Citations

7563 Background: Subcutaneous (SC) drug delivery options have become more widely available in multiple myeloma (MM). SC delivery of isatuximab (Isa), an anti-CD38 monoclonal antibody, has been investigated across clinical trials via a novel hands-free on-body injector (OBI). Isa SC OBI features a small, retractable needle, establishing the first device-enabled delivery of an oncologic treatment. The Phase 3 IRAKLIA, Phase 2 IZALCO, and Phase 1b (TCD15484) trials consistently demonstrated similar efficacy and safety of Isa SC OBI vs Isa IV in relapsed/refractory MM (RRMM) patients (pts). Here, we present a cross-trial analysis exploring safety and reliability of Isa SC OBI in RRMM pts. Methods: Pts with RRMM in IRAKLIA (N=263) and the Phase 1b expansion cohort (N=22) received 1400 mg Isa SC OBI plus pomalidomide and dexamethasone (d). In IZALCO, RRMM pts (N=64) received 1400 mg Isa SC OBI + carfilzomib (K)-d. Pts were monitored for 4 hrs (IRAKLIA) or 1-2 hrs (IZALCO) following first administration and for 1 hr for the following cycle (C) 1 administrations to assess local tolerability. Pre-infusion medications included montelukast (C1), steroids, acetaminophen and H1 antihistamines. Pts without systemic infusion-related reactions (IRRs) after 4 consecutive administrations of Isa SC OBI had subsequent pre-medication reassessed at investigator’s discretion. Safety and device performance explored in this cross-trial analysis of company sponsored studies were assessed in the Isa SC OBI cohorts by the duration of injection, IRRs, local injection-site reactions (ISRs), and injection/device success, which were defined similarly across all trials. Results: The median duration of Isa SC OBI injection was 13 mins in IRAKLIA, 12 mins in IZALCO, and 10 mins in the Phase 1b trial (6426 total injections, N=349 pts). IRRs across trials occurred in 6/6426 (0.09%) injections and 4/349 (1.15%) pts. IRRs were mostly grade 1 (G; 3/6426, 0.05%) with 1 G3 (0.02%); none leading to discontinuation. In IRAKLIA, 80/263 (30.4%) pts did not require premedication (931/5145 injections, 18.1%); no IRRs occurred in this group. Across trials, ISRs occurred in 21/349 (6.02%) pts resulting in 35 (0.54%) ISR events. Most ISRs were G1 (33, 0.51%), the remaining were G2 (2, 0.03%) and generally occurred on the day of injection. 99.9% (6421/6426) of injections in 98.6% (344/349) pts were successful (completed without interruption) across all trials. Conclusions: These findings support overall low, self-limiting rates of IRRs and ISRs across trials, with >6000 (99.9%) Isa SC OBI injections successfully delivered. Isa SC OBI shows reproducible safety and reliability in IRAKLIA, IZALCO and Phase 1b trials, supporting it as a novel administration option for MM pts and its potential for future exploration in at-home administration. Clinical trial information: NCT04045795 , NCT05405166 , and NCT05704049 .

7062 Background: MCL is a rare and aggressive subtype of B-cell non-Hodgkin lymphoma that remains incurable. Bruton tyrosine kinase (BTK) inhibitors are an established standard of care for R/R MCL. However, comparative effectiveness data for different BTK inhibitors for R/R MCL are limited. This study evaluated the real-world effectiveness of zanu and acala in US patients with R/R MCL based on overall survival (OS) and time to next treatment (TTNT). Methods: A retrospective cohort study was conducted using Komodo health administrative claims data. Eligible patients were adults (aged ≥18 years) with ≥2 MCL diagnoses and continuous enrollment or activities within 1 year prior to and 3 months following the index date. Patients were required to initiate monotherapy with zanu (index period: November 2019 to August 2025) or acala (index period: October 2017 to August 2025) as a second-line or later (2L+) treatment, with index date defined as the first observed claim for zanu or acala. Patients with evidence of clinical trial participation, end stage renal disease or prior stem cell transplant were excluded. Outcomes included OS (time from index date to all-cause mortality) and TTNT (time from index date to subsequent therapy with an allowable gap of 120 days). If an outcome was not observed, patients were censored at the date of last activity or enrollment end date. Survival analyses were conducted using Kaplan-Meier estimates and Cox proportional hazards models. Inverse probability of treatment weighting (IPTW) was adjusted for age, sex, US region, treatment initiation year and Charlson Comorbidity Index (CCI). Results: In total, 2219 patients (zanu, n=931; acala, n=1288) were eligible and included in the study. The mean age was higher in the zanu (72.3 years; SD, 9.4) vs acala cohort (71.4 years; SD, 9.7). Most patients were male (zanu, 71%; acala, 75%), non-Hispanic white (zanu, 73%; acala, 74%), and the mean CCI was 3.5 (SD, 3.2) and 3.6 (SD, 3.1) in the zanu and acala cohorts, respectively. Median follow-up was 14.8 and 18.2 months in zanu and acala cohorts, respectively. Median TTNT was 26.7 months for zanu and 20.8 months for acala. Median OS was not reached for zanu and was 60.6 months for acala. In the unadjusted model, zanu had a longer TTNT (HR, 0.86; 95% CI, 0.76-0.97; P =.012) and OS (HR, 0.74; 95% CI, 0.62-0.88; P <.001). After IPTW adjustment, TTNT and OS favored zanu treatment (TTNT: IPTW-adjusted HR, 0.86; 95% CI, 0.76-0.98; P =.025; OS: IPTW-adjusted HR, 0.81; 95% CI, 0.68-0.98; P =.03). Conclusions: In this real-world analysis of US health claims data, zanu monotherapy demonstrated significantly longer TTNT and improved OS compared with acala in patients receiving 2L+ therapy for MCL. These findings support zanu as an effective BTK inhibitor for R/R MCL.

6028 Background: RET alterations are targetable oncogenic drivers in multiple solid tumors and TCs. Pralsetinib is an oral, potent, selective RET inhibitor granted accelerated approval by the FDA for adults and children aged ≥12 y with advanced/metastatic RET fusion-positive TC who require systemic therapy and are radioactive iodine-refractory, based on ARROW trial (NCT03037385) results. Accelerated approval for medullary TC (MTC) was withdrawn by the sponsor in 2023 due to recruitment challenges in the confirmatory trial. We report final efficacy and safety in ARROW patients with RET -altered TC and MTC. Methods: Phase 2 ARROW patients were enrolled from 84 sites in 13 countries. Primary end points were overall response rate (ORR; per RECIST v1.1) and safety. Progression-free survival (PFS), overall survival (OS), and safety were assessed in patients with advanced/metastatic TC and MTC who received ≥1 dose of pralsetinib (Efficacy Population [EP]). ORR and duration of response (DOR) were assessed in the Measurable Disease Population (MDP). Results: At the May 20, 2024, data lock, 28 patients with RET -altered TC and prior systemic treatment and 145 patients with RET -altered MTC received pralsetinib 400 mg/d (median treatment duration: 24.7 mo [TC]; and 35.4 mo [MTC]). In the TC and MTC groups, median age was 58 and 57 y; 39% and 64% were male; median (range) prior lines of treatment was 2 (1, 9) and 1 (1, 6). 53.8% of MTC patients had prior systemic treatment. In TC and MTC patients, ORRs (95% CI) were 91.7% (73.0, 99.0) and 68.2% (59.5, 76.0) (Table). Treatment-related adverse events (TRAEs) occurred in 27 (96%) TC and 142 (98%) MTC patients; 68% and 67% had grade ≥3. TRAEs in ≥35% of TC and MTC patients were increased AST (50% and 38%) and ALT (43% and 30%), decreased white blood cell count (39% and 30%), and anemia (39% each). Death due to a TRAE occurred in 1 TC patient (liver injury) and 1 MTC patient (pneumonia). Safety was consistent with prior reports. Conclusions: The final analysis of ARROW confirms that pralsetinib yields clinically meaningful and durable responses in patients with RET -altered TC and MTC with a manageable safety profile consistent with prior reports. Clinical trial information: NCT03037385 . Efficacy summary. All MTC MTCPrior Cabozantinib/Vandetanib MTC Treatment-Naïve TCPrior Systemic Treatment MDP, n 132 60 62 24 ORR, % (95% CI) 68.2(59.5, 76.0) 56.7(43.2, 69.4) 79.0(66.8, 88.3) 91.7(73.0, 99.0) Complete response, n (%) 12 (9.1) 2 (3.3) 7 (11.3) 4 (16.7) Partial response, n (%) 78 (59.1) 32 (53.3) 42 (67.7) 18 (75.0) DOR, median, mo (95% CI) 39.6(29.4, NE) 21.7(15.1, 34.8) NR(36.8, NE) NR(16.0, NE) DOR follow-up, median, mo (95% CI) 45.7(41.0, 48.4) 48.9(36.9, 58.7) 45.1(40.4, 47.8) 35.4(26.9, 40.0) EP, n 145 67 67 28 OS, median, mo (95% CI) NR(54.6, NE) 42.2(31.2, NE) NR(NE, NE) NR(25.4, NE) PFS, median, mo (95% CI) 37.2(27.5, 55.5) 24.9(19.9, 35.0) 55.3(36.8, NE) NR(14.7, NE) NE, not evaluable; NR, not reached.

4157 Background: IDH1/2 mutations occur in ~25% of cholangiocarcinomas (CCAs). Preclinical studies suggest synergy between PARP inhibition and PD-L1 blockade. We previously conducted a phase II trial of olaparib plus durvalumab in advanced IDH -mutant CCA. We report matched baseline tissue and serial cell-free DNA (cfDNA)-based correlative analysis of pts samples. The primary objective was to develop a cfDNA methylome signature as a non-invasive biomarker. Methods: This single-arm, open-label phase II study (NCT03991832) enrolled patients with unresectable/metastatic IDH -mutant CCA and ≤2 prior lines of systemic therapy. Patients received olaparib 300 mg orally twice daily and durvalumab 1500 mg IV every 4 weeks. Blood samples were collected at baseline and monthly while on treatment for planned correlatives to examine R2HG, S2HG, and artemin levels using HPLC (High-Performance Liquid Chromatography). Cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq) was performed on pts cfDNA samples and case-matched IDH -wildtype pts. Formalin-fixed, paraffin-embedded blocks of baseline tumor biopsies were used for multispectral fluorescent IHC (FL-IHC) using a 6-marker panel composed of pan-cytokeratin, CD4, CD8, CD163, PD-L1, and CD68. Results: Ten patients were enrolled (median age 63.5 y; 50% female; 90% received prior platinum). Median treatment duration was 1.95 mo (range 1.8–13.5). No complete or partial responses were observed. DCR was 30% (3 patients with stable disease); one patient remained on therapy for 13.5 mo before progression. Median PFS was 1.97 mo (95% CI 1.73–3.93). HPLC from baseline plasma showed lower baseline artemin levels correlated with stable disease (p=0.038), while R2HG/S2HG ratios showed no association with outcome. FL-IHC showed enriched immune cell populations, specifically CD4 + T cells (p=0.0032) and a trend for CD68 + macrophages (p=0.062), in the tumor stroma compared with tumor core. 54 plasma samples (from 8 patients) were profiled with cfMeDIP-seq along with 8 IDH -wildtype controls. Using top 100 differentially methylated regions, the circulating tumour DNA methylome exhibited a highly specific signature, accurately discriminating IDH -mutant and IDH -wildtype CCA regardless of treatment status. The specific differentially methylated gene pathways between groups were comprehensively examined in both on-treatment and baseline plasma samples. Conclusions: Advanced IDH -mutant CCA harbors an immune-excluded phenotype, which may underlie primary resistance to immunotherapy. Plasma cfDNA methylome signature can accurately discriminate CCA with IDH mutations. Clinical trial information: NCT03991832 .

4122 Background: BTCs are rare and aggressive malignancies. The first-line standard of care regimen for advanced BTC (aBTC) is gemcitabine (GEM), cisplatin, and an immune checkpoint inhibitor. Although FOLFOX is a preferred second-line treatment, it is limited by neuropathy. Nal-IRI contains IRI free base in liposome nanoparticles, which shelter IRI from conversion to its active metabolite (SN-38) and increase intratumoral SN-38 compared with IRI alone. The NAPOLI-1 trial of FU/LV/nal-IRI vs. FU/LV in second-line advanced pancreatic adenocarcinoma showed an overall survival (OS) benefit. The NIFTY trial (South Korea) demonstrated median OS (mOS) benefit of FU/LV/nal-IRI over FU/LV in a second-line aBTC population (8.6 vs. 5.3 months [mo], HR 0.68, 95% CI 0.48-0.95); however, the NALIRICC trial (Germany) did not (6.9 vs. 8.2 mo, HR 1.08, 95% CI 0.68-1.72). We sought to characterize second-line FU/LV/nal-IRI efficacy in US patients (pts) with second-line aBTC. Methods: This was a single-arm, open-label, multicenter phase II study of pts with aBTC previously treated with GEM/platinum chemotherapy. Pts received nal-IRI 70 mg/m 2 IV over 90 minutes, LV 400 mg/m 2 IV over 30 minutes every 14 days, and FU 2400 mg/m 2 IV over 46 hours every 14 days. The primary objective was to determine progression-free survival rate at 4 mo (PFS 4mo ) using RECIST v. 1.1 criteria. Median PFS reported for pts receiving second-line 5-FU doublet chemotherapy was 3 mo with a PFS of 30%. FU/LV/nal-IRI was of interest if it could increase the PFS 4mo to 50% or higher. Using a one-sided α of 0.05 and 80% power, 17 of 39 evaluable pts had to be progression-free at 4 mo to detect a difference in PFS 4mo between 30% and 50%. Results: Forty-eight pts were enrolled: median age 64.5 years; 69% women; 27% gallbladder primary; 54% intra- and 19% extrahepatic. Ten pts came off study due to toxicity without disease progression before 4 mo on study and were replaced to evaluate the PFS 4mo endpoint. Of 38 evaluable pts, 18 pts (PFS 4mo 47%) were alive and progression-free at 4 mo, meeting the primary endpoint. With a median follow-up of 7.1 mo, median time to disease progression or study discontinuation due to toxicity for all pts was 2.3 mo (95% CI 1.8-4.6, PFS 4mo 38%), and for pts evaluable for the primary endpoint, median PFS was 3.5 mo (95% CI 1.8-5.5). Five pts (10%) had PFS beyond 12 mo. mOS for all pts was 7.9 mo (95% CI 5.7-11.7). Of 41 evaluable pts, the response rate was 2% (1 PR), and the disease control rate was 54%. Adverse events (AEs) were consistent with known toxicities from the FU/LV/nal-IRI regimen. Conclusions: FU/LV/nal-IRI is an effective second-line regimen for aBTC in US pts. There was significant early toxicity as 21% of pts came off study due to AEs before 4 mo. Correlative studies, including longitudinal analyses of circulating tumor DNA using banked blood specimens, are planned (NCT04005339). Clinical trial information: NCT04005339 .

1633 Background: CAR-T cell therapy has transformed outcomes of hematologic malignancies and is poised to expand into solid malignancies. However, broader use of CAR-T remains constrained by the need for timely cytokine release syndrome (CRS) detection. Current episodic monitoring may miss early physiologic changes. Wearable digital health technologies (DHTs), offering continuous monitoring and real-time alerts, could enable earlier CRS detection, further support outpatient delivery, and expand access to CAR-T and potentially other immunotherapies associated with CRS. Methods: This single-center observational study (NCT05018208) enrolled patients receiving FDA-approved CAR-T products in the outpatient setting at Mayo Clinic, Rochester MN. Management of post-CAR-T complications (e.g. CRS) followed the institution’s standard of care. Patients were monitored from day -5 to day +30 post infusion with intermittent remote patient monitoring (SoC) and an arm-worn wearable device for continuous monitoring (DHT). Patients were included in this analysis if DHT data were available for ≥ 5h of data/day or ≥ 2h of data/night on ≥2 days or nights for baseline and ≥1 day or night within 72h prior to CRS, or at least 2h within 4h of CRS onset, or if DHT was available for ≥7 days/nights post infusion with no CRS event. CRS detection time by DHT was defined as the onset of pyrexia or threshold-based deviation from an individual’s baseline pulse distributions. Results: 32 patients were included in this report (median age 64 years, gender 12 F/20 M, diagnoses 18 MM/14 NHL). 25 patients experienced a CRS event, with maximum CRS grades ranging from 1-3 (16 G1, 8 G2, 1 G3). 24/25 patients with CRS required tocilizumab/steroid. Median CRS onset time was 3.4 days (range 0.4-18.4). 12/32 patients had sufficient DHT data (7 CRS, 5 no CRS) for analysis. 5 patients with CRS had a DHT detection time in advance of the SoC by a median of 13h (range 2.8 - 69.2). The DHT prediction of CRS by baseline HR change was earlier than the first episodic fever by a median of 14.5h (range 13-77.5). The remaining 2/7 patients who did not have CRS detected by the DHT had missing DHT data for more than 45h before a treated CRS event. DHT detected CRS in 2/5 patients without CRS according to SoC. One patient had fever caught with intermittent monitoring. The other was treated for neutropenia fever with suspicion of CRS and/or infection. Conclusions: These results offer evidence that continuous DHT can identify CRS events earlier than intermittent monitoring (SoC). Despite limitations related to compliance with wearable device use and data missingness, and variability in clinical management of CRS, we highlight the usability of DHT and its potential for future studies with optimized strategies to address these limitations. Clinical trial information: NCT05018208 .

Estimates of fibromyalgia prevalence vary widely worldwide due to differences in diagnostic criteria, study methodology, and population characteristics. Accurate estimates are essential to inform population-level surveillance, guide resource allocation, and highlight disparities in disease recognition and access to care. The objective of this systematic review and meta-analysis was to determine the global prevalence of fibromyalgia in the general population, and secondarily to identify factors moderating prevalence variation and to assess prevalence in defined at-risk subpopulations. Pooled prevalence estimates with 95% confidence intervals (CIs) were calculated using the inverse variance heterogeneity model with Freeman–Tukey transformation. Subgroup analyses were performed by sex, diagnostic criteria, country, and other study characteristics, and meta-regression assessed moderators including publication year and Human Development Index (HDI). Of 21,645 records identified, 1,728 underwent full-text review and 882 studies were included in the final analysis. Across 38 countries and 30,070,032 individuals (188 studies), the pooled fibromyalgia prevalence in the general population was 1.40% (95% CI, 0.49–2.47), with substantial heterogeneity (I 2 = 100%) and very low certainty of evidence. Among at-risk subpopulations (9,771,123 participants; 768 studies), prevalence was markedly higher in autoimmune and inflammatory conditions, such as chronic urticaria (37.1%), interstitial cystitis (30.8%), systemic sclerosis (20.6%), celiac disease (20.5%), and inflammatory bowel disease (19.9%), and elevated in chronic pain, rheumatologic, and post-infection cohorts. Meta-regression identified publication year (β = 0.008, P < .001) and HDI (β = 0.725, P = .002) as significant moderators of prevalence. In conclusion, fibromyalgia affects 1% to 2% of the global population, with substantially higher rates in at-risk subpopulations. Temporal and socioeconomic trends emphasize diagnostic inconsistency and global disparities in care.

BACKGROUND: Atherothrombosis, which underlies most acute coronary syndromes and is driven by intraplaque thrombosis, preferentially occurs in regions of disturbed blood flow (d-flow). Although LATS1/2 (large tumor suppressor kinases 1 and 2) are known regulators of endothelial mechanotransduction, the mechanisms by which d-flow connects endothelial senescence, proliferation, and intraplaque thrombosis remain poorly understood. METHODS: We investigated endothelial cell (EC)-specific roles of Lats1/2 using inducible EC-specific knockout mice in a partial carotid ligation model. Spatial multiomics of human and mouse plaques was performed using imaging mass cytometry, COMET sequential immunofluorescence, and spatial metabolomics. RESULTS: Tamoxifen-induced deletion of both Lats1 and Lats2 (homozygous) in ECs caused fatal edema and increased vascular permeability. In contrast, Lats1 het ( ± ) / Lats2 homo ( −/−) -EC-specific knockout mice survived and developed spontaneous atherothrombotic plaques with neovascularization. Spatial proteomics revealed that LATS1/2 loss induced a senescence-associated stemness phenotype driven by CD38 upregulation. Spatial metabolomics showed sulfite and taurine accumulation, indicating SUOX (sulfite oxidase) deficiency. CD38 suppressed SUOX, demonstrated a switch into the reverse mode of mitochondrial complex V, increased succinate dehydrogenase activity, and promoted ATP consumption. Despite ATP depletion, glutamate metabolism and the citric acid cycle flux increased, sustaining EC proliferation under energetic stress. This senescence-associated stemness state promoted both proliferation and senescence, leading to fragile, leaky neovessels and intraplaque thrombotic lesions. Pharmacological CD38 inhibition attenuated these phenotypes. Similar EC states were observed in human plaques. CONCLUSIONS: Loss of Lats1/2 in ECs induces a CD38-associated senescence-associated stemness-like phenotype that promotes intraplaque thrombosis through mitochondrial metabolic reprogramming, including changes consistent with reverse-mode operation of mitochondrial complex V. These findings define a mechanistic link between disturbed flow, endothelial metabolic reprogramming, and intraplaque thrombosis and hemorrhage.

Abstract Introduction Transthoracic echocardiography (TTE) identifies a hypercontractile phenotype (HP) in chronic coronary syndromes (CCS), characterized by elevated resting left ventricular (LV) elastance (force = systolic blood pressure/end-systolic volume). To evaluate the prognostic significance and functional correlates of HP. Methods In a prospective multicentre study, 10 677 patients with CCS underwent resting TTE to assess LV ejection fraction (EF), stroke volume, and force by quantitative volumetric echocardiography. All patients were followed for the endpoint of all-cause mortality. In a subset of 5834 patients, stress echocardiography (exercise or dobutamine) was performed for LV contractile reserve and heart rate reserve. Results Patients were stratified into Force quintiles (Q1–Q5). Patients with hypercontractile phenotype exhibited lower stroke volume at rest (Q5 = 34.8 ± 12.3 vs Q1–Q4 = 57.4 ± 19.1 mL; P &lt; .01) and higher EF at rest (Q5 = 64.8 ± 6.9% vs Q1–Q4 = 58.1 ± 8.7%, P &lt; .01). During a median follow-up of 24 months (interquartile range = 12–40 months), 509 deaths occurred. The exposure-adjusted death rate was lowest in Q3 (3.53–4.51 mmHg/mL; 1.03 per 100 person/years) and higher in Q1 (≤2.62 mmHg/mL, 2.88), Q2 (2.63–3.52 mmHg/mL, 1.86), Q4 (4.52–6.11 mmHg/mL, 1.56), and Q5 (HP, &gt;6.11 mmHg/mL; 1.88; P &lt; .0001 vs Q1 and Q3). Multivariable analysis identified HP (Q5; HR 1.531 vs Q3, 95% CI 1.116–2.099; P = .006) and EF (HR 0.963, 95% CI 0.953–0.972; P &lt; .0001) as independent predictors of death. During exercise or dobutamine stress, HP showed reduced LV contractile reserve (ΔEF: Q5 = 4.3 ± 9.4% vs Q1–Q4 = 7.0 ± 9.3%; P &lt; .001) and blunted heart rate reserve (Q5 = 1.77 ± 0.33 vs Q1–Q4 = 1.85 ± 0.39; P &lt; .01). All patients with force-based LV contractile reserve &gt;4.1 (present in 185, 3.2% of the population) survived. Conclusion Patients with CCS with HP assessed by resting TTE demonstrate higher mortality and multilayered functional impairment, including reduced LV contractile and chronotropic reserves. Hypercontractile phenotype improved the prediction of mortality by EF. A ‘stronger’ heart is, in fact, functionally and prognostically weaker.