Stratified Cox Proportional Hazards Regression Research Articles

Neoadjuvant Immune Checkpoint Inhibitors Plus Chemotherapy in Early Breast Cancer

Recent studies have investigated the combination of immune checkpoint inhibitors (ICIs) with (neo)adjuvant chemotherapy in early-stage breast cancer. However, there is an ongoing debate about the optimal approach for integrating this strategy. To evaluate the association of neoadjuvant ICIs with pathologic complete response (pCR) across molecular phenotypes, to quantify the survival benefits of ICIs beyond pCR status, and to estimate the incidence of specific adverse events. The PubMed database was searched on December 10, 2023, to identify all potential eligible studies. Randomized clinical trials (RCTs) that assessed (neo)adjuvant ICI plus chemotherapy in early breast cancer. Data from the eligible RCTs were extracted by 2 reviewers. An extracted individual patient data meta-analysis and a trial-level random-effect meta-analysis were performed. Outcomes were pCR, event-free survival (EFS) in patients with and without pCR, and adverse events. Hazard ratios were estimated using stratified Cox proportional hazards regression models. Nine RCTs involving 5114 patients met the inclusion criteria (2097 triple-negative breast cancer [TNBC], 1924 hormone receptor-positive [HR+]/ERBB2-negative [ERBB2-], and 1115 ERBB2+ tumors). In TNBC, the addition of ICIs was associated with an improved pCR rate regardless of programmed cell death ligand 1 (PD-L1) status (absolute improvement, >10%). In HR+/ ERBB2- tumors, the administration of ICIs was associated with improved pCR only in the PD-L1-positive (PD-L1+) population (absolute improvement, +12.2%), whereas no benefit was observed in ERBB2+ tumors. In patients with TNBC achieving a pCR, the addition of ICIs was associated with improved EFS (hazard ratio, 0.65; 95% CI, 0.42-1.00), resulting in a 5-year EFS of 92.0% with ICIs compared with 88.0% without them. In patients with residual disease, ICIs also showed better EFS (hazard ratio, 0.77; 95% CI, 0.61-0.98), resulting in a 5-year EFS of 63.3% with ICIs and 56.1% without them. Adjuvant ICI did not show numerical improvement in patients with either pCR or residual disease (all hazard ratios >1). During the neoadjuvant treatment, the incidence of grade 3 or greater immune-related adverse events with ICI was 10.3%. These findings suggest that neoadjuvant ICI therapy improves efficacy outcomes in early-stage TNBC and PD-L1+ HR+/ERBB2- tumors with an acceptable safety profile; however, no benefit was observed with adjuvant ICI. Given the financial and toxicity costs associated with ICIs, future research should prioritize identifying patients most likely to benefit from the addition of ICIs to neoadjuvant chemotherapy.

Contextual Deprivation, Race and Ethnicity, and Income in Air Pollution and Cardiovascular Disease

Socioeconomically disadvantaged subpopulations are more vulnerable to fine particulate matter (PM2.5) exposure. However, as prior studies focused on individual-level socioeconomic characteristics, how contextual deprivation modifies the association of PM2.5 exposure with cardiovascular health remains unclear. To assess disparities in PM2.5 exposure association with cardiovascular disease among subpopulations defined by different socioeconomic characteristics. This cohort study used longitudinal data on participants with electronic health records (EHRs) from the All of Us Research Program between calendar years 2016 and 2022. Statistical analysis was performed from September 25, 2023, through February 23, 2024. Satellite-derived 5-year mean PM2.5 exposure at the 3-digit zip code level according to participants' residential address. Incident myocardial infarction (MI) and stroke were obtained from the EHRs. Stratified Cox proportional hazards regression models were used to estimate the hazard ratio (HR) between PM2.5 exposure and incident MI or stroke. We evaluated subpopulations defined by 3 socioeconomic characteristics: contextual deprivation (less deprived, more deprived), annual household income (≥$50 000, <$50 000), and race and ethnicity (non-Hispanic Black, non-Hispanic White). We calculated the ratio of HRs (RHR) to quantify disparities between these subpopulations. A total of 210 554 participants were analyzed (40% age >60 years; 59.4% female; 16.7% Hispanic, 19.4% Non-Hispanic Black, 56.1% Non-Hispanic White, 7.9% other [American Indian, Asian, more than 1 race and ethnicity]), among whom 954 MI and 1407 stroke cases were identified. Higher PM2.5 levels were associated with higher MI and stroke risks. However, disadvantaged groups (more deprived, income <$50 000 per year, Black race) were more vulnerable to high PM2.5 levels. The disparities were most pronounced between groups defined by contextual deprivation. For instance, increasing PM2.5 from 6 to 10 μg/m3, the HR for stroke was 1.13 (95% CI, 0.85-1.51) in the less-deprived vs 2.57 (95% CI, 2.06-3.21) in the more-deprived cohort; 1.46 (95% CI, 1.07-2.01) in the $50 000 or more per year vs 2.27 (95% CI, 1.73-2.97) in the under $50 000 per year cohort; and 1.70 (95% CI, 1.35-2.16) in White individuals vs 2.76 (95% CI, 1.89-4.02) in Black individuals. The RHR was highest for contextual deprivation (2.27; 95% CI, 1.59-3.24), compared with income (1.55; 95% CI, 1.05-2.29) and race and ethnicity (1.62; 95% CI, 1.02-2.58). In this cohort study, while individual race and ethnicity and income remained crucial in the adverse association of PM2.5 with cardiovascular risks, contextual deprivation was a more robust socioeconomic characteristic modifying the association of PM2.5 exposure.

Analyzing risk factors for second malignancies in early gastric carcinoma from the SEER database

This retrospective study analyzed a large population of gastric cancer (GC) patients treated between 2010 and 2015 to investigate the clinical features and predictive risk factors for developing secondary primary malignancies (SPMs). The cumulative incidence of SPM was assessed using Kaplan–Meier analysis. Competing risk analyses adjusted for mortality were conducted using stratified Cox proportional hazard regression models and multivariate analyses to identify independent predictors of SPM. A total of 3289 out of 167,747 GC patients were included in the analytic cohort, with 155 patients diagnosed with SPM. Patients whose histologic type other than adenocarcinomas (AC) and signet ring cell carcinoma (SRCC) emerged as an independent risk factor for developing SPM (hazard ratio [HR] 2.262, 95% confidence interval [CI] 1.146–4.465, P = 0.019) in multivariate Cox regression analysis. The surgical method, including biopsy/local excision (HR 2.3, [CI] 1.291–4.095, P = 0.005) and subtotal/total resection ([HR] 1.947, [CI] 1.028–3.687, P = 0.041), chemotherapy ([HR] 1.527, [CI] 1.006–2.316, P = 0.047), and histologic type ([HR] 2.318, [CI] 1.193–4.504, P = 0.013)), were identified as independent risk factors in the competitive risk model. Subgroup analyses, stratified by chemotherapy, revealed an increased risk of SPM among older patients. Furthermore, a nomogram was developed and internally validated to predict the cumulative incidence of SPM in GC patients (C-index = 0.73 for 72 months). These findings suggested that in specific histologic types of GC, the lymph node infiltration region missed after local surgical resection, and concomitant chemotherapy would have an increased risk of SPM for cancer survivors.

Effects of ACE inhibitor/ARB therapy and long COVID on kidney disease: a retrospective cohort study using real-world data.

The association between angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) and severe acute respiratory syndrome coronavirus 2 susceptibility, particularly via ACE-2 receptor upregulation in the kidneys, raises concerns about potential kidney disease risks in long coronavirus disease (COVID) patients. This study explores the association of ACEI/ARB therapy on acute kidney injury (AKI), chronic kidney disease (CKD) and all-cause mortality in patients with and without long COVID. A retrospective cohort study using TriNetX datasets was conducted, with diagnoses of long COVID via International Classification of Diseases, Tenth Revision (ICD-10) codes and prescription for ACEI/ARB as the classification of four cohorts: long COVID ACEI/ARB users (LCAUs), long COVID ACEI/ARB non-users (LCANs), non-long COVID ACEI/ARB users (NLCAUs) and non-long COVID ACEI/ARB non-users (NLCANs). Multivariable stratified Cox proportional hazards regression models assessed the adjusted hazard ratios (aHRs) across groups. Additional analyses were conducted, including time-dependent exposure analysis and comparison with an active comparator, calcium channel blockers. Our study included 18 168 long COVID and 181 680 propensity score-matched non-long COVID patients from October 2021 to October 2023. ACEI/ARB use did not significantly affect the risk of AKI or CKD when comparing LCAUs with LCANs and NLCAUs with NLCANs. However, a protective effect against all-cause mortality was observed {aHR 0.79 [95% confidence interval (CI) 0.65-0.93]} in the NLCAU group compared with the NLCAN group. Conversely, long COVID was associated with increased risks of CKD [aHR 1.49 (95% CI 1.03-2.14)] and all-cause mortality [aHR 1.49 (95% CI 1.00-2.23)] when comparing LCANs with NLCANs. The additional analyses support the primary findings. ACEI/ARB treatment does not increase the incidence of CKD or AKI, regardless of long COVID status. However, long COVID itself is associated with increasing risks of kidney diseases and all-cause mortality.

Comparison of safety and efficacy between Nirmatrelvir-ritonavir and molnupiravir in the treatment of COVID-19 infection in patients with advanced kidney disease: a retrospective observational study

Nirmatrelvir-ritonavir is used in patients with coronavirus disease 2019 (COVID-19) with normal or mild renal impairment (eGFR ≥30ml/min per 1.73m2). There is limited data regarding its use in advanced kidney disease (eGFR <30ml/min per 1.73m2). We performed a retrospective territory-wide observational study evaluating the safety and efficacy of nirmatrelvir-ritonavir when compared with molnupiravir in the treatment of patients with COVID-19 with advanced kidney disease. We adopted target trial emulation using data from a territory-wide electronic health record database on eligible patients aged ≥18 years with advanced kidney disease (history of eGFR <30ml/min per 1.73m2) who were infected with COVID-19 and were prescribed with either molnupiravir or nirmatrelvir-ritonavir within five days of infection during the period from 16 March 2022 to 31 December 2022. A sequence trial approach and 1:4 propensity score matching was applied based on the baseline covariates including age, sex, number of COVID-19 vaccine doses received, Charlson comorbidity index (CCI), hospitalisation, eGFR, renal replacement therapy, comorbidities (cancer, respiratory disease, myocardial infarction, ischaemic stroke, diabetes, hypertension), and drug use (renin-angiotensin-system agents, beta blockers, calcium channel blockers, diuretics, nitrates, lipid lowering agents, insulins, oral antidiabetic drugs, antiplatelets, immuno-suppressants, corticosteroids, proton pump inhibitors, histamine H2 receptor antagonists, monoclonal antibody infusion) within past 90 days. Individuals were followed up from the index date until the earliest outcome occurrence, death, 90 days from index date or the end of data availability. Stratified Cox proportional hazards regression adjusted with baseline covariates was used to compare the risk of outcomes between nirmatrelvir-ritonavir recipients and molnupiravir recipients which include (i) all-cause mortality, (ii) intensive care unit (ICU) admission, (iii) ventilatory support, (iv) hospitalisation, (v) hepatic impairment, (vi) ischaemic stroke, and (vii) myocardial infarction. Subgroup analyses included age (<70; ≥70 years); sex, Charlson comorbidity index (≤5; >5), and number of COVID-19 vaccine doses received (0-1; ≥2 doses). A total of 4886 patients were included (nirmatrelvir-ritonavir: 1462; molnupiravir: 3424). There were 347 events of all-cause mortality (nirmatrelvir-ritonavir: 74, 5.06%; molnupiravir: 273, 7.97%), 10 events of ICU admission (nirmatrelvir-ritonavir: 4, 0.27%; molnupiravir: 6, 0.18%), 48 events of ventilatory support (nirmatrelvir-ritonavir: 13, 0.89%; molnupiravir: 35, 1.02%), 836 events of hospitalisation (nirmatrelvir-ritonavir: 218, 23.98%; molnupiravir: 618, 28.14%), 1 event of hepatic impairment (nirmatrelvir-ritonavir: 0, 0%; molnupiravir: 1, 0.03%), 8 events of ischaemic stroke (nirmatrelvir-ritonavir: 3, 0.22%; molnupiravir: 5, 0.16%) and 9 events of myocardial infarction (nirmatrelvir-ritonavir: 2, 0.15%; molnupiravir: 7, 0.22%). Nirmatrelvir-ritonavir users had lower rates of all-cause mortality (absolute risk reduction (ARR) at 90 days 2.91%, 95% CI: 1.47-4.36%) and hospitalisation (ARR at 90 days 4.16%, 95% CI: 0.81-7.51%) as compared with molnupiravir users. Similar rates of ICU admission (ARR at 90 days-0.09%, 95% CI:-0.4 to 0.2%), ventilatory support (ARR at 90 days 0.13%, 95% CI:-0.45 to 0.72%), hepatic impairment (ARR at 90 days 0.03%, 95% CI:-0.03 to 0.09%), ischaemic stroke (ARR at 90 days-0.06%, 95% CI:-0.35 to 0.22%), and myocardial infarction (ARR at 90 days 0.07%, 95% CI:-0.19 to 0.33%) were found between nirmatrelvir-ritonavir and molnupiravir users. Consistent results were observed in relative risk adjusted with baseline characteristics. Nirmatrelvir-ritonavir was associated with significantly reduced risk of all-cause mortality (HR: 0.624, 95% CI: 0.455-0.857) and hospitalisation (HR: 0.782, 95% CI: 0.64-0.954). Patients with COVID-19 with advanced kidney disease receiving nirmatrelvir-ritonavir had a lower rate of all-cause mortality and hospital admission when compared with molnupiravir. Other adverse clinical outcomes were similar in both treatment groups. Health and Medical Research Fund (COVID1903010), Health Bureau, The Government of the Hong Kong Special Administrative Region, China.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial

Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Exclusive Breastfeeding Duration and Risk of Childhood Cancers

Breastfeeding has been suggested to protect against childhood cancers, particularly acute lymphoblastic leukemia (ALL). However, the evidence stems from case-control studies alone. To investigate whether longer duration of exclusive breastfeeding is associated with decreased risk of childhood ALL and other childhood cancers. This population-based cohort study used administrative data on exclusive breastfeeding duration from the Danish National Child Health Register. All children born in Denmark between January 2005 and December 2018 with available information on duration of exclusive breastfeeding were included. Children were followed up from age 1 year until childhood cancer diagnosis, loss to follow-up or emigration, death, age 15 years, or December 31, 2020. Data were analyzed from March to October 2023. Duration of exclusive breastfeeding in infancy. Associations between duration of exclusive breastfeeding and risk of childhood cancer overall and by subtypes were estimated as adjusted hazard ratios (AHRs) with 95% CIs using stratified Cox proportional hazards regression models. A total of 309 473 children were included (51.3% boys). During 1 679 635 person-years of follow-up, 332 children (0.1%) were diagnosed with cancer at ages 1 to 14 years (mean [SD] age at diagnosis, 4.24 [2.67] years; 194 boys [58.4%]). Of these, 124 (37.3%) were diagnosed with hematologic cancers (81 [65.3%] were ALL, 74 [91.4%] of which were B-cell precursor [BCP] ALL), 44 (13.3%) with central nervous system tumors, 80 (24.1%) with solid tumors, and 84 (25.3%) with other and unspecified malignant neoplasms. Compared with exclusive breastfeeding duration of less than 3 months, exclusive breastfeeding for 3 months or longer was associated with a decreased risk of hematologic cancers (AHR, 0.66; 95% CI, 0.46-0.95), which was largely attributable to decreased risk of BCP-ALL (AHR, 0.62; 95% CI, 0.39-0.99), but not with risk of central nervous system tumors (AHR, 0.96; 95% CI, 0.51-1.88) or solid tumors (AHR, 0.87; 95% CI, 0.55-1.41). In this cohort study, longer duration of exclusive breastfeeding was associated with reduced risk of childhood BCP-ALL, corroborating results of previous case-control investigations in this field. To inform future preemptive interventions, continued research should focus on the potential biologic mechanisms underlying the observed association.

Enfortumab vedotin (EV) in combination with pembrolizumab (P) versus chemotherapy in previously untreated locally advanced metastatic urothelial carcinoma (la/mUC): Subgroup analyses results from EV-302, a phase 3 global study.

LBA530 Background: EV-302/KEYNOTE-A39 (NCT04223856) is a phase 3, open-label, randomized, global study comparing EV+P with platinum-based chemotherapy for first-line (1L) treatment of patients (pts) with la/mUC regardless of cisplatin eligibility or PD-L1 expression status. In EV-302, EV+P demonstrated a statistically significant and clinically meaningful benefit compared with platinum-based chemotherapy for the dual primary endpoints of progression-free survival (PFS) (hazard ratio [HR]: 0.45; P&lt;0.00001) and overall survival (OS) (HR: 0.47; P&lt;0.00001) in the overall pt population (Powles ESMO 2023). Here we present results not previously presented of prespecified subgroup analyses. Methods: Pts with previously untreated la/mUC were randomized 1:1 to receive 3-week cycles of EV (1.25 mg/kg; Days 1 and 8; IV) and P (200 mg; Day 1; IV) or gemcitabine with cisplatin or carboplatin. Select secondary endpoints included confirmed objective response rate (cORR), duration of response, and safety. For PFS and OS, an HR between treatment arms was estimated using a stratified Cox proportional hazards regression model controlling for the stratification factors (cisplatin eligibility, PD-L1 status [high/low], liver metastases [yes/no]) for each predefined subgroup. Results: 886 pts (EV+P: 442, chemotherapy: 444) were randomized; baseline pt and disease characteristics were balanced between groups. PFS and OS were prolonged for EV+P among prespecified subgroups, including race, cisplatin eligibility, PD-L1 expression, metastatic site, liver involvement, and renal function. Select subgroup data not previously presented for OS are presented in the Table. Kaplan-Meier curves for PFS (liver metastases, cisplatin eligibility, and PD-L1 status) and OS (liver metastases) will also be presented. Conclusions: EV+P significantly improved outcomes in pts with previously untreated la/mUC compared with chemotherapy; OS benefit was consistently observed across select prespecified subgroups, including those historically associated with poor prognosis. The results of these subgroup analyses support the findings of the primary analysis, which indicate that EV+P is a potential new standard of care for 1L la/mUC. Clinical trial information: NCT04223856 . [Table: see text]

Association of Long COVID with mental health disorders: a retrospective cohort study using real-world data from the USA

ObjectivesMental health disorders (MHD) rank third for US adult hospitalisations. Given the substantial prevalence of ‘Long COVID’ in SARS-CoV-2 survivors, this study aims to assess its association with increased MHD...

Risk of cardiocerebrovascular diseases is increased in Korean women with polycystic ovary syndrome: a nationwide cohort study

To investigate the relationship between polycystic ovary syndrome (PCOS) and risk of cardiocerebrovascular disease in Korean women. This longitudinal cohort study using data from the Korean National Health Insurance Service included the women aged 15–44 years diagnosed with PCOS between 2002 and 2019, and the controls were matched 1:3 by age group, income, and region of residence. The endpoint outcomes of this study were the occurrence of ischemic heart disease, cerebrovascular diseases, and combined cardiocerebrovascular diseases in the PCOS and control groups. A stratified Cox proportional hazards regression analysis for matched data was performed to evaluate the relative hazard of events in the PCOS group compared to that in the control group. Among a total of 549,400 participants in the cohort, 137,416 women had a diagnosis of PCOS and 412,118 women did not have it. During a median follow-up of 54 months (interquartile range, 30–78 months), the incidence rates of all cardiovascular, ischemic heart, and cerebrovascular diseases were 6.6, 4.0, and 2.9, respectively, per 1000 person-years for women with PCOS, and 4.8, 2.8, and 2.3, respectively, per 1000 person-years for healthy control women. Women with PCOS had a higher hazard ratio of 1.224 (95% confidence interval, 1.18–1.27) of the composite cardiocerebrovascular diseases than those in the controls after propensity score matching for confounding variables, including body mass index, diabetes mellitus, hypertension, dyslipidemia, physical exercise level, alcohol consumption, current smoking, systolic and diastolic blood pressures, total cholesterol, and triglyceride levels. Hazard ratio for ischemic heart and cerebrovascular diseases was higher in women with PCOS than in the control group (hazard ratio, 1.254; 95% confidence interval, 1.20–1.31 and hazard ratio, 1.201; 95% confidence interval, 1.14–1.27, respectively). PCOS is associated with an increased risk of cardiocerebrovascular diseases in Korean women irrespective of their obesity. Counselling on the management of long-term risk of cardiovascular diseases should be offered to women with PCOS in East Asian countries where PCOS is characterized by a relatively low BMI.

Association of pancreatitis with risk of diabetes: analysis of real-world data.

Diabetes is a major cause of disease burden with considerable public health significance. While the pancreas plays a significant role in glucose homeostasis, the association between pancreatitis and new onset diabetes is not well understood. The purpose of this study was to examine that association using large real-world data. Utilizing the IBM® MarketScan® commercial claims database from 2016 to 2019, pancreatitis and diabetes regardless of diagnostic category, were identified using International Classification of Diseases, Tenth Revision [ICD-10] codes. We then performed descriptive analyses characterizing non-pancreatitis (NP), acute pancreatitis (AP), and chronic pancreatitis (CP) cohort subjects. Stratified Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of diabetes across the three clinical categories. In total, 310,962 individuals were included in the analysis. During 503,274 person-years of follow-up, we identified 15,951 incident diabetes cases. While men and women had higher incidence rates of CP and AP-related diabetes, the rates were significantly greater in men and highest among individuals with CP (91.6 per 1000 persons-years (PY)) followed by AP (75.9 per 1000-PY) as compared to those with NP (27.8 per 1000-PY). After adjustment for diabetes risk factors, relative to the NP group, the HR for future diabetes was 2.59 (95% CI: 2.45-2.74) (P<0.001) for the CP group, and 2.39 (95% CI: 2.30-2.48) (P<0.001) for the AP group. Pancreatitis was associated with a high risk of diabetes independent of demographic, lifestyle, and comorbid conditions.

Utilization of Autologous Hematopoietic Cell Transplantation Over Time in Multiple Myeloma: A Population-Based Study

PurposeAutologous hematopoietic cell transplantation (autoHCT) is associated with survival benefits in multiple myeloma (MM), but utilization remains low and differs by sociodemographic factors. Prior population-based studies have not fully captured autoHCT utilization or examined relationships between sociodemographic factors and autoHCT trends over time. Patients and MethodsWe used a novel data linkage between the California Cancer Registry, Center for International Blood and Marrow Transplant Research, and hospitalizations to capture autoHCT in a population-based MM cohort (n = 29, 109; 1991-2016). Due to interactions by treatment era, stratified multivariable Cox proportional hazards regression models determined factors associated with autoHCT. ResultsThe frequency of MM patients who received autoHCT increased from 5.7% (1991-1995) to 27.4% (2011-2016). In models by treatment era, patients with public/no (vs. private) health insurance were less likely to receive autoHCT (2011-2016 Medicare hazard ratio (HR) 0.70, 95% confidence interval (CI): 0.63-0.78; Medicaid HR 0.81, CI: 0.72-0.91; no insurance HR 0.56, CI: 0.32-0.99). In each treatment era, Black/African American (vs. non-Hispanic White) patients were less likely to receive autoHCT (2011-2016 HR 0.83, CI: 0.72-0.95). Hispanic patients were less likely to undergo autoHCT, most prominently in the earliest treatment era (1991-1995 HR 0.58, 95% CI: 0.37-0.90; 2011-2016 HR 1.07, CI: 0.96-1.19). Patients in lower socioeconomic status neighborhoods were less likely to utilize autoHCT, but differences decreased over time. ConclusionsDespite increases in autoHCT utilization, sociodemographic disparities remain. Identifying and mitigating barriers to autoHCT is essential to ensuring more equitable access to this highly effective therapy.

All-Cause and Cause-Specific Mortality Among Individuals With Hypochondriasis

Hypochondriasis, also known as health anxiety disorder, is a prevalent, yet underdiagnosed psychiatric disorder characterized by persistent preoccupation about having serious and progressive physical disorders. The risk of mortality among individuals with hypochondriasis is unknown. To investigate all-cause and cause-specific mortality among a large cohort of individuals with hypochondriasis. This Swedish nationwide matched-cohort study included 4129 individuals with a validated International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis of hypochondriasis assigned between January 1, 1997, and December 31, 2020, and 41 290 demographically matched individuals without hypochondriasis. Individuals with diagnoses of dysmorphophobia (body dysmorphic disorder) assigned during the same period were excluded from the cohort. Statistical analyses were conducted between May 5 and September 27, 2023. Validated ICD-10 diagnoses of hypochondriasis in the National Patient Register. All-cause and cause-specific mortality in the Cause of Death Register. Covariates included birth year, sex, county of residence, country of birth (Sweden vs abroad), latest recorded education, civil status, family income, and lifetime psychiatric comorbidities. Stratified Cox proportional hazards regression models were used to estimate the hazard ratios (HRs) and 95% CIs of all-cause and cause-specific mortality. Of the 4129 individuals with hypochondriasis (2342 women [56.7%]; median age at first diagnosis, 34.5 years [IQR, 26.3-46.1 years]) and 41 290 demographically matched individuals without hypochondriasis (23 420 women [56.7%]; median age at matching, 34.5 years [IQR, 26.4-46.2 years]) in the study, 268 individuals with hypochondriasis and 1761 individuals without hypochondriasis died during the study period, corresponding to crude mortality rates of 8.5 and 5.5 per 1000 person-years, respectively. In models adjusted for sociodemographic variables, an increased rate of all-cause mortality was observed among individuals with hypochondriasis compared with individuals without hypochondriasis (HR, 1.69; 95% CI, 1.47-1.93). An increased rate was observed for both natural (HR, 1.60; 95% CI, 1.38-1.85) and unnatural (HR, 2.43; 95% CI, 1.61-3.68) causes of death. Most deaths from unnatural causes were attributed to suicide (HR, 4.14; 95% CI, 2.44-7.03). The results were generally robust to additional adjustment for lifetime psychiatric disorders. This cohort study suggests that individuals with hypochondriasis have an increased risk of death from both natural and unnatural causes, particularly suicide, compared with individuals from the general population without hypochondriasis. Improved detection and access to evidence-based care should be prioritized.

Liver Metastases and Immune Checkpoint Inhibitor Efficacy in Patients With Refractory Metastatic Colorectal Cancer

Immune checkpoint inhibitors (ICIs) have limited activity in microsatellite-stable (MSS) or mismatch repair-proficient (pMMR) colorectal cancer. Recent findings suggest the efficacy of ICIs may be modulated by the presence of liver metastases (LM). To investigate the association between the presence of LM and ICI activity in advanced MSS colorectal cancer. In this secondary analysis of the Canadian Cancer Trials Group CO26 (CCTG CO.26) randomized clinical trial, patients with treatment-refractory colorectal cancer were randomized in a 2:1 fashion to durvalumab plus tremelimumab or best supportive care alone between August 10, 2016, and June 15, 2017. The primary end point was overall survival (OS) with 80% power and 2-sided α = .10. The median follow-up was 15.2 (0.2-22.0) months. In this post hoc analysis performed from February 11 to 14, 2022, subgroups were defined based on the presence or absence of LM and study treatments. Durvalumab plus tremelimumab or best supportive care. Hazard ratios (HRs) and 90% CIs were calculated based on a stratified Cox proportional hazards regression model. Plasma tumor mutation burden at study entry was determined using a circulating tumor DNA assay. The primary end point of the study was OS, defined as the time from randomization to death due to any cause; secondary end points included progression-free survival (PFS) and disease control rate (DCR). Of 180 patients enrolled (median age, 65 [IQR, 36-87] years; 121 [67.2%] men; 19 [10.6%] Asian, 151 [83.9%] White, and 10 [5.6%] other race or ethnicity), LM were present in 127 (70.6%). For patients with LM, there was a higher proportion of male patients (94 of 127 [74.0%] vs 27 of 53 [50.9%]; P = .005), and the time from initial cancer diagnosis to study entry was shorter (median, 40 [range, 8-153] vs 56 [range, 14-181] months; P = .001). Plasma tumor mutation burden was significantly higher in patients with LM. Patients without LM had significantly improved PFS with durvalumab plus tremelimumab (HR, 0.54 [90% CI, 0.35-0.96]; P = .08; P = .02 for interaction). Disease control rate was 49% (90% CI, 36%-62%) in patients without LM treated with durvalumab plus tremelimumab, compared with 14% (90% CI, 6%-38%) in those with LM (odds ratio, 5.70 [90% CI, 1.46-22.25]; P = .03). On multivariable analysis, patients without LM had significantly improved OS and PFS compared with patients with LM. In this secondary analysis of the CCTG CO.26 study, the presence of LM was associated with worse outcomes for patients with advanced colorectal cancer. Patients without LM had improved PFS and higher DCR with durvalumab plus tremelimumab. Liver metastases may be associated with poor outcomes of ICI treatment in advanced colorectal cancer and should be considered in the design and interpretation of future clinical studies evaluating this therapy.

Quantum-First (Q-F): Clinical Bridging Study for FMS-like Tyrosine Kinase 3-Internal Tandem Duplication ( FLT3-ITD) Companion Diagnostic Development

Background Q-F (NCT02668653) showed that the highly potent, selective, type 2 FLT3 inhibitor quizartinib (Q) + standard chemotherapy ± transplantation, followed by Q monotherapy for ≥36 cycles, reduced the relative risk of death by 22.4% vs placebo (P) in newly diagnosed (nd) FLT3-ITD+ AML, with HR of 0.776 and P value of 0.0324 (PMID: 37116523). In Q-F, FLT3-ITD mutation status was determined using a FLT3-ITD mutation detection clinical trial assay (CTA) validated under design control by Navigate BioPharma Services, Inc. We describe the results of the bridging study, aimed to show agreement between the CTA &amp; the LeukoStrat CDx FLT3 Mutation Assay (CDx, by Invivoscribe) in FLT3-ITD+ pt selection and to determine if Q efficacy (overall survival [OS]) was maintained in nd FLT3-ITD+ AML pts from Q-F, if pts had been selected using the CDx. Methods In both CTA &amp; CDx, DNA, extracted from bone marrow (n=884 each) or peripheral blood (n=139 each), was amplified via PCR and amplicons were detected via capillary electrophoresis. A sample was considered CTA+ if the variant allele frequency ( FLT3-ITD/total FLT3) was ≥3% and CDx+ if the signal ratio (SR; FLT3-ITD/ FLT3 WT) was ≥0.05. The agreement between CTA &amp; CDx was based on evaluating CTA+ &amp; CTA− samples with the CDx assay. A primary analysis included the CDx detected (CDx+ &amp; CDx−) and the CDx invalid results. A secondary analysis used CDx+ and CDx− results only. To establish agreement between CDx &amp; CTA, positive % agreement (PPA) and negative % agreement (NPA) were determined using CTA results as reference for the agreement analysis set (AAS). Concordance was established if the lower bounds of the 95% CIs for both PPA &amp; NPA exceeded 90% for the analysis that included the invalid CDx results. Median OS in the subgroups was calculated based on Kaplan-Meier estimates. Stratified Cox proportional hazards regression model was used to estimate HRs, 95% CI, and P value. Results Full analysis set (N=3468) included all Q-F screened CTA+ pts (n=863), all screened CTA− pts (n=2556), and pts with unknown CTA status not eligible for randomization due to other criteria (n=49). Of these, 1032 pts formed the primary analysis set (PAS), including all pts randomized in Q-F with samples available for CDx testing (N=513: Q, n=254; P, n=259) and a randomly selected subset of CTA− pts (n=519). The ascertainment rate was 95.2% (513/539), as 26 of the 539 pts randomized in Q-F were excluded from the bridging study. Within the PAS, 3 samples were not tested by CDx due to insufficient volume/DNA amount. The AAS (N=1029: CTA+, n=513; CTA−, n=516) included pts in the PAS with valid CTA results and tested with CDx. In the AAS, 6 samples (3 CTA+, 3 CTA−) did not yield valid CDx results, resulting in 1023 CDx-evaluable total pts (CTA+, n=510; CTA−, n=513). Among 510 CTA+ samples, 483 were CDx+. Among 513 CTA− samples, 513 were CDx−. Therefore, 996 samples yielded concordant results, 27 samples yielded discordant results, and 6 samples did not yield a valid CDx result for comparison. Point estimates of PPA &amp; NPA were 94.2% &amp; 99.4%, respectively, with invalid CDx results included in the calculation, and 94.7% &amp; 100%, respectively, without invalid CDx results. The lower bounds of the 95% CIs were all above the corresponding acceptance criterion of 90% for PPA &amp; NPA (Table 1). In Q-F, the prevalence of CTA+ was 24.9% among screened pts (863/3468), whereas in the bridging study, 49.9% (510/1023) of pts were CTA+: this enrichment in CTA+ pts could lead to a biased estimate of the agreement between CDx &amp; CTA when using CDx as reference. The positive predictive value (PPV) and negative predictive value (NPV) of the CDx adjusted for this enrichment ± invalid CDx results, showed that the lower bounds of the 95% CIs were all &amp;gt;95% (Table 1). The efficacy OS analysis in the intent-to-treat (ITT) CDx+ population (ITT CDx+=CTA+ &amp; CDx+; N=483: Q, n=242; P, n=241) demonstrated a clinically relevant OS improvement with Q (median OS of 29.4 months) vs P (median OS of 14.8 months), resulting in 14.6 months prolongation of median OS, with an HR of 0.794 (95% CI 0.621-1.014), corresponding to a 20.6% reduction in relative risk of death (Figure 1). Conclusions This study showed 1) agreement between CDx &amp; CTA in identifying nd FLT3-ITD+ AML pts and 2) that OS benefit provided by Q in the ITT CDx+ population is comparable with the OS benefit in the ITT population of Q-F. The LeukoStrat CDx FLT3 Mutation Assay aids in assessing AML pts for Q therapy.

Prevalence, Characteristics, and Clinical Impact of Clonal Hematopoiesis of Indeterminate Potential in AL Amyloidosis

Backgrounds: AL Amyloidosis is a plasma cell dyscrasia whose hallmark is the circulation and deposition of immunoglobulin free light chains in target organs. The extent and severity of cardiac involvement are the primary determinants of mortality in AL amyloidosis. Patients harboring clonal hematopoiesis of indeterminate potential (CHIP) have an increased cardiovascular risk compared to the general population. In the setting of multiple myeloma receiving autologous stem cell transplants, CHIP presence has been associated with decreased overall survival. Still, large studies looking at the incidence and outcome of patients with concurrent CHIP and AL amyloidosis are missing. Herby, we present the results of a single-center, retrospective cohort study, where we assessed the prevalence of CHIP in AL amyloidosis and associated disease characteristics and outcomes. Methods: We collected the demographics and clinical characteristics of patients with AL amyloidosis at Dana Farber Cancer Institute (DFCI) from January 2018 to April 2023 who underwent a bone marrow aspirate/biopsy with a rapid heme panel. Variables of interest included age, ethnicity, Mayo 2004 stage, Palladini renal stage, involved organs, FISH abnormalities, left ventricular ejection fraction (LVEF), documented coronary artery disease (CAD), orthostatic hypotension (OH), chemotherapy (CT) treatment received and related response. The primary outcome was major organ dysfunction progression-free survival (MOD-PFS), defined by Kastritis et al. The variant allele fraction (VAF) to define CHIP was set at 2%. Two samples t-test, Wilcoxon rank sum test, and Fisher's exact test were used to compare groups. Univariate and stratified multivariate Cox proportional hazard regression models were used to estimate the association between CHIP status and MOD-PFS. Analyses were carried out with the Stata statistical package. This study was approved by the DFCI Institutional Review Board and performed in accordance with the Declaration of Helsinki. Results: We identified 76 patients as meeting the inclusion criteria. The median age was 67 years. FISH was available for 54 patients. All patients received cytoreductive CT (CyborD 47%, DaraCyborD 37%). CHIP was identified in 16 patients (21%), a significantly higher figure as compared to historical age-matched healthy controls. DNMT3A was the most frequently involved gene (7/16, 44%), followed by GNB1, TET2, ATM (each 2/16, 12.5%), and SF3B1, ZRSR2, EZH2, BRCC3, PPM1D, ASXL1 (6%) (Figure 1). The presence of CHIP strongly associated with t(11;14) (11/13, 85% in patients with CHIP, versus 15/41, 37%, in patients without CHIP, p=0.004) and with a lower Palladini renal stage in patients with renal involvement (p=0.001). The median follow-up time for the entire cohort was 25 months (range 1 - 175 months). In a univariate analysis, CHIP presence was not associated with lower MOD-PFS (hazard ratio [HR] 0.998, 95% CI 0.38 - 2.64). In a univariate analysis, a Mayo stage &amp;gt;2 (HR 4.82, 95% CI 1.95 - 11.91, p = 0.001), the presence of CAD (HR 4.97, 95% CI 1.79 - 13.79, p=0.02), LVEF ≤40% (HR 3.18, 95% CI 1.17 - 8.66, p = 0.023), and OH requiring treatment (HR 2.65, 95% CI 1.74 - 5.97, p = 0.019) were associated with a decreased MOD-PFS. In a multivariate model stratified for age, only the presence of CAD and OH requiring treatment remained associated with worse MOD-PFS (HR 5.65, 95% CI, 1.33 - 23.99, p = 0.019; HR 4.57, 95% CI, 1.30 - 16.05, p = 0.018, respectively). In the multivariate Cox regression model (Figure 2), CHIP presence was not associated with a decreased MOD-PFS (HR 1.32, 95% CI, 0.44 - 3.98, p = 0.624). When focusing on the impact of only DNMT3A, a tendency towards a statistically significant association with worse MOD-PFS was noted in the multivariate model (HR 3.72, 95% CI 0.92 - 15.01, p = 0.065). Conclusion: We present the largest dataset exploring the prevalence of CHIP in AL amyloidosis patients and its clinical correlates. We noted an association between the presence of CHIP and t(11;14), the most frequent cytogenetic abnormality in AL amyloidosis, and adverse prognostic factors. Patients with CHIP were also found to have a lower Palladini renal risk score. Harboring CHIP was not associated with worse MOD-PFS; however, DNMT3A mutation tended to correlate with worse MOD-PFS. Larger prospective studies are warranted to validate these findings and better elucidate the impact of CHIP in patients with AL amyloidosis.

Patient-Reported Outcomes (PRO) of Luspatercept Versus Epoetin Alfa in Erythropoiesis-Stimulating Agent (ESA)-Naïve, Transfusion-Dependent (TD), Lower-Risk Myelodysplastic Syndromes (LR-MDS): Results from the Phase 3 COMMANDS Study

Background: For symptomatic anemia in patients with LR-MDS, supportive treatment with erythropoietin stimulating agents (ESAs), such as epoetin alfa, remains the current standard of care, which has limited and transient effect. The phase 3, open-label, randomized, controlled COMMANDS study demonstrated that luspatercept significantly improved the rate of transfusion independence and hemoglobin levels, when compared to epoetin alfa in ESA-naïve and transfusion-dependent (TD) patients with LR-MDS (Platzbecker U, et al. Lancet. 2023;S0140-6736(23)00874-7). Objective: The objective of this interim analysis was to assess the effect of luspatercept versus epoetin alfa on patient-reported outcome (PRO) using data from the first 24 weeks of the COMMANDS study. Methods: In COMMANDS, 356 patients were randomized 1:1 to luspatercept (Q3W) or epoetin alfa (QW). PROs, as one of the secondary objectives, were assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire - Core 30 (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Anemia (FACT-An) questionnaire.The EORTC QLQ-C30 was assessed on Day 1 prior to the first dose (baseline) and every 6 weeks thereafter; the FACT-An was administered at baseline, weekly for 3 weeks, and then every 3 weeks thereafter. Time to sustained improvement on domains of the EORTC QLQ-C30 and FACT-An was assessed between treatment arms using a stratified Cox proportional hazards regression model. Sustained improvement was defined as improvement from baseline ≥ pre-specified responder definition, sustained for at least 42 days through Week 25 Day 1 (W25D1). Overall treatment tolerability, assessed by the FACT-An item GP5 (“I am bothered by side effects of treatment”), was descriptively summarized at W25D1 by treatment arm. All analyses were conducted on the respective PRO-evaluable populations for each instrument, including patients who had completed the assessment at baseline and at least one post-baseline visit, unless otherwise specified. Results: The EORTC QLQ-C30 evaluable population consisted of 150 and 144 patients randomized to luspatercept and epoetin alfa, respectively (median age 74.5 years and 54% male). Population sizes were similar for other PRO measures. Demographics, disease characteristics, and PRO domain scores at baseline were generally comparable between treatment arms. Completion rates of PRO assessments were moderately high for both arms (approximately 70-90%) through the W25D1 visit. Luspatercept resulted in a higher probability of sustained improvement through W25D1 in almost all domains of the EORTC QLQ-C30 and FACT-An compared to epoetin alfa, with significant differences (nominal p-value &amp;lt;0.05) in dyspnea (hazard ratio [HR] [95% confidence interval]: 3.18 [1.03, 9.81]) and 7 other domains of the EORTC QLQ-C30 (role functioning, cognitive functioning, pain, insomnia, appetite loss, constipation, and financial difficulties). Patients in both arms experienced similar overall treatment tolerability, with &amp;gt;67% of all patients still on treatment reporting to be “not at all” bothered by treatment side effects through W25D1. Conclusions: The findings from these interim PRO analyses indicate that treatment with luspatercept increased sustained improvement across quality-of-life domains when compared to epoetin alfa. Luspatercept was also found to be well-tolerated by the majority of patients. All of these PRO findings further support the benefits of luspatercept in ESA-naïve and TD patients with LR-MDS.

Effects of Idecabtagene Vicleucel (Ide-Cel) Versus Standard Regimens on Health-Related Quality of Life (HRQoL) in Patients with Triple-Class-Exposed (TCE) Relapsed/Refractory Multiple Myeloma (RRMM) Who Received at Least 3 Lines of Prior Antimyeloma Regimens in the KarMMa-3 Phase 3 Randomized Controlled Trial

Introduction: Patients with TCE RRMM have a high disease burden and often report worsening HRQoL with additional lines of therapy. The single-arm, phase 2 KarMMa study demonstrated that ide-cel, a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T cell therapy, improved HRQoL from baseline in patients with TCE RRMM who had received ≥ 3 prior regimens (Delforge M, et al. Blood Adv 2022;6:1309-1318). Furthermore, in the phase 3 KarMMa-3 clinical trial (NCT03651128), ide-cel significantly improved progression-free survival and response compared with standard regimens in patients with TCE RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014). Here we assessed the comparative effects of ide-cel versus standard regimens on HRQoL in patients with TCE RRMM who had received 3-4 prior regimens including an immunomodulatory agent, a proteasome inhibitor, and daratumumab (an anti-CD38 monoclonal antibody) using data from the KarMMa-3 study. Methods: Patient-reported outcomes (PROs) were assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. The pre-specified primary domains of interest included EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D-5L visual analog scale (EQ-5D VAS). PROs were collected at screening (baseline), the day of ide-cel infusion (ide-cel) or first treatment dose (standard regimens), monthly from 2 to 28 months, and thereafter every 3 months. Comparisons were performed on least squares (LS) mean changes from baseline through 28 months between arms using constrained longitudinal data analysis (cLDA). Effect size was estimated by Hedges' g. The comparative effects of ide-cel versus standard regimens on time to confirmed improvement and time to confirmed deterioration (defined by prespecified change thresholds) were assessed via stratified Cox proportional hazards regression analyses. All P values are nominal and not adjusted for multiple testing. Statistical significance was set at P &amp;lt; 0.05. Results: Baseline characteristics were well balanced among the patients in the ide-cel arm (n = 167) and the standard regimen arm (n = 93), with a median age of 63 years and a median time of 4.7 years from RRMM diagnosis to study screening. Completion rates of HRQoL assessments were high over time for most visits (&amp;gt; 75%). At baseline, mean HRQoL domain scores were similar between arms. Overall LS mean changes from baseline to 28 months showed significant differences in favor of ide-cel versus standard regimens (nominal P &amp;lt; 0.05) for 11 domains (effect sizes of 0.26-0.82), and 7 (4 primary: global health status/QoL, cognitive functioning, pain, EQ-5D VAS; 3 secondary: dyspnea, insomnia, constipation) of them exceeded the prespecified MID thresholds (Table). Time to confirmed improvement was significantly shorter (nominal P &amp;lt; 0.05) in the ide-cel arm than in the standard regimen arm for 10 domains, including all primary domains except pain. Time to confirmed deterioration was longer in the ide-cel arm than the standard regimen arm for most domains, with significant differences in emotional functioning, cognitive functioning, and dyspnea (EORTC QLQ-C30). Finally, side effects of treatment favored the ide-cel versus standard regimen arm (EORTC QLQ-MY20) (Table). Conclusions: These patient-reported findings demonstrate that compared with standard regimens, treatment with ide-cel improved MM-relevant disease symptoms, functioning, and overall health status/HRQoL of patients with TCE RRMM in the KarMMa-3 trial. These data further substantiate the superior treatment outcomes of ide-cel over standard regimens in this patient population. Overall, treatment with ide-cel may help alleviate detriments to HRQoL in these patients with complex disease.

Effects of Idecabtagene Vicleucel (Ide-Cel) Versus Standard Regimens on Health-Related Quality of Life (HRQoL) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Who Had Received 2-4 Prior Regimens: Updated Results from the Phase 3 KarMMa-3 Trial

Background: An interim analysis (data cutoff date April 18, 2022) of the international, open-label, phase 3 KarMMa-3 trial (NCT03651128) showed the chimeric antigen receptor T cell therapy idecabtagene vicleucel (ide-cel) significantly improved progression-free survival and treatment response rates, as well as HRQoL, as compared with standard regimens, in patients with triple-class exposed (TCE) RRMM who had received 2-4 prior regimens (Rodriguez-Otero P, et al. N Engl J Med 2023;388:1002-1014; Delforge M, et al., HemaSphere, 2023;7(S3):P905). The aim of the present study was to analyze the effect of ide-cel versus standard regimens (daratumumab [DARA], pomalidomide, and dexamethasone [DEX]; DARA, bortezomib, and DEX; ixazomib, lenalidomide, and DEX; carfilzomib and DEX; or elotuzumab, pomalidomide, and DEX) on HRQoL in KarMMa-3 trial participants with an extended follow-up of patient-reported outcomes (PRO) data collection (data cutoff date April 28, 2023). Methods: In KarMMa-3, HRQoL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire-Core 30 (QLQ-C30), EORTC Quality of Life Questionnaire Multiple Myeloma Module (QLQ-MY20), and EQ-5D-5L. HRQoL assessments were completed at screening (baseline); the day of ide-cel infusion or the first dose of standard treatment; and monthly from 2 to 28 months; and every 3 months thereafter. The prespecified primary outcomes of interest were EORTC QLQ-C30 global health status/QoL, physical functioning, cognitive functioning, fatigue, and pain; EORTC QLQ-MY20 disease symptoms and side effects of treatment; and the EQ-5D visual analog scale (EQ-VAS). Least squares (LS) mean changes from baseline through month 25 for ide-cel and standard regimens were compared by constrained longitudinal data analysis (cLDA). Effect sizes were estimated by Hedges' g. The effect of ide-cel versus standard regimens on time to confirmed improvement and deterioration in HRQoL (defined by prespecified change thresholds and sustained duration) were compared by stratified Cox proportional hazards regression. There was no adjustment for multiple testing, and all P values reported are nominal. Results: Overall, 254 patients were randomized to the ide-cel arm and 132 to the standard regimens arm. Baseline characteristics were well balanced across treatment arms; both arms had a median age of 63 years, a median of 3 prior anti-myeloma regimens, and median time from MM diagnosis to screening was 4 years. The baseline HRQoL scores were generally comparable between treatment arms. Overall LS mean changes from baseline to month 25 showed significant differences (nominal P value &amp;lt; 0.05) in favor of ide-cel for 18 out of 21 HRQoL domains, with effect sizes (Hedges' g) of 0.27 to 0.82 (Table). For 13 of these domains (including 6 primary domains of interest), the difference in overall LS mean change from baseline exceeded the prespecified minimum important difference (MID) threshold. Time to confirmed improvement was significantly shorter in the ide-cel arm than the standard regimens arm for 19 domains, including all primary domains of interest (Table). Time to confirmed deterioration showed trends of being longer in the ide-cel arm than the standard regimens arm for most domains and was significantly longer for emotional functioning, cognitive functioning, social functioning, dyspnea, and constipation as measured by the EORTC QLQ-C30. The time to confirmed deterioration in side effects of treatment (based on the EORTC QLQ-MY20) was significantly longer for patients in the ide-cel arm and time to confirmed improvement was significantly faster, as compared with the standard regimens arm (Table). Conclusions: In the KarMMa-3 trial, patients with TCE RRMM who had received 2-4 prior regimens, ide-cel significantly and meaningfully improved MM-relevant symptoms, functioning, and overall health status/HRQoL compared with standard regimens. Confirmed HRQoL improvements in the ide-cel arm occurred sooner than standard regimens. PRO improvements were sustained over more than 2 years, which is notable after a single infusion treatment with ide-cel. These patient-reported findings further support the benefit of ide-cel in this patient population.

Human Immunodeficiency Virus (HIV) Treatment With Antiretroviral Therapy Mitigates the High Risk of Mental Health Disorders Associated With HIV Infection in the US Population.

Whether treatment of human immunodeficiency virus (HIV) with antiretroviral therapy (ART) is associated with lower risk of mental health disorders (MHDs) among people with HIV (PWH) remains unknown. We aim to determine the association between HIV and MHDs and whether ART alters the risk of MHDs among PWH in the US adult population. We conducted a real-world study using the Merative MarketScan claims database (2016-2020), identifying individuals with HIV (diagnosed using International Classification of Diseases, Tenth Revision, Clinical Modification codes) and those without HIV. A multivariable stratified Cox proportional hazard regression model was conducted to examine the association of HIV treatment status with MHDs, adjusting for potential confounders. Additionally, we sought to determine the effect modification of ART on the relationship between living with HIV and MHDs. A total of 313 539 individuals, with a mean age of 44.2 (standard deviation, 11.4) years, predominantly males (81.2%), residing in the South region of the US (50.9%) were included in the present analysis. During 671 880 person-years of follow-up, 46 235 incident MHD cases occurred. In the multivariable Cox proportional hazard model, living with HIV was associated with higher risk of incident MHDs. Relative to those without HIV, the adjusted hazard ratio was 1.85 (95% confidence interval [CI], 1.79-1.92; P < .001) for those with HIV on treatment, and 2.70 (95% CI, 2.59-2.82; P < .001) for those with HIV without any treatment. Stronger associations between HIV and MHDs were observed in men relative to women, among those aged 18-34 years relative to those aged 55-63 years, and among those with no overweight/obesity relative to obese individuals (Pinteraction < .001 for all). HIV was associated with an increased risk of developing MHDs. However, HIV treatment mitigated the risk.