Months Of Study Entry Research Articles

Long term outcomes in patients with recurrent/metastatic (R/M) salivary gland cancer (SGC) treated with immune checkpoint inhibitors (ICI).

e18063 Background: There is no standard of care systemic therapy in R/M SGC. Regimens containing ICIs are of interest, but overall response rates (ORRs) are low, and median duration of response (mDOR) and long term overall survival (OS) data are limited. We pooled mature data from two clinical trials evaluating the use of ICIs in SGC to evaluate long term outcomes. Methods: We combined the results of two phase I/II, open label, single arm trials utilizing ICIs in R/M SGC. NCT02538510 administered pembrolizumab 200 mg IV q3 weeks and vorinostat 400 mg PO 5 days on/2 days off. NCT03749460 administered nivolumab 3mg/kg IV q2 weeks x 12 doses, followed by 480 mg IV q4 weeks x 8 doses and ipilimumab 1 mg/kg IV q6 weeks x 4 doses with hypofractionated radiotherapy at 1-5 metastatic sites to a total dose of 24Gy/3 fractions over 1 week initiated 2 weeks after immunotherapy. All patients were ≥18 years with R/M disease, evidence of progression within 3 months of study entry, measurable disease per RECIST 1.1, EGOG PS 0-1, and adequate organ function at enrollment. PDL1 expression was not required for participation and prior ICI was not allowed. ORRs were evaluated by RECIST 1.1. OS and progression free survival (PFS) were estimated via the Kaplan-Meier method. Results: 45 patients were enrolled in the two studies from 11/2015-5/2022. The combined median age was 57 (IQR 46, 66). 26 (57.8%) were male; 33 (73.3%) were white and 10 (22.2%) were Asian. 27 (60.0%) had an ECOG PS of 0. Most common histology types were adenoid cystic carcinoma (21, 46.7%), acinic cell carcinoma (5, 11.1%), and salivary duct carcinoma (5, 11.1%). The ORR was 17.8% with all responders having a PR (n=8, histology types: 3 acinic cell, 2 adenoid cystic, 1 adenocarcinoma, 1 salivary duct, 1 lymphoepithelioma-like carcinoma). 20 (44.4%) had SD, with 16 (80.0%) of these responses lasting greater than 6 months. 16 (35.6%) had PD. One patient was not evaluable for RECIST due to rapid disease progression and death. At analysis, median follow up was 29.2 months (IQR 27.1-50.0) among survivors, mDOR was 26.7 months (range 7.1-69.5+), with three patients with ongoing response. Median OS and PFS were 25.4 (95% CI 14, 43.2) and 6.2 months (95% CI 3.9, 15.5) respectively. 23 (51.1%) patients received systemic therapy after trial ICI. Patients received: 4 additional ICI (3 PD-1 monotherapy, 1 ipi/nivo), 5 androgen deprivation therapy, 5 chemotherapy, 9 other treatments (dabrafenib/trametinib, everolimus, fam-trastuzumab deruxtecan, osimertinib, lenvatinib, investigational agents). Conclusions: Although SGC is heterogenous, responses to ICI were observed in multiple subtypes and were durable, similar to observations in other solid tumors. A significant proportion received subsequent lines of therapy post ICI, and exploration of ORR and PFS to next lines of therapy is of interest. Clinical trial information: NCT02538510 and NCT03749460 .

Phase II trial of pembrolizumab and epacadostat in recurrent clear cell carcinoma of the ovary: An NRG oncology study GY016

IntroductionEarly reports of PD-1 inhibition in ovarian clear cell carcinomas (OCCC) demonstrate promising response. We evaluated the combination of pembrolizumab and IDO-1 inhibitor epacadostat in patients with recurrent OCCC. MethodsThis single arm, two-stage, phase 2 trial included those with measurable disease and 1–3 prior regimens. Patients received intravenous pembrolizumab 200 mg every 3 weeks and oral epacadostat 100 mg twice a day. Primary endpoint was overall response rate (ORR), secondary endpoints were toxicity, progression-free survival (PFS) and overall survival (OS). The study was powered to detect an absolute 25% increase in response (15% to 40%). ResultsBetween September 28, 2018 and April 10, 2019, 14 patients enrolled at first stage. Rate of accrual was 2.3 patients per month. Median age was 65 years (44–89), 10 (71.4%) had ≥2 prior regimens. ORR was 21% (95% CI 5–51%) within 7 months of study entry with 3 partial responses, and 4 had stable disease (disease control rate 50%). Median PFS was 4.8 months (95% CI: 1.9–9.6), OS 18.9 months (95% CI: 1.9-NR). Most common grade ≥ 3 adverse events were electrolyte abnormalities and gastrointestinal pain, nausea, vomiting, bowel obstruction. In July 2019, the study reached the pre-specified criteria to re-open to second stage; however, the study closed prematurely in February 2021 due to insufficient drug supply. ConclusionsPembrolizumab and epacadostat demonstrated an ORR of 21% in this small cohort of recurrent OCCC. The rapid rate of accrual highlights the enthusiasm and need for therapeutic studies in patients with OCCC.

D-Mannose for Prevention of Recurrent Urinary Tract Infection Among Women

Recurrent urinary tract infection (UTI) is a common debilitating condition in women, with limited prophylactic options. d-Mannose has shown promise in trials based in secondary care, but effectiveness in placebo-controlled studies and community settings has not been established. To determine whether d-mannose taken for 6 months reduces the proportion of women with recurrent UTI experiencing a medically attended UTI. This 2-group, double-blind randomized placebo-controlled trial took place across 99 primary care centers in the UK. Participants were recruited between March 28, 2019, and January 31, 2020, with 6 months of follow-up. Participants were female, 18 years or older, living in the community, and had evidence in their primary care record of consultations for at least 2 UTIs in the preceding 6 months or 3 UTIs in 12 months. Invitation to participate was made by their primary care center. A total of 7591 participants were approached, 830 responded, and 232 were ineligible or did not proceed to randomization. Statistical analysis was reported in December 2022. Two grams daily of d-mannose powder or matched volume of placebo powder. The primary outcome measure was the proportion of women experiencing at least 1 further episode of clinically suspected UTI for which they contacted ambulatory care within 6 months of study entry. Secondary outcomes included symptom duration, antibiotic use, time to next medically attended UTI, number of suspected UTIs, and UTI-related hospital admissions. Of 598 women eligible (mean [range] age, 58 [18-93] years), 303 were randomized to d-mannose (50.7%) and 295 to placebo (49.3%). Primary outcome data were available for 583 participants (97.5%). The proportion contacting ambulatory care with a clinically suspected UTI was 150 of 294 (51.0%) in the d-mannose group and 161 of 289 (55.7%) in the placebo group (risk difference, -5%; 95% CI, -13% to 3%; P = .26). Estimates were similar in per protocol analyses, imputation analyses, and preplanned subgroups. There were no statistically significant differences in any secondary outcome measures. In this randomized clinical trial, daily d-mannose did not reduce the proportion of women with recurrent UTI in primary care who experienced a subsequent clinically suspected UTI. d-Mannose should not be recommended for prophylaxis in this patient group. isrctn.org Identifier: ISRCTN13283516.

Phase II study of pembrolizumab and lenvatinib in advanced well-differentiated neuroendocrine tumors

Immune checkpoint inhibitors (CPIs) have not been shown to be active in well-differentiated neuroendocrine tumors (NETs), with response rates <5%. Lenvatinib is a multitargeted tyrosine kinase inhibitor which binds to vascular endothelial growth factor and fibroblast growth factor receptors and has demonstrated efficacy in pancreatic and gastrointestinal NETs [44% and 16% objective radiographic response rate (ORR), respectively]. The combination of antiangiogenic and CPI therapies can be synergistic. We therefore evaluated the combination of lenvatinib and pembrolizumab in well-differentiated gastrointestinal (GI) and thoracic NETs. A prospective, phase II trial evaluated patients with advanced GI/thoracic NETs (pancreatic NETs were excluded due to high response rate of lenvatinib monotherapy in this patient population), with evidence of progression within 8 months of study entry and at least two prior lines of systemic therapy. Patients received lenvatinib 20 mg daily and pembrolizumab 200 mg intravenously every 3 weeks until unacceptable toxicity or progression of disease. Primary endpoint was objective response rate, and an interim analysis was planned once 20 patients were enrolled. Four ORRs were required to continue enrollment. Twenty patients were enrolled on protocol from April 2021 to January 2022 (nine small intestine, five lung, two thymic, two unknown primary, one cecal, one presacral primaries). Two patients (10%) achieved a partial response (atypical lung and small intestinal primaries). Median progression-free survival (PFS) was 8 months (95% confidence interval 5.8-10.2 months). Twelve (60%) patients experienced probably or definitely associated grade 3 adverse events (10 hypertension). Fourteen patients (70%) required dose reductions or discontinued one of the medications. Two patients discontinued treatment before radiographic assessment. The combination of pembrolizumab and lenvatinib did not show sufficient response in patients with NETs to warrant continued enrollment on trial.

Ravulizumab Provides Durable Control of Intravascular Hemolysis and Improves Survival in Patients with Paroxysmal Nocturnal Hemoglobinuria: Long-Term Follow-up of Study 301 and Comparisons with Patients of the International PNH Registry

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare chronic blood disorder characterized by uncontrolled terminal complement activation, leading to intravascular hemolysis (IVH), major adverse vascular events (MAVEs; including thrombotic events), organ damage and increased morbidity and mortality. Where available, ravulizumab is considered the standard of care for patients with PNH, providing immediate, complete and sustained inhibition of terminal complement activity. In study 301 (NCT02946463), complement component 5 (C5) inhibitor-naïve patients with PNH reported elevated levels of lactate dehydrogenase (LDH) and low hemoglobin (Hb) concentrations at baseline, alongside a history of MAVEs and need for transfusions. In such patients, ravulizumab provides durable control of IVH, reported for up to 2 years. Objectives: To report ravulizumab treatment outcomes for up to 6 years in C5 inhibitor-naïve patients with PNH from study 301 and compare survival with untreated patients of the International PNH Registry (NCT01374360). Methods: C5 inhibitor-naïve patients with PNH and high-disease activity (HDA; LDH level ≥ 1.5 × the upper limit of normal [ULN] and at least one sign or symptom of PNH) (N = 246) were randomized to receive ravulizumab or eculizumab. After the primary evaluation period (26 weeks), patients received ravulizumab for the 5-year open-label extension (OLE) period. LDH level change from baseline, the proportion of patients experiencing MAVEs, and transfusion avoidance were evaluated. Cox-proportional hazards regression analyses compared survival of patients treated with ravulizumab with untreated patients with HDA and clone size ≥ 5% at PNH Registry enrollment. Covariates comprised age at PNH diagnosis, gender, Hb concentration, estimated glomerular filtration rate, PNH clone size, transfusion history and medical history of MAVEs and bone marrow disease at baseline (i.e., date of ravulizumab treatment initiation [study 301] or PNH Registry enrollment). Transfusion history ( p = 0.05), age at PNH diagnosis and gender were included in the final adjusted model. Results: Ravulizumab treatment data were available for 244/246 patients (median [range] follow-up: 46.8 [0.4-69.3] months). At baseline, all 246 patients had LDH levels &amp;gt; 1.5 × ULN; at 26 weeks, 87.1% of patients achieved LDH levels ≤ 1.5 × ULN, which was maintained in 79.3% of patients at last follow-up (day 2045 [n/N = 42/53]; highest proportion reported at day 225 [n/N = 92/97; 94.9%]). At baseline, 17.1% of patients had a history of MAVEs (MAVE rate: 3.4 per 100 patient-years [PYs]). The proportion of ravulizumab-treated patients who experienced MAVEs was low throughout the study (n = 11 [4.5%], 13 events, MAVE rate: 1.4 per 100 PYs), with 9 patients (3.7%) reporting MAVEs during the OLE (11 events, MAVE rate: 1.3 per 100 PYs). Prior to randomization (≤ 6 months of study entry), 24.8% of patients did not need transfusions; at 26 weeks, this increased to 73.6% and was maintained in 53.9% of patients for the entire OLE with the highest proportion not requiring transfusions reported during the final 6 months of the OLE (75.7%). In addition, units transfused reduced from 1019 prior to randomization to 110 during the final 6 months of the OLE. Overall, 33 patients (13.4%) discontinued ravulizumab treatment during the entire study period (30 [12.2%] during the OLE). Reasons for discontinuation were death (n = 8), patient choice (n = 7), physician decision (n = 5), pregnancy (n = 4), adverse event (n = 3), lost to follow-up (n = 1) and other (n = 5). When compared with 413 untreated patients, ravulizumab was associated with an adjusted survival probability (95% confidence interval [CI]) of 84.1% (77.4, 91.3) at 4 years (hazard ratio [95%CI]: 0.14 (0.06, 0.32), p &amp;lt; 0.001; Figure 1) and mortality was 3.5-fold lower than that observed in untreated patients in the PNH Registry. Conclusions: This study reports the longest duration of ravulizumab treatment exposure in C5-inhibitor-naïve patients with PNH (925.7 PYs) to date. For up to 6 years, ravulizumab provided effective long-term control of IVH, evidenced by the maintenance of LDH ≤ 1.5 × ULN and low incidence of MAVEs and death. No new safety signals were identified and ravulizumab improved survival compared with untreated patients in the PNH Registry, further supporting the use of ravulizumab as the first-line treatment of choice for patients with PNH, where available.

The intestinal microbiome of children with initial and recurrent nephrolithiasis: A pilot study and exploratory analysis

Kidney stone disease in children is rising disproportionate to the general population, representing a disease population with a distinct biological mechanism as compared to adults. Factors influencing recurrent kidney stone disease in children are poorly characterized and the associations of the intestinal microbiome within sub-populations of kidney stone formers, however, are not well described. We evaluated a pilot cohort of children with nephrolithiasis comparing patients based on recurrent kidney stone episodes and abnormal 24-h urinary parameters, with dual aims to compare the microbiome signal in children with initial and recurrent nephrolithiasis and to explore additional associations in microbiome composition and diversity within this population. Children aged 6-18 with a history of nephrolithiasis, without an active ureteral calculus or antibiotic exposure within 30 days of study entry were eligible to participate. All participants had a 24-h urine study within 6 months of study entry and provided a fecal sample. Microbiome samples were analyzed using 16S ribosomal DNA sequencing techniques for alpha and beta diversity comparing initial and recurrent stone formers as well as microbiome multivariate association (MaAsLin2) to determine differentially abundant taxa. Shotgun sequencing reads were aligned to custom oxidase degradation and butyrate production gene databases (5 databases total). Comparisons for MaAsLin2 and shotgun metagenomics, normalized to sequencing depth, were based on stone recurrence, sex, hypercalcuria (≤4mg/kg/day), hyperoxaluria (≥45 mg/1.73m2), and hypocitraturia (<310 mg/1.73 m2 [females] or<365 mg/1.73 m2 [males]). A total of 16 enrolled children provided samples sufficient for analyses, including 9 girls and 7 boys, of whom 5 had experienced recurrent kidney stone events. Three participants had hypercalcuria, 2 had hyperoxaluria, and 4 had hypocitraturia. Comparisons of Formyl-CoA transferase between index and recurrent urinary stone disease revealed a trend towards higher mean abundance of the gene in initial stone formers (0.166% vs 0.0343%, p=0.2847) (Summary Figure), while trends toward lower biodiversity were also noted in the recurrent stone cohort on both Faith (p=0.06) and Shannon (p=0.05) indices. Exploratory analyses found Eubacterium siraeum to be significantly greater in relative abundance in children with documented hypercalciuria (p=0.001). Our pilot study demonstrates possible signals in both microbial diversity and oxalate gene expression, both of which are lower in recurrent pediatric kidney stone patients. These findings warrant further investigation as a potential diagnostic marker for future kidney stone events.

PD06-02 THE INTESTINAL MICROBIOME VARIES ACROSS PHENOTYPES OF PEDIATRIC NEPHROLITHIASIS

You have accessJournal of UrologyCME1 Apr 2023PD06-02 THE INTESTINAL MICROBIOME VARIES ACROSS PHENOTYPES OF PEDIATRIC NEPHROLITHIASIS Jonathan Ellison, Samantha Atkinson, Michael Hayward, Elise Hokanson, Katherine Sheridan, and Nita Salzman Jonathan EllisonJonathan Ellison More articles by this author , Samantha AtkinsonSamantha Atkinson More articles by this author , Michael HaywardMichael Hayward More articles by this author , Elise HokansonElise Hokanson More articles by this author , Katherine SheridanKatherine Sheridan More articles by this author , and Nita SalzmanNita Salzman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003230.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The intestinal microbiome has been implicated in calcium oxalate kidney stone formation, thought to be driven predominantly through altered breakdown of dietary oxalate. The associations of the intestinal microbiome within sub-populations of kidney stone formers, however, is not well described. We evaluated a pilot cohort of children with nephrolithiasis comparing patients based on recurrent kidney stone episodes and abnormal 24-hour urinary parameters. METHODS: Children aged 6-18 with a history of nephrolithiasis, without an active ureteral calculus or antibiotic exposure within 30 days of study entry were eligible to participate. All participants had a 24-hour urine study within 6 months of study entry and provided a fecal sample. Microbiome samples were analyzed using 16S ribosomal DNA sequencing techniques for alpha and beta diversity comparing initial and recurrent stone formers as well as microbiome multivariate association (MaAsLin2), using a general linear model with fixed effects. Shotgun sequencing reads were aligned to custom oxidase degradation and butyrate production gene databases (5 databases total). Comparisons for MaAsLin2 and shotgun metagenomics, normalized to sequencing depth, were based on stone recurrence, sex, hypercalcuria ( < 4 mg/kg/day), hyperoxaluria ( > 45 mg/1.73 m2), and hypocitraturia (< 310 mg/1.73 m2 [females] or < 365 mg/1.73 m2 [males]). RESULTS: A total of 16 enrolled children provided samples sufficient for analyses, including 9 girls and 7 boys, of whom 5 had experienced recurrent kidney stone events. Three participants had hypercalcuria, 2 had hyperoxaluria, and 4 had hypocitraturia. Alpha and beta-diversity did not differ across initial vs recurrent kidney stones. Exploratory analyses found Eubacteriumsiraeum to be significantly greater in relative abundance in children with documented hypercalciuria (Figure 1). There was no statistical difference in relative gene abundance between groups. CONCLUSIONS: Comparisons across phenotypes of kidney stone disease in children revealed taxonomic differences associated with hypercalcuria. While the mechanisms of these differences are not well defined, these findings support further exploration into non-oxalate related mechanisms of lithogenesis related to the renal-gut axis. Source of Funding: Research Affairs Committee Pilot Grant © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e155 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jonathan Ellison More articles by this author Samantha Atkinson More articles by this author Michael Hayward More articles by this author Elise Hokanson More articles by this author Katherine Sheridan More articles by this author Nita Salzman More articles by this author Expand All Advertisement PDF downloadLoading ...

ASC4START: A Phase IIIb, Open-Label, Randomized Study of Tolerability and Efficacy of Asciminib Versus Nilotinib in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia in Chronic Phase

Objectives: Tyrosine kinase inhibitors (TKIs) have greatly improved treatment outcomes for patients with newly diagnosed chronic myelogenous leukemia in chronic phase (CML-CP), transforming it into a chronic disease requiring long-term treatment. This emphasizes the need for treatments that combine high efficacy with a favorable safety profile, improving over currently available options. Asciminib is a first-in-class BCR::ABL1 inhibitor specifically targeting the ABL myristoyl pocket (STAMP) which has been approved by the FDA with subsequent approvals worldwide for patients with Philadelphia chromosome-positive (Ph+) CML-CP, previously treated with ≥2 prior TKIs based on the results of the ASCEMBL (NCT03106779) trial. The ABL specificity of asciminib compared with the selectivity of second-generation (2G) TKIs can reduce off-target effects and improve tolerability while maintaining efficacy and reducing the probability of developing resistance. The ongoing ASC4FIRST (NCT04971226) study will evaluate the efficacy and safety of asciminib vs investigator-selected TKI in patients with newly diagnosed Ph+ CML-CP. Additional data on asciminib in newly diagnosed Ph+ CML-CP may help to address patient-centric objectives, in particular the ability of patients to remain on treatment without having to permanently discontinue due to adverse events (AEs). The ASC4START study (NCT05456191) will primarily evaluate the tolerability of asciminib vs the 2G TKI nilotinib in adult patients with newly diagnosed Ph+ CML-CP, as measured by the time to study treatment discontinuation due to adverse event (TTDAE). The study will also report on further safety, efficacy and quality of life (QoL) outcomes. Methods: This is a phase IIIb, multi-center, open-label, randomized study in patients ≥18 years of age with newly diagnosed Ph+ CML-CP. The trial will enroll approximately 541 patients with CML-CP diagnosed within 3 months of study entry and an Eastern Cooperative Oncology Group (ECOG) performance status ≤1. Patients cannot be included if they have received previous treatment for CML with any other anticancer agents (except hydroxyurea and/or anagrelide), have confirmed central nervous system infiltration, or present impaired cardiac function or abnormalities in cardiac repolarization. Patients will be randomized 1:1 to receive asciminib 80 mg once daily or nilotinib 300 mg twice daily, both administered orally under fasting conditions; randomization will be stratified based on European Treatment Outcome Study long-term survival (ELTS) score at diagnosis (high vs intermediate vs low) to help achieve balance between the treatment arms (Figure). The primary endpoint is TTDAE, defined as the time from the date of the first dose of study treatment to the date of discontinuation of study treatment due to an AE. Secondary endpoints include type, frequency and severity of AEs; dose modifications due to AE; changes in laboratory values that fall outside pre-determined ranges; clinically notable ECG changes; time to discontinuation due to selected reasons (lack of efficacy/treatment failure/disease progression/suboptimal response/death); major molecular response (MMR), MR4, MR4.5, complete hematological response (CHR), and BCR::ABL1 ≤1% at and by all scheduled data collection time points; duration of and time to first MMR, MR4 and MR4.5; time to treatment failure; event-free survival, progression-free survival and overall survival. Secondary endpoints related to QoL include change from baseline in overall scores and individual scales of the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires QLQ-C30 and QLQ-CML24. Participants will be treated in the study until approximately 64 discontinuations due to AEs are met; treatment duration for an individual patient is expected to be 2‒4.5 years. Current status: The study is recruiting as of October 2022. This study was sponsored by Novartis Pharmaceuticals. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Salivary Gene Expression of RANK, RANKL, and OPG in Type 1 Diabetes Mellitus and Periodontal Disease Patients.

The relationship between type 1 diabetes mellitus (T1DM) and periodontal disease may exhibit by the alteration of bone metabolism. However, evidence for this relationship is scarce and inconclusive. Thus, the aims of the present study were to investigate salivary receptor activator of nuclear factor kappa-β (RANK), receptor activator of nuclear factor kappa-β ligand (RANKL), osteoprotegerin (OPG) gene expression and the RANKL:OPG ratio in T1DM and non-T1DM. Secondary objective was to determine the relationships of RANK, RANKL and OPG gene expression to clinical parameters of T1DM and periodontal disease. Twenty patients with T1DM and twenty age-matched non-T1DM were recruited. Clinical periodontal parameters were measured. Total RNA was isolated from non-stimulated saliva, and the relative gene expressions of RANK, RANKL, OPG and RANKL:OPG ratio were determined by quantitative real-time polymerase chain reaction. The T1DM group had significantly higher mean periodontal parameters than the non-T1DM group, while the mean plaque scores of both groups were not significantly different. There was a trend of higher relative gene expression of RANK, RANKL, and the RANKL:OPG ratio and lower expression of OPG in T1DM group but no statistic significant different when compared to non-T1DM. In the T1DM group, RANKL:OPG correlated with the percentage of bleeding sites, whereas RANK, RANKL, and HbA1c levels correlated with pocket depth. Bone metabolisms demonstrating by decreased OPG gene expression and upregulated of RANK, RANKL, RANKL:OPG with higher pocket depth and bleeding in T1DM may play an important role in periodontal destruction in T1DM.

Residential exposure to greenspace and life satisfaction in times of COVID-19: a cross-sectional analysis of 9444 participants from a population-based study in Basel-Stadt and Basel-Landschaft.

Subjective well-being is an important target in the COVID-19 pandemic. Residential greenness may help cope with stress and hence influence subjective well-being during this mentally and physically challenging time. We analysed the association between residential greenness and life satisfaction in 9,444 adults in the COVCO-Basel cohort. We assessed if the association is modified by age, sex, household income, financial worries, canton of residence, or month of study entry. In addition, we assessed if the association is attributed to specific types of greenspace or accessibility to greenspace. The association between residential greenness and life satisfaction varied by age groups, household income, and financial worries. Residential greenness was positively associated with life satisfaction in those with high household income and the least financially worried, and negatively associated with life satisfaction in the youngest age group (18-29 years) and the most financially worried. Living closer to a forest, but not to a park or an agricultural area, was associated with lower life satisfaction in the youngest age group. Residential greenness effects on life satisfaction vary according to sociodemographic characteristics. Living in a greener area does not benefit all dwellers in Basel and its region equally, with the most apparent benefit for those with high household income and without financial concerns.

INNV-08. LOW AND INTERMEDIATE GRADE GLIOMA UMBRELLA STUDY OF MOLECULAR GUIDED THERAPIES (LUMOS) STUDY

Abstract BACKGROUND Grade 2 and 3 (G2/3) gliomas are the second largest group of brain tumors in adults. Although the prognosis for G2/3 gliomas at the time of relapse mirror those of glioblastoma, there are few trials in this space. METHODS LUMOS was a national multi-center pilot study for patients with relapsed G2/3 gliomas designed to match contemporaneous tissue obtained at the time of disease progression with subsequent targeted therapies. The objective was to establish the feasibility of a precision oncology, umbrella approach to obtain and type tissue within a useful timeframe. As a key feature of LUMOS, a multidisciplinary Molecular Tumor Advisory Panel (MTAP) with subspecialty neuro-oncology expertise was formed to interpret the complex genomic information and provide a simplified recommendation to the treating physician. RESULTS Ten patients (median age 42: range 32-62; four G2 astrocytoma, one G3 astrocytoma, three G2 oligoendroglioma, one G3 oligodendroglioma, one mixed tumor) were enrolled in the study. Eight patients had biopsies within 6 months of study entry whilst two underwent a biopsy during the study. All patients had potentially targetable alterations (10 IDH, 3 FGFR, 2 PIK3K, CCND3, NRAS, CDK4, PRPRZ1-MET fusion and MET amplification). Matched therapies were delivered for two patients via compassionate access outside the study. The median turnaround time (TAT) of MTAP reports was 6.2 weeks (range 4.2-9.7 weeks) but 4.6 weeks when lag time for shipping was removed. CONCLUSION LUMOS confirmed that this design was feasible with good turnaround times. The MTAP facilitated education and support for treating physicians. Thes findings support moving to a larger study using contemporaneous and longitudinal tissue samples matched with targeted therapies as part of a comprehensive umbrella study design. Delivery and interpretation of molecular data is a challenge shared across oncology which may be mitigated with a neuro-oncology specific molecular tumor board.

Outcomes of Triple-Class (proteasome inhibitor, immunomodulator, CD38 monoclonal antibody) Exposed Relapsed or Refractory Multiple Myeloma (RRMM) in United States (US) Real-World Practice

Background: As new therapeutics for multiple myeloma (MM) are approved in earlier lines of therapy, drug classes with demonstrated benefit may be exhausted after initial therapy, including proteasome inhibitors (PI), immunomodulatory imides (IMiD), and CD38 targeting monoclonal antibodies (MoAB). Clinical recommendations are to utilize unique drug classes at relapse. This study aims to describe relapsed or refractory multiple myeloma treatments and outcomes in clinical trial eligible patients with prior treatment of at least 1 PI, IMiD, and CD38 MoAB and their outcomes (real world overall response rate (rwORR), progression free survival (rwPFS), overall survival (rwOS)) in US community practice.Methods: This study used Flatiron Health electronic health record (EHR)-derived de-identified database (New York, NY). These data represent ~280 cancer clinics (mostly community-based practices). Inclusion criteria included ≥18 years old, 2+ clinic visits after 2015, measurable disease, prior PI/IMiD/CD38 MoAB exposure, ECOG ≤2, adequate hematologic/renal/hepatic function, and no stem cell transplant within six months of study entry. Study period was treatment initiation at ≥ second line from November 2015 through December 2019, follow-up through December 2020. Patients with multiple eligible lines of therapy, the last eligible line was evaluated. Real world overall response rate was adapted from Foster et al 2019, rwPFS was measured from treatment until death, progression, or start of new line of therapy, and rwOS was measured from treatment until death.Results: 120 patients were eligible for this study. Median time from diagnosis to study entry was 3.8 years. Half were 70 years or older (n=62, 52%), with 20% (n=24) ISS III, 35% (n=42) high-risk cytogenetics, and 64% (n=77) at ≥5L treatment. At study start, 38% (n=46) had a prior transplant, 73% (n=88) were triple-class refractory, and 21% (n=25) penta-refractory. The most common regimens were either daratumumab-based (n=35), carfilzomib-based (n=25), or elotuzumab-based (n=15). The most frequent regimens were daratumumab/pomalidomide/dexamethasone (n=8), carfilzomib/cyclophosphamide/dexamethasone (n=7), carfilzomib/pomalidomide/dexamethasone (n=7), carfilzomib/dexamethasone (n=5), elotuzumab/lenalidomide/dexamethasone (n=5), and elotuzumab/pomalidomide/dexamethasone (n=5).The rwORR in this population was 18.33% (95% CI: 11.41-25.26, n=22). The rwORR was lower in key subgroups: younger age (<65 years old: 13.79% [95% CI: 1.24-26.34], n=4/29), high risk cytogenetics (0%, n=0/10), ISS III (12.12% [95% CI: 0.99-23.26], n=4/33), triple-class refractory (15.91% [95% CI: 8.27-23.55], n=14/88), and penta-refractory (4.00% [95% CI: 0-11.68], n=1/25).The median rwPFS in this population was 3.5 months (95% CI: 2.3-4.8). The rwPFS were shorter in key subgroups: younger age (<65 years old: 2.1 months [95% CI: 1.8-3.5]), high risk cytogenetics (2.0 months, [95% CI: 0.7-5.0), ISS III (2.2 months [95% CI: 1.6-6.5]), triple-class refractory (3.2 months [95% CI: 2.1-4.8]), and penta-refractory (2.1 [95% CI: 0.9-3.6]).The median rwOS in this population was 15.8 months (95% CI: 9.9-26.0). The OS was shorter in key subgroups: younger age (10.8 months [95% CI: 4.9-.]), high risk cytogenetics (9.4 months [95% CI: 2.2-27.9]), ISS III (14.6 months [95% CI: 6.1-27.9]), triple class refractory (15.1 months [95% CI: 7.5-25.5]), and penta refractory (7.1 months [95% CI: 3.6-26.0]).Discussion: In this study of patients that were majority triple-class refractory (PI, IMiD, CD38 MoAbB), low rwORR and short rwPFS were observed. Most patients received re-treatment with at least one drug they had previously failed or were refractory to. Additionally, many patients had additional therapies including novel agents and combinations that could be effective at prolonging OS despite short rwPFS. Compared to academic center patients (Gandhi et al 2019), survival was longer (mOS 15.8 months versus 9.3 months), but in Gandhi 2019, the median time to study entry was 4.5 versus 3.8 years, patients were more penta-refractory (26%) and had prior transplant (72%). Patients who were penta-refractory (bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab) had particularly dismal outcome. Overall, these data suggest need for continued development of effective novel classes of therapies for late line myeloma patients. [Display omitted] DisclosuresKim: Amgen: Current Employment, Current equity holder in publicly-traded company. Braunlin: Amgen: Current Employment, Current equity holder in publicly-traded company. Mehta: Amgen: Current Employment. Payne: Amgen: Consultancy.

A Bridge Too Far? Real-World Practice Patterns of Early Glucocorticoid Use in the Canadian Early Arthritis Cohort.

ObjectiveTo describe patterns of glucocorticoid use in a large real‐world cohort with early rheumatoid arthritis (RA) and assess the impact on disease activity and treatment.MethodsData are from adults with new RA (≤1 year) recruited to the Canadian Early Arthritis Cohort (CATCH) and are stratified on the basis of whether a person was prescribed oral glucocorticoids within 3 months of study entry. Disease activity was compared over 24 months. Mixed‐effects logistic regression was used for adjusted odds ratios (aORs) of escalation to biologics separately for 12 and 24 months, with random effects terms to account for prescribing patterns clustering by study site.ResultsAmong 1891 persons, 30% received oral steroids. Users were older, were less often employed, and had shorter disease duration and higher disease activity. Disease activity improved over time, with early glucocorticoid users starting at higher levels of disease activity. Participants with early oral glucocorticoids were more likely to be on a biologic at 12 months (aOR = 2.4; 95% confidence interval [CI], 1.5‐3.7) and 24 months (aOR = 1.9; 95% CI, 1.3‐3.0). Despite Canadian clinical practice guidelines to limit corticosteroid use to short‐term or ‘bridge’ therapy, 30% of patients who used oral glucocorticoids still used them 2 years later.ConclusionEarly steroids were prescribed sparingly in CATCH and were often indicative of more active baseline disease as well as the need for progression to biologics.

MM-171: Melflufen Plus Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Exposed or Refractory to Prior Alkylators: A Pooled Analysis of the O-12-M1 and HORIZON Studies

Context Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and rapidly releases alkylating agents inside tumor cells. Melflufen has a mechanism of action distinct from other alkylating agents (Slipicevic et al. AACR 2020. Abs. 1843). In the O-12-M1 (NCT01897714) and HORIZON (OP-106; NCT02963493) studies, melflufen plus dexamethasone showed meaningful efficacy and a clinically manageable safety profile in patients with RRMM (Richardson et al. Lancet Haematol. 2020;7:e395-e407; Richardson et al. J Clin Oncol. 2021;39:757-767). Objectives To conduct a pooled analysis of outcomes in patients exposed to prior alkylators in these studies. Methods The O-12-M1 and HORIZON studies included patients with RRMM who received ≥2 prior lines of therapy (LoTs) and had a primary endpoint of overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and safety. Data from the two studies were pooled and analyzed according to exposure and refractoriness to alkylators before study entry. Results Of 202 patients (HORIZON: n=157, cutoff January 14, 2020; O-12-M1: n=45, cutoff October 29, 2019), 178 (88%) had been exposed to alkylators. Patients exposed and refractory to alkylators in ≥2 LoTs had the highest number of patients refractory to an alkylator in the last LoT (61%), and 82% were refractory to an alkylator within 12 months of study entry. ORR was 33.9% in all patients exposed to alkylators in ≥1 prior LoT, not refractory (n=62); 23.3% in patients exposed and refractory to an alkylator in 1 prior LoT (n=43); 35.0% in patients exposed to alkylators in ≥2 prior LoTs and refractory in 1 LoT (n=40); and 9.1% in patients refractory to alkylators in ≥2 prior LoTs (n=33). PFS trended toward being shorter with higher exposure and refractoriness to prior alkylators. Results should be interpreted with caution due to limited patient numbers. Safety was not adversely impacted by prior exposure to alkylators; grade 3/4 adverse events were similar between patients exposed to prior alkylators (O-12-M1: 85%; HORIZON: 89%) and the overall population (O-12-M1: 84%; HORIZON: 89%). Conclusions Melflufen in combination with dexamethasone showed meaningful efficacy and a clinically manageable safety profile in patients with RRMM exposed/refractory to prior alkylators.

Results from Ongoing Phase 1/2 Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with Minimal Residual Disease (MRD)

Results from Ongoing Phase 1/2 Trial of SL-401 As Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with Minimal Residual Disease (MRD)

Thrombin Generation As a Predictive Biomarker for Venous Thromboembolism in Patients with Pancreatic and Lung Cancer Undergoing Systemic Therapy

Introduction: Venous thromboembolism (VTE) is a leading cause of death in cancer patients, but routine thromboprophylaxis is untenable due to an unacceptably high rate of bleeding complications and judicious patient selection is critical. The Khorana score (KS) predicts the risk for chemotherapy-associated VTE, but the score has limitations because it is assessed only at one time point prior to initiation of treatment. Thrombin generation (TG) is a novel biomarker that assesses global coagulation activation and predicted increased VTE risk in cancer patients in the Vienna Cancer and Thrombosis Study (CATS). In CATS, patients with high peak TG had a 3- fold increased risk for VTE compared to those with low peak TG. A limitation of the study was that it enrolled a heterozygous cancer patient population, and peak TG was not reported by tumor type. Additionally, TG was only measured at enrollment into the study, not over time. The primary aim of our study was to determine if assessment of TG (both peak TG and endogenous thrombin potential (ETP)) improves VTE risk prediction compared to the KS alone during systemic therapy for lung and pancreas cancer. A secondary objective was to evaluate the impact of systemic therapy on peak TG and ETP over time.Methods: This is an ongoing prospective study enrolling adults with newly diagnosed locally advanced or metastatic adenocarcinoma of the lung or pancreas who will receive their cancer therapy at Dartmouth Hitchcock Medical Center. Those with a history of active VTE or use of full dose anticoagulant medication within 30 days prior to enrollment are excluded. After informed consent, KS is calculated and blood is collected in sodium citrate tubes at 3 different time points (at initiation of therapy, and at the beginning of the 2nd and 3rd cycles of systemic therapy). Platelet-poor plasma is prepared by centrifugation and stored at -80°C until analysis by calibrated automated thrombogram (CAT; Thrombinoscope BV, Maastricht, Netherlands) using 1 pM tissue factor and 4 uM phospholipids to trigger coagulation reactions. Measurements are performed in triplicate for each specimen, and raw data are converted to peak TG and ETP. Information about symptomatic VTE events within 6 months of study entry is collected from the medical record.Results: We present the results for 15 patients who have completed study-related procedures to date, including 6 lung and 9 pancreatic cancer patients with a median age 61 and 69 years, respectively. The majority of patients had metastatic disease and all patients received systemic therapy. The KS breakdown for the cohort is: KS1, 7%; KS2, 60%; KS3 27%; KS4 7%. Mean peak TG were 341, 324, 641 and 890 nmole, and mean ETP were 1459, 1685, 2155, 2051 nmole/min for KS 1,2,3 and 4, respectively, and both peak TG and ETP decreased over time after cancer therapy. VTE occurred in 4 patients (27%), and the median KS was 2 for patients with and without VTE. Mean peak TG prior to initiation of chemotherapy was similar in patients with and without VTE (359 and 389 nmole, respectively) but mean ETP was higher in patients with VTE (1959 vs 1760 nmole/min, respectively).Conclusions: Though our sample size to date is small, preliminary results suggest that there is a direct correlation between KS and peak TG and ETP, and that ETP at diagnosis may be a more reliable predictor VTE than KS in lung and pancreatic cancer patients. Peak TG and ETP decreased progressively after initiation of systemic therapy, suggesting that the degree of coagulation activation is proportional to tumor burden. Though preliminary, these data suggest that TG is a promising biomarker of VTE risk. Enrollment to the study is continuing.Funding: This study was funded by Northern New England Clinical Oncology Society. DisclosuresNo relevant conflicts of interest to declare.

Preconception Dietary Folate Intake and Risk of Spontaneous Abortion

ObjectivesPrevious studies suggest a beneficial effect of supplemental folic acid use and dietary folate intake on fertility, while results for fetal loss are conflicting. Most previous research on fetal loss focused on folic acid supplement use. We therefore, investigated the association between dietary folate intake and spontaneous abortion (SAB) in a Danish preconception cohort of couples trying to conceive. MethodsWe recruited couples who were trying to conceive and did not receive fertility treatment. Pregnancies were ascertained through bimonthly follow-up questionnaires completed up to 12 months after study entry. SABs were identified by self-report on the follow-up questionnaires and through the Danish National Patient Registry. Dietary folate intake at study entry was estimated using a validated food frequency questionnaire (FFQ). Folate intake was adjusted for total energy intake using the residual method and categorized as < 250,250–399 and > = 400μg/day. We used Cox proportional hazards regression models with gestational weeks as time scale to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for SAB, adjusting for age, partner’s age, educational attainment, smoking status, anthropometry, physical activity, alcohol intake, folic acid supplement use, time-to-pregnancy, gravidity and parity. In sensitivity analyses, we stratified by folic acid supplement use, body mass index (BMI) and alcohol intake. ResultsOf the 2,957 women who became pregnant within 12 months of study entry and completed the FFQ, we identified 432 SABs. HRs for an SAB among women who consumed 250–399 and >= 400 μg/day of dietary folate compared with <250 μg/day were 0.83 (95% CI: 0.53; 1.29) and 0.87 (95% CI: 0.54; 1.39), respectively. Comparing intake > = 400 with <250 μg/day, the association was stronger when the analysis was restricted to folic acid supplement users, 0.74 (95% CI: 0.39; 1.40), to women with a BMI >= 25, 0.67 (95% CI: 0.31; 1.43), and to a reported alcohol intake >4 drinks/week, 0.66 (95% CI: 0.16; 2.66). ConclusionsOur study may suggest that high dietary folate intake among folic acid supplement users is associated with a lower risk of SAB, although our estimates are imprecise. Funding SourcesNational Institute of Child Health and Human Development.

Single-arm phase II study of low-dose paclitaxel and pembrolizumab in platinum-refractory metastatic urothelial carcinoma (UC).

433 Background: Single agent checkpoint inhibition is effective in a small proportion of platinum-refractory UC patients but improvements are needed. UC is highly inflammatory, and low-dose chemotherapy may enhance the response to immunotherapy. We evaluated whether combination therapy with low-dose paclitaxel and pembrolizumab is more efficacious than single-agent pembrolizumab which had an objective response rate (ORR) of 21% in a similar patient population in the KEYNOTE-045 study. We also incorporated multiple novel biomarker studies to explore immune regulatory mechanisms in UC. Methods: This is a prospective, single-arm phase II trial (NCT02581982) of pembrolizumab combined with low-dose paclitaxel in patients with platinum-refractory metastatic UC. Key inclusion criteria included measurable progression of disease within 12 months of platinum therapy and ECOG ≤1. Patients received pembrolizumab 200mg day 1 and paclitaxel 80 mg/m2 days 1 and 8 of a 21 day cycle for up to 8 cycles unless clinical or radiographic disease progression or unacceptable adverse events (AEs) were observed. Responding patients could remain on pembrolizumab maintenance for up to 2 years. The primary endpoint was ORR; key secondary endpoints included overall survival (OS), 6-month progression free survival (PFS), and safety. Results: Twenty-seven patients were treated between 4/2016 - 6/2020, with a median follow up of 9.9 months. At baseline, the median age was 68 years (range 49-80), with 81% men and 78% non-Hispanic white. The majority (59%) were ECOG 1. Twenty-one of 27 (78%) received prior definitive therapy: chemoradiation in 24% and surgery in 76%. The majority (78%) of patients received prior cisplatin. 70% progressed on a cisplatin-based regimen while 30% progressed on carboplatin-based regimen within 12 months of study entry. The ORR by intention to treat was 9 of 27 patients (33%) and in patients evaluable for response by imaging was 9 of 25 (36%), including 3 with complete response. Disease control rate in evaluable patients was 72%. Six-month PFS was 46.8% (95% CI: 27.2%, 64.2%) and median OS was 11.7 months (95% CI: 8.7 mo, NR). Common ≥ grade 2 AEs were anemia (44%), lymphopenia (37%), hyperglycemia (33%), and fatigue (33%). Possible treatment-related at least grade 3 or 4 AEs occurred in 56% of subjects, including 2 immune-mediated AEs (pneumonitis and nephritis) resulting in therapy cessation but a durable partial response. There were no grade 5 events. Conclusions: This study illustrates that the addition of low-dose paclitaxel to pembrolizumab improves outcomes in patients with platinum-refractory UC, relative to single-agent pembrolizumab. No unanticipated safety signals emerged. Exploratory analyses including PDL1 status, tumor mutational burden, and change in circulating microRNAs and in immune cell populations are ongoing. Clinical trial information: NCT02581982.

Effects of α-Cyclodextrin on Cholesterol Control and Hydrolyzed Ginseng Extract on Glycemic Control in People With Prediabetes

Effective strategies for preventing type 2 diabetes are needed. Many people turn to complementary medicines, but there is little well-conducted scientific evidence to support their use. To assess the efficacy of α-cyclodextrin for cholesterol control and that of hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. This 6-month double-blind, placebo-controlled, randomized clinical trial, with a 2 × 2 factorial design, was conducted between July 2015 and October 2018 at 2 locations in Sydney, Australia. Eligible participants were aged 18 years or older, had a body mass index (weight in kilograms divided by height in meters squared) of 25 or higher, and had prediabetes within 6 months of study entry according to the American Diabetes Association guidelines. Data analysis was performed from May to August 2019. Participants were randomized to 1 of 4 groups to take active or placebo versions of each supplement (α-cyclodextrin plus hydrolyzed ginseng, α-cyclodextrin plus placebo, placebo plus hydrolyzed ginseng, or placebo plus placebo) for 6 months. All participants received dietetic advice for weight loss. The primary outcomes were the differences in total cholesterol and fasting plasma glucose between groups after 6 months. The primary analysis used the intention-to-treat principle. Multiple predetermined subsample analyses were conducted. A total of 401 participants were eligible for the study (248 women [62%]; mean [SD] age, 53.5 [10.2] years; mean [SD] body mass index, 34.6 [6.2]). One hundred one patients were randomized to receive α-cyclodextrin plus hydrolyzed ginseng, 99 were randomized to receive α-cyclodextrin plus placebo, 101 were randomized to receive placebo plus hydrolyzed ginseng, and 100 were randomized to receive placebo plus placebo. For 200 participants taking α-cyclodextrin compared with 201 participants taking placebo, there was no difference in total cholesterol after 6 months (-1.5 mg/dL; 95% CI, -6.6 to 3.5 mg/dL; P = .51). For 202 participants taking hydrolyzed ginseng compared with 199 participants taking placebo, there was no difference in fasting plasma glucose after 6 months (0.0 mg/dL; 95% CI, -1.6 to 1.8 mg/dL; P = .95). Use of α-cyclodextrin was associated with constipation (16 participants vs 4 participants; P = .006) and cough (8 participants vs 1 participant; P = .02). Use of hydrolyzed ginseng was associated with rash and pruritus (13 participants vs 2 participants; P = .006). Only 37 of 401 participants (9.2%) experienced these adverse events. Although they are safe for use, there was no benefit found for either α-cyclodextrin for cholesterol control or hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Australian New Zealand Clinical Trials Registry Identifier: ACTRN12614001302640.

Progression Free Survival of Relapsed or Refractory Multiple Myeloma (RRMM) after Failure of Three Prior Lines of Therapy in United States (US) Real-World Practice

Background: Given the approval of a vast array of potent therapies and treatment combinations in multiple myeloma, it is important to understand outcomes of patients who relapse and/or become refractory to these commonly used drugs such as proteasome inhibitors (PI), immunomodulatory agents (IMiD), and CD38 targeting monoclonal antibodies (MoAB; ie. daratumumab). This study aims to describe clinical characteristics and progression free survival (PFS) after failure of at least 1 PI and IMiD +/- daratumumab in US community practice to provide context for the outcomes of RRMM patients after exposure to at least three lines of anti-myeloma therapies. Methods: Data analyzed were from electronic health record (EHR) generated by Flatiron Health (New York, NY). These data represent over 280 cancer clinics representing over 2 million active patients treated at primarily community-based hematology/oncology practices in the US. Inclusion criteria included adult patients ≥18 years with a diagnosis of MM, at least two clinic visits after 2015, failure of a PI and IMiD, ECOG ≤2, adequate hematologic/renal/hepatic function, and no stem cell transplant within three months of study entry. Study eligibility began as early as treatment initiation in ≥ fourth line (4L+) from January 2015 through March 2020. Progression free survival was measured from treatment until death, progression, or start of new line of therapy, and PFS was estimated for patients who were eligible for study inclusion (index date) between 2015-2018. Last follow-up occurred at March 2020. Results: In total, 141 patients had prior daratumumab exposure (64 included in time-to-event analysis) and 294 patients were daratumumab naïve (56 of these 294 had daratumumab exposure in a later line of therapy, at which point they were counted in the 141 daratumumab exposed patients group; 230 included in time-to-event analysis) once meeting the inclusion criteria for this study. Of patients exposed to daratumumab, 50% qualified for the study after 3-4 lines versus 87% of daratumumab naive patients. The median age at study entry was 69-70 years (Table 1). Approximately 36% of daratumumab exposed patients and 33% of non-previously daratumumab exposed patients presented with either intermediate or high-risk cytogenetics at study entry for patients with available cytogenetics. About half (48%) of daratumumab-exposed patients and over a quarter (29%) of non-previously daratumumab-exposed patients had a prior transplant. Median time from diagnosis until study entry was 49 months for the daratumumab exposed and 39 months for the non-previously daratumumab exposed groups. Median follow-up for the daratumumab exposed group was 8 months and 15 months for the non-previously daratumumab exposed group. At study entry for the daratumumab exposed patients, 4% received monotherapy, 18% received a doublet (5% carfilzomib/dexamethasone and 4% daratumumab/dexamethasone), 56% received a triplet (11% daratumumab/pomalidomide/dexamethasone, 7% carfilzomib/pomalidomide/dexamethasone), and 12% a quadruplet. In total, 56 (40%) patients received re-treatment with a daratumumab combination. Among the non-previously daratumumab exposed patients, 12% received monotherapy, 29% received a doublet (8% carfilzomib/dexamethasone, 7% daratumumab/dexamethasone), 48% received a triplet (12% daratumumab/pomalidomide/dexamethasone, 5% bortezomib/daratumumab/dexamethasone), and 8% received a quadruplet. PFS was short in both groups (Figure 1). In the daratumumab exposed group, the median PFS was 3.3 months (95% CI: 2.1-5.8) and the in the non-previously daratumumab exposed group, the median PFS was 4.4 months (95% CI: 3.6-5.9). Discussion: In this study with majority of patients having 3-4 prior lines of treatment, short PFS was observed for RRMM patients regardless of prior daratumumab exposure. Strikingly, many patients received re-treatment with a drug they had previously failed, suggesting many patients may have run out of effective therapies to utilize. Additionally, the daratumumab exposed group had a higher proportion with prior transplant which may also lead to differential outcome between these groups. Overall, these data suggest that these patients have poor outcomes and the need for effective novel classes of therapies remains high within the US community practice setting. Disclosures Kim: Amgen: Current Employment. Braunlin:Amgen: Current Employment. Belani:Amgen: Current Employment. Wheeling:Amgen: Consultancy.