Fortuna, Gliceida Galarza

90 Background: Poly(ADP) ribose polymerase inhibitors and pembrolizumab are approved for patients with metastatic prostate cancer (mPC) with susceptible genomic alterations based on NGS testing. We recently reported that the rate of NGS testing in mPC remains low at 29.3% in the United States (1). Herein, we investigated the rates of NGS testing at the end of life in a real-world patient population. Methods: This study utilized the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Eligibility: diagnosis of mPC, with information on receipt of NGS testing (blood/tissue) and recorded date of death. The time between each patient’s first NGS testing result date and date of death was measured and categorized into 3 groups: NGS test results delivered more than 3 months (mo) before death, within 3 mo of death, and delivered after death. Frequencies and percentages of these 3 categories were reported, also by the year of death. Results: Out of 24,105 patients with mPC in the database, 3,397 had both a recorded date of death and underwent NGS testing and were eligible and included. The median age was 74 (IQR 67–80), 70% were White non-Hispanic, and 83% were treated in a community-based practice. In these patients, 2,901 (85.4%) NGS results were reported more than 3 mo before death, 457 (13.5%) within 3 mo of death, and 39 (1.1%) after death. From 2015 to 2024, the percentage of patients receiving their result more than 3 mo before death increased from 27% to 91%, while those receiving it within 3 mo before death decreased from 55% to 8.5%, and the percentage of NGS results reported after death declined from 18% to 0.6%. Baseline characteristics (including race-ethnicity, insurance plan, practice type [academic vs. community]) in these categories will be presented at the meeting. Conclusions: Despite the availability of life-prolonging targeted therapies based on NGS testing results for patients with mPC, in ∼14% of patients, the first NGS testing results were reported within 3 mo before death or after death. The lack of timely NGS testing limits patients' access to life-prolonging personalized treatments in earlier settings, resulting in missed opportunities for improved outcomes. 1. Hage Chehade, Swami, JAMA Network Open, 2024.

109 Background: C and Lu are associated with overall survival benefit and approved for pts with mCRPC after prior treatment with docetaxel and an androgen receptor pathway inhibitor (ARPI). However, in real-world settings, administering Lu requires coordination across specialties and resources [PMID: 36637862], which could delay its administration. Herein, we sought to compare the time from medication order to administering the first dose of C versus Lu. Methods: This study used pt level data from the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Inclusion criteria: availability of the date of the first order of single-agent C or Lu and the date of first administration of the drugs. The time between the first medication order to the administration of single-agent C or Lu was measured. Wilcoxon rank-sum test was used to compare the median days between medication order to administration between these 2 agents and a stratified analysis by practice type and insurance was performed. Results: Of 2,329 orders, 2,045 orders were for C between 1/1/2013 and 1/26/2024, while 284 were for Lu between 8/1/2013 and 12/6/2023. The time from medication order to administration was significantly longer with Lu (median 22 days, IQR 12-43) compared to C (median 7 days, IQR 3-14, p < 0.001). Time from medication order to administration of C and Lu by practice type and insurance is summarized (Table). At the time of the first order, pts in Lu cohort, compared to C cohort, were significantly older (median age 74 vs. 72, p < 0.001), more likely to be treated at an academic practice (27% vs. 15%, p < 0.001), and more likely to be covered by a commercial health plan (80% vs. 73%, p < 0.001). Conclusions: Our results show that it takes significantly longer to administer Lu compared to C across different practice types and most insurance plans. These results could inform healthcare policies aimed at improving access to Lu and guide treatment selection in the clinic. Time from medication order to administration of C and Lu by practice type and insurance. Category Subtype (number of orders for C/number of orders for Lu) CN = 2045 LuN = 284 p-value Practice type, mean (range) (days) Academic (315/77) 1.3 (0 – 59) 9.2 (0 – 55) < 0.001 Community (1730/207) 13 (0 – 243) 44 (1 – 282) < 0.001 Insurance, mean (range) (days) Commercial (1494/226) 11 (0 – 163) 32 (0 – 215) < 0.001 Medicare/other government programs (266/46) 10 (0 – 120) 46 (0 – 282) < 0.001 Medicaid (32/2) 9 (0 – 76) 28 (0 – 55) 0.8 Others (72/6) 12 (0 – 42) 21 (0 – 41) 0.2 Unknown (181/4) 14 (0 – 243) 76 (39 – 91) < 0.001

Abstract Background: Several immune effector cell (IEC) therapies have been approved for multiple myeloma (MM), including chimeric antigen receptor T-cell (CAR-T) therapies such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We report 14 cases of IEC-associated enterocolitis, in five cases fatal, following CAR-T therapy in MM. Methods: We performed a retrospective analysis of cases of diarrhea, enterocolitis, or colitis following commercial ide-cel or cilta-cel (including out-of-specification products) at 10 centers within the United States Myeloma Immunotherapy Consortium. Patients were treated according to the local standard of care at each participating center. Results: We identified 14 cases of IEC-associated enterocolitis out of 1159 CAR-T infusions, corresponding to a 1.2% incidence (0.2% for ide-cel and 2.3% for cilta-cel). This proportion excludes 3 cases of potential or confirmed T-cell lymphoproliferative disorders of the bowel. Patients developed acute-onset symptoms (typically non-bloody Grade 3+ diarrhea) with negative infectious workup beginning a median of 79 days (range: 22-210 days) after CAR-T therapy and a median of 74 days after cytokine release syndrome resolution (range: 2-202 days). Biopsies uniformly demonstrated inflammation, with specific findings including intra-epithelial lymphocytosis, crypt dropout on colon biopsies, and villous blunting on duodenal biopsies. Systemic corticosteroids were initiated in 10 patients (71%) a median of 26 days (range: 1-80 days) following symptom onset. Only 40% of steroid-treated patients had symptomatic improvement; subsequent infliximab or vedolizumab led to improvement in 50% and 33% of corticosteroid-refractory patients, respectively. With a median follow-up of 224 days, n = 4 have had diarrhea resolution, n = 5 have had improved or stable symptoms, and n = 5 (36%) have died from IEC-associated enterocolitis or treatment-emergent infections. Conclusions: IEC-associated enterocolitis is a distinct but rare complication of CAR-T therapy characterized by non-bloody diarrhea typically beginning 1-3 months after infusion. Thorough diagnostic workup (including evaluation for potential T-cell malignancies) and appropriate management with an expert gastroenterologist are essential. Further research is critical to understand the pathogenesis of this novel toxicity. In the interim, the early use of infliximab or vedolizumab may potentially hasten symptom resolution and lower reliance on high-dose corticosteroids during the post-CAR-T period.

Kaiser et al. offer management recommendations for transplant‐eligible, high‐risk multiple myeloma (HRMM), derived from recent trials exploring treatment intensification in the various phases of front‐line therapy. The definition of HRMM continues to evolve with emergence of novel genomic insights and impact of modern therapies, underscoring the need to expand beyond traditional interphase fluorescence in situ hybridization cytogenetics and International Staging System staging for a precise risk assessment. Despite progress, ongoing challenges in treatment delivery and tolerability underscore the urgency for exploring novel approaches like T‐cell redirecting bispecific antibodies and chimeric antigen receptor T‐cell to enhance outcomes in this complex patient population.Commentary on: Kaiser et al. Diagnosis and initial treatment of transplant‐eligible high‐risk myeloma patients: A British Society for Haematology/UK Myeloma Society Good Practice Paper. Br J Haematol 2024; 205:833‐839.

Introduction: Extra copies of chromosome 1q21 (+1q: gain=3 copies, amp=4 or more copies) have been associated with worse outcomes for patients with multiple myeloma (MM). We performed a systematic review to evaluate current reporting of +1q, efficacy of existing regimens for +1q, and prognostic implications of +1q in MM randomized controlled trials (RCTs). Methods: We searched three databases for MM RCTs. Our inclusion criteria were all published MM RCTs from 2012-2022. Each MM RCT was analyzed for reported data on +1q. The following features specific to +1q were collected: +1q reported or not as a high-risk cytogenetic alteration, definition of gain1q with respect to percentage of cells with abnormality detected, documentation of distinction between Gain1q and Amp1q in analysis, prevalence of +1q in enrolled population, outcomes of patients [Overall Survival (OS) and Progression Free Survival (PFS)] in patients with +1q in the experimental versus control arm and in patients with and without +1q. Results: A total of 124 trials were included. Among these trials, 28 (23%) studies reported data on +1q, including 26 studies that reported data in the primary manuscript and two studies that reported in separate publication. These trials reported a total of 2692 patients with +1q which represented 25% of all the patients enrolled. Out of 28 trials, three trials (11%) specified the criteria for categorizing patients as +1q (example in IKEMA and IFM-99: the presence of at least three copies in at least 30% of analyzed plasma cells was required). Only four trials (14%) reported survival data on gain and amp separately and the remaining 24 (86%) studies reported for gain or did not specify gain vs amp. Amongst the trials that reported +1q, 22 (79%) considered this to be a high-risk cytogenetic abnormality. Amongst trials that met primary endpoint showing improvement in PFS and clearly reported on +1q, the following drugs also improved PFS for those with +1q (when comparing hazard ratio (HR) for intervention versus control arm in the +1q subgroup): lenalidomide (len) maintenance in Myeloma XI, selinexor in BOSTON, and isatuximab in IKEMA and ICARIA. Several trials met their endpoint and showed improvement in PFS in the +1q cohort in same direction as overall study results but had confidence intervals for +1q subgroup that crossed 1. These included addition of carfilzomib in Myeloma XI, addition of carfilzomib vs bortezomib to len and dex for +1q (but not in Amp1q) in ENDURANCE, addition of elotuzumab to pomalidomide and dex, and bortezomib-based treatment before and after autologous stem cell transplantation (auto-SCT) vs no bortezomib (Table 2). Seven studies reported HR for patients with +1q in the trial (across both arms) compared to those without. In six studies (all studies other than SWOG1211), worse outcomes were seen with respect to OS and PFS for those with +1q versus without (Table 2). Important interventions for which subgroup analysis of +1q was not presented in trial results, and hence conclusions about the efficacy of the drugs specifically for patients with +1q cannot be ascertained included pomalidomide and ixazomib. Although subgroup analysis of various daratumumab trials has shown improvement for high-risk MM, the effect on gain1q was not isolated. Two recent contemporary trials that isolated effect of auto-SCT (DETERMINATION and IFM-2009) did not report +1q. However, in FORTE Trial, adverse prognostic implications of +1q were not seen in the arm receiving carfilzomib, len, dex and auto-SCT, indicating a possible role of carfilzomib and auto-SCT in ameliorating the adverse prognostic implications of +1q. Although len maintenance improved PFS after auto-SCT as maintenance in Myeloma XI overall for those with +1q, it did not appear to improve PFS for patients with isolated +1q (with no other concurrent genetic abnormalities). Conclusion: This systematic review of MM RCTs finds considerable heterogeneity in the reporting of +1q abnormalities in the literature, and +1q to be inconsistently classified as a poor prognostic factor in subgroup analysis of randomized myeloma trials. Most interventions that have shown to be successful in randomized trials and have clearly reported on the +1q subgroup have shown concordant direction of results and benefit of the applied intervention in the +1q subgroup. A more standardized approach to reporting of this abnormality is needed.