Citations

Abstract The therapeutic landscape for systemic immunoglobulin light chain (AL) amyloidosis has been revolutionized by daratumumab-based regimens, achieving 76% 5-year overall survival in the landmark ANDROMEDA trial. However, the current prognostic models were developed using patient populations treated with now-suboptimal therapies, creating a critical gap between risk stratification models and contemporary outcomes. This comprehensive review analyzes prognostic factors and progression biomarkers in AL, categorizing them into disease-specific (clone-related and organ-related) and patient-specific factors. Notably, traditional baseline biomarkers including difference between involved and uninvolved free light chains and bone marrow plasma cell burden are losing prognostic significance with effective clone-directed therapies. Emerging approaches show promise, including dynamic markers such as minimal residual disease by free light chain mass spectrometry, cardiac imaging parameters such as global longitudinal strain, and functional measures. There is an urgent need for validation studies and prognostic model refinement to identify patients at high risk who may benefit from interventions beyond anti–plasma cell therapy.

PURPOSE The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. Methods We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. RESULTS PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)–defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. CONCLUSION PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator–naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.

Cancer health disparities represent profound inequalities in incidence, outcomes, and survivorship across populations. While traditionally examined through distinct lenses of either molecular biology or social epidemiology, these disparities arise from the complex interplay of genetic susceptibility, epigenetic dysregulation, and social determinants of health (SDoH). This review proposes that DNA damage and genomic instability serve as a critical mechanistic bridge, integrating exposures from the societal level to cellular dysfunction. We synthesize evidence demonstrating how SDoH—such as systemic inequities, environmental exposures, and chronic stress—converge with genetic and epigenetic factors to disproportionately increase DNA damage burden, impair repair mechanisms, and accelerate tumorigenesis in marginalized communities. Using the elevated gastrointestinal cancer rates among Native Hawaiians and Pacific Islanders (NH/PI) as a case study, we illustrate how historical, environmental, and socioeconomic factors interact with biological pathways to drive disparities. The review highlights key advances in DNA damage research—from somatic mutation theory to the modern understanding of chronic genomic stress—and explores how innovations in single-cell genomics, biomarker discovery, and computational modeling can unravel disparity etiologies. We argue that a translational framework linking social exposure data to molecular biomarkers of DNA damage is essential for moving beyond descriptive disparities to mechanistic understanding. Ultimately, addressing cancer equity requires interdisciplinary strategies that bridge molecular oncology, public health, and community-engaged research, targeting the root causes where social inequities become biologically embedded as genomic instability.

Objectives: Cerebral hemodynamic impairment in patients with asymptomatic high-grade internal carotid artery (ICA) stenosis confers a risk of stroke and cognitive decline, but correlations between degree of stenosis and hemodynamic impairment are derived from small case series only. Using baseline data from 282 participants in the Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis – Hemodynamics (CREST-H) study, we hypothesized that degree of stenosis, measured by peak systolic velocity (PSV) and end diastolic velocity (EDV) in the ipsilateral ICA, would correlate with time-to-peak (TTP) delay using MR (n=275) or CT (n=7) perfusion scans, adjusting for demographic and cardiovascular risk variables. Methods: Using a 7-10MHz Doppler probe, ICA PSV and EDV were assessed. Doppler results were adjudicated centrally. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using sequential T2*-weighted time-sequence scanning (e.g. TR=1500, TE=25ms, flip angle=60deg, phase=128, slice thickness=5mm for GE 3T magnet). CTP was acquired with standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral MCA/ACA territories using OLEA software. Linear regression used TTP delay as the outcome variable and PSV and EDV as predictor variables, adjusting for covariates.The 282 with complete data for all variables were included in the analysis. Results: Among 392 CREST-H participants, 63% were men, 7% Black, 3% Hispanic, 33% with less than college education. Tables 1a/b show the regression results for PSV and EDV as main predictor variables. PSV and EDV on the index side significantly correlated with TTP delay (p=0.004, p=0.002 respectively). Neither PSV nor EDV on the non-index side correlated with TTP delay (p=0.49, p=0.82). Compared with moderate exercise, vigorous exercise correlated with lower TTP delay in both models (p=0.05. p=0.04). Compared with college graduates, those with HS education had longer TTP delays in both models (p=0.03. p=0.02). Conclusions: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher flow velocities correlated with greater TTP delays, suggesting an increasing hemodynamic impairment with greater degree of stenosis above 70%. Our findings have implications for management of asymptomatic carotid stenosis which are being tested in the CREST-H and CREST-2 studies. Exercise and education may independently impact cerebral hemodynamics.

BACKGROUND: Cerebral hemodynamic impairment in patients with asymptomatic high-grade (>70%) internal carotid artery (ICA) stenosis is associated with risk of stroke and cognitive decline, but correlations between the degree of stenosis and hemodynamic impairment are derived from small case series. Using baseline data from 242 participants in the CREST-H study (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis–Hemodynamics), we hypothesized that the degree of stenosis in the ICA would correlate with time-to-peak (TTP) delay in ipsilateral cerebral blood flow using MR/CT perfusion scans, adjusting for demographic and cardiovascular risk variables. METHODS: From all participants, ICAs were insonated using a 7 to 10 MHz probe for peak systolic velocity (PSV) and end diastolic velocity. Dynamic contrast perfusion imaging was standardized across 61 CREST-H sites, using standard sequential T2*-weighted perfusion imaging. CT perfusion used standard clinical protocols. TTP delay was calculated in the ipsilateral versus contralateral hemispheres. In cross-sectional analysis, linear regression was used to model TTP delay as the outcome variable and PSV, end diastolic velocity, and PSV ICA/common carotid artery ratio on the index and nonindex side as primary predictor variables in 6 separate models, adjusting for covariates, followed by automated backward elimination model reduction. RESULTS: Among 392 CREST-H participants, the 242 with complete data for all variables were included in the regression analysis (age, 70±7.6; 62% M). End diastolic velocity on the index side correlated with TTP delay (β=0.003, P =0.005). PSV had a similar correlation but did not reach significance (β=0.001, P =0.099), nor did ICA/common carotid artery ratio (β=0.003, P =0.126). Nonindex side PSV, end diastolic velocity, and ICA/common carotid artery ratio showed no correlation with TTP delay ( P =0.268, P =0.495, P =0.380, respectively). Circle of Willis completeness did not correlate with TTP. CONCLUSIONS: In this large cohort of patients with high-grade asymptomatic carotid stenosis, higher end-diastolic flow velocities correlated with greater TTP delays, supporting a definition of hemodynamically significant stenosis. Our findings have implications for the management of asymptomatic carotid stenosis, which will be tested in the CREST-H study. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03121209.

Abstract Purpose: Rearranged during transfection (RET) alterations are oncogenic drivers across solid tumors. Selective RET inhibitors (SRI) selpercatinib and pralsetinib have transformed outcomes for patients with RET-altered malignancies. Limited knowledge exists on genomic mechanisms of resistance to SRI. Experimental Design: We established “RETgistry,” a global consortium of patients with advanced RET-altered solid tumors who received SRI and underwent postprogression tissue or plasma biopsies assessed by next-generation sequencing. Frequencies of secondary RET resistance mutations and acquired non-RET gene alterations were determined. Progression-free survival (PFS) and time to treatment discontinuation (TTD) on first SRI were estimated with the Kaplan–Meier method. Results: RETgistry included 109 patients with RET-altered advanced solid tumors (lung, n = 94; thyroid, n = 15) who underwent 143 post-SRI progression biopsies (tissue, 91; plasma, 52). The median PFS and TTD were 13.9 months [95% confidence interval (CI), 10.1–16.6] and 17.3 months (95% CI, 14–20.2), respectively. Secondary RET mutations were detected in 20 (14%) biopsies [lung cancer, 15 (12.4%) and thyroid carcinoma, 5 (22.7%)]. Common acquired off-target alterations involved MET (18.2%; amplification, 15%), TP53 (8.2%), APC (7.6%), KRAS (7.1%), KEAP1 (5.9%), and CDKN2A/B (5.3%). MET alterations were enriched in post-SRI versus pre-SRI specimens (full cohort, 17.6% vs. 2.0%, P = 0.022; lung cancer, 19.1% vs. 2.1%, P = 0.022). Conclusions: The prevalence of secondary RET mutations after SRI was low, underscoring a greater role for off-target resistance. Recurrent acquired alterations involving tumor suppressor genes or upstream regulators of MAPK and PI3K pathways were identified, most commonly MET amplification. Continued efforts to characterize SRI resistance biology are critical to guide the development of novel therapeutic strategies.

707 Background: Due to insufficient data, therapy for unresectable, locally advanced pancreatic adenocarcinoma (LAPAC) is based on trials in metastatic disease, and outcomes remain poor. TTFields disrupt cancer cell division using alternating low-frequency electric fields delivered externally by a portable device. In the phase 3 PANOVA-3 trial (NCT03377491), TTFields with gemcitabine/nab-paclitaxel (GnP) significantly improved overall survival (OS; HR 0.82) and pain-free survival (HR 0.74) vs GnP in patients with unresectable LAPAC. Methods: In PANOVA-3, patients with newly diagnosed LAPAC were randomized 1:1 to receive GnP with or without concomitant TTFields. Kaplan-Meier methodology was used for time-to-event analyses. Response evaluations were based on RECIST V1.1. OS, pain-free survival, and safety were analyzed post-hoc in subgroups based on sex (male, female), age ( < 65, ≥65 years), and BMI (<25, ≥25 kg/m 2 for efficacy; ≤20, 20–25, 25–30, ≥30 kg/m 2 for safety). Differences between treatment arms were compared using the log-rank test. Results: Efficacy outcomes are shown in the table. TTFields significantly extended pain-free survival in females and patients ≥65 years. Device-related adverse events (AEs) were comparable between sexes, older and younger patients, and across BMI ranges. Some device-related skin adverse events occurred more frequently in females (e.g. dermatitis, 33.1% vs 22.7%; rash 21.8% vs 13.5%, females vs males, respectively); others occurred more often in males (e.g. maculo-papular rash, 9.8% vs 14.2%; erythema, 9% vs 12.1%, females vs males, respectively). Dermatitis and pruritus had a higher incidence in the BMI ≥30 kg/m 2 subgroup (38.5%), whereas patients with BMI <30 kg/m 2 did not show noticeable differences in device-related AEs. Skin irritation (11.5% vs 5.5%) and skin reactions (8.5% vs 2.8%) were more common in patients ≥65 years than patients <65 years. Conclusions: Median OS and pain-free survival in these post-hoc subgroup analyses are generally consistent with the overall analysis, supporting use of TTFields with GnP in unresectable LAPAC. No new safety concerns were noted; observations were consistent with the general PANOVA-3 population. Clinical trial information: NCT03377491 . Survival outcomes for the subgroup analyses. Median OS, months TTFields + GnP GnP P value Age<65 years≥65 years 18.6 (n=113)15.4 (n=172) 16.0 (n=114)12.9 (n=172) 0.2060.061 SexFemaleMale 16.8 (n=138)15.7 (n=147) 14.5 (n=161)13.4 (n=125) 0.1140.145 BMI<25≥25 16.7 (n=166)16.2 (n=117) 14.2 (n=174)14.5 (n=108) 0.1550.105 Median pain-free survival, months Age<65 years≥65 years 16.5 (n=113)13.1 (n=172) 9.2 (n=114)8.3 (n=172) 0.4070.035 SexFemaleMale 16.5 (n=138)15.2 (n=147) 8.3 (n=161)9.3 (n=125) 0.0260.478 BMI<25≥25 16.6 (n=166)14.7 (n=117) 9.1 (n=174)8.3 (n=108) 0.1170.088

Abstract Rapid and profound reduction of free light chains (FLCs) improves outcomes in AL amyloidosis; however, early FLC kinetics with daratumumab‐based frontline therapy remain undefined. We retrospectively analyzed 315 patients treated with daratumumab–bortezomib–cyclophosphamide–dexamethasone (Dara–VCd) or Dara–Vd at eight centers. Involved FLC (iFLC), the difference between iFLC and uninvolved FLC (dFLC), and hematologic response (≥very good partial response [VGPR]) were assessed at baseline and at 1, 3, and 6 months, and correlated with light chain isotype, disease burden (bone‐marrow plasma‐cell percentage [%BMPC], baseline dFLC), and cytogenetics. Hematological ≥VGPR increased from 49.8% at 1 month to 66.0% at 3 months. The kappa isotype showed slower responses, with higher iFLC/dFLC and lower ≥VGPR at each time point compared to lambda. Higher %BMPC or baseline dFLC predicted persistently elevated iFLC/dFLC and reduced ≥VGPR. The t(11;14) translocation was associated with lower baseline FLC but similar subsequent kinetics. BMPC < 10% and dFLC < 18 mg/dL independently predicted early ≥VGPR (in ≤1 month). Early ≥VGPR conferred superior hematologic event‐free survival (heme‐EFS) and overall survival (OS) versus later responders (P < 0.001). At a 3‐month landmark, achieving dFLC < 1 mg/dL further stratified prognosis, conferring longer heme‐EFS and OS (P < 0.01). Frontline Dara‐based therapy elicits rapid, deep responses in AL amyloidosis; early ≥VGPR (within 1 month) and dFLC < 1 mg/dL by 3 months predict durable EFS and OS, whereas higher baseline disease burden delays hematologic response.

Abstract Background: The t(11;14) translocation occurs in 50-60% patients with systemic AL amyloidosis. Venetoclax, an oral BCL2 inhibitor, has shown promising efficacy across t(11;14)-positive plasma cell disorders. However, till date, there are no prospective data in patients with previously treated AL amyloidosis, including those with prior exposure to anti-CD38 monoclonal antibodies (mAbs). Methods: We conducted an investigator-initiated phase 1/2 multicenter open-label trial of venetoclax (± dexamethasone) in patients with relapsed/refractory AL amyloidosis. Key inclusion criteria were central-laboratory confirmed t(11;14) by FISH analysis in ≥5% of CD-138-selected cells on bone marrow aspirate, measurable hematologic disease (dFLC≥2 mg/dL and/or M-spike ≥0.5 g/dL), prior exposure to anti-CD38 mAb, and ≥1 prior line of therapy. Key exclusion criteria were NT-proBNP&gt;8500 pg/mL, NYHA class IIIb/IV, and ECOG&gt;2. Phase 1 dose escalation utilized Bayesian Optimal Interval Network (BOIN) design to determine maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) across four levels: DL1 (venetoclax 200mg), DL2 (400mg), DL3 (400mg + dexamethasone 10mg weekly), and DL4 (400mg + dexamethasone 20mg weekly). A maximum of 6 cycles of therapy on the protocol were planned, with dose limiting toxicities (DLTs) being evaluated in cycle 1. The design accommodated 12-15 patients with ~67% probability of selecting the dose closest to the 25% target toxicity rate. Here, we present the results of the Phase 1 portion of the study, which has completed enrollment. Accrual in Phase 2 portion is currently ongoing. Results: Of 16 patients screened, 12 were enrolled and evaluable for safety and efficacy. Screen failures were attributed to second malignancy (n=2), t(11;14) positivity in &lt;5% CD-138-selected cells (n=1), and t(11;14) negativity (n=1). Enrolled patients had a median age of 64 years, with 25% female, and 17% Black representation. At screening, the median percentage of CD-138-selected cells with t(11;14)-positivity on FISH was 65%. All patients had prior anti-CD38 mAb-exposure by protocol design, with 11/12 patients also exposed to bortezomib. The median number of prior lines of therapy was 1 (range, 1-5). Disease markers at treatment initiation included median dFLC of 14.35 mg/dL (range, 2.13-186.28), median NT-proBNP of 712.5 pg/mL (range, 54-8831), and the median serum creatinine of 0.99 mg/dL (range, 0.69-3.01). Regarding safety, there were no DLTs encountered during the specified timeframe. One patient each received DLs 1, 2, and 3, with all remaining patients receiving DL 4 (400mg + dexamethasone 20mg weekly), which is the RP2D in this trial. There was only one patient that developed grade 3 infection (lung infection; COVID-19). No tumor-lysis syndrome, grade 3 or higher cytopenia, or treatment-emergent deaths occurred. Hematologic overall response (PR or better) was achieved in 11/12 patients (91.7%), with 9/12 (75%) attaining ≥VGPR [4/12 (33.3%) heme-CR, with the remaining being VGPR]. The median time from treatment initiation to best response was 29 days. Among 7 patients that were evaluable for cardiac response, one underwent heart transplant after 3 cycles of study treatment (while in heme-CR), hence was no longer evaluable for cardiac organ response. Of the remaining 6 patients, 2 have achieved cardiac response till date. Renal organ response was observed in 4/7 evaluable patients. At a median follow-up of 8.8 months, 4 out of 12 patients have completed 6 treatment cycles, with 2 receiving ongoing therapy. Six patients discontinued treatment early due to hematologic progression (n=1), suboptimal hematologic response (n=2), patient preference (n=2), and heart transplant (n=1). Patient-reported outcomes (assessed by PROMIS-29) showed no significant changes in Physical Functioning and Fatigue domains among 5 patients with paired baseline and end-of-treatment assessments. Updated follow-up data will be presented at the meeting. Conclusions: To our knowledge, this represents the first prospective evaluation of venetoclax-dexamethasone in relapsed/refractory t(11;14) AL amyloidosis. The combination demonstrated substantial hematologic efficacy (75% ≥VGPR rate) and a favorable safety profile without dose-limiting toxicities. Our results support investigation of venetoclax-based combinations in the frontline treatment of newly diagnosed t(11;14) AL amyloidosis.

Abstract Introduction: The first-generation BCL2 inhibitor,venetoclax, is an effective treatment for CLL/SLL, but its usage may be limited by toxicity. Sonrotoclax, a next-generation BCL2 inhibitor, is a more selective and pharmacologically potent inhibitor of BCL2 than venetoclax, with a shorter half-life and no drug accumulation. BGB-11417-101 (NCT04277637) is an ongoing, phase 1/1b, dose-escalation/expansion study in patients with B-cell malignancies. Presented here are preliminary data for sonrotoclax + obinutuzumab in patients with treatment-naive (TN) CLL/SLL in BGB-11417-101. Methods: Obinutuzumab is administered intravenously at 100 mg on day (D) 1, 900 mg on D2, 1,000 mg on D8 and D15 of cycle (C) 1, and then 1,000 mg on D1 of C2-6 of each 28-day cycle. Beginning on C2D1, sonrotoclax is administered orally once daily with ramp-up to the target doses, 160 or 320 mg. Patients can continue treatment until progressive disease (PD), unacceptable toxicity, or undetectable minimal residual disease (uMRD4; &lt;1 CLL cell per 10,000 leukocytes [&lt;0.01%]) in peripheral blood (PB) by next-generation sequencing (NGS; ClonoSEQ) after 15 treatment cycles. Study endpoints include safety per NCI-CTCAE v5.0, overall response rate (ORR) per iwCLL guidelines, and MRD status in PB per modified ERIC flow cytometry (FC) assay or NGS, depending on the timepoint. Tumor lysis syndrome (TLS) is assessed per Howard (2011) criteria. Results: As of May 16, 2025, 55 patients with TN CLL/SLL were enrolled (160 mg, n=20; 320 mg, n=35), and 21 patients (all 320 mg) have discontinued sonrotoclax + obinutuzumab (due to uMRD4 per NGS as protocol-mandated [n=17], PI decision uMRD4 per FC [n=2], and PD [n=2]). Four patients discontinued obinutuzumab only per PI decision (160 mg, n=1), thrombocytopenia (320 mg, n=2), and prostate cancer prior to starting sonrotoclax (160 mg, n=1). For all patients, the median age was 62 y, 65% were male, and 89% were White. At baseline, 14% of patients (8/55) had high tumor burden and 58% (31/53) had unmutated IGHV. Median study follow-up was 8.9 months (range, 0.4-25.4 months) for all patients; 6.4 months (range, 0.4-9.0 months) for 160 mg; and 16.0 months (range, 2.9-25.4 months) for 320 mg. Maximum tolerated dose was not reached. The most common any-grade treatment-emergent AEs (TEAEs) were thrombocytopenia (56%), infusion-related reaction (56%), and neutropenia (49%). Neutropenia was the most common grade ≥3 TEAE (38%). No deaths due to TEAEs occurred, and no TEAEs led to sonrotoclax discontinuation. Two cases of laboratory TLS occurred after C1D1 of obinutuzumab prior to starting sonrotoclax; no clinical or laboratory TLS occurred during sonrotoclax ramp up. No meaningful safety differences were observed among sonrotoclax dose cohorts. In 37 efficacy-evaluable patients (160 mg, n=7; 320 mg, n=30), the ORR was 89%; for the 320-mg cohort, ORR was 93% (28/30). Complete response (CR) rates (CR + CR with incomplete marrow recovery [CRi]) were 46% (all patients) and 43% (320 mg). For 23 patients in the 320 mg cohort who reached the C15 MRD assessment, the best C15 uMRD4 rate per FC was 87% (20/23; 2 not evaluable; 1 missing); per NGS, the uMRD4 rate at C15 was 78% (18/23; 5 missing). All patients with an available C15 MRD assessment achieved uMRD4 and remain in remission as of the data cutoff date. The median time from reaching sonrotoclax target dose to uMRD4 was 2.3 months (range, 1.4-5.6 months) in the 320-mg cohort. Three patients experienced PFS events: 1 died from an indeterminate cause (160 mg, discontinued treatment after C1D9 of obinutuzumab) and 2 had PD (320 mg; both Richter's transformation at C6 and C2). Conclusions: Sonrotoclax + obinutuzumab was generally well tolerated in patients with TN CLL/SLL, with no sonrotoclax discontinuations or deaths due to TEAEs. No laboratory or clinical TLS events occurred during sonrotoclax ramp-up. Encouraging antitumor activity was observed with sonrotoclax 320 mg. High rates of blood uMRD4 occurred early and deepened over time. All patients with an available C15 MRD assessment by NGS or FC achieved uMRD4 and remain in remission. A registrational phase 3 study (CELESTIAL-RRCLL, BGB-11417-303) assessing this combination with sonrotoclax 320 mg is currently recruiting.