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Background and significance: There are typically high response rates to first line TKI therapies in chronic phase chronic myeloid leukemia (CP-CML). However, responses in later lines (second line and beyond) are diminished and highly dependent on the specific tyrosine kinase inhibitors (TKIs) used. Asciminib received FDA approval in October 2021 for the treatment of adult patients with Philadelphia chromosome-positive (Ph+) CML-CP who were previously treated with two or more TKIs, and in patients with Ph+ CML-CP with the T315I mutation. Our goal in this study is to evaluate the role of asciminib therapy for patients with CML beyond clinical studies, in routine clinical practice. Study Design and methods: Data for this study will be abstracted from the HJKC3 (H. Jean Khoury Cure CML Consortium) CML registry project (HJKC3-0005); the HJKC3 CML Registry is a collaborative academic multi-site registry. Patients will be consented to allow collection of both retrospective and prospective data for the HJKC3 CML Registry. The data forms and surveys will be built and managed through the Research Electronic Data Capture (REDCap), a secure web application managed by the Clinical & Translational Science Institute. Participating sites include members of the HJKC3 (curecml.org). This study will be an opportunity to evaluate asciminib usage in ‘real-world’ academic practices across the United States. This observational study will include cohorts of patients diagnosed with CP-CML previously treated with two or more tyrosine kinase inhibitors and/or receiving asciminib and/or those with a T315I mutation, not currently enrolled in a randomized controlled trial. The HJKC3 CML Registry intends to collect clinical and patient reported outcome (PRO) data. After obtaining patient consent, patients will be invited to complete PRO assessments. The study will attempt to collect PRO data regardless of disease or treatment status. PRO assessments will be primarily administered online, though study staff will offer alternatives (e.g., phone) for participants without internet access. Study subjects will be emailed a link to access a secure platform hosted by one of the study sites, Medical College of Wisconsin (MCW), using the REDCap platform. Study Objectives: The primary objective of the study is to describe characteristics of patients who were previously treated with two or more TKIs and treated with asciminib or with any other TKIs. The secondary objectives are to describe the clinical outcomes and PRO of those patients. Exploratory objectives include description of characteristics, treatment outcome and PRO for patients with T315I mutation. Statistical plan: The sample size of approximately 225 participants during the 5-year recruitment period is based on the available clinical expertise and ongoing recruitment data in the HJKC3 CML registry in lieu of statistical power analysis. We estimate that 150 patients in the HJKC3 CML registry will be treated with other TKI and 75 treated with asciminib. Among a total of 225 patients, we estimate that 75 patients with the T315I mutation will be enrolled in the registry. No formal statistical inference will be drawn to compare the outcomes between these two groups. Bayesian predictive probability (PP) will be utilized for the exploratory analysis of Major Molecular Response (MMR). Survival probabilities will be computed using the Kaplan-Meier method, and the p-values from the log-rank test will be provided. Different PRO domains of the patient's symptoms and functioning will be analyzed separately (e.g., depression separate from fatigue, separate from GI symptoms, etc.) since combining them into a summary score may dilute the effects of the individual (and not necessarily related) components and mask actual change. The main objective for the analyses of PRO data from the registry is to describe any differences by treatment type in patients treated with asciminib and other TKIs.

Background: Chimeric Antigen Receptor (CAR) T-cell clinical trials are growing exponentially. Database analysis can help identify scientific trends and generate projections regarding potential approvals before the results of the studies are completed or published. This is particularly interesting in pediatric oncology, where available analyses from repository databases are scarce or not available. Because of that reason, we sought to analyze the clinical trial public records from entries related to CAR T-cell clinical studies in pediatric patients (18 years or younger) uploaded to the clinicaltrials.gov database. Methods: We query the available data from clinicaltrials.gov using the following keywords: “CAR T cell in pediatrics”, “CAR T cell and cancer”, “chimeric antigen receptor”, “CAR T AND tumor antigen”, 'CAR T cell antigens“, ”Tumor antigens targeted by CAR T cells“, ”engineered T cells“, ”modified T cell“, ”CAR T cells in Cancer“, ”CAR T cell therapy“, ”CAR T cell therapy AND Cancer“ (data cut off July-2023). The data were tabulated, and the trials that did not meet the search criteria were excluded manually. Data cleansing was performed using published scientific data, web search-based information, and patent databases. Results: We found 4297 results in the Clinicaltrials.gov platform; we excluded 3978 clinical trials that did not involve the pediatric population (<18 years) or CAR T-cell intervention. The final analysis included 319 clinical trials posted on the clinicaltrials.gov website by the cut-off date. 207 (64.9%) were conducted in China, 74 (23.2%) in the US, and 21 (6.5%) in Europe. Most CAR T-cell trials focused on hematological cancer (89%), followed by non-CNS solid tumors 8%, and CNS tumors 3%. The most frequent targets were CD19 (46%), CD7 (7%), followed by GD2, CD22, CD123, CD19 + CD22 and CD30. Most clinical trials did not report the construct generation used in their CAR T cell product (58%). Among the trials with that information, second-generation constructs (2G) were used in 32% of the studies, followed by 3G and 4G constructs (5% of studies each). Most clinical trials were in early stages of development, Phase 1 or 2 (75%). We observed a continuous increase in the number of clinical trials registered yearly, except for a small reduction in 2022 and 2021, probably related to COVID restrictions and challenges. Overall, the general trend predicts at least a 50% yearly increase in registered studies ( Figure 1). Similarly, to what is observed in adult clinical trials, the most common signaling domains are 2G CAR constructs expressing either CD28 or 4-1BB as costimulatory domains. Among those, 4-1BB being is the most popular choice. Conclusion: Our findings indicate a growing interest in the clinical development of CAR T-cell therapies applied to pediatric oncology. Most of these studies are in early phase I and II and focus primarily on hematological cancers using second-generation constructs targeting CD19. The is a steady increase in the number of studies registered each year that predicts future FDA approvals using CAR T-cell products.

Background: In patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT), low gastrointestinal (GI) microbial diversity is associated with risk of bloodstream infections (BSIs), acute graft-versus-host disease (aGvHD), and death. SER-155 is an investigational cultivated microbiome therapeutic rationally designed to improve clinical outcomes in allo-HCT patients by preventing pathogen domination, promoting epithelial barrier integrity, and reducing colonic inflammation. SER-155-001 is a 2-part, Phase 1b study evaluating the safety, tolerability, pharmacokinetics, and efficacy of SER-155 in adults undergoing allo-HCT. Here, we present preliminary safety and tolerability data from the open-label Cohort 1 through Day 100 post HCT. Study Design and Methods: Adult recipients of allo-HCT were eligible for screening. Patients were excluded if they: a) were planned for umbilical cord blood or ex vivo T-cell depletion, b) had received a fecal microbiota transplant or any live biotherapeutic product within 3 months prior to screening, and/or c) had evidence of relapse or progression of hematologic malignancy (minimal residual disease was allowed). HCT conditioning and aGvHD prophylaxis were per investigator discretion. Following screening, patients received two treatment courses (before conditioning and after neutrophil engraftment) comprised of microbiome conditioning with 4 days of oral vancomycin (to facilitate engraftment of SER-155 strains) followed by 10 days of oral SER-155 (see study design schematic, Figure 1). The primary endpoint was the incidence and severity of adverse events (AEs), serious adverse events (SAEs), and adverse events of special interest (AESIs), designated as invasive infection, BSI, and GI infection. Results: Fifteen adult patients were enrolled and 13 received study drug (safety population). Of these 13 patients, the median age was 67.0, all were White, and 54% were male. Underlying diseases included acute myeloid leukemia (6 patients [46.2%]); myelodysplastic syndromes and myeloproliferative neoplasms (2 patients each [15.4%]; and acute lymphoblastic leukemia, chronic myeloid leukemia, and classic Hodgkin's lymphoma (1 patient each [7.7%]). Ten patients (76.9%) received peripheral blood stem cells; 9 (69.2%) had an unrelated donor, 8 (61.5%) underwent a reduced-intensity conditioning regimen, and 3 (23.1%) received myeloablative conditioning. Eleven patients received allo-HCT, all patients had neutrophil engraftment within the expected timeframe and 10 had 100-day follow-up data available. Nine of these patients (81.8%) received tacrolimus/methotrexate-based GvHD prophylaxis. SER-155 was generally well-tolerated ( Table 1). Treatment-emergent AEs (TEAEs) were observed in all patients as is expected in this patient population. One TEAE considered unrelated to study drug, resulted in study discontinuation. Most AEs were gastrointestinal in nature with diarrhea being the most common AE. No SAEs were considered related to SER 155, and most SAEs and AESIs occurred after HCT and before starting the second course of SER-155. No deaths occurred prior to Day 100. Three deaths occurred after Day 100, all deemed to be unrelated to study drug by the investigators. No BSIs attributable to organisms in SER-155 occurred. Commencement of the double-blind, randomized, placebo-controlled Cohort 2 (n=60) was initiated following approval of the Data Safety Monitoring Committee. Conclusions: In patients enrolled in this open-label Cohort 1 of this Phase 1b study, SER-155 was well-tolerated through Day 100. Although sample size is limited, the observed safety and tolerability profile of SER-155 in this patient population is consistent with multiple preclinical assessments supporting the safety of SER-155 for therapeutic use. Enrollment in the double-blind, randomized, placebo-controlled second cohort to assess safety, efficacy, and changes in microbiome composition and function is ongoing.

Introduction: Lineage switch (LS) refers to the transformation of acute leukemia from one cell lineage to another (e.g., lymphoid (ALL) to myeloid (AML)). This rare phenomenon, distinct from treatment induced malignancy (i.e., t-AML) and mixed phenotype acute leukemia (MPAL), is increasingly being observed following cell surface antigen targeting. Given challenges in the diagnosis and treatment of LS, Project EVOLVE was developed to globally identify cases of LS following immunotherapy. Methods: A protocol and data collection form for this IRB exempt study was widely disseminated to capture deidentified LS case information across multiple centers and cancer consortia. This included collection of data from published reports of LS, with authors contacted to obtain additional information. For this analysis, LS was defined by the emergence of cell-surface markers warranting reclassification of the original leukemia as a different lineage derivation based on the immunophenotype, including cases of AML emerging alongside the original ALL. “Confirmed” LS cases included those where retention of original cytogenetic or molecular aberrations and/or the clonal immunoglobulin rearrangement patterns were verified to confirm the clonal relationship. “Suspected” LS cases included those where samples to confirm clonality marker retention could not be obtained, but the clinical presentation was consistent with LS. The term “transition” was applied when immunophenotypic shifts were transient. Cases with new cytogenetic abnormalities unrelated to the original diagnosis and compatible with t-AML were excluded. Statistical analysis was primarily descriptive. Data cut-off was July 26, 2023. Results: A total of 58 cases were identified, including 19 cases referenced in prior publications. Of the 58, 11 cases were excluded from this initial analysis, including: 4 cases of t-AML, 2 cases of T-ALL to AML, and 5 “transition” cases. Collectively, 47 cases of LS (43 “confirmed”; 4 “suspected”), spanning across 3 continents and 8 countries, were analyzed. (Fig. 1A) Cases included transition from B-ALL to AML in 36 (76.6%) and to MPAL/biphenotypic/ambiguous lineage in 11 (23.4%). Two likely had MPAL at diagnosis and a third with chronic myeloid leukemia. The median age at initial diagnosis was 8.4 years (range, 1 day-76.5 years); median age at LS presentation was 11.0 years (range 0.4-77.3 years). Twenty-three (48.9%) were male and 19 (40.4%) had prior stem cell transplant (SCT). Baseline cytogenetics showed KMT2A rearrangement in 27 (57.4%). Baseline myeloid antigen co-expression was seen in 22 of 23 patients with submitted data, but variation in degree of expression across patients and antigens was substantial. The most proximal immunotherapy prior to development of LS was CAR T-cells in 23 (48.9%) and blinatumomab in 24 (51.1%). The median time from the most proximal immunotherapy to development of LS was 1.6 months (range, 7 days-36.5 months). In 7 (29.2%) patients receiving blinatumomab, LS developed during the infusion. LS presented as isolated marrow relapse in 27 (57.4%), isolated CNS in 2 (4.3%), isolated non-CNS extramedullary disease in 3 (6.4%), combined relapse in 14 (29.8%) and unreported in 1. First line treatment for LS was chemotherapy induction in 31 (66.0%), palliative care/no therapy in 8 (17.0%), and alternative therapies in the remaining 8 (17.0%). In 35 (74.5%) patients, remission induction was the goal of first line therapy. Fifteen (31.9%) achieved a complete remission (CR) of whom 2 were treated with palliative intent. Across all patients, 8 (17.0%) are alive in remission, the longest being 4.7 years from LS diagnosis; 2 (4.3%) are alive with active LS and 37 (78.7%) died from LS, their original disease, or complications of treatment of LS (Fig 1B). For those alive in CR (n=8), 7 (87.5%) proceeded to a consolidative SCT for treatment of LS and 1 patient, an octogenarian remains in remission after AML directed therapy. Conclusions: LS is emerging as an important mechanism of immune escape following immunotherapy. Project EVOLVE provides the largest dataset of patients with LS to date. This systematic, international effort reveals substantial complexity and variability in diagnosing and managing LS. Unfortunately, outcomes following LS are grim, underscoring the critical need to identify risk factors of and optimal therapies for this leukemia transformation.

Multiple myeloma (MM) is an incurable plasma cell malignancy. Despite therapeutic advances that have vastly improved survival, all patients are expected to relapse. One mechanism that may contribute to MM relapse is tumor dormancy. Dormant MM cells may persist in the bone marrow, where they exhibit reduced proliferative capacity and resistance to treatment. These cells may then exit dormancy following treatment to drive disease relapse. Dormancy shares many features with cellular senescence, a state of stable growth arrest induced by cell stress. Chemotherapies that produce genotoxic stress have been associated with therapy-induced senescence (TIS). One such genotoxic agent, melphalan (Mel), is routinely administered to MM patients for myeloablation prior to autologous bone marrow transplant. We hypothesized that High Dose Mel (HDM) induces a senescent-like dormant phenotype in surviving MM cells. To test our hypothesis, we developed an in vitro model for HDM. We identified 10µM Mel as a concentration to induce >90% cell toxicity (HDM) in 5TGM1 mouse MM cells over 10 days. 5TGM1-GFP MM cells were cultured with HDM or vehicle (Veh) for 6 hours; cells were then cultured in normal growth medium in the presence of primary mouse (C57BL/6) bone marrow stromal cells (BMSCs). Co-cultures were imaged by fluorescent microscopy every other day to quantify cumulative population doublings (CPD) and cell morphology over the following 10 days. The effect of HDM on CPDs was also evaluated in the human RPMI-8226 MM cell line. 5TGM1-GFP cells were isolated by FACS on day 10 for evaluation of senescence histological characteristics and gene expression. All studies represent n=3 independent experiments unless otherwise indicated. HDM-5TGM1 cells exhibited a significant reduction in mean CPDs over 10 days compared to Veh (HDM 0.32±0.31, Veh 6.72±0.69, p<0.0001), indicating stable growth arrest in HDM treated cells consistent with senescence. HDM-5TGM1 cells were also significantly larger versus Veh (median size in pixels units: HDM 413.2±99.98, Veh 207±8.88, p<0.05), consistent with classical enlarged morphology in senescent cells. Preliminary assessment (n=1) of HDM-RPMI-8226 cells showed similar growth arrest (mean cumulative doublings: HDM 0.058±0.101, Veh 4.185±0.358) and enlargement (mean size in pixel units: HDM 804.1±6.048, Veh 526.9±2.115), suggesting a translatable mechanism in humans. FACS-sorted 5TGM1-GFP cells were stained for telomere associated foci (TAF), a marker of persistent DNA damage characteristic of senescent cells. HDM-5TGM1 cells showed a higher percentage of TAF+ cells (Percent TAF+ cells: HDM 39.7%±9.1%, Veh 10.6%±0.8%, n=2). Sorted HDM-5TGM1 cells also exhibited significant increases over Veh (p<0.001) in senescence markers ( Cdkn1a, Cdkn1c, Glb1), senescence cell anti-apoptosis pathway genes (SCAPs, Bcl2l1), and senescence associated secretory phenotype (SASP) genes ( Ccl5, Icam1, Mmp13). In addition, HDM-5TGM1 cells showed significant increases in myeloid markers that have previously been shown to be increased in dormant 5TGM1 ( Axl, Fcer1g, Mpeg1). Single cell RNA-sequencing was used to further evaluate senescence gene expression changes in growth arrested HDM-5TGM1 cells. Gene set enrichment analysis (GSEA) of genes differentially expressed in HDM-5TGM1 versus Veh cells was performed for custom senescence phenotyping gene sets (Senescence Up, SenUp; Senescence Growth Arrest, SenGA; Inflammatory SASP, iSASP; SCAPs; and Plasma Cell Senescence; PCSen) as well as mouse ortholog versions of a published senescence and biological aging gene set (SenMayo) and KEGG curated gene sets. GSEA of HDM-5TGM1 versus Veh cells confirmed significant (FDR<0.25) upregulation of iSASP, MayoSen, PCSen, SenUp, SCAPs, and SenGA gene sets. Concurrently, GSEA revealed significant downregulation of KEGG DNA replication, cell cycle, and nucleotide excision repair gene sets, supporting our observations of proliferative arrest and persistent DNA damage TAF. Our findings demonstrate that HDM-MM cells exhibit multiple features of senescence, suggesting a potential mechanistic role for TIS in MM dormancy and highlight a novel therapeutic target that may be present in patients post-HDM. Thus, targeting senescence may be a novel approach to eliminate dormant MM cells and prevent relapse.

Keywords: Chimeric Antigen Receptor T cell, Pharmacoeconomic, Pediatric, Clinical Trials With the success of Chimeric Antigen Receptor (CAR) T-cell therapy in the pediatric population, new clinical trials have surged worldwide. To date, no previous study has analyzed the effect of socioeconomic factors on the development of clinical trials for CAR T-cells in the pediatric population. In recent years new countries and emerging economies have contributed significantly to the development of CAR T-cell clinical trials. A better understanding of the socioeconomic factors that influenced these trends will facilitate the future development of this cellular therapy field. To assess the impact of socioeconomic factors related to the development of clinical trials on CAR T-cell therapies in the pediatric population, we analyzed data entries from clinical trials registered to the Clinicaltrials.gov database. To query the information, we used the following keywords “(leukemia OR cancer OR lymphoma OR malignancies OR tumor OR solid tumor) AND (CAR OR chimeric antigen receptor OR CAR T-cell OR adoptive immunotherapy OR immune effector OR cellular therapy) AND (Child)”. In addition, we used different filters that allowed the selection of studies that focused on patients 18 years of age and younger. Data corresponding to entries with a data cut-off of July-2023 were included. In addition, we use the World Bank country's macroeconomic database (January 1 st, 2009 to December 31 st, 2022). We found 4,297 results in the Clinicaltrials.gov platform; we excluded 3,978 clinical trials that did not involve the pediatric population (≤18 years) or CAR T-cell intervention. There were 319 clinical trials included, sponsored in 19 countries, as shown in Figure A. Of those studies, 207 (64.9%) were conducted in China, 74 (23.2%) in the U.S., and 21 (6.5%) in Europe. Not surprisingly, the number of clinical trials is strictly proportional to each country's Gross Domestic Product (GDP) and Research and Development (R&D) expenditure, as shown in Figure B. Pearsons' coefficient between GDP and the number of trials registered per country is 0.8 (p-value < 0.001); similarly, Pearsons's coefficient between R&D expenditure and the number of problems reported per country is 0.64 (p-value < 0.004). The United States and China are developing 88% of the Clinical trials, and 96% of the clinical trials occur in countries ranked in the top 10 highest GDP. Our database analysis shows a notable disparity in the countries leading cutting-edge research in CAR T-cell therapy for pediatric oncology. The primary locations for these clinical studies are countries ranked in the top 10 in terms of GDP, with China and the USA being the main contributors. Access to clinical trials plays a crucial role in improving cancer patients' outcomes, and this disparity in the development of cellular therapies is likely to impact children from middle and low-GDP countries significantly. Urgent strategies are required to address this issue and ensure more equitable access to advanced technologies and clinical trials in cellular therapy for pediatric cancers. These strategies should become a high priority for national and international health departments and organizations in the coming years. By promoting more comprehensive clinical trial access and collaboration, we can work towards reducing these disparities and providing better treatment options for all children facing pediatric cancer.

Background Janus kinase inhibitors are actively investigated for treating various hematological, rheumatological, gastrointestinal and dermatological indications. Thus, we have initiated a living systematic review to define the toxicity profile of JAKi agents. Here, we report an up-to-date assessment of toxicity profile of JAKi in patients with myelofibrosis. Methods MEDLINE, EMBASE and CENTRAL were systematically searched from each database's inception through June 13, 2023, to identify phase I/II/III clinical trials assessing JAKi in myelofibrosis reporting adverse events. The main outcomes of interest included incidence rates of all-cause and treatment-related grade ≥ 3, grade 5 and all-grade AEs of interest (infections, hematological, gastrointestinal, and cardiovascular adverse events). Incidence rates (incidence per 100-person-years) for AEs of interest were calculated at the level of each trial. A random-effects meta-analysis was conducted to pool the incidence rates of AEs using an inverse-variance approach. Results The literature search identified 2044 studies from which 28 clinical trials (33 references) met the inclusion criteria - 4 (14%) trials were phase I, 4 (14%) trials were phase I/II, 13 (46%) trials were phase II, and 7 (25%) trials were phase III. A total of 4505 participants received JAKi and were eligible for analysis. All-cause and treatment-related hematological toxicities were reported in 28 (100%) and 18 (64%) trials, all-cause and treatment-related gastrointestinal toxicities were reported in 28 (100%) and 18 (64%) trials, all-cause and treatment-related cardiovascular toxicities were reported in 20 (71%) and 12 (43%) trials whereas all-cause and treatment-related infections were reported in 26 (93%) and 14 (50%) trials, respectively. The incidence rate per 100-person years for all-cause and treatment related adverse events of interest are summarized in Table 1a and 1b respectively. For treatment-related AEs, the incidence of grade ≥ 3 diarrhea with JAKi is 8.50 (95% CI: 5.34-13.53) events per 100-person years. The incidence of treatment-related grade ≥ 3 anemia and thrombocytopenia is 39.40 (95% CI: 25.57-60.71) and 29.25 (95% CI: 20.12-42.51) events per 100-person years respectively. The incidence of treatment-related grade 5 diarrhea with JAKi is 2.15 (95% CI: 1.07-4.29) events per 100-person years whereas the incidence of treatment-related grade 5 anemia and thrombocytopenia is 2.03 (95% CI: 1.04-3.97) and 2.01 (95% CI: 1.02-3.93) events per 100-person years respectively. For all-cause AEs, the incidence of grade ≥ 3 nausea, vomiting and diarrhea with JAKi is 1.72 (95% CI: 0.97-3.05), 3.56 (95% CI: 1.92-6.61) and 5.29 (95% CI: 3.48-8.04) events per 100-person years respectively. The incidence of all-cause grade ≥ 3 infections with JAKi is 4.38 (95% CI: 1.95-9.83) events per 100-person years whereas the incidence of all-cause grade ≥ 3 respiratory tract infections with JAKi is 4.21 (95% CI: 2.41-7.36) events per 100-person years. The incidence of all-cause grade ≥ 3 anemia, neutrophil decrease and thrombocytopenia is 46.83 (95% CI: 32.68-67.11), 29.11 (95% CI: 14.86-57.02) and 34.39 (95% CI: 23.82-49.64) events per 100-person years respectively. Moreover, the incidence of all-cause grade 5 nausea, vomiting and diarrhea with JAKi is 1.25 (95% CI: 0.72-2.18), 2.01 (95% CI: 1.08-3.74) and 1.60 (95% CI: 0.94-2.72) events per 100-person years respectively. In addition, the incidence of all-cause grade 5 infections and infestations is 3.71 (95% CI: 1.96-7.04) events per 100-person years with the incidence of grade 5 respiratory tract infections being 1.66 (95%CI: 0.89-3.10) events per 100-person years. Furthermore, the incidence of all-cause grade 5 anemia, neutrophil decrease and thrombocytopenia is 2.10 (95% CI: 1.26-3.52), 3.00 (95% CI: 1.25-7.21) and 1.95 (95% CI: 1.15-3.33) events per 100-person years respectively. Conclusions This report of living systematic review provides the best current evidence on toxicity profile of JAKi in patients with myelofibrosis. Current evidence suggests an overall higher incidence of all grade and grade ≥ 3 treatment related gastrointestinal adverse events in patients receiving JAKi. This living review will be updated as soon as new data becomes available.

Background: A pivotal clinical trial comparing the efficacy and safety of ibrutinib with zanubrutinib in patients with Waldenström macroglobulinemia (WM) did not achieve its primary endpoint of complete response or very good partial response. In addition, median progression-free survival was not reached in either treatment arm. In the absence of treatment effectiveness differentiation based on clinical trial evidence, we conducted a real-world study to assess patient characteristics, treatment patterns, and all-cause healthcare resource utilization (HRU) in patients with WM who received ibrutinib or zanubrutinib as first-line (1L) therapy. Methods: In this retrospective cohort study, we used the ConcertAI Database to collect claims data of patients with WM aged ≥18 years who initiated single-agent ibrutinib (420 mg/day) or zanubrutinib (320 mg/day) as 1L therapy on or after 9/1/2021 (index date). A 6-month washout period of guideline-recommended WM antineoplastic agents was required to confirm 1L status. Patients were excluded if they were receiving ibrutinib and zanubrutinib concurrently, died within 30 days of the index date, had a record of hematopoietic stem cell transplant, had a record of other ibrutinib indications in the 6 months before index, or were participating in a clinical trial. Baseline demographics and clinical characteristics, therapy duration (number of days between the first and last day of the medication supply), and HRU (all-cause and WM-specific) per-patient-per-month (PPPM) were assessed. Results: The study included 51 patients (ibrutinib, n=30; zanubrutinib, n=21). In both cohorts, most participants were male (ibrutinib, n=20 [67%]; zanubrutinib, n=16 [76%]), and the mean age at baseline was 73 years and 75 years, respectively. At baseline, the median Charlson Comorbidity Index was 0, and the WM-related and ibrutinib/zanubrutinib-related clinical events were similar between the two cohorts. While the zanubrutinib cohort had a higher prevalence of infections (33% vs 3%) and musculoskeletal pain (24% vs 7%) at baseline, the ibrutinib cohort had a higher prevalence of hypertension (20% vs 14%). The baseline prevalence of anemia was similar in both cohorts (ibrutinib, 27%; zanubrutinib, 29%). Mean follow-up was 6.9 months (ibrutinib) and 6.3 months (zanubrutinib). The mean ± SD duration of therapy was 152 ± 112 days (ibrutinib) and 113 ± 99 days (zanubrutinib; p=0.195). The ibrutinib cohort had a significantly lower all-cause HRU PPPM (4.53 ± 3.96 vs 8.53 ± 6.66, p=0.020) and lower WM-specific HRU PPPM (0.11 ± 0.26 vs 0.54 ± 1.14, p=0.104). Conclusions: In this real-world analysis, patients with WM treated with 1L ibrutinib had a numerically longer duration of therapy and lower all-cause and WM-specific HRU PPPM, compared to those treated with 1L zanubrutinib. Due to a small sample size and short follow-up, these findings should be interpreted cautiously.

BACKGROUND Several studies have highlighted the poor outcomes observed among patients with relapsed/refractory multiple myeloma (MM), particularly those with triple-class refractory (TCR; refractory to at least one PI, one IMiD, and one anti-CD38 mAb) disease. The aim of this study was to describe the longitudinal changes in quality of life (QOL) and other patient-reported outcomes (PROs) among TCR MM patients in real-world clinical practice who initiate a new line-of-therapy. METHODS A prospective, multi-site observational study of patients with TCR MM was conducted through the Mayo Clinic system. Patients initiating a new post-TCR therapy (defined as the index date) were followed for a 12-month observation period during which PRO surveys were administered for the first 6 months. For patients initiating a CAR-T therapy, a survey assessment was conducted at apheresis, lymphodepletion chemotherapy, and every month after T-cell infusion until Month 6. All other patients received a survey assessment before index and then every month thereafter until Month 6. PRO measures included the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-C30; including the Global Health Score [GHS]), the EORTC Multiple Myeloma Questionnaire (QLQ-MY20; including the Disease Symptoms [DS] domain score), the EORTC QLQ for Chemotherapy-Induced Peripheral Neuropathy (CIPN20), the EuroQoL-5 Dimensions (EQ-5D), the Patient Global Impression of Severity (PGIS), and the Patient Global Impression of Change (PGIC). Patient surveys were supplemented with retrospective chart reviews conducted 3 months and 12 months following the index date to obtain clinical information. Descriptive data were reported at each timepoint separately for patients who received CAR-T and non-CAR-T index therapies. The study is ongoing and this abstract reflects all patient visit data as of April 2023. RESULTS N=55 patients (60% male, 96% White, mean age 66 years) were included in this interim analysis. The median time interval between becoming TCR and the index date was 3.9 months (interquartile range [IQR]: 1.7, 15.5). Most patients had an ECOG score of 0 or 1 (53% and 38%, respectively) and were R-ISS I or II (36% and 54%, respectively); 53% of patients had high-risk cytogenetics and 20% had extramedullary disease. The median (IQR) number of prior treatment lines was 4 (4.0, 5.5). N=24 patients initiated a CAR-T therapy as their index therapy (equally split between ide-cel and cilta-cel); the remaining N=31 patients predominantly initiated a treatment regimen containing an IMiD (52%), a PI (55%), an anti-CD38 antibody (13%), or an alkylating agent (36%). Among CAR-T patients, QOL and disease-related symptoms worsened from baseline through Month 2-3 (eg, mean GHS was 65.9 at apheresis, 64.9 at lymphodepletion, and 53.3 at Month 2 [higher scores indicate better QOL]; mean DS domain score from the QLQ-MY20 was 24.1 at apheresis, 23.4 at lymphodepletion, and 33.7 at Month 2 [higher scores indicate more symptoms]; see Table 1). These decrements were followed by improvement back to baseline levels and, in some cases, improvement above baseline levels (eg, GHS was 67.9 and 65.0 at Months 4 and 5, respectively; DS was 18.3 and 17.8 at Months 4 and 5), though few patients had sufficient follow up to analyze QOL at later timepoints. Based on the PGIC, 77.8% of patients reported being “a little better” or “much better” as early as Month 1, though this number declined over time. Among non-CAR-T patients, QOL largely plateaued (GHS was 62.2 at baseline and 58.3 at Month 6), though disease symptoms improved over time (DS was 28.6 at baseline and 24.5 at Month 6; pain was 42.3 at baseline and 29.2 at Month 6). Based on the PGIC, 34.7% of patients reported being “a little better” or “much better” at Month 1, which improved to 50% by Month 6. CONCLUSIONS In this interim analysis of an ongoing prospective observational study, QOL and symptom measures generally worsened over the first few months for CAR-T patients in the real-world though improved to baseline levels and beyond at later time points. Patients did, however, directly report improvement in their disease state as early as Month 1 based on the PGIC. Non-CART patients generally showed a QOL plateau with some modest improvement in disease symptoms which was also reflected in their self-reported assessment of disease state improvement based on the PGIC.

Background: The management of multiple myeloma (MM) continues to evolve with the emergence of new classes of therapy, most recently including BCMA-targeted therapies. Considering the expanding MM treatment armamentarium, we sought to identify contemporary practice patterns among healthcare professionals (HCPs) for MM and compare them with those of experts using an online decision support tool. Methods: An online decision support tool was developed with input from 5 experts providing therapy recommendations for 192 unique patient case scenarios based on considerations including disease setting, treatment history, access to therapy, and specific comorbidities. HCP tool users entered specific patient criteria to define a case along with their intended management for that case. The tool then showed the 5 expert recommendations for that same case scenario, and users were asked if the recommendations impacted their intended approach. An analysis of expert recommendations and user-selected therapy was performed. Results: Between April 2023 and July 2023, 207 patient cases were entered by 144 participating HCPs. HCP and expert treatment recommendations were frequently discordant, regardless of treatment setting (Table). The highest concordance between HCP and expert recommendations (47%; P <.0001) was in the induction setting (n = 111). In this setting, experts were more likely to recommend quadruplet regimens compared with HCPs (62% vs 27%, respectively; P <.0001). Treatment selection concordance was lower in the maintenance (n = 17; 24%; P <.0001) and relapsed/refractory settings (n = 79; 20%; P <.0001). The lowest concordance (10%; P <.0001) between HCP and expert treatment recommendations was noted in the relapsed/refractory setting specifically among patients who were refractory to earlier lines of therapy (n = 41; P <.0001). For patients who are refractory to earlier lines of therapy, experts were more likely to recommend an anti-CD38-based combination regimen compared with HCPs (81% vs 32; P <.0001). When recommending treatment for patients with triple- or penta-refractory disease, experts were significantly more likely to recommend BCMA-targeted agents (83% vs 39%; P <.0001). For HCPs whose treatment plan did not match expert recommendations in these scenarios, 53% of respondents indicated that expert recommendations confirmed or changed their intended therapy, but 31% indicated that there were barriers to implementing those recommendations. Conclusions: These data suggest ongoing challenges with incorporating the newest therapies and combinations across the spectrum of MM into patient care, particularly multidrug regimens in the induction and maintenance settings and BCMA-targeted therapies in those with triple- or penta-refractory disease. Continued education and development of resources for HCPs, including online decision support tools, may be increasingly important as the treatment of MM continues to grow in complexity.