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Abstract Introduction: Circulating tumor DNA (ctDNA) has emerged as a promising biomarker for treatment response monitoring, risk stratification, and early recurrence detection for patients with lymphoma. Tumor-informed ctDNA testing for detecting molecular residual disease (MRD) is seeing early adoption in this setting, demonstrating technical feasibility and clinical need for personalized monitoring tools. However, the prognostic utility of ctDNA across indolent and aggressive subtypes of lymphoma remains poorly understood. Here, we present real-world data on ctDNA detection and clearance dynamics in patients with various lymphoma subtypes, including patients who are newly diagnosed and those in the relapsed/refractory setting receiving chimeric antigen receptor (CAR)-T therapy. Methods: We performed a retrospective, real-world analysis of ctDNA testing in 148 patients with either B-cell (n=129) or T-cell lymphoma (n=19). Among the 129 patients with B-cell lymphoma, 113 patients had aggressive subtypes (n=84 with DLBCL; n=29 with other), and 16 had indolent lymphoma subtypes. ctDNA was analyzed using a tumor-informed 16-plex mPCR-NGS assay (SignateraTM, Natera, Inc.) from September 2020 - May 2025. Plasma samples (n=1,122; median: 7 per patient, range: 1-31) were collected at baseline, during therapy, at end-of-treatment (EOT), and during follow-up per physician's discretion. ctDNA status at baseline and EOT, and clearance kinetics during first-line (1L) induction therapy were correlated with clinical outcomes. Results: The median patient age was 61 years (range: 18.3–84), and median follow-up was 18.7 months (range: 0.6–54.4 months). Disease stage at diagnosis was available for 139 patients: stage I (n=15, 11%), stage II (n=31, 22%), stage III (n=16, 12%), and stage IV (n=77, 55%). Stage was unknown in 9 patients. Overall, ctDNA detection at baseline was 95.7% (90/94), including 100% in patients with indolent B-cell (11/11), and T-cell lymphomas (6/6), and 94.8% (73/77) in patients with aggressive B-cell lymphomas. Across all subtypes, EOT ctDNA status was strongly prognostic for event-free survival (EFS). Patients with ctDNA-positivity at EOT had significantly worse EFS (HR: 7.33, 95%CI: 2.8-19.18, p<0.0001). In aggressive lymphomas, particularly in DLBCL, ctDNA positivity at EOT was associated with a markedly worse prognosis (Aggressive: HR: 7.69, 95%CI: 2.62-22.56, p=0.0002; DLBCL only: HR: 5.74, 95%CI: 1.71-19.23, p<0.01). Among patients with evaluable ctDNA time points relative to 1L therapy (N=60), ctDNA clearance at any time point during treatment correlated with improved EFS. (HR: 18.55, 95%CI: 4.82-71.32, p<0.0001). All patients who did not clear ctDNA relapsed, yielding a positive predictive value of 100% (11/11); the negative predictive value for those who did clear was 88% (43/49). The remaining six patients turned positive during surveillance prior to relapse. Of 15 patients treated with CAR-T cell therapy, 11 had pre- and post-infusion timepoints for ctDNA analysis. Of these, 82% (9/11) were ctDNA-positive prior to CAR-T, and 55% (5/9) achieved post-infusion ctDNA clearance and a complete clinical response, though one became ctDNA-positive and relapsed (13.3 months post-CAR-T), and another suffered non-disease mortality (22.3 months post-CAR-T). In contrast, all 4 patients remaining ctDNA-positive post-CAR-T relapsed or died within a median of 3.3 months (range: 1.3–6.4 months). Two patients persistently ctDNA-negative remain disease-free. Taken together, the PPV and NPV for 12-month EFS following CAR-T therapy using a single ctDNA timepoint were both 100%. Conclusions: This is the first report of the largest, real-world study evaluating the utility of ctDNA across a broad spectrum of heterogeneous lymphoma subtypes in patients receiving various standard of care therapies. ctDNA status at EOT and on-treatment clearance were strong predictors of clinical outcomes across multiple histological subtypes of lymphoma treated with standard-of-care agents including CAR-T cell therapy. The robustness of these findings across biologically distinct subgroups highlight the broad applicability of ctDNA testing for risk stratification and recurrence monitoring for both aggressive and indolent disease. Further prospective studies are needed to validate these findings.

Abstract The current European Leukemia Net guidelines (ELN22) classify AML patients with intermediate-risk cytogenetics and MDS-associated mutations (MDSm, mutations in ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2, U2AF1, ZRSR2) as adverse-risk but do not use MDSm+ to alter the risk stratification of patients who otherwise classify as favorable-risk. NPM1 mutations (NPM1+) are one of the most common alterations in AML and remain a favorable-risk biomarker for patients without co-occurring FLT3-ITD mutations or adverse-risk cytogenetics (NPM1+/ITD-/ARcyto-). However, prior studies have shown that older patients (≥65 years) with favorable-risk AML, including NPM1+/ITD-/ARcyto- genotype, have significantly higher relapse rates and decreased survival despite receiving comparable intensive chemotherapy regimens to their younger counterparts. Given that MDSm frequency increases with age in patients with NPM1+ AML, it raises the question as to whether MDSm contribute to poorer outcomes in older patients. To date, there have been differing results in retrospective studies examining the effect of MDSm on NPM1+ AML. Some cohorts demonstrate worse outcomes in those that have NPM1+/MDSm+ AML (Chan et al., Blood Adv. 2024), whereas others do not show a significant difference in NPM1+ AML with or without MDSm (Eckardt et al., Leukemia 2023; Othman et al., Blood 2024; Ruhnke et al., Blood Adv. 2025). We examined the mutational landscape in a large group of pre-treatment, diagnostic specimens from 271 patients, which included 119 patients enrolled in SWOG clinical trials (SWOG-9031, SWOG-9333, S0106, and S0112), 96 patients from the UW/FHCC Hematopoietic Repository, and 56 patients from the BeatAML cohort. All patients were treated with curative intent as per standard practice or on clinical trials and had adequate cytogenetic information and long-term follow-up data. Event-free and overall survival (EFS, OS) were estimated using the Kaplan-Meier method and compared using Cox regression models stratified by cohort. MDSm+ occurred in 17% of patients, with the most common mutations being in SRSF2 (7%) and SF3B1 (3%). To assess the impact of MDSm on outcomes of favorable-risk NPM1+ AML, we performed univariate analyses comparing OS and EFS for NPM1+ AML grouped by ELN22 favorable risk/MDSm-, ELN22 favorable/MDSm+, and ELN22 intermediate/adverse risk. Compared to NPM1+/MDSm- (n=116), favorable-risk NPM1+/MDSm+ (n=33) had worse OS with HR 2.0 [95% CI (1.1, 3.3), p=0.008] and had similar OS to those that are classified as ELN22 intermediate/adverse risk (n=122). There was no significant difference in EFS or complete remission rates between NPM1+ favorable risk with and without MDSm (p=0.36 and p=0.6, respectively). When we grouped the ELN22 favorable risk patients by age (<65 years vs. 65+ years), MDSm+ in younger patients did not show a difference for OS (HR 0.99, p=0.98). Older ELN22 favorable-risk patients (≥65) had poor OS regardless of presence of MDSm compared to younger MDSm- patients: older MDSm- (n=91) with HR 2.4, 95% CI (1.3, 4.6), p=0.005 and older MDSm+ (n=25) with HR 3.5, 95% CI (1.9, 6.3), p<0.0001. There was a trend toward worse OS in MDSm+ compared to MDSm- older patients, but this was not statistically significant (HR 1.42, p=0.33). Since most MDSm are in splicing factor genes (SF3B1, SRSF2, U2AF1, ZRSR2), we examined the effect of splicing factor mutations vs. other MDSm+ in ELN22 favorable risk and did not find a significant difference in OS (HR=1.01, p=0.97). Those with non-splicing MDSm+ had worse EFS compared to MDSm- and splicing MDSm+ (HR 4.12, p=0.0037), although no difference in OS. In this study, MDSm+ in the context of favorable-risk NPM1+ AML are associated with worse OS in a univariate analysis. However, this difference is likely due to the increased prevalence of MDSm with increasing age and overall worse outcomes of NPM1+ AML in older patients. When stratified by age, older NPM1+ AML patients had worse OS than younger NPM1+ patients overall, although presence of MDSm trended toward even worse OS in older patients. In younger patients, MDSm+ are not associated with a significant difference in OS, which is a similar finding compared to prior studies. Our findings suggest that NPM1+ AML is not necessarily “favorable-risk” in older patients, particularly with concurrent MDSm. Therefore, further understanding of the underlying biology of age in the context of NPM1+ AML is needed to improve outcomes for older patients.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) has shown high efficacy in relapsed MM, but further efforts are needed to mitigate non-ICANS delayed neurotoxicity (DNT) and non-relapse mortality (NRM). Identifying risk factors associated with DNT and NRM may help with risk mitigation by aiding the development of interventions for potentially modifiable risk factors and also help with clinical decision making. Methods: In this multi-center retrospective study from the US MM Immunotherapy Consortium, we evaluated 761 patients treated at 15 centers receiving standard of care cilta-cel for relapsed MM between May 2022 to December 2024. Risk factors for DNT, particularly Parkinsonism and NRM were evaluated in by univariable and multivariable analysis. Any NRM events occurring after disease progression were censored for NRM evaluation. Results: The median age of the cohort was 65 years old (range: 30-88), median prior lines of therapy (pLoT) were 5 (range: 1-23). Cilta-cel was used in earlier relapse (1-3 pLOT) in 16% (n=120) patients. High-risk cytogenetics [del 17p, t(14;16) or t(4;14)] were present in 39%, with extramedullary disease (EMD) in 27% and R-ISS stage III in 18% of patients, respectively. Majority of patients (86%) received bridging therapy with response to bridging (≥ partial response, PR) seen in 33% of patients, respectively. Median follow up was 10.1 months, with response rate of 92% and CR rate of 70%. DNT was seen in 10% (n=75) of patients, with distribution as follows: Parkinsonism in 2.9% (n=22), cranial nerve palsy in 4.6% (n=35) and other DNT in 2.4% (n=18), with some patients manifesting more than one type of DNT. Risk of DNT was higher in patients who did not respond to bridging therapy (Any DNT: 12% vs 6%; Parkinsonism: 5% vs 0.5%, both p<0.05) Of the 22 cases of Parkinsonism, 21 patients (95%) did not respond to bridging, even though they achieved a post CAR-T response with ORR of 91% and ≥ CR in 68%. Absolute lymphocyte count (ALC), a surrogate measure of CAR expansion was higher in patients who developed DNT, particularly Parkinsonism, including ALC at days 7,14,21,28 and as peak ALC in the first month post cilta-cel (p<0.05 for all). Median peak ALC for patients with vs without Parkinsonism was: 5.88 vs 1.17/uL (p<0.001). We evaluated risk of Parkinsonism with various thresholds of peak ALC expansion. Amongst patients who developed Parkinsonism vs. not, peak ALC was as follows, > 1000/uL: 100% vs 57%, > 2500/uL: 73% vs 19% and > 3000/uL: 68% vs 14% (all p<0.001). The absolute risk of Parkinsonism with ALC > 3000 vs ≤ 3000/uL was 12% vs 1%, p<0.001; for ALC 2500 vs ≤ 2500uL was 9% vs 1%, p<0.001. On multivariable analysis, peak ALC > 3000/uL (OR: 12.7, p<0.001) and non-response to bridging therapy (OR: 9.9, p=0.03) were independent risk factors for developing Parkinsonism after cilta-cel. After cilta-cel, 1 and 2 year NRM estimates were 9% and 10%, respectively. Amongst 63 (8%) patients experiencing NRM events, the most common cause of NRM was infectious complications (35, 56%), followed by acute immune-mediated adverse events (AEs) like CRS, ICANS, IEC-HS in 14 (22%), delayed immune mediated AEs like DNT and colitis in 6 (9.5%), second cancers in 5 (8%) and other causes in 3 (5%) patients, respectively. When evaluating the timing of NRM events, the risk of infection related mortality remained relatively stable in the first year, though immune mediated toxicty deaths were uncommon after 6 months, while SPMs were uncommon within the first 6 months. On multivariable analysis, non-response to bridging (HR 2.41, p=0.046), poor performance status ≥ 2, high-risk cytogenetics and age ≥ 70 years were independent predictors for NRM. Conclusion: In a large cohort of over 750 patients receiving cilta-cel, we identified potentially modifiable risk factors for Parkinsonism and NRM. Non-response to bridging therapy and peak ALC > 3000/uL were independent predictors of developing Parkinsonism. Peak ALC of > 2500/uL and > 3000/uL were associated with 9% and 12% absolute risk of Parkinsonism. This indicates that peak ALC of 2500/uL or 3000/uL in the first month after cilta-cel may be a potential biomarker to identify patients for pre-emptive interventions such as steroids that can suppress rapid CAR expansion and perhaps decrease the risk of Parkinsonism. In addition, we need to focus on effective bridging strategies to further decrease the risk of Parkinsonism, as well as NRM with cilta-cel.

Abstract Introduction Pronounced disparities in pediatric B-lymphoblastic leukemia (B-ALL) outcomes by race and ethnicity persist in the contemporary era. Gaps in overall survival (OS) from initial diagnosis are wider than event-free survival, suggesting that post-relapse mechanisms may contribute. However, data on treatment and outcomes after relapse are lacking. In a large, multicenter, real-world cohort of children and young adults with high-risk 1st relapse of B-ALL, we sought to (1) define survival outcomes by race/ethnicity and (2) explore if differences in therapy utilization drive outcomes. Methods We conducted an analysis within the Retrospective Study of Contemporary Approaches to 1st Relapse in B-ALL (ReCALL-1) cohort, which includes patients <30 years who initiated 1st relapse therapy between 2018-2022. This analysis was restricted to patients treated at US centers for “high-risk” 1st relapse, defined as relapse for which hematopoietic cell transplant (HCT) is generally standard-of-care: Early relapse (medullary <36m; isolated extramedullary <18m), late relapse with persistent end of reinduction disease, Ph+ B-ALL or age ≥18 years. Patients with Trisomy 21, those who received cell therapy before relapse and those who died during reinduction were excluded. The primary exposure was race/ethnicity categorized as Hispanic, non-Hispanic Black (NHB), non-Hispanic White (NHW), and other/unknown. The primary outcome was OS from relapse. Multivariable Cox regression models were constructed to include other social drivers of health (SDOH; health insurance, preferred language) and disease characteristics. Results Of 479 patients in ReCALL-1, 311 from 31 centers met inclusion for this analysis (41% Hispanic, 7% NHB, 46% NHW, 5% NH-other/unknown). With a median follow-up of 47m, OS differed by race/ethnicity (log-rank p=0.017): Hispanic, 4y OS 59%; NHB, 37%; NHW, 68%. Compared to NHW patients, NHB patients had an increased hazard of death (HR 2.3, 95% CI 1.3-4.3, p=0.006), while Hispanic patients were more similar to NHW patients (HR 1.3, 95% CI 0.9-2.0, p=0.16). Adjustment for SDOH only marginally attenuated the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.031) and led to equivalent outcomes for Hispanic patients (aHR 0.9, 95% CI, 0.5-1.5, p=0.66). Adjusting for disease characteristics that differed by race/ethnicity at p<0.2 (time to relapse, Ph+, Ph-like, KMT2Ar, age ≥18, or relapsed infant ALL) did not diminish the risk for NHB patients (aHR 2.0, 95% CI, 1.1-3.7, p=0.032) while outcomes remained equivalent for Hispanic patients (aHR 1.2, 95% CI, 0.8-1.8, p=0.40). Point estimates of cumulative incidence of non-relapse mortality (NRM) were highest in NHB patients (Hispanic, 4y NRM 13%, NHB 22%, NHW 11%), but this trend was not statistically significant (Gray’s p=0.52). Only 17% of patients initiated therapy for relapse on a clinical trial with no differences observed by race/ethnicity. Most patients received definitive treatment for relapse with either CAR T cell therapy (CART) or HCT: 79% overall, 74% Hispanic, 91% NHB, and 83% NHW. CART and HCT were utilized equally (39% and 40%, respectively) and the proportion that received each therapy did not vary by race/ethnicity. Time to CART/HCT, external referral for treatment, receipt of investigational v commercial CART, and use of post-CART consolidative HCT revealed no differences by race/ethnicity. Of the 66 patients (21%) who did not receive cell therapy, 26 had planned for CART or HCT, but did not receive due to disease progression or NRM (n=24; 12 Hispanic, 10 NHW), or insurance barriers (n=2, both Hispanic). After HCT, OS was worse for NHB patients (log-rank p=0.03) with 4y OS of 42% v 85% for NHW and 75% for Hispanic. Post-CART, 4y OS was 40% for NHB v 59% for NHW and 51% for Hispanic, but this difference was not statistically significant. Conclusion In a large real-world cohort of children with high-risk 1st relapse of B-ALL, we found a two-fold increased hazard of death for NHB patients compared to NHW patients, even after adjustment for other SDOH factors and high-risk disease features. In contrast to previous studies of adult patients, children appeared to have equal access to cell therapies across races/ethnicities. We found that Hispanic patients, who comprised >40% of the cohort, had similar survival to NHW children, suggesting that availability of cellular and immunotherapies may be mitigating historically observed disparities for children with relapsed B-ALL.

Abstract Introduction Ciltacabtagene autoleucel (cilta-cel) has demonstrated unprecedented response rates and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM), but a proportion of patients experience early relapse. Identifying these patients is essential to guide future therapeutic strategies, such as enhanced bridging therapy or consolidation, while avoiding overtreatment in those likely to achieve durable disease control. Methods We conducted a multi-center study of patients treated with cilta-cel at 15 U.S. academic centers. Outcomes were evaluated based on high-risk (HR) features, including functional HR disease (FHR; relapse within 18 months of first-line therapy initiation), true extramedullary disease (EMD), traditional HR cytogenetics as defined in CARTITUDE-1 [deletion 17p, t(4;14), t(14;16)], and a 2024 IMS-IMWG-adapted HR definition (deletion 17p; t(4;14) or t(14;16) with gain 1q or deletion 1p; and gain 1q with deletion 1p). Multivariable Cox regression was used to examine the association of HR features (FHR, adapted IMS-IMWG HR, and EMD, individually and collectively) with PFS while adjusting for baseline ferritin, prior BCMA, and ECOG performance status (PS ≥2). Among patients with ≥18 months of follow-up, we evaluated predictors of early relapse (≤18 months post infusion) using logistic regression. Results Our cohort included 598 patients treated with cilta-cel between 5/2022 and 12/2024 who had available data on all HR features. The median age was 65 years (range 33-83), and the median prior lines of therapy (pLOT) was 5 (range: 1-18, 84% with >3 pLOT); 8% had received prior BCMA-directed therapy, and 27% were penta-refractory. Most patients (88%) received bridging therapy and 30% achieved ≥ partial response. In our cohort, 33% (n=195) had FHR, 43% (n=258) had traditional HR cytogenetics, 42% (n=253) had adapted IMS-IMWG HR disease, and 11% (n=64) had EMD. Median follow up was 10.6 months (range 0.4-34.1). Overall response rate (ORR) and complete response (CR) rates were lower in patients with vs without HR features: FHR (ORR: 89% vs 94%, CR: 61% vs 75%), traditional HR (ORR: 90% vs 94%, CR: 65% vs 74%), adapted IMS-IMWG HR (ORR: 91% vs 94%, CR: 64% vs 75%) and EMD (ORR: 77% vs 94%, CR: 61% vs 71%). Corresponding 12-month PFS was also lower in patients with vs without HR features: FHR (55% vs 79%), traditional HR (63% vs 78%), adapted IMS-IMWG HR (61% vs 80%) and EMD (59% vs 73%). ORR, CR rate, and 12-month PFS in patients without any HR features compared to those with ≥1 HR feature were 96% vs 90%, 81% vs 64%, and 83% vs 65%, respectively. In multivariable models, each HR feature (FHR, adapted IMS-IMWG HR, and EMD) was independently associated with inferior PFS after adjusting for baseline ferritin, prior BCMA, and ECOG PS ≥ 2. However, because early relapse cannot always be identified a priori based on traditional risk factors, we sought to identify predictors of relapse within 18 months of cilta-cel in a subset of patients with ≥18 months of follow-up (N=247; infused by 12/2023). Notably, while FHR (OR=3.04, 95% CI=1.59-5.89) and adapted IMS-IMWG HR (OR=2.07, 95% CI=1.10-3.89) were independently associated with odds of relapse within 18 months, EMD was not (OR=0.90, 95% CI=0.32, 2.40) when accounting for prior BCMA, ECOG PS ≥ 2, and baseline ferritin. We also used a time-varying Cox model to examine each HR feature associated with PFS at two time periods, <18 and ≥18 months, while adjusting for baseline ferritin, ECOG PS, and prior BCMA. We confirmed that FHR and adapted IMS-IMWG HR were both associated with relapse <18 months (HR=2.05, 95% CI=1.48-2.83 and HR=1.56, 95% CI=1.11-2.19) but not in the ≥18-month time period (HR=0.70, 95% CI=0.19-2.59 and HR=0.76, 95% CI=0.24-2.40). The magnitude of the association for EMD with PFS was similar across both time periods (<18 months HR=1.67, 95% CI=1.09-2.57 and ≥18 months HR=2.17, 95% CI=0.45-10.40). Conclusion While cilta-cel leads to high response rates and durable PFS in RRMM, a subset of patients with FHR and adapted IMS-IMWG HR remains at increased risk for early relapse. In this large multi-center cohort, we describe PFS outcomes across high-risk subgroups and identify key predictors of relapse within 18 months of cilta-cel. These findings inform risk-adapted therapeutic strategies and interventional trials, including bridging, consolidation, or maintenance approaches, to improve outcomes in the highest-risk RRMM patients.

Abstract Introduction: Monoclonal gammopathy of undetermined significance (MGUS) affects over 2 million individuals aged ≥70 in the US. Earlier detection of smoldering multiple myeloma (SMM) and multiple myeloma (MM) in individuals with suspected MGUS via bone marrow biopsy allows for earlier active monitoring and potential intervention, including with daratumumab for high-risk SMM. Risk prediction for the presence of SMM or MM with the iStopMM and Mayo Clinic models leads to decreased individual-patient and population-level resource utilization burden of bone marrow testing with the tradeoff of some missed non-MGUS diagnoses. We sought to quantify the value of earlier diagnosis, while additionally accounting for the recent results of the AQUILA trial, by assessing the lifetime cost-effectiveness of bone marrow testing strategies for patients with suspected MGUS. Methods: In this independent analysis free of industry influence, we used a decision tree with nested Markov cohort models to evaluate diagnosis and disease progression from MGUS and SMM to MM across 3 diagnostic strategies employing: (1) iStopMM risk prediction model versus (2) Mayo Clinic risk stratification and prediction model versus (3) a test-all strategy. Both risk prediction model performance characteristics were derived from the largest population-level prospective cohort study. Individuals in the MGUS state were monitored annually for disease progression with blood tests. The SMM state included two groups: those correctly diagnosed through biopsy and those misclassified as MGUS due to not undergoing biopsy under the prediction model triage rules (missed SMM diagnosis). As recommended by guidelines, diagnosed patients with non–low-risk SMM were monitored with blood tests every three months; those with low-risk SMM were tested every six months. All diagnosed SMM patients underwent imaging for bone lesions at diagnosis and annually for up to five years. Missed SMM patients were monitored at the same frequency as those with MGUS until disease progression. Early versus delayed myeloma diagnosis complications were informed by real-world multi-institutional quasi-experimental data of consecutively diagnosed patients with MM. MM treatment and outcomes across up to four lines of therapy were modeled exactly as previously published in a validated model. In additional scenario analyses, we assessed the impact of daratumumab monotherapy in the care of people with high-risk SMM across all 3 testing strategies by incorporating the progression free survival and overall survival benefit as reported in the phase 3 AQUILA study. The primary outcome was the incremental net monetary benefit (iNMB), reported across all accepted US willingness-to-pay (WTP) thresholds from a US health system perspective. We concluded with extensive deterministic sensitivity analyses and additionally quantified uncertainty across all model parameters simultaneously with 10,000 Monte Carlo simulations. Results: The iStopMM model was the cost-effective strategy yielding the highest NMB of all strategies at every WTP threshold, with per-patient cost and effectiveness of $188,300 and 10.21 QALYs, respectively. This strategy was dominant—costing less and producing more QALYs—than both the Mayo Clinic and test-all strategies. At the population level, use of the iStopMM model over the Mayo Clinic model and the test-all strategy yields iNMBs of $0.67 [95% CI: 0.2 – 1.14] billion and $3.13 [95%CI: 2.80-3.47] billion, respectively, in favor of the iStopMM strategy. The iStopMM strategy was the cost-effective strategy in 100% of 10,000 second order Monte Carlo iterations. In deterministic sensitivity analyses, the top three parameters the iNMB was most sensitive to were prediction model test characteristics (i.e., sensitivity and specificity) as well as the baseline prevalence of SMM. However, no parameter variation could change the conclusion that iStopMM is the cost-effective strategy. In scenario analyses incorporating benefit of daratumumab monotherapy in the care of individuals with high-risk SMM, the iStopMM model remained the cost-effective strategy. Conclusion: Using the iStopMM risk prediction model for marrow sampling in patients with suspected MGUS leads to cost savings per patient evaluated, both with and without incorporating daratumumab benefit in the care of individuals with high-risk SMM, as compared to both the Mayo Clinic model and testing all with bone marrow biopsy.

Abstract Background: Intravenous (IV) isatuximab plus pomalidomide and dexamethasone (Isa-Pd) is approved for treatment in patients with relapsed/refractory multiple myeloma (RRMM) based on the ICARIA-MM study. Subcutaneous (SC) administration of Isa offers potential advantages such as shorter administration duration and greater patient comfort compared with IV routes. Isa SC via an on-body injector (OBI), an investigational wearable bolus injector, demonstrated safety and efficacy in a Phase 1b study in patients with RRMM. The IRAKLIA trial (NCT05405166) was the first Phase 3 trial evaluating the non-inferiority of Isa-Pd SC via an OBI vs Isa-Pd IV in patients with RRMM. Here, we report the findings of the IRAKLIA trial in the East Asian subgroup with RRMM. Methods: This global, multicenter, open-label study enrolledpatients aged ≥18 years with RRMM who had received ≥1 prior line of therapy (LOT) including lenalidomide and a proteasome inhibitor (PI). Patients were randomized 1:1 to Isa SC (1400 mg) or Isa IV (10 mg/kg) weekly in Cycle (C)1, then every 2 weeks in addition to P (4 mg orally daily, Day [D]1-21) and d (40 mg orally [20 mg if age ≥75 years] weekly). Treatment was administered in 4-week cycles and continued until disease progression, unacceptable toxicity, or patient withdrawal. Co-primary endpoints included overall response rate (ORR) and observed Isa concentration before dosing (Ctrough) at steady state (predose at C6D1). Key secondary endpoints included rate of very good partial response or better (≥VGPR), Ctroughlevel Cycle 2 Day 1 (C2D1), infusion reaction incidence, and patient satisfaction rate based on the patient experience and satisfaction questionnaire (PESQ) at C5D15. Results: The East Asian subgroup consisted of 105 patients from China (Mainland, n=82 and Taiwan, n=1) and Japan(n=22) (SC, n=50; IV, n=55). Baseline characteristics of the East Asian subgroup were generally balanced between the two arms and generally comparable to the overall global population (median age 62 years; median 2 prior LOT; 29.5% high-risk cytogenetics; 82.9% refractory to lenalidomide; 7.6% prior exposure to daratumumab). After a median of 13.0 months follow-up, ORR in the SC and IV arm was 74.0% and 70.9%, respectively (relative risk [95% CI] = 1.044 [0.815 – 1.335]). The mean (SD) of Ctroughat C6D1 was 502 (232) µg/mL for SC arm and 282 (123) µg/mL for IV arm. The geometric mean ratio (90% CI) comparing SC to IV for Ctrough at steady state was 1.756 (1.346 – 2.290). The ≥VGPR rates were 58.0% for SC and 50.9% for IV (relative risk [95% CI] = 1.139 [0.798 – 1.631]). The mean(SD) of C2D1 Ctroughlevel was 420 (161) µg/mL for the SC arm and 262 (111) µg/mL for IV arm. The geometric mean ratio (90% CI) comparing SC to IV for Ctrough at C2D1 was 1.673 (1.321 to 2.120). The infusion reaction incidence was 0% and 21.8% for SC and IV, respectively. Grade ≥3treatment-emergent adverse events were observed in 82.0% and 87.3% of patients in the SC and IV arms, respectively. Treatment discontinuation rates were 6% for the SC arm and 12.7% for the IV arm. Injection site reactions (ISRs) occurred in 4% (2/50) of patients in the SC arm and in 0.21% (2/964) of SC injections (all Grade 1), with 99.3% of SC injections completed successfully. Isa SC patients expressed higher satisfaction with their injection method, with 64.0% of patients reporting “satisfied” or “very satisfied” vs 52.7% of Isa IV patients (odds ratio [95% CI] = 1.594 [0.728 – 3.489]). Conclusions: The efficacy, safety and pharmacokinetic results between Isa SC vs IV + Pd in the East Asian population from the IRAKLIA study were consistent with the results of the overall global population, in which non-inferiority of ORR, Ctrough at C6D1, ≥VGPR and Ctrough at C2D1 was demonstrated and statistically significantly fewer infusion reactions and higher patient satisfaction were also noted for SC vs IV. These results support the potential use of Isa SC delivered via OBI in East Asian patients and demonstrate the potential of this delivery method to improve patient experience and practice efficiency.

Abstract Background Myelodysplastic syndromes (MDS) develop from the acquisition of somatic mutations over years or decades. While some mutations are random stochastic events, others derive from extrinsic agents that promote genomic instability, including environmental exposures. Agent Orange (AO) is a phenoxy herbicide used by the U.S. military as a defoliant during the Vietnam War (1962-71), often diluted with gasoline to promote aerosolization, contaminated with the carcinogen dioxin during the manufacturing process, and linked to various cancers. We studied AO as a risk factor for MDS. Methods The prospective National Heart, Lung, and Blood Institute National MDS Natural History Study includes patients (pts) with suspected or recently diagnosed MDS enrolled from 6/2016-6/2024. Bone marrow samples underwent central pathology review, resulting in diagnoses including MDS, MDS/myeloproliferative neoplasm overlap (MDS/MPN), or clonal cytopenia of undetermined significance (CCUS). Pts completed detailed assessment for AO exposure and other risk factors for MDS development. Associations between AO exposure, mutation prevalence, and key covariates (demographics, diagnosis, military service, clinical history, cytogenetics and smoking) were assessed using univariate tests of association, multivariable regression and Cox regression models for survival and progression. Results Among 2115 enrolled pts, 1191 (56%) had a myeloid malignancy or precursor condition and 130 (6.1%) reported AO exposure, the majority (96%) male. Compared to unexposed pts, AO exposed pts were more likely to derive from the 1945-54 birth cohort (p<.001), of age to serve in Vietnam, and to have an ultimate diagnosis of MDS or CCUS vs. a non-clonal diagnosis (57% vs. 44%, p=.046). AO exposure was more common among Blacks (12% vs 6%, p=.02), specifically Black males (21% vs 9%, p=.006). AO exposure was marginally associated with International Prognostic Scoring System (IPSS)-R poor-risk cytogenetics (p=.066) and lower baseline platelet count (p=.072). In multiple regression analyses, risk of AO exposure was significantly higher for the 1945-1954 birth cohort (OR [95% CI]=10.3 [4.4-30.6], p<.001), among those with military service (OR=24.1 [11.9-55.8], p<.0001), and for Blacks vs Whites (OR=2.6 [1.2-5.5], p=.017). The crude risk of AO exposure trended higher for patients with MDS compared to idiopathic cytopenia of undetermined significance (ICUS; OR=2.1 [0.9-6.0],p=.13), but not in multivariable analysis (OR=1.3 [0.5-4.4, p=.60]). AO exposure trended toward an association with younger age at MDS diagnosis (p=.06) and toward having a prior primary malignancy (49% vs. 41%, p=.09): Compared to non-AO exposed pts, AO exposed pts had higher rates of prior prostate cancer (16% vs. 8%), notable given its documented association with AO exposure. AO exposure was not associated with a history of or intensity of cigarette smoking (p=.67). After accounting for age, diagnosis, sex, and military service, AO exposure was significantly associated with increased numbers of pathogenic variants in 53 genes (OR=1.2 [1.0-1.4], p=.02) and with having Very Poor/Poor risk IPSS-R cytogenetics (OR=3.7 [1.2-11.1], p=.02). AO exposed and non-exposed pts had similar overall survival (HR=1.1 [0.8-1.7], p=.50), but those exposed to AO had a higher risk of disease progression in the first two years following diagnosis (HR =1.9 [1.2-2.8], p=.004). AO exposed pts appeared more likely to have del (5q) (15% vs. 8%) and del (20q) (13% vs. 5%) karyotypic abnormalities, and TP53 (7.7% vs. 4.5%), STAG2 (5.1% vs. 2.8%), and NRAS mutations (3.4% vs. 1.7%), although sample sizes were small. Focusing on gene pathways, AO exposed pts appeared more likely to have abnormalities in RAS signaling (10.3% vs. 5.7%), cell cycle (7.7% vs. 4.5%), and cohesion complex pathways (6.0% vs. 3.1%), but less likely to have abnormalities in cytokine receptor pathways (0% vs. 4.5%). ConclusionsIn our representative national cohort of pts with at least one cytopenia, and for the first time, we demonstrated that AO exposure is associated with younger age at MDS diagnosis, ultimate MDS diagnosis, genetic complexity of MDS, increased risk of disease progression, and with Black race, despite Black individuals comprising just 16% of men who served in the Vietnam War and being less likely to have MDS than white individuals. AO should formally be recognized as a risk factor for the development of MDS.

Abstract Background: There remains an opportunity for new therapies to improve long-term outcomes for patients with low-tumor burden follicular lymphoma (FL). Mosunetuzumab is an off-the-shelf CD20xCD3 bispecific antibody, approved as an intravenous therapy for patients with relapsed/refractory FL after ≥2 lines of systemic therapy. Mosunetuzumab can be administered in the outpatient setting as a fixed-duration regimen. In an open-label, multicenter, Phase II study conducted mainly across US community sites (MorningSun; NCT05207670), mosunetuzumab administered subcutaneously (SC) induced high response rates with a manageable safety profile in patients with previously untreated low-tumor burden FL (Burke et al. ASH 2024). Here we present updated efficacy and safety data for mosunetuzumab SC in patients with previously untreated, low-tumor burden FL. Methods: Patients had untreated Grade 1 or 2 low-tumor burden FL per Groupe d'Etude des Lymphomes Folliculaires criteria, Ann Arbor stage III/IV disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2. Mosunetuzumab SC was administered with step-up dosing in Cycle 1 (Day [D]1, 5mg; D8, 45mg; D15, 45mg), then 45mg on D1 of each 21-day cycle. Hospitalization was not mandatory. Patients with a complete metabolic response after 8 cycles could complete therapy and patients with a partial metabolic response or stable disease continued treatment for up to 17 cycles. The primary endpoint was progression-free survival (PFS) at 24 months. Key secondary endpoints included objective response rate (ORR), time to response (TTR), overall survival (OS), duration of response (DOR), duration of complete response (DOCR), and safety. Exploratory analyses assessed pharmacodynamic changes in B-cell subsets. Here, we report interim data. Results: As of February 10, 2025 (clinical cut-off date), 101 patients were enrolled from US community (n=56) and academic (n=45) centers; 52 patients had completed treatment, 21 had discontinued (mainly due to adverse events [AEs; n=6] and progressive disease [n=5]), and 28 were ongoing on treatment. Median age was 65 years (range: 34–82). Most patients had an ECOG PS of 0 (81.2%) or 1 (18.8%) and 43 patients (42.6%) had extranodal involvement. Median duration of follow-up was 13.8 months (95% confidence interval [CI]: 11.5–16.9) and median number of cycles received was 10 (range: 3–17). The ORR was 98.0% (95% CI: 93.0–99.8) and the complete response rate was 89.1% (95% CI: 81.3–94.4). Median TTR was 2.8 months (range: 1.4–8.3). Landmark DOR and DOCR rates at 12 months were 91.8% (95% CI: 81.5–96.5) and 95.7% (95% CI: 82.6–99.0), respectively. The 12-month PFS and OS rates were 92.0% (95% CI: 83.8‒96.1) and 99.0% (95% CI: 93.2‒99.9), respectively. The most common AE was injection-site reaction (ISR, 81.2%; Grade 1, 74.3%; Grade 2, 5.9%; Grade 3, 1.0%). Grade 3/4 AEs were reported in 51.5% of patients; the most common (≥10%) events were cytopenias (36.6%) and infections (11.9%). Cytokine release syndrome (CRS) was reported in 48.5% of patients (Grade 1, 40.6%; Grade 2, 7.9%). Overall,infections occurred in 63.4% of patients (Grade 1, 7.9%; Grade 2, 42.6%; Grade 3, 11.9%; Grade 5, 1.0%) with the most common (≥10%) being upper respiratory tract infection (21.8%), COVID-19 (17.8%), sinusitis (13.9%), and pneumonia (11.9%). At the time of data cut-off, ISR, CRS, and infection AEs were resolved at rates of 98.2%, 100%, and 89.0%, respectively. Two patients had a Grade 5 AE (sepsis, n=1; unknown cause, n=1).No immune effector cell-associated neurotoxicity syndrome events were reported. B-cell depletion was observed following the first dose of mosunetuzumab, with subsequent B-cell recovery observed within six months of treatment completion. Conclusions: Fixed-duration mosunetuzumab SC demonstrates high efficacy rates with deep and sustained responses in patients with previously untreated, low-tumor burden FL. The manageable safety profile supports ease of outpatient administration without mandatory hospitalization, including in community oncology practices. Additionally, exploratory analyses demonstrating B-cell recovery after treatment completion also substantiate the use of mosunetuzumab SC as a fixed-duration regimen. These data support further evaluation of mosunetuzumab SC in patients with previously untreated, low-tumor burden FL.

Abstract INTRODUCTION Outcomes for 1st relapse of pediatric B-lymphoblastic leukemia (B-ALL), especially high/intermediate-risk (HR/IR) relapse, remain unacceptably poor. Limited enrollment of this population on cooperative group clinical trials has impeded our ability to study potentially effective regimens. In the current era, patients can access innovative immunotherapies commercially. However, there is no mechanism to capture outcomes for these off-study patients and no comparative effectiveness data to guide treatment selection. METHODS We conducted a multicenter, retrospective study of patients <30 years who initiated 1st relapse therapy at a participating center from 2018-2022 (ReCALL-1 Study). Objectives were to define real-world survival outcomes, compare response rates of reinduction strategies, describe the post-reinduction treatment landscape, and, for patients with HR/IR relapse, assess the comparative effectiveness (CE) of blinatumomab to hematopoietic cell transplant (blina/HCT) v CD19 CAR T cells (CART). For the CE analysis, we emulated an open-label, randomized study of blina/HCT v CART who achieved an M1/M2 marrow at the end of an intensive reinduction (EoRI). Patients were classified by their intended treatment at EoRI. Cox regression models were used to adjust for unbalanced patient and disease features by arms. The primary outcome was overall survival (OS) from EoRI. RESULTS The full cohort included 479 patients from 33 centers (31 US, 2 international). Median time to relapse was 31 months (m); 77% had bone marrow (BM) involvement and 31% central nervous sytem involvement. With a median follow-up of 49m from relapse, 4 year (y) OS, event-free survival (EFS), and non-relapse mortality (NRM) were 64%, 43%, and 13%, respectively. Among patients with very early BM (<18m, n=79), early BM (18-35m, n=76), late BM (≥36m, n=162), and isolated CNS (n=85) relapses, 4y OS/EFS were 29%/20%, 57%/35%, 78%/49%, and 84%/61%, respectively. Only 19% received reinduction therapy on a clinical trial. Among patients with BM disease, R3 reinduction (n=179) and VXLD (n=61) had identical MRD-negative (<0.01%) CR rates of 38% (p=1.00) and equivalent treatment failure (TF; M3 or extramedullary disease) rates: R3, 8% v VXLD 7%, p=0.79. Blina (n=33) and inotuzumab-based (n=21) reinductions achieved MRD-negative CR rates of 39% and 52%, respectively, but higher TF rates of 39% and 24%. Reinduction mortality was 2%: R3, n=5; VXLD, n=3; 3-drug reinduction, n=1. Overall, as part of 1st relapse therapy, 36% received CART (78% commercial product), 44% HCT, 40% blina, and 11% inotuzumab. The emulated trial included 159 patients, 95 on blina/HCT and 64 on CART. Study arms were well matched by demographics, cytogenetics, and relapse sites, but CART patients were more likely to have relapsed <18m from diagnosis (34% v 24%) and have EoRI M2 marrows (31% v 11%), and less likely to have private insurance (36% v 51%). Unadjusted OS was comparable between arms (log rank p=0.18): CART, 60% at 4y; blina/HCT, 71%, as was NRM (10% v 13% at 4y). EFS was lower for CART (p=0.049): 4y EFS 35% v 49% for blina/HCT. After adjustment for unbalanced covariates, the hazard of death was equivalent for CART as compared to blina/HCT (aHR 1.1, 95% CI 0.6-2.1, p=0.67) and EFS became more comparable (aHR 1.3, 95% CI 0.8-2.1, p=0.22). 91% of blina/HCT and 97% of CART received their intended cell therapy; time from EoRI to cell therapy was shorter for CART (67 v 86 days, p<.001). In the CART arm, 34% underwent consolidative HCT; 1/3 were preplanned and 2/3 due to loss of B cell aplasia or NGS-MRD positivity. Of those with a 2nd relapse, CART patients were more likely to be CD19 negative (47% v 10%, p=0.003). CONCLUSION In this multicenter, real-world cohort of children treated for 1st relapse in the immunotherapy era, suboptimal outcomes for early BM relapse persisted, with particularly dismal 4y OS of 29% for relapses <18m after diagnosis. In contrast, survival for late BM and isolated CNS relapses compared favorably to historic data. Only 1 in 5 patients initiated relapse therapy on a clinical trial and although 1st relapse is not an approved indication for commercial CART in pediatrics, 36% received CART. In an emulated trial of post-reinduction blina/HCT v CART, adjusted EFS and OS were comparable, suggesting that CART may be a viable alternative to HCT for select patients. Post hoc analyses will identify whether specific subgroups may benefit more from one strategy.