis2Scleroderma1Juvenile systemic lupus erythematosus1Mixed connective tissue disease1Granulomatosis with polyangiitis1Immunosuppressive or immunomodulatory agent usedAdalimumab65Methotrexate42Tocilizumab22Mycophenolate mofetil10Etanercept10Infliximab5Sulfasalazine5Prednisolone4Abatacept4Leflunomide4Canakinumab2Colchicine2Anakinra2Rituximab2Cyclophosphamide1Number of immunosuppressive or immunomodulatory agents per patient3 agents52 agents441 agent92Number of acute presentations by diagnosis or presenting complaint (n = 19)Fever4Chickenpox4Viral upper respiratory tract infection2Joint pain2Abdominal pain2Rash2Eye infection1Tonsilitis1Wheeze1Yes (%)No (%)Named local consultant (n = 129)3763Correct diagnosis recorded locally (n = 130)8020Correct immunosuppressive or immunomodulatory agent recorded locally (n = 130)5050Open access for febrile illness (n = 116)4159Reviewed in past 2 years for acute illness (n = 109)1783Note: presented numbers for immunosuppressive or immunomodulatory agents are not mutually exclusive. JIA, juvenile idiopathic arthritis Conclusion IM agents are central to modern paediatric clinical care across a wide range of diseases. This staged project identified significant variation in IM prescribing and monitoring practice between specialties at GNCH. Communication between specialty and local teams is inadequate. Particular areas of concern include limited diagnostic, blood monitoring and medication information sharing and limited local information governing management of intercurrent illness and vaccination. Although different disease processes can necessitate different advice and prescribing practices, sharing examples of good practice will minimise unnecessary variation. We propose the development of a regional immunosuppression working group to improve quality and safety across our region. Disclosure J.L. Bennett: None. C. Tsilifis: None. A. Flinn: None. T. Altmann: None. N. Jansen: None. H. Tumelty: None. K. Aitken: None. S. Bhopal: None. E. Harrison: None. S. Ravenscroft: None. E. Sen: None. E. Williams: None. T. Flood: None. S. Sampath: None. A. Battersby: None. F. McErlane: None.