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Background Mantle cell lymphoma (MCL) is more common in males, with a male to female ratio of approximately 3:1. However, it is unclear whether disease characteristics and survival outcomes differ by sex. Additionally, the impact of race and ethnicity in MCL is understudied due to underrepresentation of minorities in clinical studies and trials. In this study, we utilized the National Cancer Database (NCDB) to examine patient and disease characteristics and survival outcomes of MCL by sex, race and ethnicity. Methods Patients diagnosed with MCL in 2004-2020 were identified from NCDB. Patient and disease characteristics were compared between groups using Chi-squared tests. Overall survival (OS) analysis was performed using the Kaplan-Meier method and the Cox proportional hazards model. Results A total of 35,135 patients was included. The median follow-up was 83.0 months (95% CI 81.9-84.1). 24,980 (71.1%) patients were male and 10,155 (28.9%) were female. Females had more elderly (age ≥65: 65.9% vs 59.0%; p<0.001), lower Charlson-Deyo Score (CDS ≥2: 7.0% vs 8.6%; p<0.001) and fewer stage III-IV diagnoses (80.5% vs 82.6%; p<0.001). Females were less likely to receive upfront treatment (80.7% vs 85.3%; p<0.001), treatment at academic centers (36.8% vs 40.9%; p<0.001) or transplant (11.0% vs 13.7%; p<0.001). Compared to males, females were more likely to live in metropolitan areas (83.7% vs 81.6%; p<0.001), had similar incomes, had more Medicare (60.4% vs 53.1%) and fewer private insurance (33.2% vs 38.6%; p<0.001). Female patients had better OS, with a median OS of 76.0 (95% CI 72.4-79.6) vs 67.8 months (95% CI 65.9-69.6; p<0.001). In the multivariable Cox model adjusting for age, race, ethnicity, CDS, stage, upfront treatment (vs surveillance or no treatment), facility (academic vs nonacademic), transplant, residence (metropolitan vs urban or rural) and insurance, female sex remained associated with superior OS (HR 0.84, 95% CI 0.793-0.890; p<0.001). For race, 32,399 (92.2%) patients were White, 1,465 (4.2%) were Black, 942 (2.7%) were others and 329 (0.9%) were unknown. Compared to White patients, Black patients had fewer elderly (52.9% vs 61.7%; p<0.001), higher CDS (≥2: 11.4% vs 7.9%; p<0.001), similar stage III-IV (80.7% vs 82.1%; p=0.276) and upfront treatment (84.7% vs 84.0%; p=0.074), were more likely to be treated at academic centers (50.6% vs 38.9%; p<0.001), were less likely to receive transplant (11.1% vs 13.0%; p=0.042), were more likely to live in metropolitan areas (91.0% vs 81.5%; p<0.001), had lower income, had more uninsured (4.4% vs 2.0%) and Medicaid (9.8% vs 3.7%) and fewer Medicare (47.4% vs 56.0%; p<0.001). Black and White patients had similar OS, with a median of 67.9 (95% CI 57.5-78.2) vs 69.6 months (95% CI 67.8 vs 71.3; p=0.697). In the multivariable Cox model, Black vs White race was not associated with OS (HR 1.086, 95% CI 0.952-1.240; p=0.219). For ethnicity, 31,717 (90.3%) patients were non-Hispanic, 1,894 (5.4%) were Hispanic and 1,534 (4.3%) were unknown. Hispanics had fewer elderly (51.3% vs 61.5%; p<0.001), lower CDS (≥2: 6.4% vs 8.2%; p=0.018), similar stage III-IV (81.2% vs 82.1%; p=0.467), were more likely to receive upfront treatment (86.0% vs 83.9%; p<0.001), more likely to be treated at academic centers (49.9% vs 39.5%; p<0.001), equally likely to receive transplant (13.0% vs 13.1%; p=0.943), more likely to live in metropolitan areas (95.4% vs 81.6%; p<0.001), had lower income, had more uninsured (9.6% vs 1.8%) and Medicaid (15.2% vs 9.6%) and fewer Medicare (40.3% vs 55.9%; p<0.001). Hispanics had better OS, with a median OS of 84.4 (95% CI 71.7-97.1) vs 70.5 months (95% CI 68.7-72.2; p<0.001). However, in the multivariable Cox model, Hispanic ethnicity was not associated with OS (HR 0.952, 95% CI 0.839-1.080; p=0.448). Conclusion This study is the first of its scale to demonstrate that female MCL patients have superior survival outcomes compared to males. It also demonstrated that neither Black race nor Hispanic ethnicity appears to be associated with worse survival outcomes. Despite its size, the NCDB is limited in the treatment information and disease characteristics it provides, including MIPI score, Ki-67, blastoid/pleomorphic morphology, and TP53 status. Thus, additional real-world dataset studies are needed to gain a deeper understanding of potential differences in sex, race and ethnicity with regards to disease characteristics and survival outcomes.

Background Primary Central Nervous System Lymphoma Patients (PCNSL) is a rare and aggressive form of NHL in the central nervous system or vitreoretinal space. Despite high initial response rates of high dose methotrexate-based regimens, most patients will relapse in less than two years with poor prognosis. There are no approved treatments for Relapsed/Refractory (R/R) PCNSL, representing a clear unmet medical need. IRAK4 kinase activity is required for TLR and IL-1R signaling in a variety of myeloid and lymphoid cell types, including PCNSL. Recruitment of IRAK4 to these receptors and subsequent activation is facilitated by the MyD88 adaptor protein, which is mutated in ~70% of PCNSL. This leads to constitutive activation of the NF-κB signaling pathway, increased inflammation, and tumor growth. Emavusertib is a novel and potent oral inhibitor of IRAK4, which has demonstrated the ability to cross the blood-brain barrier in PCNSL xenografts. In preclinical studies, the combination of emavusertib with Bruton tyrosine kinase inhibitors (BTKi) showed in vitro synergy of inhibition and re-sensitization of BTKi-resistant cell lines. Emavusertib + ibrutinib has demonstrated an acceptable safety profile across a broad population of R/R NHL patients, including PCNSL. Aim We present updated safety and efficacy of emavusertib in combination with ibrutinib in patients with R/R PCNSL most recently treated with BTKi regimen. Methods The safety, clinical activity, and potential biomarkers of emavusertib in R/R PCNSL are being investigated in the ongoing open-label, Phase 1/2 TakeAim Lymphoma trial (NCT03328078). The eligible patients with R/R PCNSL received emavusertib (100-300 mg BID) in combination with ibrutinib (560 mg QD) continuously until tumor progression or unacceptable toxicity. Disease staging at screening and anti-cancer therapeutic responses were evaluated according to the IPCG Response Criteria Guideline for PCNSL. Results As of 10 July 2024, 13 R/R PCNSL patients, with prior BTK exposure, received emavusertib at 100 - 300 mg BID in combination with ibrutinib at 560mg QD. The median age was 60 years (range 44 - 79). The median number of prior lines of anti-cancer therapies was 2 (range 2 - 5). Median emavusertib/ibrutinib treatment duration was 51 days (range 17 - 503). The preliminary efficacy data in 12 evaluable patients whose most recent treatment regimen included a BTKi and were treated with the combination of emavusertib and ibrutinib showed 3 complete remission (CR), 1 unconfirmed complete Response (CRu) and 2 partial responses (PR) and an overall response rate of 50%. Treatment is on-going for 5 patients with one patient pending the first assessment. All responders demonstrated more than 80% reduction in target lesion size compared to baseline. Two of the responders with a CR demonstrated durable response, with 1 patient having a duration of response (DOR) of approximately 9 months, and the second patient having a DOR of 12 months with response ongoing. Grade ≥3 Treatment-emergent adverse events (TEAEs) were reported in 7 (53.8%) patients, while Grade ≥3 treatment-related adverse events (TRAEs) were reported in 4 (30.8%) patients. No fatal TRAE were reported and the majority of Grade ≥ 3 TEAEs and all Grade ≥ 3 TRAEs were reversible and manageable. Conclusion Emavusertib in combination with ibrutinib shows promising efficacy and was well tolerated with an acceptable safety profile in R/R PCNSL patients with prior BTKi exposure. The combination of emavusertib + ibrutinib may overcome BTKi resistance and has the potential to show improved anti-cancer activity. Enrollment in this trial is ongoing (NCT03328078).

Introduction: Over 80,000 new cases of Non-Hodgkin's Lymphoma (NHL) are diagnosed annually, but modifiable risk factors are largely unknown. Circadian disruption has been identified as a risk factor for several cancers, including breast and prostate cancer, and affects immune cells such as Natural Killer (NK) cells and T-helper cells. Disruptions in circadian rhythms can lead to aberrant immune cell trafficking and proliferation. Despite this biological connection, evidence linking circadian disruptions to NHL remains inconclusive. Only single Mendelian Randomization (MR) study (PMID: 32895918) has explored the causal relationship between sleep traits and overall NHL risk, without examining NHL subtypes. Studies have shown distinct risk factor profiles among NHL subtypes. Therefore, this study aims to investigate the causal relationship between sleep traits and NHL subtypes in European populations using MR. Methods: We conducted a two-sample MR analyses using genome-wide association studies (GWAS) summary data on sleep traits and NHL subtypes. The GWAS summary statistics on sleep traits were obtained from publicly available UKBiobank datasets. The sleep traits analyzed included chronotype (N=449,734), insomnia (N=237,627), sleep duration (N=446,118), daytime sleepiness (N=452,071), short sleep (N=411,934), and long sleep (N=339,926). Only independent, genome-wide significant SNPs (p < 5×10-8) were considered as valid instruments. The NHL subtype-specific summary statistics came from the InterLymph including follicular lymphoma (FL: N=6,508 cases / 64,183 controls), mantle cell lymphoma (MCL: N=1,169 cases / 61,603 controls), and Waldenström macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL: N=1,697 cases / 59,333 controls). Our primary analysis used the random-effects inverse-variance weighted (IVW) method. In addition, we employed MR-Egger to adjust for directional pleiotropy. Heterogeneity in the MR results was evaluated with Cochran's Q statistic. Results: The IVW method did not identify any statistically significant causal association between sleep traits and the risk of NHL subtypes (FL,MCL,WM/LPL), but did yield several intriguing associations. Chronotype (early rising) showed a tendency towards a marginally an increased NHL risk across subtypes [Odds ratio (OR) range: 1.07 - 2.56]. Conversely, a decreased risk was noted for long sleep (≥ 9 hours vs. 7-8 hours) [OR range: 0.19 - 0.62], insomnia [OR range: 0.72 - 0.88], and short sleep (excludes MCL) [OR range: 0.12 - 0.72]. Confidence limit for long sleep was wide due to small number of variants (N=8). The MR-Egger regression analysis did not provide evidence of significant directional horizontal pleiotropy. The F-statistics for all sleep traits were greater than 10 indicating absences of weak instrument bias. Conclusions: Our study found no statistically significant associations between sleep traits and three NHL subtypes (FL, MCL, WM/LPL) in European populations. However, we observed potential influences of chronotype, long and short sleep, and insomnia on NHL risk. These findings align with and extend previous MR study by providing subtype-specific insights. Future directions include expanding our analysis to additional NHL subtypes, generating polygenic risk scores, and conducting stratified analyses using the InterLymph population. These efforts aim to further elucidate the complex relationship between sleep characteristics and NHL risk across diverse subtypes and populations.

Introduction: Bispecific antibodies (BsAbs) epcoritamab (Epco) and glofitamab (Glofit) are approved in the US for the treatment of patients (pts) with relapsed or refractory (r/r) large B-cell lymphomas (LBCLs) based upon high response rates and manageable toxicity profiles reported in pivotal trials. However, data on outcomes for pts treated with BsAbs outside of clinical trials are limited. As such, we sought to investigate the safety and efficacy of Epco and Glofit for the treatment of pts with r/r LBCLs in real-world settings. Methods: We performed a retrospective study including 19 US centers evaluating pts with r/r LBCLs receiving commercially available Epco or Glofit between 2023 and 2024. Baseline characteristics and outcomes were extracted from medical records. Efficacy outcomes included overall response rate (ORR), complete and partial response (CR, PR) rates, progression-free survival (PFS) and overall survival (OS), analyzed using the Kaplan Meier method. Key safety outcomes included cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Results: As of May 31, 2024, a total of 209 pts with r/r LBCLs were treated with Epco (n=139) or Glofit (n=70). Median age at BsAb start was 67 years (interquartile range [IQR] 58-76). Most were male (62.2%), and the most common histology was diffuse large B-cell lymphoma (n=155 [74.2%]). Of pts with molecular testing (n=168), 34 (20.2%) had double/triple hit lymphoma. Most (78.9%) had Ann Arbor stage III-IV disease and 91% had an ECOG performance status of ≤1. Median number of lines of treatment before BsAb was 3 (range 1-12). Of pts with known response assessment following front-line therapy, 54 (32.1%) had primary refractory disease, defined as failure to achieve PR or CR to front-line therapy. Most pts (n=126 [60.3%]) received prior chimeric antigen receptor (CAR) T-cell therapy and 21 (10.0%) received prior autologous hematopoietic progenitor cell transplant. CD20 expression was assessed in 106 biopsies (50.7%) prior to BsAb and was positive in 90 (84.9%). A total of 172 pts were response-evaluable. The best ORR was 50.6%, with CR in 41 (23.8%), PR in 46 (26.7%), stable disease in 10 (5.8%), and progressive disease in 75 (43.6%). The ORR and CR rates were 49% and 23% for Epco, and 53% and 25% for Glofit, respectively. With a median follow-up of 5 months, the median PFS was 2.7 months (95% CI 2.0, 3.9) and median OS was 7.2 months (95% CI 6.1, not reached [NR]). The estimated PFS and OS at six months were 35% (95% CI 29%-43%) and 59% (95% CI 52%-67%), respectively. For pts who relapsed after CAR T-cell therapy, the median PFS and OS were 2.5 (95% CI 1.8, 4.7) and 7.8 (95% CI 6.2, NR) months, respectively. Pts without detectable CD20 expression via immunohistochemistry or flow cytometry prior to BsAb therapy had significantly inferior outcomes (PFS 1.1 vs 3.4 months, P < 0.001 and OS 1.3 vs 13 months, P < 0.001) compared to pts with detectable CD20. CRS of any grade occurred in 82 pts (39.2%), corresponding to 51.1% and 28.6% of pts treated with Epco and Glofit, respectively. Grade ≥3 CRS occurred in 9 (4.3%), all of whom received Epco. CRS was treated with tocilizumab in 43 pts (53.1%). ICANS occurred in 24 (11.5%) pts; any grade ICANS occurred in 13.7% and 7.1% of pts treated with Epco and Glofit, respectively. Grade ≥3 ICANS occurred in 6 pts (2.9%), 5 of which received Epco (3.6%). Of those experiencing ICANS, 66.0% were treated with corticosteroids. Two pts had deaths attributed to ICANS and one to CRS. A total of 122 (58.4%) pts discontinued therapy after a median of 3 cycles (range 0-48), 91 (74.6%) due to disease progression and 31 (25.4%) due to adverse events (15 due to infection, 3 due to ICANS, 2 due to CRS, and 11 for other reasons). Conclusions: In this heavily pretreated group with adverse disease features and high rate of CAR T exposure, the response rates, PFS, and OS following BsAb therapy were lower compared to pivotal trials. Poor outcomes were observed for those without detectable CD20. Rates of ICANS and grade ≥3 CRS were higher than reported in pivotal trials, as was the rate of discontinuation of therapy due to adverse events. Future efforts to improve outcomes may include intensified dose escalation protocols to more rapidly achieve disease control, combination therapies, and characterization of clinicopathologic factors that predict response to BsAb to identify subgroups of pts who can derive maximal benefit from these agents.

Abstract Background Dermatological health-related quality of life (HRQoL) among solid organ transplant recipients (SOTRs) may be adversely affected by various factors, including skin cancer. However, there has been limited assessment of dermatological HRQoL in SOTRs. This study aimed to evaluate the impact of skin cancer on quality of life (QoL) in SOTRs and to compare HRQoL measures between SOTRs with and without skin cancer. Methods This cross-sectional study was conducted at the Mayo Clinic Florida from June 2023 to March 2024. Adult patients who underwent solid organ transplantation between June 1995 and December 2023 were assessed using the Dermatology Life Quality Index (DLQI) and Skindex-29 questionnaires. For SOTRs with keratinocyte carcinoma (KC), the Basal and Squamous Cell Carcinoma Quality of Life (BaSQoL) questionnaire was also administered. Results A total of 150 adult SOTRs were included, with 82 having developed post-transplant skin cancer, including melanoma and keratinocyte carcinomas (KC). SOTRs with skin cancer were older at first transplant (Median: 61.8 vs. 57.3 years, P = 0.0073) and had a higher proportion of males (76.8% vs. 55.9%, P = 0.0086). Fitzpatrick skin type III-VI was less prevalent (8.5% vs. 38.2%, P < 0.0001). The frequency of SCC and BCC was 92.7% and 41.5%, respectively. DLQI scores were higher in SOTRs with skin cancer, however, the difference was not statistically significant (P ≥ 0.065). SOTRs with skin cancer had higher total Skindex-29 scores (P = 0.012) and “emotion” subscale scores (P = 0.0049), indicating a negative impact on QoL. BaSQoL scores showed a moderate negative effect on QoL, with a higher number of KCs correlating with lower QoL (P < 0.05). Female gender had higher DLQI total score (P = 0.0042) and BaSQoL diagnosis and treatment (P = 0.031). Conclusions: SOTRs with skin cancer exhibited lower overall QoL, with a greater number of skin cancers linked to more pronounced negative impacts on QoL across all assessment instruments. Female gender was also associated with lower QoL scores. Recognizing the potential for reduced QoL in SOTRs is essential for developing tailored management strategies to support this population.

Abstract Purpose Pharmacogenomics is the study of how individual responses to medication are influenced by genetics. As medication experts, pharmacists are uniquely suited to practicing this application of precision medicine. Fundamental operational aspects of developing a pharmacy clinical pharmacogenomics practice are described, and the specific experience of a multisite health system in developing a pharmacogenomics service is discussed. Summary Considerations for the development of a clinical pharmacy–driven pharmacogenomics service include understanding testing selection, targeting the appropriate patient population, exploration of reimbursement, design of the practice, and education of the pharmacogenomics workforce. Testing can be preemptive or reactive, can occur in house or as a send-out service, and can be panel based or specific to a single gene. Pharmacogenomics is applicable to many medicine specialties, making deployment of services to strategic groups essential. Reimbursement for pharmacogenomics is variable and may pose a barrier to implementation. The demand for pharmacogenomics education for pharmacy students and as a formal postgraduate career path is growing. Pharmacogenomics service planning and implementation details for a multisite health system are described. Conclusion The practice of pharmacogenomics presents a remarkable opportunity for clinical pharmacists and health systems to improve patient care outcomes and experiences.

Background: Right ventricular pacing (RVP) can have adverse cardiac effects and cause pacing induced cardiomyopathy (PiCM). His bundle pacing (HBP)&Left Bundle Branch area pacing (LBBAP) mimic physiologic conduction (PhysioP) and maintain biventricular synchrony. Hypothesis and Aims: Reduced left ventricular (LV) systolic function reserve in the presence of normal baseline LV ejection fraction (EF) could precede development of RV PiCM. Our aim was to compare the effects of RVP vs. PhysioP on bicycle exercise cardiopulmonary performance in patients with normal LVEF who required pacing for bradyarrhythmias. Methods: Patients with sinus rhythm and RVP or PhysioP&ventricular pacing burden of >70% who completed cardiopulmonary exercise test and simultaneous stress echocardiography (SE) were included. Pulmonary gas exchange was calculated using Ventilation/CO2 production at rest and during exercise. Changes in LV size, EF, longitudinal strain and diastolic function and gas exchange parameters were compared post and pre exercise in the 2 groups. Results: 25 of 29 patients completed the study [68 ± 23 yrs, 48% M; LVEF 56±5%, 11 RVP, 14 PhysioP]. There was no difference in baseline demographic&clinical variables, exercise duration, rest and peak heart rate and blood pressure between 2 groups. Pacing duration was 2.61±1.48 yrs in RVP vs. 0.84±0.67 yrs (p=0.003) in the Physio group. Resting echocardiographic parameters ( Table 1A) were comparable. Compared to RVP, reduction in LV end-diastolic volume (EDV) 3.4±14.1 ml vs. -23.1±18.1ml, p=0.006)&LV end-systolic volume (ESV -5.7±11.6 ml vs. -18.0±9.5ml, p=0.01) was more pronounced in the PhysioP group. Changes in LVEF, LV strain&diastolic function were not different between the 2 groups ( Table 1B ). There were no significant differences in changes in pulmonary gas exchange parameters in the 2 groups. Conclusions: In patients with normal LVEF and pacemaker dependent, RVP is associated with impaired but PhysioP with preserved LV systolic function reserve, which can be detected by exercise SE. SE may help identify patients at risk for RV PiCM. Benefit of PhysioP needs to be determined by larger studies with longer follow-up.

Abstract Purpose: Squamous cell carcinoma of the anus (SCCA) is primarily driven by human papillomavirus (HPV) infection. Up to 30% of patients experience recurrence, necessitating improved surveillance strategies. Liquid biopsies have shown promise as a tool in oncology. This study investigates the clinical performance of circulating tumor tissue modified viral (TTMV)- HPV DNA in the post-treatment surveillance of SCCA. Patients and methods: This central IRB-approved retrospective cohort study included 117 patients diagnosed with HPV-driven SCCA from seven U.S. centers who had ≥1 TTMV-HPV DNA tests (NavDx®, Naveris, Inc., Waltham, MA) performed between March 2020 and June 2024. TTMV-HPV DNA for HPV subtypes 16, 18, 31, 33, and 35 were analyzed using droplet digital PCR. The diagnostic accuracy of TTMV-HPV DNA was evaluated by comparing test results with clinical evidence of SCCA recurrence determined through anoscopy, radiology, and/or tissue biopsy. Recurrence is defined as either a positive biopsy or subsequent salvage therapy. Results: Patients were primarily female (73%) with a median age 63 years. Median follow-up after initial treatment was 19 months. Forty-seven patients (40%) had pretreatment TTMV-HPV DNA testing, with a baseline detectability of 85.1% (40/47, 95% CI: 74.9–95.3). Of these, 24 were re-tested within 3 months post-treatment and 18 had undetectable TTMV-HPV DNA (75%). Those patients whose scores became undetectable had significantly longer recurrence-free survival than those whose scores remained detectable (log-rank test, p=0.01). One hundred and four patients (89%) underwent post-treatment testing, of which 91 provided relevant data for the analysis. Of these 91 patients, 27 (29.7%) experienced recurrence. Post-treatment testing demonstrated a per- patient sensitivity of 85.7% (24/28, 95% CI: 72.8-98.7). Of four patients with a false negative test, only one had biopsy-confirmed recurrence, whereas the remaining recurrences were not biopsied prior to starting salvage treatment. The positive predictive value of a single positive test was 97.6% (40/41; 95% CI: 92.8–100.0). One patient remains in active follow-up. Of the true positive post-treatment tests, 58% (14/24) predicted recurrence before clinical detection, with a median lead time of 59 days (range: 10–536). There were 141 negative post-treatment tests across 66 patients. This yielded a per-test specificity and negative predictive value of 99.3% (136/137, 95% CI: 97.8-100.0) and 97.2% (136/140, 95% CI: 94.9-99.9), respectively. Indeterminate TTMV-HPV DNA tests were rare (5/268,1.9%). However, clinically indeterminate findings (CIFs) were common, with 141 post-treatment CIFs identified across 52/117 patients (44.4%). TTMV-HPV DNA testing was able to correctly predict recurrence status in 94.3% of CIF cases. Conclusion: TTMV-HPV DNA testing is a sensitive and specific surveillance method for detecting early recurrence of HPV-driven SCCA. Citation Format: Shane Lloyd, Rafi Kabarriti, James Jabalee, Tyler Slater, Corbin Jacobs, Sean Inocencio, Michael Rutenberg, Chance Matthiesen, Kasha Neff, Gene-Fu F Liu, Tiffany M Juarez, Catherine DV Fitz, Stanley Liauw. Plasma-based circulating tumor tissue modified viral (TTMV)-HPV DNA for detection of recurrent HPV-driven anal cancer [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B018.

AbstractBackground and ObjectivesNonmedical use of prescription tranquilizers/sedatives (NMUPTS) is associated with a 15‐times increased likelihood of polysubstance use (PSU). This is correlated with an increased risk for use disorders and death, therefore, to inform prevention efforts, we identified PSU profiles among adults reporting sleep‐related NMUPTS.MethodsNational Survey on Drug Use and Health 2015–2019 participants with past 12‐month sleep‐related NMUPTS and use of an additional drug(s) (n = 2603) were studied. Latent class analyses identified unique latent profiles, and multivariable logistic regressions identified covariates associated with each profile.ResultsAlcohol (90.4%), tobacco (61.5%), and marijuana (55.5%) were most commonly reported, with an average of 3.6 additional substances. Two latent PSU profiles were identified: marijuana/alcohol/tobacco (MAT) (68.3%) and MAT + cocaine/hallucinogens/prescription drugs (MAT + CHPR) (31.7%). In comparison to those likely in the MAT profile, those likely in the MAT + CHPR profile had lower odds of being older than 18–25 years (26–34: adjusted odds ratio [AOR]: 0.5, 95% confidence interval [CI]: 0.3, 0.6; 35–49: AOR: 0.2, 95% CI: 0.1, 0.2; 50+: AOR: 0.1, 95% CI: 0.0, 0.1), female (AOR: 0.4, 95% CI: 0.3, 0.6), non‐Hispanic Black (AOR: 0.5, 95% CI: 0.4, 0.8) or Hispanic in comparison to non‐Hispanic White (AOR: 0.5, 95% CI: 0.4, 0.8), and to not have past 12‐month insurance coverage (AOR: 1.7, 95% CI: 1.3, 2.3).Conclusions and Scientific SignificanceTwo PSU profiles were identified among people with NMUPTS, with noted variations in sociodemographic characteristics. In comparison to previous studies, sleep‐related NMUPTS was associated with higher rates of stimulant use, suggesting stimulant use and sleep‐related NMUPTS may be related.