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Background: Despite the development and approval of effective therapies for multiple myeloma (MM), MM remains an incurable disease. Moreover, patients with high-risk cytogenetics, like translocation t(4;14), continue to have a poor prognosis compared to standard-risk patients. No novel agents have been approved specifically for this population. There remains an unmet need for precision therapies for MM that can target specific drivers of high-risk MM like t(4;14). Multiple myeloma SET domain-containing protein (MMSET) overexpression observed in 100% of patients with t(4;14) acts through the MMSET-H3K36me2 axis, which promotes malignant transformation through regulation of multiple oncogenic programs. KTX-1001, a methyl transferase inhibitor, is a novel, first-in-class, potent, oral, small molecule that inhibits MMSET and the methylation of lysine K36. KTX-1001 had favorable drug-like properties, demonstrated in vivo activity, and was well tolerated in non-clinical studies. Based on these data, KTX-1001 is now being studied in a Phase 1 dose escalation and expansion study in relapsed and refractory multiple myeloma (RRMM). Study Design and Methods: This multi-country, Phase 1, open-label study (NCT05651932) is designed to assess the safety, tolerability, and initial clinical activity of KTX-1001. The study will also examine the recommended phase 2 dose (RP2D), pharmacokinetics (PK) and pharmacodynamics (PD). Part A of this trial includes an accelerated titration, followed by 3+3 dose escalation with backfill of cohorts for dose optimization prior to moving to Part B, which is an expansion phase at the RP2D (please see Figure 1 for study design schematic). The expansion phase will only include patients with t(4;14). KTX-1001 will be administered orally daily and given until disease progression, unacceptable toxicity, or withdrawal from the study. Estimated enrollment for Parts A and B will be approximately 60 patients. The study will enroll patients with RRMM who have received ≥3 prior lines of therapy, including a proteasome inhibitor (PI), immunomodulatory drug (IMiD), and anti-CD38 antibody. Patients must have measurable disease, be ≥18 years of age, have an Eastern Cooperative Oncology Group score of ≤2, and adequate bone marrow, liver, and kidney function. Key exclusion criteria include history of or current plasma cell leukemia, active central nervous system (CNS) disease, or active unstable cardiovascular function. The primary endpoints of safety and tolerability include incidence of dose-limiting toxicity (DLTs), treatment-emergent adverse events (AEs), and treatment-related AEs. Secondary endpoints include plasma concentrations of KTX-1001 and efficacy outcomes such as objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker and pharmacodynamic assessments will also be performed. The sample size was not determined by formal statistical methods but will be sufficient to provide preliminary information on safety, PK, PD, and efficacy. Statistical analyses will be primarily descriptive. Conclusion: This Phase 1 study will evaluate a potential treatment for RRMM utilizing KTX-1001, which is a novel, first-in-class, potent, oral small-molecule MMSET inhibitor. The study is open and actively enrolling patients at centers in the United States, Spain, France, and Canada.

Background HPN217 is a B Cell Maturation Antigen (BCMA)-targeting tri-specific T cell engager (TCE). HPN217 contains three binding domains including anti-BCMA for MM cell binding, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. HPN217 is a small (~50 kDa) globular protein, designed to increase the therapeutic window by minimizing off-target toxicities and cytokine release syndrome (CRS). HPN217 is under investigation in patients (pts) with heavily pretreated relapsed/refractory MM (RRMM). Methods This study is designed to assess the safety, pharmacology and early clinical activity of HPN217 using fixed and step-dose (prime dose followed by target doses) regimens in dose escalation cohorts along with expansion of selected regimens for further evaluation. Pts with RRMM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and CD38-targeted therapy are eligible. Prior exposure to a BCMA-targeting agent is permitted. Primary objectives include evaluation of safety, tolerability, pharmacokinetics (PK), and determination of the Recommended Phase 2 Dose(s) (RP2D). Secondary objectives include preliminary efficacy. HPN217 is administered IV once weekly or once every 2 weeks. Adverse events (AEs) are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS) and ICANS. Clinical activity is assessed per IMWG Response Criteria. Results Dose escalation has been completed. 97 pts were enrolled across 15 dose escalation cohorts and expansion of 3 regimens with the highest target dose levels from dose escalation (12mg weekly; 24mg every 2 weeks; 24mg weekly for 1 cycle followed by 24mg every 2 weeks). As of 26 June 2023, across all cohorts, 94 pts were treated and had received a median (range) of 6 (2-19) prior lines of treatment (62% penta-exposed, 17% BCMA-targeted therapy, 68% prior transplantation). Median age was 70 (38-85) years. 36 pts (38%) remain on treatment. The most common (≥25%) treatment-emergent adverse events (TEAEs) across all cohorts and in the 12mg and 24mg cohorts are summarized in Table 1. Dose limiting toxicities (DLTs) of reversible transaminitis (Gr 3, n=1; Gr 4, n=1) in 2 pts at 2.86 mg fixed dose during dose escalation informed the choice of 2.15 mg as priming dose in the highest step dose cohorts; a maximum tolerated dose (MTD) has not been reached in step dose cohorts. All CRS events were grade 1-2 except one event of grade 3 CRS at 24 mg. Grade 1 ICANS was reported in 2 pts. Responses were observed at doses ≥ 2.15 mg. Among the 12mg and 24mg cohorts, 55% (22/40) of efficacy-evaluable pts currently have had a confirmed response (PR or better) including 2 pts with prior BCMA directed CAR-T cell therapy; disease assessments for recently enrolled patients are pending. Among pts with a response, 73% (16/22) have had a confirmed response of VGPR or better. Across all dose levels, the median time on treatment for pts with a confirmed response was 40 weeks (range 8.3-114 weeks), including 9 patients on treatment for over 12 months, with data maturing to include longer follow-up on patients recently enrolled. HPN217 exhibited linear and dose proportional PK across all dose groups with a median half-life of 68 hours (range 26-197 hours). Transient cytokine increases were higher with the initial/priming dose compared to subsequent/target doses. Conclusions Dose escalation of HPN217, a novel half-life extended BCMA-targeting T-cell engager, has been completed; the MTD was not reached in step dose cohorts. The 12mg and 24mg target doses are well tolerated with manageable adverse event profiles similar to those at lower dose levels and are associated with robust and durable clinical responses. Additional follow up of recently enrolled pts in 12 mg and 24 mg cohorts will inform the choice of the RP2D(s), and complete data on all pts enrolled will be presented. NCT04184050

Introduction Multiple myeloma (MM) is a clonal plasma cell malignancy and is the second most common type of hematologic cancer worldwide. Treatment options for MM have evolved in the last two decades with the introduction of novel therapeutic agents such as immunomodulatory drugs (IMiDs), proteasome inhibitors (PI), anti-CD-38 monoclonal antibodies (anti-CD38 MoAb), and recently BCMA-directed therapies (BDT). The variable access globally, especially for novel agents, has been a concern. We aim to study the global availability of 14 chemoimmunotherapy options in addition to autologous stem cell transplant (ASCT) which is approved in the US (excluding BDT due to limited availability), to identify regions with restricted access and analyze the main barriers to access. Methods A global cohort of oncologists outside the USA who treat MM participated in an online survey to evaluate the patterns of accessibility of MM therapies worldwide. The survey, conducted in collaboration with the US Myeloma Innovations Research Collaborative (USMIRC), was sent electronically to 176 oncologists worldwide (outside the US) from June 18th, 2023, to July 17th, 2023. It included questions on demographics, access, and perceived barriers. The respondents chose a response for each therapy as being “easily accessible”, “moderately accessible,” “not readily accessible” or “no access”. Countries were then classified as having “adequate access” if 80-100% of respondents affirmed easy/moderately easy access, while <30% were considered “limited access”, 60-79% were “high-intermediate access” and 30-59% were “low-intermediate access”. We classified countries into low- and high-income (LIC and HIC) based on the United Nations (UN) World Economic Classifications based on per capita gross national income (GNI). Means were calculated for regions of interest. An interim analysis is reported. Results Demographics: Ninety-Five (54%) oncologists from 33 countries completed the survey. Most were from Asia (56%). Others were Europe (19%), South America (12%), Africa (7%), Oceania (3%), and North America (Canada and Mexico, excluding the US) (3%). Only 17% specialized in plasma cell disorders; 50.5% were affiliated with university academic centers; 18% with private or community practices; 12% with community academic centers; and 17% were hybrid. Public-funded centers represented 61.1%, while 76% were transplant centers. Global Patterns: Most countries had adequate access to chemotherapies, IMiDs, PIs, Anti-CD38, MoAbs, and ASCT (Figure 1). Notably, ixazomib, isatuximab, and selinexor had low intermediate access, while elotuzumab had limited access. Access by Income: Most MM therapies were available in LIC and HIC. Of the therapies listed, 6 were adequately available in LIC and HIC: cyclophosphamide, lenalidomide, pomalidomide, daratumumab, bortezomib, and ASCT (Table 1). Elotuzumab and selinexor were limited in both LIC and HIC. Ixazomib and isatuximab were also limited in LIC but were low-intermediate in HIC. Access by Continent: Out of the 14 therapies, Europe had adequate or high-intermediate access to most modalities (12), followed by Oceania and Asia (10), and South America (9). North America and Africa had the lowest number of adequate or high intermediate access therapies (7) (Table 1). Barriers: The most common reason cited for limited access to MM therapies globally was the financial burden for the healthcare system, followed by limitations in local agency approval, inadequate chemotherapy suite resources, and inadequate staffing. Conclusion While most therapies were available, novel therapies such as isatuximab, ixazomib, selinexor, and elotuzumab were less readily accessible. Moreover, North America and Africa had the least access to therapies. This is likely because LIC and HIC have prioritized access to treatments with the best evidence of cost-effectiveness, while those with lower cost-effectiveness are generally limited. The financial burden on healthcare is a major limiting factor. USMIRC plans to investigate potential solutions and pursue global collaborative efforts to reduce disparities in therapies.

CONCLUSION The most widely used multiple myeloma (MM) staging system, the Revised International Staging System (R-ISS), is based on lactate dehydrogenase (LDH), albumin, high-risk genetic markers by FISH, and beta-2 microglobulin (B2M). However, it does not account for additional risk impacted by multiple genetic abnormalities, or the risk imparted by presence of gain of chromosome 1q, and most patients are staged as R-ISS Stage 2. Two new staging systems, the Mayo Additive Staging System (MASS), and the Second Revision of the International Staging System (R2-ISS) have been recently proposed. A comparison of the performance of these two systems has not previously been done. We aimed to externally demonstrate the application of these staging systems and compare their performances in a large, contemporary cohort of patients in the United States. We conducted a retrospective cohort study using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database, comprising de-identified patient-level structured and unstructured data, curated via technology-enabled abstraction and originating from approximately 280 US cancer clinics (~800 sites of care). The study included newly diagnosed MM patients initiating treatment between January 1, 2016 and October 1, 2022. We used the Kaplan-Meier method to evaluate real-world overall survival (rwOS) and patients were followed from first-line treatment initiation (index date) until the first of death, end of the study period or last recorded activity. The log-rank test to compare survival curves across derived stages. Multivariable analysis was conducted using stratified Cox models to account for non-proportional hazards by age with covariate adjustment for race/ethnicity, sex, practice type (academic or community) and diagnosis year (2016-2019 vs 2020-2022). Discrimination and calibration were evaluated in crude models using Harrell's c-index and the Hosmer-Lemeshow goodness-of-fit test, respectively. There were 497 patients with MM included. Patient characteristics are listed in Panel A. The distribution of patients across R-ISS stages were as follows, 24%, 63% and 13% for Stage 1, 2 and 3 respectively. rwOS differed across R-ISS stage (log-rank p = 0.0006) and the median OS (OS) was not reached (NR), 63, and 37 months for R-ISS stage 1, 2, and 3, respectively. 34%, 35% and 31% for MASS 1, 2, and 3, respectively. The corresponding survival curves were significantly different (p < 0.0001), with associated mOS of 77, 61 and 45 months for MASS stages 1, 2, and 3, respectively. R2-ISS includes four risk categories (stages I-IV) and in our cohort, 20% (n = 100) were stage I (low), 126 (25%) were stage II (low-intermediate), 229 (46%) were stage III (intermediate), and 42 (9%) were stage IV (high). Survival across stages were significantly different (p<0.0001), though the survival curves for low and low-intermediate, and intermediate-high and high, were clustered, suggesting comparable outcomes in stages I-II and stages III-IV. mOS for R2-ISS stages I, II, III, and IV was NR, 69, 50 and 51 months respectively (Panel B). In fully adjusted analyses, as compared to MASS I, the hazards of death were 2.0 (95% CI 1.3-3.2) for MASS II and 2.7 (1.7-4.2) for MASS III. The hazards of death were similar for R2-ISS low and low-int (HR for low-int vs low: 1.2 [0.7, 2.3]). As compared to R2-ISS low, the hazards of death were similarly higher for int-high and high (HRs: 2.4 [1.4, 4.1] and 2.6 [1.3, 5.2], respectively). Discrimination and calibration were similar across all staging systems (c = 0.6, and Hosmer-Lemeshow p>0.05 for all three staging systems). Application of contemporary MM staging systems in a large cohort of US patients shows that they are prognostic for OS in MM. MASS demonstrated a greater separation for OS across stages, whereas R2-ISS intermediate-high and high were largely overlapping. Although our results demonstrate similar accuracy and reliability of MASS and R2-ISS, the discrimination of patients across different stages seen with the newer staging systems, as opposed to R-ISS, calls for greater use of these newer staging systems in routine clinical practice.

Background: Daratumumab-based combination with proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) have revolutionized the treatment outcomes of relapsed/refractory multiple myeloma (RRMM). Several daratumumab-based triplet combinations have been approved for the management of RRMM, but outcomes of daratumumab-based triplets in patients with high-risk cytogenetics RRMM (HC-RRMM) are not well described in the literature. This study aimed to evaluate the clinical outcome of daratumumab-based regimens in patients with HC-RRMM who are daratumumab-naïve. Methods: A retrospective review of 110 patients with HC-RRMM who received daratumumab-containing regimens from 6/2016 through 2/2023 at the University of Kansas Medical Center, in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC) was conducted. Daratumumab was combined with bortezomib/dexamethasone (DVd), carfilzomib/dexamethasone (DKd), and pomalidomide/dexamethasone (DPd) for treatment of RRMM. HC-RRMM was defined as patients with one or more cytogenetic abnormalities (on FISH panel) including -17/del(17p), t(4;14), t(14;16), t(14;20), or amplification of 1q. Responses to therapy including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Descriptive statistics were used to summarize patient and disease characteristics, along with efficacy outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier methods. Results: Of the 110 patients with HC-RRMM, the median age was 66 years (range 43-84), 83 (75%) were Caucasian, 60 (54%) had IgG isotype, 41 (37%) had revised international staging system (R-ISS) stage III disease, 35 (32%) had extramedullary disease (EMD), 57 (52%) patients had one high-risk cytogenetic (HC) abnormality, 49 (44%) had 2 HC abnormalities, while four (4%) had 3 HC abnormalities. The median number of previous lines of therapy was 2 (1-4). Eighty-eight patients (80%) were lenalidomide refractory, while 53 patients (48%) had double refractory disease to both a PI and IMiD treatment. A total of 19 (17%), 27 (25%), and 64 (58%) patients received DVd, DKd, and DPd, respectively. The overall response rate (ORR) for the entire patient population was 73%, 45% had VGPR or better, and 35% achieved ≥CR. Median follow-up was 28 months (12.07-53.57), the median OS was 28 months (95% CI 23.2 - 43.9) and PFS was 8.03 months (95% CI 5.8 - 12.2) for all treatment groups. The median PFS for 1 HC vs ³ 2 HC was 14.8 vs 4.57 months (HR 1.72, 95%CI 1.17-2.72 p = 0.006), respectively. Similarly, median OS for 1 HC vs ³ 2 HC was 43.93 vs 22.47 months (HR 1.87, 95%CI 1.15-3.05, p = 0.011), respectively. (Figure 1). On multivariate analysis, R-ISS stage III, -17/del(17p), and the presence of more than one HC abnormality were associated with poor OS. The most common cause for treatment discontinuation was progressive disease, accounting for 73% of patients in the whole cohort. As for each daratumumab-based triplet, discontinuation due progression occurred in 78%, 48%, and 83% in DVd, DKd, and DPd, respectively. Other causes of discontinuation included > grade 3 neuropathy, which occurred in 16% of patients receiving DVd, and cardiac events, which occurred in 11% of patients receiving DKd. Treatment-related mortality occurred in 2% of patients in the whole cohort. At the time of evaluation, 14 patients remain on treatment. Conclusion: Advanced stage R-ISS disease at diagnosis, presence of -17/del(17p), and 2 or more HC abnormalities were associated with poor prognosis reflected by worse PFS and OS in HC-RRMM treated with daratumumab-based therapies. A larger cohort or a prospective study in patients with HC-RRMM is needed to compare long-term outcomes between daratumumab-based therapies (DKd, DVd, and DPd).

Background: Frailty is a state of decreased reserve affecting multiple organ systems, thereby increasing vulnerability to stressors. Several tools have been proposed to measure frailty in multiple myeloma (MM), such as the IMWG frailty index, and the Revised Myeloma Comorbidity Index. However, these are based on clinical trial datasets, and include chronological age as one of the indicators of frailty. A frailty index based on the principle of accumulation of health deficits (Rockwood doi:10.1093/gerona/62.7.738), provides a measure of physiologic age. This index can be readily calculated using various combinations of health deficits and has been shown to predict outcomes in several populations. Social support has been associated with improved outcomes in various populations, however its impact on survival in patients with MM has not been well studied. The objective of this study was to assess the impact of frailty measured by a deficit accumulation frailty index and the impact of relationship status on outcomes in patients with newly diagnosed MM. Methods: This is a retrospective study including patients diagnosed with MM between January 6 th, 2005, and September 19 th, 2018. We calculated a deficit accumulation frailty index using previously published methods (McNallan et. al doi.org/10.1016/j.ahj.2013.07.008, Searle et al. doi.org/10.1186/1471-2318-8-24). We used the electronic medical record system at Mayo Clinic in Rochester, MN, to extract data on activities of daily living (14 items) provided by patient-completed questionnaires, and data on comorbidities as recorded by treating providers (16 items), within 6 months prior to diagnosis. Each item was scored as 0, 0.5, or 1, with 1 indicating the presence of deficit (Table 1). The frailty index was defined as the sum of individual scores divided that by the total number of non-missing items. Patients who had N >2 missing items were excluded. Patients with a frailty index ≥0.15 were considered frail. We also extracted data on self-reported relationship status within 6 months prior to diagnosis. Variables were compared between groups using Fisher's exact test and Wilcoxon signed-rank test for categorical and continuous variables, respectively. Univariate and multivariate analysis were performed using Cox proportional hazard models. Overall survival (OS) was estimated using the Kaplan-Meier method and compared between groups using the Log-rank test. P values <0.05 were considered statistically significant. Results: We included 578 patients. Median age was 67 (interquartile range: 59-74) years, and 40% were female. Among all patients, 226 (39%) were frail. Compared to fit patients, patients who were frail were older (median age: 70 vs. 65 years, P<0.001) and more likely to have International Staging System (ISS) III (vs. I/II) disease (47% vs. 27%, P<0.001) and ECOG performance status ≥2 (vs. 0 or 1) (45% vs. 17%, P<0.001). There was no difference in R-ISS III disease or presence of high-risk cytogenetic abnormalities between fit and frail patients. Median OS was 7.6 and 4.1 years in fit and frail patient, respectively (P<0.001). Physician assessed ECOG performance status was available for 268 patients. Among patients with ECOG performance status 0 or 1 (193 patients), 136 (70%) were fit, and 57 (30%) were frail. The OS was 8.3 and 4.6 years in the 2 groups, respectively (P=0.006) (table 2). On multivariate analysis including age, frailty status, and R-ISS stage (III vs. I/II), all were associated with OS with frailty's hazard ratio (HR): 1.4 (95%CI [1.1-1.8]), P=0.004; the HR was 1.4 (95%CI [1.1-1.9]), P=0.02, when analysis was restricted to patients ≥60 years. Among all patients, those who were married or in a committed relationship (474 patients) had improved survival (median OS: 7.0 vs. 3.7 years, respectively, P<0.001) compared to patients who were divorced/separated, widowed, or single (96 patients). On multivariate analysis, which included age, R-ISS III, frailty status, and relationship status, all were associated with OS. The HR for relationship status was 1.4 (95%CI [1.0-1.8]), P=0.0465. Conclusion: Frailty, defined by the deficit accumulation frailty index, is independently associated with decreased survival in patients with newly diagnosed MM. Being married or in a committed relationship is associated with improved survival independent of age, disease stage, and frailty.

Introduction: Novel B cell maturation antigen (BCMA) directed therapies including chimeric antigen receptor- T (CART) such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have been approved since 2021. More recently in 2022, the first BCMA-directed T-cell-engager (TCE), teclistamab (tec), was also approved for the treatment of relapsed/ refractory multiple myeloma (RRMM). Unfortunately, limited access to these therapies worldwide appears to be a major challenge. This study aims to gain insight into the variation in access to these therapies, and barriers to access. Methods: This study was an electronic survey of 176 hematologists/oncologists in centers across the globe outside the USA who treat MM and was conducted in collaboration with US Myeloma Innovations Research Collaborative (USMIRC). The survey was distributed from June 18 th 2023, to July 15 th 2023. Sections included demographics of respondents, availability of drugs in the country, and barriers to access. The respondents categorized each medication as “easily accessible”, “moderately accessible,” “not readily accessible” or “no access”. To categorize a country/region as having “adequate access”, the cut-off was 60% of responders affirming easy/moderately easy access. We investigated whether higher healthcare spending in a country is associated with better drug accessibility. Health expenditure (HE) of a country's Gross domestic product (GDP) from the World Bank was utilized to categorize countries into two groups: “High healthcare investing nations” (HHIN), which included countries spending >10% of their GDP on healthcare, while “Low healthcare investing nations” (LHIN) included countries spending <10% on healthcare. An interim analysis is reported. Results: There were 95 (54%) completed responses from 33 countries. Most (51%) were university-based academic centers and only 17% were centers with a dedicated focus in plasma cell disorders. Only 17% reported adequate access to ide-cel and 16% to cilta-cel, while a limited, yet higher number of respondents had adequate access to tec (23%). Refer to Table 1 Access to CART (ide-cel and cilta-cel): Globally, only 3 of the 33 (9%) countries had access to ide-cel, cilta-cel or both (France, Morocco, Saudi-Arabia). All other countries had limited access. When grouped by continent, none of the continents had adequate access to CART. Both HHIN and LHIN countries had limited access to CART. Access to TCE (tec): Seven of the 33 (21%) countries had adequate access to tec (Switzerland, Netherlands, France, Portugal, Czech Republic, Morrocco, Saudi Arabia). All other countries had limited access. When grouped by continent, although Europe had the most access, none of the continents had adequate access to TEC. Both HHIN and LHIN countries had limited access to TCE, although relatively, TEC was more accessible compared to CART. Figure 1 summarizes access to CART and TCE Barriers to access: Other than Europe, the most common barrier for ide-cel, cilta-cel and tec was cited as financial burden for patients. Financial burden for patients as a top barrier for each of the products by continent was as follows: Asia (83%), South America (64%), Africa (71%) Australia (100%), and North America (100%). In Europe, for CART, financial burden remained a top barrier (50%) along with local agency approval (50% for ide-cel, 44% for cilta-cel). In Europe, the most cited barrier for TCE was the financial burden for patients (44%), while (33%) of oncologists reported no barrier to TCE. Reimbursement for CART and TCE in Europe requires phase 3 randomized controlled trial data, which is just emerging since 2022 for CART and relatively increased access may be due to the presence of compassionate use programs. Conclusion : The survey is the first attempt to highlight the significantly limited global access to novel therapies (ide-cel, cilta-cel, and tec) for the treatment of RRMM. All continents including HHIN had limited access to CART and TCE. Noticeably, CART is less accessible than TCE, even though approved earlier. The main barrier to both CART and TCE is reported as financial burden for patients. USMIRC in collaboration with oncologists worldwide, global agencies, governments, regulatory agencies, policymakers and industry partners, is planning to further explore restrictions to access to CART and TCE and strategies to overcome these barriers.

INTRODUCTION: Whether dye spray chromoendoscopy (DCE) adds value in surveillance colonoscopy with high-definition (HD) scopes remains controversial. This updated meta-analysis compares dysplasia detection using DCE and high-definition white light endoscopy (HD-WLE) in patients with inflammatory bowel disease (IBD) undergoing surveillance colonoscopy. METHODS: A comprehensive search was performed for randomized controlled trials (RCT) comparing HD-WLE and DCE in patients with IBD. The primary outcome was to compare the proportion of patients with at least 1 dysplastic lesion detected by DCE vs HD-WLE. Odds ratios (OR) and 95% confidence intervals (CI) were pooled using the random-effects model, with I 2 > 60% indicating substantial heterogeneity. The Grading of Recommendations, Assessment, Development, and Evaluation approach was used to assess the certainty of evidence (CoE). RESULTS: Six RCT involving 978 patients were analyzed (DCE = 479 vs HD-WLE = 499 patients). DCE detected significantly more patients with dysplasia than HD-WLE (18.8% vs 9.4%), OR 1.94 (95% CI 1.21–3.11, I 2 = 28%, P = 0.006, high CoE). This remained significant after excluding 2 RCT published as abstracts. A sensitivity analysis excluding a noninferiority RCT with a single experienced operator eliminated the results' heterogeneity, OR 2.46 (95% CI 1.56–3.90, I 2 = 0%). Although high-grade dysplasia detection was numerically higher in the DCE group (2.8% vs 1.1%), the difference was statistically insignificant, OR 2.21 (95% CI 0.64–7.62, I 2 = 0%, low CoE). DISCUSSION: Our updated meta-analysis supports DCE as a superior strategy in overall dysplasia detection in IBD, even with HD scopes. When expertise is available, DCE should be considered for surveillance colonoscopy in patients with high-risk IBD, with the acknowledgment that virtual chromoendoscopy shows equivalence in recent studies. Further multicenter trials with multiple endoscopists with varying expertise levels and longer-term outcome data showing a reduction in cancer or cancer-related death are needed.