Citations

Abstract Immune checkpoint inhibitor–associated immune thrombocytopenia (ICI-ITP) has been described in case reports and small case series, but comprehensive data on its incidence, risk factors, clinical features, treatment, and outcomes are lacking. We reviewed medical records of all adults initiating ICI therapy between 2016 and 2023 at 29 US hospitals across 7 major cancer centers to identify patients with ICI-ITP. Multivariable logistic regression was used to identify risk factors, and Cox modeling was performed to assess the association between ICI-ITP, its severity, and mortality. Among 86 467 patients, ICI-ITP occurred in 214 (0.25%). Independent risk factors included lower baseline platelet count, combination ICI therapy, stage IV cancer, and additional immune-related adverse events. ICI-ITP occurred at a median of 8 weeks (interquartile range [IQR], 4-18) after ICI initiation, with a median nadir platelet count of 41 × 109/L (IQR, 17 × 109/L to 64 × 109/L). Patients were treated with glucocorticoids (n = 106 [49.5%]), immune globulin (n = 39 [18.2%]), and thrombopoietin receptor agonists (n = 29 [13.6%]). Recovery occurred in 161 patients (75.2%) at a median of 2.3 weeks (IQR, 1.0-5.3). Of 76 patients rechallenged with ICIs, 23 (30.3%) developed recurrent ICI-ITP. ICI-ITP and its severity were associated with higher all-cause mortality, with a nearly threefold increase in risk among patients with severe ICI-ITP than those without ICI-ITP (adjusted hazard ratio, 2.96 [95% confidence interval, 2.14-4.08]). These findings establish ICI-ITP as a rare but clinically significant complication of ICI therapy, provide, to our knowledge, the first large-scale description of its risk factors and clinical course, and underscore the importance of timely recognition and management.

Abstract Background: Routine laboratory testing prior to chemotherapy administration is a cornerstone of hematology and oncology practice, aimed at ensuring the safety and efficacy of treatment. However, over time, standardized protocols may accumulate excessive or low-yield laboratory tests that offer limited value to clinical decision-making. In 2018, Mayo Clinic implemented standardized treatment protocols using Epic Beacon, an electronic health record module that integrates chemotherapy regimens with associated laboratory testing and clinical workflows. While well-intentioned, these protocols may include redundant tests that delay treatment initiation, increase patient discomfort and anxiety, and burden providers with excessive in-basket communications. We hypothesize that many laboratory tests currently embedded within prechemotherapy workflows are unnecessary and can be safely omitted without compromising patient care. Methods: We conducted a retrospective cohort study evaluating the pre-treatment laboratory testing associated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy protocol within the Mayo Clinic Rochester Division of Hematology. The study included 100 patients diagnosed with diffuse large B-cell lymphoma who received treatment between January 1 and December 31, 2024. Patients were excluded if they had incomplete medical records or received treatment outside the Mayo Clinic system. Data was abstracted via chart review using the Mayo Data Explorer. We analyzed complete blood counts (CBC), which include 12 individual tests, and comprehensive metabolic panels (CMP), which include 16 individual tests, obtained prior to each treatment cycle. For each cycle, we assessed the proportion of abnormal laboratory results and the proportion of abnormal results deemed clinically relevant which were defined as those that prompted a treatment delay, dose reduction or early termination of a cycle. Results: The cohort comprised 100 patients with a mean age of 68.2 years (SD 13.4) and a median age of 71 years (IQR 58.75–77); 57 were male and 43 were female. Based on available documentation, disease stage was classified as limited (stage I/II; n=41) or extensive (stage III/IV; n=59). A total of 519 R-CHOP cycles were administered, including 419 subsequent cycles (cycles 2–6). Fifteen patients discontinued treatment early, although none of the discontinuations were attributable to abnormalities in pre-infusion laboratory testing. Among the 419 subsequent cycles, 34 (8.1%) experienced treatment delays, with only one delay resulting from a clinically significant laboratory abnormality (hyperglycemia). Additionally, 23 patients underwent regimen modification (dose reduction or drug holding), but none of these were due to pre-infusion lab abnormalities.Of the 411 comprehensive metabolic panels (CMPs) obtained prior to these cycles, 315 (76.6%) contained at least one abnormal value, yielding a total of 786 abnormal results. Similarly, 405 of 415 (97.6%) complete blood counts (CBCs) demonstrated at least one abnormality, generating 2,696 abnormal values in total. Despite the high frequency of abnormal findings, the overall clinical yield was minimal, with only 1 of 826 pre-infusion laboratory panels (0.12%) leading to a modification in clinical management. Conclusion: Routine pre-infusion laboratory testing prior to R-CHOP chemotherapy frequently identifies abnormal results. However, these abnormalities are rarely clinically significant and do not affect treatment decisions. These findings support the reconsideration of current testing protocols to reduce unnecessary testing, enhance workflow efficiency, and minimize patient and provider burden without compromising safety.

Abstract Background: Minimal residual disease (MRD) is a critical prognostic and therapeutic response marker in multiple myeloma (MM). Two main technologies are used for MRD assessment in bone marrow: next-generation flow cytometry (NGF) and next-generation sequencing (NGS), from clonoSEQ. While both methods are FDA-cleared and clinically relevant, they differ in sensitivity, sample handling requirements, and technical differences. Comparative performance in real-world matched samples is understudied. Here we compared the detection rates and concordance between MRD by NGF (flow cytometry) and NGS-based clonoSEQ, using paired bone marrow aspirates collected at the same clinical timepoint. Methods We identified 246 paired bone marrow samples from MM patients, which were evaluated by both flow cytometry (Euroflow, typically sensitivity of 10-5) and clonoSEQ (sensitivity of up to 10-6) on the same collection date.MRD-negativity for clonoSEQ was defined as no detectable clones and below the assay's level of detection (LoD). Continuous variables (clonoSEQ and flow CPS) were analyzed using the Mann-Whitney U test. Categorical variables were assessed using chi-square tests with Yates continuity correction for 2x2. A cox proportional hazards model was used to evaluate the association between overall survival and cytogenetic abnormalities, MRD status, and other clinical covariates including age, sex, treatment type, and disease setting (newly diagnosed, relapsed/refractory). A p-value < 0.05 was considered significant. Results Out of 246 paired bone marrow samples, we identified 173 concordant samples, out of which 26 were concordant positive (clonoSEQ+/NGF+), 147 were concordant negative (clonoSEQ-/NGF-), and 73 were discordant (clonoSEQ+/NGF-). clonoSEQ detected MRD in all cases missed by NGF, including some with relatively high tumor burden, reflecting its higher sensitivity. Among discordant samples, 45 (61.6%) were following treatment of newly diagnosed MM (NDMM) and 28 (38.4%) treatment of relapsed/refractory (RRMM). Among the MRD-positive samples, the concordant group (n=26) showed a mean clonoSEQ count of 11923.5 cells per million (CPM) and a mean NGF CPM of 305.5 (p<0.01). In contrast, the 73 discordant samples had a lower mean clonoSEQ CPM of 156.1. For the 147 MRD-negative samples with concordant results, no residual disease was detected by either assay (CPM = 0 for both). When evaluating sex, race, ethnicity, chromosomal abnormalities, prior treatments to sample collection (immunomodulatory drugs, proteasome inhibitors, CD38 antibodies, CAR Ts/bispecific antibodies), and disease stage (NDMM, RRMM, untreated), patients with t(11;14) were significantly higher in the discordant group (17.9% concordant vs. 32.9% discordant; p = 0.016), while CAR T/bispecific antibody-treated patients were more likely concordant for the tests (27.2% concordant vs. 4.1% discordant; p<0.01). High-risk cytogenetics (t(4;14), t(14;16), gain 1q) were associated with worse survival (HR 6.22, 95% CI 2.02 – 19.2; HR 16.2, 95% CI 3.38-77.1; HR 4.0, 95% CI 1.28 – 12.5, respectively). Discordant MRD status did not impact survival, though only 13/246 patients were deceased (median follow-up approximately 50.6 months).Conclusion: ClonoSEQ demonstrates higher sensitivity compared to NGF for MRD detection in MM, identifying residual disease missed by NGF particularly in t(11;14) cases. Discordance did not affect survival, however, only 13 patients were deceased at the time of last follow up, suggesting longer follow up is needed.

Abstract Abstract Introduction: Leukemia, a heterogeneous group of hematologic malignancies, has established associations with modifiable risk factors such as tobacco use. Despite the widespread implementation of tobacco control measures over the past three decades, disparities persist in tobacco-attributable leukemia mortality across sex and socio- demographic strata. This study aimed to quantify and compare long-term global and regional trends in mortality due to tobacco-associated leukemia between 1990 and 2021, with a focus on sex-based and income-level disparities. Methods: We obtained age-standardized mortality rates (ASMRs) for leukemia attributable to tobacco use from the Global Burden of Disease (GBD) 2021 dataset for 204 countries and territories. ASMRs were analyzed for the years 1990 and 2021 and stratified by sex (male, female, both) and socio-demographic index (SDI) regions (high, high-middle, middle, low- middle, low). Temporal trends were assessed using Average Annual Percent Change (AAPC) with corresponding 95% confidence intervals (CI). Additionally, univariate linear regressions by location were conducted to quantify associations between time and mortality. Results: Globally, tobacco-related leukemia mortality decreased substantially between 1990 and 2021. The overall ASMR declined from 0.64 to 0.40 per 100,000 population (AAPC: –1.51%; 95% CI: –1.59 to –1.43). Sex-disaggregated data revealed a more favorable reduction in females (from 0.23 to 0.12; AAPC: –2.25%; 95% CI: –2.41 to –2.09) compared to males (from 1.20 to 0.77; AAPC: –1.45%; 95% CI: –1.51 to –1.39), suggesting persistent gender disparities in tobacco exposure and/or access to care. These trends were statistically significant (p < 0.001), and global univariate regression confirmed a significant negative slope (–0.0088; p = 0.021). Marked regional differences emerged by SDI status. High-SDI countries experienced the steepest declines in mortality. In these regions, ASMRs dropped from 1.16 to 0.69 among both sexes combined (AAPC: –1.70%; 95% CI: –1.80 to –1.61), with females improving from 0.56 to 0.31 (AAPC: –1.90%; 95% CI: –2.03 to –1.76) and males from 2.07 to 1.17 (AAPC: –1.88%; 95% CI: –1.96 to –1.80). The associated regression slope (–0.0183) was statistically significant (p = 0.0014), with an R² of 0.10, indicating a strong temporal association. High-middle SDI regions showed moderate progress: ASMRs declined from 0.62 to 0.45 among both sexes (AAPC: –0.99%; 95% CI: –1.10 to –0.88). Reductions were steeper in females (0.12 to 0.07; AAPC: –1.32%; 95% CI: –1.55 to –1.09) than in males (1.40 to 0.96; AAPC –1.19%; 95% CI: –1.29 to –1.09). However, regression slopes were not statistically significant (p = 0.18), suggesting heterogeneous trends within this group. Low-SDI regions, in stark contrast, exhibited minimal improvements. Between 1990 and 2021, ASMRs decreased marginally from 0.098 to 0.074 (AAPC: –1.01%; 95% CI: –1.10 to –0.91), with male mortality decreasing from 0.17 to 0.12 (AAPC: –1.22%; 95% CI: –1.32 to –1.13) and female rates from 0.037 to 0.027 (AAPC: –0.88%; 95% CI: –1.04 to –0.72). However, the regression slope (–0.00084) was not statistically significant (p = 0.17), and the effect size (R² = 0.02) suggested only a weak temporal association. Middle and low-middle SDI countries also demonstrated underwhelming progress. In low- middle SDI settings, the combined-sex ASMR dropped from 0.21 to 0.16 per 100,000, with a weak negative slope (–0.0012; p = 0.43), and an AAPC of –0.83% (95% CI: –0.95 to –0.71). These results highlight stagnation and growing inequities in health burden mitigation. Conclusion: From 1990 to 2021, global mortality due to tobacco-attributable leukemia significantly declined, with the greatest improvements seen in high-SDI countries and among females. However, regions with lower income levels lagged, showing minimal or no significant decline in mortality despite decades of global tobacco control efforts. The pronounced disparities by sex and socioeconomic status underscore the need for context- specific, equity-focused tobacco cessation initiatives and leukemia screening programs, especially in underserved populations. Without urgent intervention, the global burden of leukemia attributable to tobacco may continue to disproportionately affect those with the fewest resources and weakest health infrastructure.

Abstract Background: The phase II and III GRIFFIN and PERSEUS studies evaluated DVRd vs. VRd in NDMM pts that were transplant eligible (TE). These studies included consolidation (cons) and dual agent maintenance (maint) with dara and len (DR). Little is known about the efficacy of DVRd in RW practice including frequency of bor use, use of cons, use of DR maint, and subsequent treatment after progression (PD) on DVRd. We aim to evaluate the RW efficacy of NDMM pts treated with DVRd across the tri-site Mayo Clinic Comprehensive Cancer (MCCC). Methods: We retrospectively analyzed the medical records of pts treated with DVRd between June 2018 and June 2024 at the MCCC. Outcomes were estimated using the Kaplan-Meier method. Results: 464 pts were included; 278 pts were male, and the median (m) age of MM diagnosis was 64 years (yr). 114 pts had ISS III, 205 pts had R-ISS III, 266 pts had high risk (HR) FISH, 80 pts had extramedullary disease, 165 pts had ultra HR disease (dz) (as per 2025 IMS/IMWG consensus), and 47 pts had renal insufficiency (RI) with creatinine >2 mg/dL. Starting len dose was 25mg in 356 pts, 15 mg in 40 pts and ≤10mg in 65 pts. 399 pts received bor 1x per week and 63 2x per week, 91 pts received 1-2 cycles of a different regimen prior to DVRd due to hospitalization (n=23), RI (n=38), poor performance status (n=6), other (n=34). 315 (67.9%) pts underwent autologous transplant (ASCT). The m number of induction cycles was 5; 4 for pts who underwent ASCT and 6 for pts who did not. The best ORR to induction for pts who underwent ASCT was 98% with 247 (79%) achieving ≥VGPR, and 82 (26%) achieving minimal residual disease negativity (MRD-) to at least 10-5. The best ORR for pts who did not undergo ASCT was 87%. For those who underwent ASCT, (96% with melphalan 200mg/m2), the ORR at day 100 was 97% with 56% achieving MRD-. At 1-yr post ASCT, 30% (93/312) were MRD-. 42 pts (13%) received post ASCT cons with DVRd for a m of 2 cycles. 281 pts received post ASCT maint including 107 (38%) len, 53 (19%) bor-len, 91 (32%) dara-len, 14 (5%) dara, 16 (6%) other. 61(13%) pts had change in treatment, due to change to second line therapy (35; 55%), discontinuation (d/c) of len (11; 17%), d/c of dara (3; 5%), d/c of bor (15; 23%), d/c of dex (0; 0%). The m follow-up time for all pts was 26 months (mo) (17-39). The m PFS of pts who underwent ASCT was not reached (NR), and was 57 mo (52-NA) for pts who did not undergo ASCT. For pts who underwent ASCT, the PFS at 24mo for pts who did not have HR FISH was 93% (88-99%) compared to 80% (73-88%) for pts with HR FISH (p=0.12) and 77% (68-87%) for pts with ultra-HR dz (p=0.013).The PFS at 24mo of pts with RI who underwent ASCT was 81% (66-98%) compared to 86% (82-92%) for those without RI, p=0.57. The PFS at 24mo of pts with RI who did not undergo ASCT was 53% (28-100%) compared to 64% (55-75%) for those without RI, p=0.42. The ORR and MRD- rate for pts who received once-weekly bor was 94% and 24%, compared to 94% and 27% for pts who received 2x weekly bor (p=0.85, p=0.93). For pts who underwent ASCT, the PFS at 24mo for pts who received len maint was 91% vs. 83% for pts who receive dual agent maint (DR or VR) (p=0.25), although pts who got dual agent maint were more likely to have HR FISH than pts who received len maint (p<0.001). The PFS at 24mo for pts that received post-ASCT cons was 91% compared to 85% for those that did not (p=0.53); pts who got post-ASCT cons were more likely to have HR FISH (p=0.07). For pts that underwent ASCT, the 3 yr PFS rate is 85% and the 3 yrs OS rate is 96%. For pts that did not undergo ASCT the 3 yrs PFS rate is 60% and the 3 yr OS rate is 85%. 55 pts had functional HR (FHR) MM (relapse within 18 mo) and m PFS for FHR pts who underwent ASCT was 15 mo (11-NA), while m PFS was NR for pts without FHR MM (p<0.001). 79 pts relapsed after 1st line DVRd. The most common 2nd line therapies (tx) were dara-carfilzomib (K)-D, dara-pomalidomide(P)-D, KPD, and other. The m follow-up time from 2nd line tx was 10 mo, the best ORR to 2nd line tx was 76%, and the m PFS with 2nd line tx was 18 mo (7-NA). Conclusion: In this RW analysis, the efficacy and survival outcomes of NDMM pts treated with DVRd was comparable to that reported in the PERSEUS and GRIFFIN trials, although MRD- rates appear lower. DR maint and post-ASCT cons use was not common and was used more frequently in pts with HR FISH. Pts can be effectively salvaged following PD on front-line DVRd with available tx.

Abstract INTRODUCTION Immune checkpoint inhibitors (ICIs) have emerged as a cornerstone of cancer therapy. However, despite their efficacy, ICIs can cause a unique spectrum of autoimmune toxicities known as immune-related adverse events (irAEs). In contrast to irAEs involving other organ systems, hematologic irAEs such as ICI-associated immune thrombocytopenia (ICI-ITP) are less common. As a result, existing data on ICI-ITP are largely confined to isolated case reports, single-center case series, and pharmacovigilance databases lacking granular clinical data. To address this key knowledge gap, we sought to comprehensively characterize the incidence, risk factors, clinical features, treatments, and outcomes associated with ICI-ITP. METHODS We performed a multicenter cohort study of adult patients who initiated ICI therapy at 29 hospitals across 7 major cancer centers in 11 geographically diverse states in the US between 2016-2023. ICI-ITP was defined as a decline in platelet count to <100 x109/L in the absence of an alternative more plausible etiology of thrombocytopenia. Patients with hematologic malignancies were excluded, as were those who received cytotoxic chemotherapy within 30 days prior to thrombocytopenia onset. For each patient identified as having ICI-ITP, we collected data on demographics, comorbidities, medications, laboratory values, treatments, and outcomes. All data were extracted by manual chart review. To identify risk factors for ICI-ITP and to examine its association with death, for each case of ICI-ITP we also collected data on two control patients who initiated ICI therapy at the same site and in the same year but without development of ICI-ITP. We used multivariable logistic regression to identify independent risk factors for ICI-ITP and its recovery (the latter defined according to criteria established by the ITP International Working Group). We used a multivariable Cox model to examine the association between ICI-ITP and its severity with all-cause mortality. RESULTS We identified a total of 214 patients who developed ICI-ITP among 86,648 examined (0.25%). The incidence was highly consistent across sites (range, 0.15–0.30%). Risk factors for ICI-ITP included simultaneous receipt of two different classes of ICIs, additional irAEs, and a lower baseline platelet count. ICI-ITP developed at a median of 8 weeks (IQR, 4–18) following ICI initiation. The median nadir platelet count was 41 x109/L (IQR, 17–64). Six out of 214 patients (2.8%) developed a major bleed, and 16 patients (7.5%) developed a clinically relevant non-major bleed. Cell-bound anti-platelet antibody testing was positive in 6 of 8 patients (75.0%) for whom it was assessed, and median circulating thrombopoietin levels (201 pg/mL [IQR, 178–295]) were similar to those seen in primary ITP. Treatments used included glucocorticoids (49.5%), immune globulin (18.2%), and thrombopoietin receptor agonists (13.6%). Overall, 161 patients (75.2%) recovered from ICI-ITP at a median of 2 weeks (IQR, 1–5) following ICI-ITP onset. Predictors of recovery included additional irAEs and a higher nadir platelet count. Treatment response was observed in 57.0%, 56.4%, and 58.3% of patients within 60 days following initiation of glucocorticoids, immune globulin, and thrombopoietin receptor agonists, respectively. Of 76 patients rechallenged with an ICI, 23 (30.3%) developed recurrent ICI-ITP at a median of 9 weeks (IQR, 2–15); 17 of these 23 patients (73.9%) recovered. Finally, ICI-ITP and its severity were monotonically associated with a higher risk of death (adjusted hazard ratio 2.96 [95% CI, 2.14–4.08] for those with severe ICI-ITP compared to those without ICI-ITP). CONCLUSION In this multicenter study involving patients treated with ICIs at 29 hospitals across the US, we identified 214 patients with ICI-ITP. For the first time, we characterize in detail the incidence, risk factors, clinical features, treatments, and outcomes of ICI-ITP, a relatively novel disease entity. We found that more than half of patients responded to conventional ITP-directed therapies, and that most patients rechallenged did not develop recurrent ICI-ITP. We also found that ICI-ITP was independently associated with an increased risk of death, including a nearly 3-fold increased risk in those with severe ICI-ITP. These findings highlight ICI-ITP as a rare but clinically significant complication of ICI therapy that hematologists must be equipped to recognize and manage.

Abstract Background The advent of T-cell redirecting bispecific antibodies (BsAb) therapies has led to deeper and durable responses in patients with RRMM. We sought to identify adverse prognostic factors for patients treated with BsAbs. We also explored whether the extent of the non-involved free light chain (niFLC) suppression could serve as a potential marker of T-cell engager activity, given the binding of BsAbs to both clonal and non-clonal plasma cells and the short half-life of serum FLCs. Methods We conducted a retrospective analysis of RRMM patients treated with BsAbs between 2022 and 2025 at Mayo Clinic. Baseline lymphocyte counts and ferritin levels were collected and analyzed both as continuous and dichotomized variables. niFLC was considered undetectable if it was below the quantification limit, while the magnitude of niFLC suppression was defined as the absolute difference between niFLC levels and the lower normal range threshold at the time of best response. In addition to standard statistical methods, interaction models were used to explore the potential effect modification of niFLC dynamics. Results A total of 158 patients were included (teclistamab, 73%; talquetamab, 15%; elranatamab, 12%). The median follow-up is 12 months (range 0 to 28 months). Median age is 71(range 65 to 77); 52% (n=85) were triple-class refractory (refractory to an IMiD, a PI, and CD38-antibody) and 37% (n=60) were penta-refractory. CAR-T therapy was previously administered in 28% (n = 46) patients, and 70% had undergone an autologous stem cell transplant. One or more high risk cytogenetic features including del(17p), gain(1q), amp(1q), del(1p), t(4;14), and t(14;16) were present in 57% (n = 90) of patients. Extramedullary disease was noted at the time of BsAb therapy in 44% of patients. Utilizing IMWG response criteria, 68% (n=107) achieved ≥partial response, and 64% (n=101) had ≥ very good partial response (VGPR) as best response following BsAb treatment. The median time to best response was 1.6 months (range 0.7 to 4.4). On multivariable analyses, baseline immunoparesis (HR 1.96; 95% CI, 1.08–3.58; p = 0.0274) and elevated ferritin levels (≥ 337 ng/mL) (HR 1.96; 95% CI, 1.24–3.09; p = 0.0041) were independent predictors of inferior progression-free survival (PFS). Lower baseline absolute lymphocyte count, analyzed as a continuous variable, was significantly associated with shorter PFS in the univariable analysis (HR 0.66; 95% CI, 0.44–0.98; p = 0.04), but not in the multivariable model (HR 0.75; 95% CI, 0.5–1.13; p = 0.166). Detectable niFLC at the time of best response was also significantly associated with inferior PFS (HR 1.80; 95% CI, 1.14–2.84; p = 0.0114). However, the magnitude of niFLC suppression did not show a statistically significant impact on PFS. The median PFS was 5 months in patients with high ferritin levels (≥ 337 ng/mL) and 21 months in those with lower ferritin (p = < 0.005). Similarly, PFS was 8 months in those with immunoparesis and not reached in those without baseline immunoparesis (p = 0.008). At the time of best response, detectable niFLC was associated with a trend toward shorter PFS (5 vs. 13 months), although the difference was not significant (p = 0.06). Logistic regression analysis supported these findings, with higher ferritin levels (OR 2.28; 95% CI: 1.09–4.96; p = 0.032) and the presence of baseline immunoparesis (OR 2.60; 95% CI: 1.18–6; p = 0.02) being significantly associated with higher likelihood of progression or death. Patients with deep reduction in niFLC achieved a VGPR or better. In contrast, those with detectable or higher-than-normal niFLC levels did worse in terms of response. Notably, niFLC became undetectable in 72% of patients with ≥VGPR (73/101), compared to 52% of those who did not achieve this level of response (30/57). Conclusion Among RRMM patients treated with BsAbs, baseline immunoparesis and elevated ferritin levels emerged as independent predictors of worse PFS. While failure to induce a deep reduction in niFLC at the time of best response suggests a tumor extrinsic mechanism of resistance, and it is also linked to inferior outcomes.

Abstract Background: As mounting numbers of patients receive allogeneic hematopoetic stem cell transplantation (allo-SCT) for hematologic malignancies, focus on survivorship and post-transplant complications is increasing. 30-60% of patients develop pulmonary complications, making the lungs the most affected organ post-transplant. While obstructive lung disease post-allo-SCT has been studied as a manifestation of graft-versus-host-disease (GVHD) in the form of bronchiolitis obliterans syndrome, many patients' post-transplant pulmonary function tests (PFTs) reveal restrictive patterns of disease which have been understudied. The pathophysiology, risk factors, and clinical course of restrictive lung disease (RLD) post-allo-SCT have not been fully elucidated. This retrospective study sought to characterize baseline characteristics, imaging findings, and possible risk factors of patients with RLD post-allo-SCT. Methods: The study included all patients receiving allo-SCT at our institution between 2005 and 2021 with at least one screening PFT with a restrictive pattern. Restriction is defined as normal forced expiratory volume in one second (FEV1) to forced vital capacity (FVC) ratio and total lung capacity (TLC) less than the lower limit of normal. Data collected via chart review included demographic information; indication for and type of transplant; myeloablative or nonmyeloablative conditioning; pre-existing lung disease; history of lung or chest-wall irradiation; acute post-transplant complications; documented acute or chronic graft-versus-host-disease (GVHD) of the lungs, skin, or other organs; and chest imaging findings on x-ray or computed tomography. For patients with at least two PFTs (n=168), average rate of change of TLC since transplant was calculated. Average monthly change in TLC post-transplant was compared between multiple groups detailed under Results. Analysis of variance or unpaired t-test and linear regression were used for comparison of categorical and continuous variables, respectively. Statistical analyses were completed using BlueSky Statistics 10.3.4, R version 4.1.3. Results: 234 patients were included. Median age at transplant was 51 years (range 18-74), and 163 (70%) were male. Average BMI at transplant was 29.6 (17.9–51.4). 107 (46.3%) underwent myeloablative conditioning, and 124 (53.2%) underwent reduced intensity or nonmyeloablative regimens. The most common indications for transplant were AML (n=87), MDS (n=41), and ALL (n=40). Most had no pre-existing lung disease (n=131, 56.2%), and 61 (26.1%) had evidence of restriction on pre-transplant PFTs. About half (n=119, 51.1%) had a history of lung or chest-wall irradiation. Within 30-days post-transplant, 55 (23.5%) had pulmonary complications (pneumonia or other hypoxic respiratory failure). 151 (64.8%) had either acute or chronic skin GVHD; 91 (39.1%) carried diagnoses of pulmonary GVHD. Most common associated imaging findings were infiltrates (n=120), scarring/atelectasis (n=73), pleural effusion (n=62), and air-trapping (n=50). Mean rate of change in TLC following transplant among all subjects was -0.0473 L/month. Comparative analysis revealed no statistically significant differences in mean values of average change in TLC between those with myeloablative and nonmyeloablative regimens (-0.0733 vs -0.0227 L/month, p = 0.176); pulmonary GVHD or not (-0.0752 vs -0.0203 L/month, p=0.141); GVHD or not (-0.0514 vs -0.0373 L/month, p=0.731); or with or without prior chest irradiation (-0.0234 vs -0.0687 L/month, p=0.226). Women had, on average, positive change in TLC compared to men (+0.00963 vs -0.0709 L/month, p=0.049). Decline in TLC was faster in overweight or obese patients (p=0.006). Conclusion: Our study establishes and describes a cohort of patients with restrictive lung disease post-allo-SCT, a poorly understood and incompletely characterized, yet highly morbid, set of diverse entities into which our findings provide insight. Based on the descriptive analysis we completed, patients experience decline in TLC due to a variety of processes – infiltrative pathology, pleural effusions, and chest wall weakness/restriction. Rate of decline increases with BMI and male gender. Diagnosis of pulmonary GVHD does not seem related to progression of restriction. As more long-term data is obtained from screening PFTs, examining larger datasets may allow for more granular analysis of the numerous possible etiologies.

Abstract Introduction Matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS, mass fix) represents a sensitive and specific alternative to electrophoresis and immunofixation for quantifying monoclonal antibodies in patients with multiple myeloma (MM). Here we report real world data utilizing mass fix and compare its test characteristics to a gold standard of minimal residual disease (MRD) quantification utilizing next generation sequencing (NGS). Results All patients who had obtained mass fix and MRD testing by NGS as part of routine clinical care at Mayo Clinic Arizona were screened for this study. In total, 343 pairs of mass fix and NGS testing within 50 days of each other representing 269 unique patients with secretory multiple myeloma were included. Cases of IgD myeloma and those secreting only free light chains were excluded. The threshold of MRD negativity was set at <1x10-6(less than one malignant cell in one million) and was assessed utilizing the clonoSEQ NGS assay. The median age of our cohort is 67, it is 44% female, and primarily Caucasian (88%) with a median follow-up of 7.3 months from testing date. FISH testing was performed in 96% of patients and at least one high risk cytogenetic abnormality (t(4;14), t(14;16), del(17p)) was found in 23% of patients. The t(11;14) translocation was found in 18%, +1q in 26%, and amp(1q) in 6% of evaluated patients. Notably, patients at all stages of treatment or disease status were included in our study. Induction treatment for newly diagnosed MM (NDMM, 133 patients) was mostly daratumumab-containing quadruplet (63%) or triplet drug regimens (36%). Autologous stem cell transplant (ASCT) was performed in 79% of NDMM and 80% of relapsed refractory MM patients (RRMM, 138 patients). Of the RRMM patients, 94% were triple class exposed and 41% were penta-exposed. Overall agreement between NGS and mass fix results was 65% (Kappa statistic: 0.31, 95% CI: 0.22 – 0.41). Most discordant cases were instances of mass fix negativity and NGS positivity (n = 89, 26% of all testing pairs). Only 7% of cases (n= 30) represented mass fix positivity with NGS negativity. Mass fix was able to define therapeutic monoclonal antibody by its unique mass spectrometric profile in 38 of the total test pairs that otherwise would have been considered disease associated. Of the 30 patients testing mass fix positive and NGS negative, 25 (83%) represent post-treatment evaluations. Thus, ongoing mass fix positivity represents monoclonal protein washout kinetics. All of these cases are noted to have declining mass fix levels at last follow up and 40% had undetectable monoclonal protein. The discordant mass fix negative and NGS positive cases were evenly distributed across NDMM and RRMM representing 32% and 20% of test pairs in each group, respectively. Amongst these 89 total test pairs, the median abundance of malignant clone by NGS was 10 cells per million (range 0.06 to 297,895). This is in contrast to 136 concordantly positive test pairs where the median was 2960 cells per million (range 0.353 to 1,017,360). The median monoclonal protein identified (in those with a quantifiable M-spike) was 0.30 g/dL. Receiver operating characteristic curves using NGS as gold standard found the optimal mass fix threshold to be 0.010g/dL (specificity 95%, sensitivity 51%) for NDMM patients and 0.046g/dL (specificity 84%, sensitivity 55%) in RRMM patients. Conclusions Development of a MRD assay based on peripheral blood sampling could greatly improve the ease and speed of obtaining these assessments. Our experience highlights both the great potential and need to identify appropriate clinical contexts for optimal use of mass fix MRD assessment. A significant limitation of our data is that low level monoclonal proteins without a previous reference above a threshold of 20mg/dL are not reported as positive and may account for a significant fraction of discordant cases reported here. All clonoSEQ NGS samples are referenced to a positive control greatly increasing specificity. The currently reported dataset is biased against mass fix as not all test pairs reported are known to have a positive reference. Further delineation of these cases is forthcoming. Previous reports have also noted that mass fix test characteristics can improve with time from treatment which will be assessed with future follow-up.

Abstract Introduction Cila-cel is associated with a 10-15% risk of delayed neurotoxicity (DNT) with rates of cranial nerve palsies (IEC-NP) and parkinsonism (IEC-PKS) seen at a rate of 10% and 1-4% respectively and can occur as early as 3-4 weeks after infusion. We and others have shown that high post-infusion peak absolute lymphocyte count (ALCpeak) of >3x10^9/L is associated with an increased risk of delayed neurotoxicity (Lim et al., ASCO 2025) whilst the risk was negligible (~1%) when ALCpeak fell below that threshold. Since December 2024, we implemented prophylactic administration of dexamethasone (PPX DEX) when ALC was >3x10^9/L (defined as high ALCpeak). Outcome of these patients are described here. Methods Analysis of clinical outcome included 230 pts treated between Feb 2022 and Nov 2024 as a historical cohort and 102 patients treated between Dec 2024 and May 2025 after the introduction of dexamethasone prophylaxis using an oral dose of 10mg twice a day for at least three days in the high ALCpeak cohort. Results No significant differences were seen between the new and historical cohort in pre-lymphodepletion disease burden (bone marrow plasma cell %, involved light chain or M-spike level), and rates of all/high-grade CRS or ICANS, IEC-HS and rates of tocilizumub use. Median follow-up in the new cohort of 102 pts was 3.6 months (95% CI 3.3-4.2). Eleven (10.8%) developed DNT [3 (2.9%) with IEC-PKS, 8 (7.8%) with IEC-NP]. High ALCpeak of >3x10^9/L was observed in 51 (50%) pts. Among pts with high ALCpeak, DNT was observed in 10 (20%) pts [3 (5.9%) with IEC-PKS, 7 (13.7%) with IEC-NP] whereas among 51 pts with ALCpeak <3x10^9/L, DNT was observed in 1 (2%) pt [1 (2%) with IEC-NP]. In the high ALCpeak cohort, 38 (75%) received DEX [6 (12%) for toxicity management, 32 (63%) PPX DEX]. Of the 38 pts treated with DEX, DNT was observed in 6 (16%) pts (2 (5.3%) IEC-PKS, 4 (10.5%) IEC-CNP). We next compared DNT rates between this new cohort of high ALCpeak pts receiving DEX (n=38) against the historical cohort with high ALCpeak (n=98). Estimated 90-day DNT by Kaplan-Meier method was (19.2% vs 20.5%; p=0.53): IEC-PKS (5.8% vs 7.2%; p=0.60) and IEC-NP (11.7% vs 13.3%; p=0.58). In patients with high ALCpeak, the use of DEX did not appear to significantly reduce the risk of DNT compared to historical controls (HR 0.76, 0.33-1.78), IEC-PKS (HR 0.67, 0.14-3.10) or IEC-NP (0.73, 0.24-2.23). We next compared ALC expansion over the first month post CAR-T infusion (area under the curve, AUC). Among the new cohort of 102 patients, no difference was seen in the AUC of pts who received DEX but did not develop DNT vs those who developed DNT (31.0 vs 57.9, p=0.28); No difference in AUC was seen in the new high ALCpeak cohort receiving DEX vs the historical cohort with high ALCpeak (36.0 vs 43.8, p=0.15) Of the eight cases of IEC-NP, 4 received PPX DEX. No noticeable differences were observed in the severity of presentation, laterality of cranial nerve involvement and rates of multiple cranial nerve involvement between these 4 cases who received PPX DEX and the 16 cases from the historical cohort. At the time of database freeze, 3 of the 4 cases had resolved and 1 was improving. Median time to complete symptom resolution was 38 days vs 69 days in the historical cohort. Of the three cases of IEC-PKS, 2 received PPX DEX. Median time to symptom onset for IEC-PKS was 46 days (vs. 24 days in historical cohort). Both cases had severe symptoms non-responsive to first line high-dose methylprednisolone, second line intrathecal chemotherapy and third line high-dose cyclophosphamide. Both pts subsequently died from sepsis 28 and 67 days post-cyclophosphamide. Conclusion While ALCpeak >3x10^9/L predicts risk of DNT in pts treated with cilta-cel, the use of PPX DEX does not appear to significantly reduce ALC expansion and does not appear to significantly reduce the risk of DNT, IEC-PKS or IEC-NP. Other strategies to reduce ALC or alter T cell functions may need to be considered.