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Abstract Introduction The treatment of newly diagnosed multiple myeloma (NDMM) has rapidly evolved. Quadruplet induction combining an anti-CD38 monoclonal antibody, lenalidomide, a proteasome inhibitor, and dexamethasone has become a standard of care. In this prospective randomized phase 2 trial, we evaluated the efficacy and safety of induction with a four-drug combination of daratumumab (Dara), lenalidomide (R), ixazomib (I), and dexamethasone (d) (Dara-RId) in older, transplant ineligible or deferred patients, followed by maintenance with Dara RI versus R for up to 2 years. We hypothesized that this quadruplet would offer improved tolerability with less peripheral neuropathy in this older population as well as the convenience of largely oral therapy. Herein, we present the initial results of the induction phase of the study. Methods Transplant-ineligible or deferred patients with NDMM were eligible to participate. This was a multicenter trial sponsored by the Alliance Foundation Trials, LLC, AFT-41 (NCT04009109). Each cycle of treatment was 28 days. All patients received 12 cycles of induction therapy with daratumumab 1800 mg subcutaneously on the conventional schedule, lenalidomide 15 mg orally (po) on days 1-21, ixazomib 4 mg po on days 1, 8, 15, and dexamethasone weekly. After 12 cycles, patients received maintenance based on prior randomization (1:1) to Dara-RI or R for up to 2 years. In maintenance, R was reduced to 10 mg and I was reduced to 3 mg. Randomization assignment occurred prior to starting induction. Stratification was based on presence of high-risk features defined as ISS stage III or high-risk FISH cytogenetics (del 17, t (14;16), t (14;20), t (4;14), del (1p), or gain (1q)). The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR) and adverse events. Results We enrolled 79 patients across 7 sites from October 2020 until December 2023. Accrual was affected by the COVID19 pandemic, leading to early closure to accrual in December 2023. Median age was 74 years (range 63-86); ≥75 years of age (45.6%); female (59.5%); white (83.5%), African American (7.6%), Asian (1.3%), and Hispanic ethnicity (6.3%). Additional baseline characteristics included ISS staging I (41.8%), II (35.4%), and III (22.8%) with high-risk features in 37% by ISS stage III and/or high-risk FISH. The 12-month PFS was 92% (95% confidence interval [CI] 86.1-98.4%). The ORR (≥ partial response [PR]) during induction was 92.4% (PR 22.8%; very good partial response [VGPR] 46.8%; complete response 15.2%; stringent complete response 7.6%). Notable grade ≥3 adverse events included neutropenia (16.5%), infections (11.4%), anemia (10.1%), thrombocytopenia (8.9%), and syncope (7.6%). There was no grade ≥3 peripheral neuropathy (grade 1, 15%; grade 2, 14%). No treatment-related mortality was reported. Sixty-one patients went on to maintenance therapy and seven patients discontinued treatment for adverse events during induction (8.9%). Conclusions Dara-RId therapy in NDMM appears to be efficacious with an ORR of 92.4%; VGPR or better of 69.6% and 12-month PFS of 92%. The combination was generally tolerated well with manageable toxicity, despite 45.6% of patients being ≥75, offering the convenience of an oral proteasome inhibitor, ixazomib, that minimizes the risk of peripheral neuropathy for older, transplant-ineligible or deferred patients. Follow-up is ongoing to determine the benefit of maintenance with Dara-RI v. R alone in this population. Support: AFT, Celgene, Janssen, Takeda.

Abstract Background Translocation of chromosomes 4 and 14 (t(4;14)) results in overexpression of MMSET and has been associated with poor clinical outcomes in patients (pts) with multiple myeloma (MM). KTX-1001 is a first-in-class, potent, and selective oral inhibitor of MMSET (also known as NSD2) developed as the first investigational therapy to directly target the high-risk t(4;14) translocation, a key molecular driver in MM. KTX-1001 binds to and inhibits the catalytic SET domain of MMSET, thereby suppressing the deposition of dimethylated histone H3 lysine 36 (H3K36me2), leading to downregulation of oncogenic histone modifications and epigenetic reprogramming of malignant plasma cells. Preclinically, KTX-1001 synergistically inhibited cell viability in MM cell lines when combined with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), or cereblon E3 ligase modulator (CELMoD™). Preliminary findings were previously reported from the initial cohort of 18 pts enrolled in a first-in-human phase 1 trial evaluating KTX-1001 in relapsed/refractory multiple myeloma (RRMM; NCT05651932; Bories et al. Blood. 2024;144[Suppl 1]:3370). Here, we present updated results from this study. Methods RRMM pts who received ≥3 prior therapies, including PI, IMiD and anti-CD38 monoclonal antibody (anti-CD38 mAb), received oral KTX-1001 across 9 dose levels using a 3+3 dose-escalation design. Primary objective was to determine the recommended Phase 2 dose (RP2D) and the maximum tolerated dose (MTD). Secondary objectives included pharmacokinetics, pharmacodynamics (PD), and primary efficacy. The dose expansion phase has been initiated to evaluate KTX-1001 in combination with either carfilzomib or the investigational CELMoD™ mezigdomide in t(4;14) RRMM pts. Results As of 13 June 2025, 40 pts have been treated in the monotherapy dose-escalation phase. The maximum tolerated dose (MTD) was exceeded due to dose-limiting toxicities (DLTs) in 2 pts: two Grade (Gr) 4 thrombocytopenia and one Gr 3 epistaxis. Backfill at selected dose levels is ongoing to further characterize safety profile and refine dose optimization. The median time from initial MM diagnosis was 8 years (range:2-20) with a median of 6.5 prior lines of therapy (range: 3-25). This included stem cell transplant (70%), BCMA CAR-T (42.5%), and non-CAR-T BCMA targeted drugs such as antibody-drug conjugates and bispecific antibodies (57.5%). The median age was69 years (range:50-83); 21 were female and 19 were male. Extra-medullary disease was present in 13 (32.5%) pts. Nineteen (47.5%) pts had t(4;14) translocation, 5 (12.5%) had 1q21 gain and 4 (10%) had deletion 17p. A total of 16 (40%) pts have shown a treatment response according to IMWG criteria or have achieved stable disease: 1 VGPR (10+ months), 1 PR (4+ months), 2 MR (3+ and 12 months), 12 SD (2-20+ months). KTX-1001 has demonstrated a favorable tolerability profile. Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 31 (77.5%) pts. The most frequent (≥20% pts) Gr 3/4 TEAEs were thrombocytopenia in 12 pts (30%; grade 4 in 8 [20%]), neutropenia in 12 pts (30%; febrile neutropenia in 2 [5%]), anemia in 10 (25%) pts. Gr 3 infections were observed in 5 (12.5%) pts and fatigue in 5 (10%) pts. The main reason for treatment discontinuation was progressive disease (57.5%), other pts discontinued due to physician decision (5%), consent withdrawal (5%), and one pt due to adverse event. Twelve (30%) pts remain on treatment. At Cycle 1 Day 15, drug exposure and steady-state concentrations of KTX-1001 increased with dose. A dose-dependent reduction in H3K36me2, the primary PD marker of KTX-1001 activity, was observed in peripheral blood at Cycle 2 Day 1 and beyond, which plateaued above dose-level 4. Paired bone marrow samples further confirmed on-target PD effects, with a marked reduction in H3K36me2 levels in MM cells at Cycle 2 Day 1 with observed anti-MM effect of reduced proliferation of MM cells with concomitant increased proliferation in immune cells in pts achieving clinical benefit. ConclusionsKTX-1001 is a novel agent showing tolerable safety profile in RRMM and demonstrating promising single agent activity in heavily pretreated, triple class refractory RRMM including those with high-risk features. KTX is currently evaluated in ongoing study in combination with carfilzomib and the investigational CELMoD™ mezigdomide in t(4;14) RRMM pts.

ABSTRACT Background Given the Centers for Medicare and Medicaid Services' coverage of screening CT colonography (CTC) beginning in January 2025, we evaluated the cost‐effectiveness of CTC for colorectal cancer (CRC) screening by race (Black and White) and gender, considering real‐world screening adherence. Methods A microsimulation model compared CRC screening strategies in average‐risk adults by race and gender, incorporating 2010–2019 U.S. data on disease progression and real‐world screening adherence for colonoscopy and fecal immunochemical test (FIT). Five strategies were compared: (1) status quo (choice between colonoscopy and FIT); (2) CTC every 5 years; (3) colonoscopy every 10 years; (4) annual FIT; and (5) multitarget stool DNA test every 3 years, plus no screening. Lifetime costs, quality‐adjusted life years gained (QALYG), and incremental cost‐effectiveness ratios were projected. A willingness‐to‐pay threshold of $100,000/QALYG was used. Results Under the status quo, Black adults showed higher CRC cases and greater utilization for FIT over colonoscopy than White adults. Compared to the status quo, the CTC strategy yielded more QALYG and fewer CRC cases among Black adults, but fewer QALYG and more CRC cases among White adults. Both status quo and CTC strategies outperformed other strategies across races. The CTC strategy was the dominant strategy for Black adults. For White adults, the status quo was cost‐effective with incremental cost‐effectiveness ratios of $34,998–$73,428/QALYG, while the CTC strategy was cost saving compared to no screening. Conclusions CTC could be cost‐effective for CRC screening in Black adults under real‐world screening adherence, supporting Medicare coverage to address specific population needs and structural barriers to screening.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Background: Patients with low gradient non-severe aortic stenosis (AS) at rest, in the context of reduced left ventricular ejection fraction (LVEF) (less than 50%), occasionally undergo dobutamine stress echocardiogram (DSE). However, limited data is available in the literature regarding the utility of DSE in this context. Methods: We conducted a retrospective study on patients with non-severe AS and LVEF less than 50% at rest who underwent DSE after Institutional Review Board approval. Retrospective data was extracted including rest and DSE parameters using an internal database. Only patients greater than 18 years old, who had an LVEF less than 50%, mean gradient (MG) less than 40 mmHg, and valve area greater than or equal to 1 cm 2 at rest were included in the study. Univariate and multivariate regression methods were used to identify which resting variables were associated with severe AS (MG greater than 40 mm Hg and valve area less than 1 cm 2 ) with DSE. Results: A total of 124 patients were included in the study. The mean age of patients was 78 years (±9) and 84% were male. The mean resting LVEF was 34% (±8%) while it was 40% (±12%) with DSE, mean stroke volume index at rest was 39 mL/m2 (±9) while it was 45 mL/m2 (±10) with DSE, MG at rest was 20 mmHg (±7) while it was 31 mmHg (±10) with DSE, and mean aortic valve area at rest was 1.27 cm 2 (±0.27) while it was 1.24 cm 2 (±0.29) with DSE. Of the 124 patients with non-severe AS at rest, 13 (10.5%) patients had severe AS with DSE. MG at rest was associated with severe AS (OR 1.3; 95% Cl: 1.1 - 1.5; p < 0.001) in a multivariate logistic regression model after adjusting for age, sex, LVEF at rest, SV index at rest. Resting aortic valve mean gradient also showed the highest AUC in relation to likelihood of having severe AS (0.87) (figure 1). Conclusion: Our study indicated that DSE remains useful in identifying severe AS in certain patients (up to 10%) who exhibit non-severe AS at rest in the setting of reduced LVEF. Additionally, MG at rest is the most reliable parameter to determine those who may benefit from undergoing DSE. This is one of the first studies to our knowledge in the literature suggesting that DSE may still be useful in identifying severe AS patients despite non-severe AS (i.e., valve area greater than or equal to 1 cm 2 ) at rest with reduced LVEF. Further research is warranted to validate our findings.

Abstract The Patient‐Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO‐CTCAE) was developed by the US National Cancer Institute to allow patients to directly report their side effects, enhancing the accuracy and patient‐centeredness of cancer clinical trial adverse event reporting. Clinician‐based reporting often misses the full range of patient symptoms, resulting in underreporting of side effects. The selection of adverse events for patient reporting must be defined in advance and consistently applied across all study arms. Investigators can use core symptom sets, including diarrhea, fatigue, and nausea, alongside tailored items specific to the treatments being studied. PRO‐CTCAE has demonstrated similar scores across electronic, paper‐based, and automated telephone administration methods. PRO‐CTCAE administration typically occurs before start of treatment and regularly throughout treatment, with the administration frequency tailored to the expected trajectory of side effects. Ensuring high survey completion rates is essential for PRO‐CTCAE success. Standard reporting can include tabular reporting of the proportion of patients with any (score ≥1) and high (score ≥3) levels of symptoms at the individual item level. A baseline‐adjustment approach should be applied to account for symptoms before start of treatment to isolate treatment‐emergent adverse events. The distribution of PRO‐CTCAE scores at each time point can be visualized using stacked bar charts. PRO‐CTCAE integration into cancer clinical trials is crucial for capturing a comprehensive range of treatment‐related symptomatic adverse events and improving the evaluation of therapy tolerability. Ongoing research continues to refine its implementation, supported by regulatory guidance.

Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs. A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories—“thyroid”, “pituitary and adrenal”, and “diabetes mellitus”. A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements. Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.

Abstract Pain is a common postpartum complaint, yet data suggest that approaches to postpartum pain management vary widely. Given the goal of improving quality and equity in postpartum pain management, we aimed to examine whether and how clinicians' perspectives on postpartum pain management differed by clinician roles. This is a qualitative study at a large, tertiary, and academic medical center. From November 2021 to June 2022, obstetric clinicians, including attending physicians, trainee physicians, and advanced practice providers (APPs), were recruited to complete in-depth interviews regarding their clinical experience managing postpartum pain using a semi-structured interview guide. Participants were asked to reflect both on their own role and that of the other clinician types. Purposive sampling was used to enroll a cohort representative of the institutional workforce in terms of clinician type and demographics. Data were analyzed using the constant comparative method. Of 46 participants, 47.8% (n = 22) were attending physicians, and 91% (n = 42) were female. Emergent themes were both self-reflected and externally directed. Data demonstrated that postpartum pain management differs by clinician type and level of experience. Themes related to the role of attending physicians included responsibilities as teachers for trainees, supervisory roles, and perceptions that attendings have greater comfort with prescribing opioids. Themes related to the role of trainee physicians included the impact of patient load on trainees' management, limitations of morning rounds, familiarity with emerging data, and perceptions of hesitancy to prescribe opioids. Themes related to the role of APPs included less reliance on opioids for postpartum pain management and emphasis on nonpharmacological approaches. Perspectives on postpartum pain management vary by clinician role. Consideration of these differences and the interplay between roles is essential when examining opioid prescribing patterns and developing interventions to improve postpartum pain management.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~ 50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience unexpectedly poor outcomes. We profiled 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival (≤ 3 years, n = 42), using whole-genome, transcriptome, and methylation analyses. All but one BRCA-deficient tumor exceeded an accepted HRD genomic scarring threshold. However, patients with BRCA1-deficient HGSC with a more elevated HRD score survived significantly longer. Patients with BRCA2-deficient HGSC and loss of NF1 survived twice as long as those without NF1 loss, whereas PIK3CA or RAD21 amplification defined BRCA2-deficient HGSC with exceptionally short survival. BRCA1-deficient tumors in short survivors had evidence of immunosuppressive c-kit signaling and EMT. In a large HGSC cohort (n = 1,389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), the location of the mutation within functional domains stratified clinical outcomes. Notably, residual disease after primary surgery had limited prognostic effect in gBRCApv-carriers compared to non-carriers. Our findings indicate that tumor HR proficiency in the context of therapy response and survival is not a binary property, and highlight genomic and immune modifiers of outcomes in BRCA-deficient HGSC.