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Objective Systemic sclerosis (SSc) is an autoimmune disease marked by immune dysregulation, leading to progressive fibrosis and multiorgan dysfunction. Autologous hematopoietic cell transplantation (autoHCT) has demonstrated superiority over conventional immunosuppression in randomized trials yet remains underused in the United States. We report outcomes following implementation of autoHCT as a standard‐of‐care strategy at our institution. Methods We performed a retrospective analysis of consecutive patients with severe SSc undergoing autoHCT between April 1, 2020, and December 31, 2023. Eligibility required progressive disease despite standard immunosuppressive therapy. Primary endpoints were overall survival (OS) and event free survival (EFS). Secondary endpoints included cumulative incidence of relapse and nonrelapse mortality (NRM), organ‐specific outcomes, and transplant‐related complications. Results Twenty‐five patients underwent autoHCT. Median age was 46 years; 80% were female. At a median follow‐up of 23 (interquartile range 16.4–31.9) months, two‐year OS was 91.67% (95% confidence interval [CI] 81.25–100.0) and EFS was 74.51% (95% CI 58.78–94.45). Two‐year cumulative incidence of relapse was 23.93% (95% CI 4.27 –43.59), and NRM was 8.33% (95% CI 2.97–19.64). Significant improvement in Modified Rodnan Skin Score was observed at day +90 and +180 ( P < 0.05), whereas pulmonary function stabilized. Infectious complications occurred in 56% of patients, primarily viral reactivations. Conclusion Implementation of autoHCT for severe SSc in a multidisciplinary care model was associated with favorable survival and meaningful improvement in skin disease, with acceptable toxicity. Earlier referral and optimization of conditioning strategies may further reduce relapse and treatment‐related morbidity.

ABSTRACT Ciltacabtagene autoleucel (cilta‐cel) has demonstrated excellent efficacy and long‐term disease control in patients with relapsed/refractory multiple myeloma (RRMM). However, a proportion of patients experience early treatment failures. We investigated clinical factors associated with early progression or death (within 12 months) in patients with RRMM receiving standard‐of‐care cilta‐cel across the three Mayo clinic centers. Patients with a follow‐up of at least 12 months or progression or death within 12 months from infusion were included. Of the patients with early treatment failure ( n = 52), 69% had progressive disease and 31% had a non‐relapse mortality (NRM) event. In patients without early treatment failure ( n = 164), 13% of events were NRM. Among pretreatment factors, prior BCMA‐directed therapy, presence of extramedullary disease and a CAR‐HEMATOTOX score of ≥ 2 were independent predictors of early progression or death. The utilization of cilta‐cel in earlier lines of treatment (1–3 vs. 4 or more) demonstrated comparable PFS (12‐month PFS 73% vs. 77%, p = 0.94). Measurable residual disease positivity in the bone marrow at 3 months (11/197 patients) identified a small but high‐risk group with an increased risk of early treatment failure (OR 5.68; p = 0.012). Patients with less than a complete response on a FDG PET/CT at 3 months also had an increased risk of early treatment failure (OR 11.8; p < 0.0001). Our findings may help identify patients at high‐risk for early adverse outcomes despite receiving highly effective therapy, and support consideration of novel therapeutic strategies within a clinical trial setting.

Background/Objectives: Patients with relapsed/refractory multiple myeloma (RRMM) have poor survival outcomes and limited treatment options. The increasing utilization of multiagent therapies for earlier lines of treatment and novel drug classes including BCMA-targeting agents in subsequent lines of therapy has created a need for innovative treatment platforms in patients who have relapsed after or are refractory to these current standard-of-care approaches. Iopofosine I 131 is a 131iodide (131I)–phospholipid conjugate that exploits the selective uptake and retention of phospholipid ethers through lipid rafts to facilitate tumor delivery of 131I. Methods: The objective of this phase 1 dose-escalation study was to assess the safety and tolerability of single and fractionated dose schedules of iopofosine I 131 + low-dose dexamethasone in heavily pretreated patients with RRMM. Results: The most common AEs overall were cytopenias, notably thrombocytopenia (93.5%), lymphopenia (74.2%), anemia (71%), leukopenia (61.3%), and neutropenia (58.1%). All patients experiencing hematologic adverse events recovered from those events with median time of recovery 21 days post-nadir. Nonhematologic adverse events were mostly limited to Grade 1 and 2. Dose-limiting toxicities included four Grade 4 thrombocytopenia events lasting longer than 7 days, one Grade 4 neutropenia, and one Grade 3 insomnia. The DMC determined 31.25 mCi/m2 was the maximum tolerated dose in the single-dose group, and 20 mCi/m2 × 2 doses was the maximum tolerated dose in the fractionated-dose group. For patients monitored through 85 days following the first infusion, 22 of 26 (84.6%) achieved stable disease after treatment, and 4 of 26 (15.4%) achieved a partial response. Conclusions: A favorable safety and tolerability profile and preliminary clinical activity support further development of iopofosine I 131 in RRMM.

TPS7101 Background: Patients with high-risk CLL/SLL not achieving a complete response (CR) after ≥ 12 months of BTK inhibitor (BTKi) monotherapy remain at risk for early progression due to residual disease and BTKi resistance. A BCL-2 inhibitor (BCL-2i) introduces a complementary, BCR-independent apoptotic mechanism that may deepen responses and prolong progression-free survival (PFS). Lisaftoclax, a selective oral BCL-2i with a short half-life (4-6 h), enables once-daily dosing and is approved in China as second-line CLL therapy. Lisaftoclax monotherapy has demonstrated overall response rates (ORRs) of 67% in relapsed/refractory CLL and 62.5% in BTKi-refractory disease, including del(17p)/ TP53 -mutated cases. Lisaftoclax combined with acalabrutinib achieved ORRs >97% with favorable tolerability. This study evaluates whether lisaftoclax plus BTKi (acalabrutinib, zanubrutinib, or ibrutinib) improves PFS and/or overall survival (OS) (vs continued BTKi monotherapy) in patients with CLL/SLL and residual disease after prolonged BTKi treatment. Methods: This study will enroll approximately 440 patients randomly allocated to receive lisaftoclax plus BTKi or BTKi alone. Eligible patients have CLL/SLL and, after ≥12 months of BTKi monotherapy (lines 1-3), have achieved neither CR nor progressive disease (PD). Randomization is stratified by del(17p)/ TP53 status. Key inclusion criteria include age ≥18 years, ECOG PS 0-2, and residual disease with either high-risk features (del(17p)/ TP53 mutation, unmutated IGHV , or complex karyotype [≥5 abnormalities]), or measurable residual disease with lymph nodes ≥2.5 cm in the absence of high-risk features. Exclusion criteria include prior BCL-2i therapy or Richter transformation. Patients in the investigational arm will undergo a 5-day oral lisaftoclax ramp-up to 400 mg once daily plus physician's choice of BTKi in 28-day cycles until progression or toxicity. Control patients continue their current BTKi monotherapy. Safety and disease assessments (CT/MRI) will occur regularly. The primary endpoint is PFS by independent review committee (iwCLL 2018); key secondary endpoint OS; and other secondary endpoints, PFS by investigator, ORR, duration of response, MRD negativity, and safety. Enrollment is ongoing across 126 sites in 18 countries (ClinicalTrials.gov ID: NCT06104566). Clinical trial information: NCT06104566 .

e19504 Background: Initiation of bsAbs requires SUD with close monitoring, typically in IP settings, to mitigate early toxicities. As bsAb use expands, it is crucial to understand the financial viability for administering bsAbs, particularly non–PPS-exempt hospitals paid via a capitated, DRG-based method where costs may exceed payout. We compared net costs and payments for Medicare pts initiating bsAbs in the IP setting at non-PPS-exempt hospitals and explored cost variations for hospital characteristics and adverse events (AEs). Methods: Using Medicare FFS Parts A/B claims (10/25/21–10/20/24), pts ≥65 years with MM, IP bsAb initiation, and 12 mos continuous pre-index coverage were identified. Pts receiving other MM therapies <30 days post-index or treated in PPS-exempt hospitals were excluded. Hospital costs were estimated by applying revenue center–specific Medicare cost–charge ratios from CMS Hospital Cost Reports to IP facility charges. Outpatient (OP) bsAb costs were estimated using ASP/unit administered/wasted at the time of the claim. Costs for other OP services were estimated using revenue center–specific cost–charge ratios. Medicare payments were defined as total allowed amounts on IP and OP claims, and net cost as payments minus estimated costs. IP resource use and net cost recovery by academic vs nonacademic hospital, length of stay (LOS), and AEs were analyzed. Results: Of 3074 pts with a bsAb claim, 1129 met inclusion criteria. Mean IP LOS was 9 days (range 1–68). Hospital mean estimated IP cost/day for index hospitalization was $3963. Mean estimated costs for index hospitalization were $36964 per pt for IP SUD and $28366 for mean Medicare payments with a mean loss of $8598 per pt (median −$5616). Payments exceeded estimated costs on average by $2764–8149 for 1–4-day hospitalizations and roughly equal costs for hospitalizations at 5 days. For pts with LOS of 6–9 days and ≥10 days, payments were lower than costs by $6735 and $16659, respectively, suggesting a loss. For pts with subsequent OP administrations (74%) observable in this sample, cumulative payments and costs were assessed following the index hospitalization, mean cumulative longitudinal payments were ≥ cumulative costs within 2–3 mos. IP stay net losses were higher among pts with infection (−$6406 vs no infection), neutropenia (−$7006), and febrile neutropenia (−$10018). Payment patterns and estimated costs were similar across hospital types. Conclusions: Results suggest a large financial burden on non-PPS-exempt hospitals for IP-administered bsAb SUD. While shorter LOS for IP SUD generally did not result in financial losses, longer LOS was associated with disproportionately higher costs relative to payments. Care models (e.g. OP SUD) are key to manage initiation costs and ensure delivery of care for bsAbs remains financially sustainable.

e19094 Background: WM/LPL is an indolent B-cell Non-Hodgkin Lymphoma with prolonged survival and predisposition to secondary malignancies (SM) influencing clinical outcomes and survivorship care. We evaluated the incidence, demography, treatment utilization, and outcomes of SM in patients with WM/LPL using population-based data. Methods: SEER-22 database was used to identify patients with LPL/WM diagnosed between 2000–2022 and stratified by SM. Overall survival (OS) was analyzed using Kaplan–Meier survival analysis and propensity score matched Cox regression was used to assess mortality risk. Hazard ratios were reported, with p<0.05 deemed significant. Results: 22,170 patients with WM/LPL were identified, with a median age of 71 years (IQR 16); the cohort was predominantly male (59.0%), White (84.0%), had a median household income of $50,000–$75,000 (48.9%), and resided primarily in urban areas (89.5%). Among all WM/LPL patients, 20.8% (n=4,615) developed a SM. Patients who developed SM were older than those without (median age 75 vs 70 years, p<0.0001) with 45.2% alive at predefined follow-up. The most common solid organ SM were gastrointestinal adenocarcinoma (16%), prostate cancer (14%), and lung adenocarcinoma (9%), while the leading hematologic SM were plasma cell myeloma (6%), diffuse large B-cell lymphoma (5%), and myelodysplastic syndrome (2%). 35.3% of the cohort received chemotherapy, while 0.1% received cancer-related surgery or radiation. On multivariable analysis, older age (OR 0.82, 95% CI 0.81–0.83), male sex (OR 0.59, 95% CI 0.44–0.80), urban residence (OR 1.99, 95% CI 1.24–3.18), and higher income (OR 2.16, 95% CI 1.13–4.15) were significantly associated with SM diagnosis. Kaplan–Meier analysis demonstrated inferior survival among patients with SM (54.8% vs 45.2%, p<0.0001), with shorter median OS (9 vs 14 years, log-rank p<0.001). Similarly, Propensity-matched analysis revealed worse OS in patients with SM (HR 1.15, 95% CI 1.09–1.22, p<0.001). Median OS varied substantially by SM site (see Table). Conclusions: Our study demonstrates a substantial burden of SMs among patients with WM/LPL and are associated with substantially inferior survival despite the indolent nature of the disease. The marked heterogeneity in SM types and outcomes highlights the need for risk-adapted surveillance, survivorship-focused care, and equitable strategies to address disparities and improve long-term outcomes in this population. SM Site Median OS (years) IQR p-value Hepatopancreatobiliary 1 0 <0.05 CNS 3.5 9 <0.05 Breast 3 6 <0.05 Colorectal 4 3.5 <0.05 Lymph Node 5 8 <0.05 Blood 6 7 <0.05 Lung 7 9 <0.05 Head & Neck 6.5 8.5 <0.05 Melanoma 9 10 <0.05 Urogenital 10.5 7 <0.05

e15708 Background: AFTT is characterized by physical, nutritional, and psychosocial decline. In GIC, AFTT arises from malnutrition, disease progression, or treatment-related toxicity resulting in poor quality of life. We evaluated the association between AFTT and IM, length of stay (LOS), and hospital charges (HC) in hospitalized GIC patients. Methods: The National Inpatient Sample (2016-21) was used to identify adult hospitalizations with GIC using ICD-10 codes, which were stratified as primary or secondary diagnoses by AFTT. Clinical characteristics and primary outcomes including IM, LOS, and HC were extracted. Multivariable regression models adjusting for demographics, insurance, comorbidity burden, census tract income, and hospital teaching status were evaluated. Results: Among 2,732,505 GIC hospitalizations, colorectal (46.9%) and pancreatic (20.4%) cancer predominated; 121,035 (4.4%) had AFTT. Patients with AFTT vs non-AFTT, were older (mean = 69.3 vs 66.5 yrs), more often male (58.1% vs 57%), and from the lowest income quartile (27.7% vs 26%). AFTT cohort had higher comorbidity burden (mean CCI = 7.24 vs 6.26), more Black patients (19.1% vs 12.8%), higher Medicare use (62.7% vs 56.0%), increased palliative care consultation (37.4% vs 13.6%), risk of malnutrition, AKI, and dementia (all p< 0.001). AFTT was associated with higher IM, longer LOS, and lower HC. Higher age, males, and self-pay were associated with increased IM and HC, but shorter LOS. Lower CCI was associated with reduced IM, LOS, HC, whereas urban hospitals showed lower IM but higher LOS and HC. Black patients had higher IM and LOS but lower HC, contrary to Hispanic patients. Conclusions: The grave impact of AFTT and variability in survival and practice patterns is driven multifactorially, raising concerns about inequitable care access and differences in healthcare utilization. Standardized guidelines and multidisciplinary interventions are urgently needed to combat AFTT in GIC. Predictor IM aOR (95% CI) LOS Adj. Ratio (95% CI) HC Adj. Ratio (95% CI) AFTT Status (vs. Non-AFTT) 1.96 (1.93-2.00) 1.13 (1.12-1.14) 0.86 (0.85-0.86) Age (/year increase) 1.02 (1.02-1.02) 1.00 (1.00-1.00) 1.00 (1.00-1.00) Sex (vs. Female) Male 1.18 (1.17-1.19) 0.99 (0.98-0.99) 1.05 (1.05-1.06) CCI Score (vs. High, ≥5) Low (≤2) Mid (3-4) 0.33 (0.32-0.33) 0.48 (0.47 - 0.48) 0.87 (0.87 - 0.88) 0.93 (0.93 - 0.94) 0.93 (0.93 - 0.94) 1.02 (1.02 - 1.02) Insurance (vs. Medicare) Private Medicaid Self-Pay 1.03 (1.01 - 1.05) Ref in model 1.29 (1.24 - 1.33) 0.92 (0.91 - 0.92) 0.96 (0.95 - 0.97) 0.98 (0.97 - 1.00) 1.03 (1.02 - 1.03) 1.06 (1.05 - 1.06) 0.96 (0.95 - 0.97) Race (vs. White) Black 1.03 (1.00 - 1.06) 1.07 (1.06 - 1.08) 0.95 (0.94 - 0.96) Facility Status (vs. Rural) Urban Non-Teaching Urban Teaching 0.87 (0.85 - 0.89) 0.78 (0.77 - 0.80) 1.10 (1.09 - 1.11) 1.18 (1.17 - 1.19) 1.64 (1.63 - 1.65) 1.86 (1.84 - 1.87)

e14111 Background: Primary CNSL (PCNSL) is a rare, aggressive B-cell non-Hodgkin lymphoma limited to the CNS, while secondary CNSL (SCNSL) represents CNS involvement from systemic lymphoma. Previous observations focused on CNSL have limited data clinically comparing PSNSL and SCNSL. We aimed to evaluate overall survival and associated factors in patients with PCNSL vs SCNSL using a large population database. Methods: We conducted a retrospective cohort study using the SEER-22 database to identify patients diagnosed with CNSL between 2020-2022. Group comparisons used t-tests or ANOVA for continuous variables, chi-square tests for categorical variables, and Kaplan–Meier survival analysis, with all analyses performed in RStudio 4.1.1 and significance deemed as p<0.05. Results: 14,964 patients with CNS lymphoma were identified, with 84.6% PCNSL and 15.4% SCNSL cases. The overall median age was 65 years (IQR 20), with 52% male, 66% White patients, residing in urban areas (90%) and median household income of $50,000–$75,000 (52%). Compared with PCNSL, patients with SCNSL were significantly older (72 vs 64 years, p<0.0001). SCNSL more frequently involved the cerebrum (39% vs 34%) and cerebellum (5.5% vs 4.5%), but less commonly affected the nerves (12.0% vs 12.5%) and spinal cord (4.2% vs 5.1%) (p<0.05). Disease was predominantly unilateral (95.8%) in both groups. Chemotherapy (55% vs 56%) and radiotherapy (19% vs 18%) utilization did not differ significantly, with external beam radiation comprising 94.3% of radiated cases. PCNSL patients were more likely to undergo surgical intervention than SCNSL patients (31.8% vs 28.7%; p=0.0027). Diffuse large B-cell lymphoma was the most common histologic subtype in both PCNSL (70.1%) and SCNSL (74.3%). Median overall survival was shorter in SCNSL (1.64 years) than PCNSL (1.99 years). Survival improved significantly across diagnostic eras (2000–2005 to 2016–2020; log-rank p<0.001), while lower income (<$50,000) and rural residence were associated with inferior outcomes (p=0.028 and p=0.033). Conclusions: Survival in CNS lymphoma remains poor, with SCNSL associated with worse outcomes compared with PCNSL. Greater understanding of treatment variation and disease differences is needed to optimize therapy and improve patient outcomes. Characteristic PCNSL SCNSL Total p-Value N 12667 2297 14964 Population Distribution 0.033 Urban 11426 2038 13464 Rural 1241 259 1500 Surgery 0.0027 Yes 3630 730 4360 No 9037 1567 10604 Months from Diagnosis to Rx(Mean, SD) 0.31 (0.86) 0.27 (0.65) 0.30 (0.83) 0.0077 Death Status <0.0001 Dead 8603 1772 10375 Alive 4064 525 4589 Overall Survival (in years, Mean, SD) 1.99 (2.85) 1.64 (2.31) 1.93 (2.77) <0.0001

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 .