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Abstract Background Subglottic stenosis (SS) is a type of laryngotracheal stenosis defined by a location of less than 1.5 cm below the glottis or the vocal cords. Approximately 20% of cases are idiopathic. Objective We performed a systematic literature review of idiopathic subglottic stenosis (ISS) complicating pregnancy. Search Strategy PubMed, Scopus, and clinicaltrials.gov databases were queried from inception through August 10, 2023 with the following terms: idiopathic subglottic tracheal stenosis, subglottic stenosis, subglottic stenoses, tracheal stenosis, tracheal stenoses, and pregnancy. This systematic review was conducted according to the methods described in the Preferred Reporting Items for Systematic Reviews and Meta‐analysis (PRISMA) guidelines for reporting systematic reviews. Selection Criteria Studies detailing cases of ISS affecting pregnancy were included and studies reporting SS in pregnancy from a known etiology were excluded. Data Collection and Analysis Our search identified 31 peer‐reviewed published cases of ISS complicating pregnancy that met the inclusion criteria. We also included two additional cases from our institution. Publication bias was checked by the Joanna Briggs Institute critical appraisal tools. Descriptive statistical analyses were performed using Excel. Main Results A majority of patients (26/33, 79%) were diagnosed with ISS during the reported pregnancy. Prior to pregnancy, 20/33 (61%) patients had a working diagnosis or reported symptoms of airway obstruction. Of these patients, 9/20 (45%) carried a diagnosis of asthma, and 6/20 (30%) carried a diagnosis of ISS. Specific symptoms prior to pregnancy were reported in 10/33 (30%) patients. The most common symptoms in these patients were dyspnea (10/10, 100%) and stridor (4/10, 40%). During pregnancy, all patients experienced worsening respiratory symptoms, with dyspnea (31/33, 94%), stridor (18/33, 55%), cough (13/33, 39%), hoarseness (7/33, 21%), and wheeze (5/33, 15%) being the most common symptoms. A total of 22/33 (67%) patients required medical and/or surgical management with dilation and/or excision during pregnancy. Postpartum outcomes were reported in 27/33 (82%) patients, and 1/27 (3.7%) required a tracheostomy immediately postpartum. The majority (18/27, 67%) of these patients required intervention postpartum, while 9/27 (33.3%) were asymptomatic. Conclusion ISS should be considered in pregnant patients with worsening respiratory symptoms despite medical management of asthma. If high clinical suspicion for upper airway obstruction exists, an otolaryngology referral for evaluation with bronchoscopy is recommended.

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 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 Background: While mutations in the fms-like tyrosine kinase 3 (FLT3) gene are well-established adverse drivers in acute myeloid leukemia (AML), their role in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML) remains insufficiently defined. Methods: We conducted a retrospective multicenter study of 115 patients with FLT3-mutated (FLT3mut) MDS (n=63) or CMML (n=52), comparing their clinical, genomic, and therapeutic characteristics at diagnosis or first referral to 677 FLT3 wild-type (FLT3wt) controls (MDS n=388; CMML n=289) using multivariate analyses and propensity score matching (PSM). Results: FLT3mut MDS and CMML exhibited a proliferative phenotype with higher leukocyte and neutrophil counts and lower platelet levels (p<0.02); in MDS, median white blood cell counts remained below 13,000/µL. In MDS, FLT3mut cases were enriched in the MDS with increased blasts subtype (57% vs 39%, p=0.01) and favorable-risk cytogenetics (64% vs 41%, p<0.01). Genomically, FLT3mut MDS showed higher frequencies of NRAS, KRAS, PTPN11, RUNX1 and CBL co-mutations (p<0.05), and a markedly lower prevalence of TP53 mutations (2% vs 36%, p<0.001). In CMML, FLT3mut cases were more often transfusion-dependent (50% vs 23%, p<0.01), classified as CMML-2 (39% vs 25%, p=0.04), and enriched in ASXL1 (68% vs 47%; p<0.01) and SETBP1 (24% vs 8%; p<0.01) mutations. Notably, they exhibited multi-hit TET2 mutations less frequently than FLT3wt CMML (27% vs 53%, p=0.01). After adjusting for age, sex, and allogeneic stem cell transplantation, FLT3 mutations were independently associated with worse outcomes. To further assess the prognostic impact of FLT3 mutations, we conducted PSM analyses using a 1:1 ratio of FLT3mut to FLT3wt patients, adjusting for key clinical and biological confounders. In MDS, matching was based on age, sex, bone marrow blast percentage, and cytogenetic risk category; in CMML, variables included age, CMML-2 subtype, peripheral blood counts, normal karyotype, and ASXL1 mutation status. After matching, FLT3mut MDS cases showed significantly shorter overall survival (OS; 19.9 vs 44.2 months, p=0.046) and leukemia-free survival (LFS; 13.8 vs 37.1 months, p=0.023) compared to FLT3wt patients. Similarly, in CMML, FLT3mut patients experienced inferior OS (30.4 vs 67.2 months, p=0.017) and LFS (17.2 vs 65.6 months, p=0.014). Competing risk models confirmed a markedly increased cumulative incidence of AML transformation in both FLT3mut MDS and CMML (p<0.001), without significant differences in the risk of non-leukemic death. Among FLT3mut cases, tyrosine kinase domain mutations (FLT3-TKD) were associated with superior survival compared to internal tandem duplications (FLT3-ITD; MDS hazard ratio [HR]: 0.28, p=0.003; CMML HR: 0.34, p=0.012). FLT3 allelic ratio (AR), assessed by conventional PCR in 63 patients (MDS n=34, CMML n=29), provided additional prognostic value. An AR ≥0.21 identified a subgroup with significantly shorter OS (MDS: 24.4 vs 38.8; CMML: 6.7 vs 30.4 months) and LFS (MDS: 9.0 vs 18.5 months; CMML: 5.8 vs 30.4 months; all p<0.05), supporting the utility of quantitative FLT3 assessment in clinical risk stratification. FLT3 inhibitors (FLT3i) were administered in combination with hypomethylating agents (HMA) to 16 (27%) FLT3mut MDS and 15 (33%) CMML patients. Compared to HMA, FLT3i treatment was associated with higher overall response rates (MDS: 69% vs 22%, p<0.01; CMML: 73% vs 35%, p=0.06). Molecular clearance, defined as post-treatment reduction in AR to ≤0.01, was observed more frequently with FLT3i than with HMA (MDS: 56% vs 10%, p=0.03; CMML: 60% vs 20%, p=0.09). FLT3 clearance was associated with prolonged survival. In MDS, median OS and LFS were 66.0 vs 14.5 (p=0.12) and 29.0 vs 9.9 months (p=0.056), respectively; in CMML, it was 37.6 vs 14.6 months for both OS (p=0.043) and LFS (p=0.032). Conclusions: This study expands the current understanding of FLT3mut MDS and CMML by characterizing their clinical, molecular, and therapeutic features in the largest multicenter cohort reported to date. These cases exhibit a proliferative phenotype, frequent co-mutations in RAS pathway genes, and an elevated risk of leukemic transformation. Quantitative assessment of FLT3 allelic burden refines prognostication beyond mutation status alone. The observed associations between FLT3 inhibitor use, molecular clearance, and improved outcomes support further evaluation of targeted strategies in selected patients.

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 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.

Abstract Introduction: Waldenström macroglobulinemia (WM) is characterized by the presence of a MYD88 mutation in >90% and a CXCR4 mutation in 30-40% of cases. The impact of these mutations on treatment responses and disease outcomes is well known. TP53 alterations (TP53ALT) have more recently been described in WM and are reported to occur in up to 25% of patients, with a higher frequency in patients with previously treated WM, especially those with prior alkylator or nucleoside analogue exposure (Tam et al Blood Adv 2024; Poulain et al CCR 2017; Tsakmaklis et al, ASH 2025). TP53 ALT WM is associated with a shorter time to disease progression, as well as worse overall survival (Poulain et al CCR 2017; Gustine et al, BJH 2019). Depth of response to BTK inhibitors is affected by TP53 status, with recent data reporting a very good partial response (VGPR) rate of 34% v. 25% and major response rates of 84% v. 73% in patients without or with a TP53 ALT (Tam et al Blood Adv 2024). No complete responses were reported and median PFS was shorter in those with a TP53ALT compared with wild-type (TP53WT). Loncastuximab tesirine is a humanized IgG1 anti-CD19 antibody that is conjugated to a pyrrolobenzodiazepine (PBD) dimer. Following internalization, the PBD dimer is released via proteolytic cleavage and binds to the DNA minor groove forming highly cytotoxic DNA inter-strand crosslinks. Cells deficient in DNA repair including TP53 alterations are vulnerable to the cytotoxic effects of loncastuximab tesirine (Tarantelli et al, Haematologica 2024). Methods: In an ongoing investigator-initiated, prospective phase II study in symptomatic patients with relapsed or refractory WM (NCT05190705), patients are receiving single agent loncastuximab tesirine. Loncastuximab tesirine is administered at 150 ug/kg in cycles 1 and 2 and 75 ug/kg in cycles 3 to 6. Each cycle is 28 days. The primary outcome measure of this study is attainment of VGPR or complete (VGPR/CR) response. The accrual goal of this trial is 20 patients, based on an alternative VGPR/CR rate ≥40% versus a null of ≤10%, with a double-sided alpha of 0.037 and a power of 87%. The study would meet its endpoint if ≥6 patients attained a VGPR/CR. Results: Of the 14 patients who have completed therapy on this trial to date, the median age is 71 years (range 53-81), 9 (64%) are male, and the median prior number of therapies is 4 (range 2-10). Median baseline hemoglobin is 9.5 g/dL (range 8.2-12.6), serum IgM is 2146 mg/dL (range 723-5955), and bone marrow involvement is 53% (range <5-90). Four patients had extramedullary disease. Twelve patients (86%) are MYD88 mutated; 8 patients (57%) are CXCR4 mutated, and 8 (57%) are TP53 altered. Nine patients completed all 6 cycles of therapy. Of the 5 other patients, treatment was stopped early due to GGT elevation (n=2), disease progression (n=1), patient decision (n=1), and skin toxicity (n=1). No IgM flare and no infusion reactions have occurred. For all patients, the median time to minor response, major response, and deepest response was 28, 55, and 172 days, respectively. The response rates include 1 (7%) CR; 9 (64%) VGPRs; 2 (14%) partial responses (PR); 1 (7%) minor response; and 1 (7%) progressive disease, for an overall response rate of 93% and a VGPR/CR rate of 71%. For the 8 patients with TP53ALT, the baseline characteristics were as follows: 50% male; median age of 70 years (range 53-77), median prior therapies is 4 (range 2-10); median IgM is 1877 mg/dL (range 723-5639); and median hemoglobin is 9.2 g/dL (range 8.2-11.6). All TP53ALT patients had an MYD88 mutation, and 6 (75%) carried a CXCR4 mutation. For those with TP53 ALT, the median time to minor response, major response, and deepest response was 28, 49, and 235 days, respectively. All TP53ALT patients attained a major response; 1 patient (13%) with a CR, 6 (75%) with a VGPR, and 1 (13%) with a PR, for an overall response rate of 100% and a VGPR/CR rate of 89%. One patient had splenomegaly and one had adenopathy, both of which resolved after treatment. Conclusion: Our findings from this ongoing, prospective trial demonstrate a high VGPR/CR rate of 71% in heavily pre-treated WM. Notable, is the VGPR/CR rate of 89% in high-risk patients with TP53ALT WM. No unexpected toxicities have been seen in this trial. Our findings identify a potentially novel time-limited therapy in relapsed or refractory WM, including patients with high-risk TP53ALT WM.

Abstract Background & aim: Myelodysplastic syndromes with isolated deletion of chromosome 5q (MDS-del(5q)) are associated with low-risk features and favorable prognosis. In contrast, TP53 multihit alterations, typically reflecting biallelic inactivation, are associated with high-risk features and adverse outcomes across MDS subtypes. Although current classification systems exclude MDS-del(5q) cases with TP53 multihit from low-risk categories, the prognostic significance of these alterations in this specific context remains unclear. Methods: We conducted an international, multicenter, retrospective study comparing MDS-del(5q) per 2017 WHO criteria with TP53 multihit alterations (MDS-del(5q) TP53 multihit) from 21 international institutions, to MDS with low blast counts with TP53 multihit alterations without isolated del(5q) (MDS-LB TP53 multihit) from the public data from the study of Bernard et al., Nat Med 2020. Clinical and biological data were collected at diagnosis. Genetic profiling included G-banding and NGS of myeloid genes. TP53 multihit was defined as >1 TP53 mutation or a single mutation with 17p deletion, copy-neutral loss of heterozygosity (LOH), or variant allele frequency (VAF) ≥50%. Patients were stratified as lower- or higher-risk based on IPSS-R and IPSS-M scores. Lower-risk included those with IPSS-R ≤3.5 points or very-low, low, or moderate-low IPSS-M, while higher-risk included those with IPSS-R >3.5 points or moderate-high, high, or very-high IPSS-M. Clinical, molecular features, overall survival (OS), and AML progression were compared between MDS-del(5q) TP53 multihit and MDS-LB TP53 multihit groups. Finally, outcomes between patients with likely biallelic TP53 multihit status, defined as harboring a single TP53 mutation accompanied by a co-occurring deletion/LOH of 17p or a TP53 VAF ≥50%, versus those considered less likely to be biallelic, thus still classified as multihit, defined as having >1 TP53 mutation but a combined VAF <50%, were compared in both MDS-del(5q) and MDS-LB groups. Statistical analysis was performed using R (version 4.2.2). Results: We included 113 patients with a median follow-up of 81.1 months (95% CI 74.9–NR). A total of 45 (39.8%) were MDS-del(5q) TP53 multihit, and 68 (60.2%) MDS-LB TP53 multihit. Compared to MDS-LB TP53 multihit, patients with MDS-del(5q) TP53 multihit had significantly higher platelet counts (209 ×10⁹/L vs. 77 ×10⁹/L) and were more frequently classified as lower-risk by both IPSS-R (75.4% vs. 9.8%) and IPSS-M (90.2% vs. 24.6%). The median number of mutations per patient, excluding TP53, was 1 in both groups, and only SF3B1 mutations were significantly more frequent in the MDS-del(5q) TP53 multihit group compared to MDS-LB TP53 multihit (20.5% vs. 2.9%; p<0.01). Regarding survival, MDS-del(5q) TP53 multihit patients showed an improved OS compared to MDS-LB TP53 multihit (median OS of 57.0 months (95%CI, 43.0–112.0) vs 14.0 months (95%CI, 8.6–19.0); p<0.01). Moreover, while the risk of progression to AML at 48 months were comparable between groups (34.9% for MDS-del(5q) TP53 multihit and 33.0% for MDS-LB TP53 multihit; p=0.8), a significant difference was observed in the timing of AML progression: median time to AML evolution of 31.7 months (IQR 23.4–55.3) in the MDS-del(5q) TP53 multihit group and 7.2 months (IQR 4.1–12.9) in the MDS-LB TP53 multihit group (p<0.01). Notably, no significant differences in outcomes were found between TP53 multihit and most likely biallelic cases in both MDS-del(5q) and MDS-LB cohorts. The impact of complex karyotype (CK) in MDS-LB TP53 multihit was also explored. MDS-LB TP53 multihitwith CK showed a significantly worse OS compared to MDS-LB TP53 multihitwithout CK (median OS of 10.0 months (95% CI 7.5–17.0) vs 40.0 months (95% CI 14.0–NA); respectively; p<0.001. However, the incidence of AML and median time to AML evolution were comparable between both groups. Finally, OS between MDS-LB TP53 multihit patients without CK and the MDS-del(5q) TP53 multihit cohort was compared. Median OS was significantly shorter in the former group (median of 40 months) compared to the latter (median of 61 months) (p <0.01) Conclusions: These findings underscore that, in contrast to other TP53-multihit MDS subtypes, MDS-del(5q) with TP53 multihit alterations constitute a clinically distinct entity with better outcomes, thereby warranting reconsideration of its place in current classification systems.