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Abstract Introduction: The therapeutic landscape for paroxysmal nocturnal hemoglobinuria (PNH) has rapidly evolved with multiple proximal complement inhibitors now available, including pegcetacoplan (C3 inhibitor) and iptacopan (oral factor B inhibitor). While clinical trials have established individual drug efficacy compared with terminal complement inhibitors, real-world evidence regarding therapeutic transitions between proximal complement inhibitors remains extremely limited. As patients and clinicians increasingly seek to optimize treatment through sequential therapy approaches, understanding the outcomes of transitioning from pegcetacoplan to iptacopan becomes critical for evidence-based treatment sequencing in this rare hematologic disorder. Methods: We conducted a retrospective multicenter analysis across 3 academic medical centers (Cleveland Clinic, Mayo Clinic, Levine Cancer Institute) that evaluated 15 consecutive patients with PNH who were considered for transition from pegcetacoplan to iptacopan. Patients had confirmed PNH by flow cytometry and ≥3 months pegcetacoplan exposure. After switching to iptacopan, we assessed treatment acceptance rates, demographic characteristics, clinical outcomes including hemoglobin and lactate dehydrogenase (LDH) levels, and safety parameters. Responses to iptacopan were classified as optimal (hemoglobin >10.5 g/dL with clinical improvement) or suboptimal. Statistical analysis used paired t tests for continuous variables. Results: Of the 15 patients evaluated (median age [range]: 53 [22-81] years; 73% female), 14 patients (93.3%) elected to transition to iptacopan, demonstrating high treatment acceptance. Disease subtypes included classic PNH (36%) and PNH (64%) in the setting of another bone marrow disorder (n=7), multiple myeloma (n=1), and myelofibrosis (n=1). Median (range) duration of pegcetacoplan treatment pre-switch was 3 months (2-7 months), and median (range) duration of iptacopan treatment was 24 months (6-36 months). Among patients who transitioned, 79% (11/14) achieved hemoglobin improvement, with a mean increase from 9.2±1.8 to 10.8±2.1 g/dL (P=.028). Overall, optimal response was achieved in 64% (9/14) of patients. Response rates varied significantly by disease subtype: 80% in patients with classic PNH vs 56% in patients with PNH and aplastic anemia, with particularly poor outcomes in patients with concurrent hematologic malignancies (0%). LDH levels improved in 86% of patients, decreasing from 400±152 to 310±95 U/L (P=.015). PNH clone sizes remained stable throughout transition (erythrocyte: 75.1%±9.2% vs 75.4%±9.4%, P=.62; granulocyte: 95.0%±3.9% versus 95.2%±4.0%, P=.45). Treatment was well tolerated with no serious adverse events, breakthrough hemolysis, thrombosis, or discontinuations required. Two patients experienced mild self-limited gastrointestinal symptoms. Conclusions: This first multicenter real-world analysis demonstrates that the pegcetacoplan-to-iptacopan transition provides clinical benefit in the majority of this initial set of patients with PNH, with significant improvements in hemoglobin and an excellent safety profile while maintaining clone stability. The high acceptance rate suggests that patients prefer oral therapy over subcutaneous administration. These findings address a critical knowledge gap in proximal complement inhibitor sequencing, suggesting that iptacopan is an effective therapeutic option for patients with inadequate pegcetacoplan response and supporting the development of evidence-based treatment algorithms for optimal PNH care in the era of multiple complement inhibitor options.

Abstract Introduction: Sexual health is an important part of overall well-being for adolescents and young adults (AYAs) after hematopoietic stem cell transplantation (HCT). AYAs have unique sexual health needs as they navigate development, relationships, and identity formation. AYA patients may experience sexual dysfunction due to conditioning chemotherapy/radiation therapy, graft-versus-host disease (GVHD), changes in body image, mental health effects, relationship shifts, and the challenges of dating with a serious illness. We surveyed both pediatric and adult HCT providers at our institution to assess current practices of discussing sexual health needs with AYAs as well as barriers to these discussions in order to guide interventions to improve communication. Methods: Adult and pediatric HCT physicians, advanced practice providers, and nurse coordinators in the Mayo Clinic Rochester HCT program completed an online survey to understand their perspectives about addressing sexual health needs in AYA HCT survivors. This survey covered current practice patterns in discussing sexual health and managing sexual health needs, barriers to providing sexual health care, and recommendations for provider education. Results: This survey included responses from 25 HCT providers (35% response rate): 22 adult providers and 3 pediatric providers. The respondents comprised of 10 physicians (40%), 8 advanced practice providers (32%), and 7 nurses (28%). Most of the providers saw 6-10 AYA patients per month (48%), while others reported: 1-5 AYAs (36%), 11-15 AYAs (12%), and 16-20 AYAs (4%); no provider saw 21 or more. While all respondents felt sexual health was an important topic for AYA HCT patients, most (80%) also reported rarely (44%) or only sometimes (36%) discussing sexual health with AYA patients. Primary barriers included inadequate knowledge of resources for referrals (72%), insufficient training on this topic (60%), limited time for discussion (56%), discomfort discussing sexual health with AYAs (32%), and concern about patient discomfort (28%). When it came to screening for GVHD, 28% of respondents reported not regularly screening for genitourinary GVHD and 40% indicated feeling uncomfortable or very uncomfortable managing it. Frequently discussed topics included fertility (64%) and contraception (52%). Almost all respondents (96%) expressed interest in further education. Topics of interest included an overview of common sexual health issues in AYA HCT survivors (88%), medical management of sexual health concerns such as erectile dysfunction, low libido, and vaginal dryness (72%), management of psychosocial concerns impacting body image and relationships (64%), cultural considerations for addressing sexual health (56%), providing inclusive care for lesbian, gay, bisexual, trans, queer or questioning (LGBTQ) AYAs (56%), genitourinary GVHD (56%), and safer sex practices during and after transplant (52%). Discussion: Although regular sexual health assessment in HCT survivors is recommended, most providers at our institution did not routinely discuss sexual health with AYAs. While genitourinary GVHD is an important HCT-specific sexual health topic, screening for this condition is not consistently performed. Providers were eager for further education and identified several topic areas for future educational interventions. Our data will aid in the development of an educational intervention for providers covering key sexual health issues in AYA HCT survivors, including medical and psychosocial management of sexual health concerns, as well as inclusive care for intercultural and LGBTQ AYAs, with the aim of improving frequency of sexual health discussions and provider confidence. Time constraints were identified as a key barrier, so patient-focused educational interventions that can occur outside of the clinical appointment may be an opportunity to deliver information and empower patients to raise specific concerns during their visits. In combination with healthcare provider-focused education, this may promote critical sexual health-related discussions during appointments.

Abstract Background Translocation of chromosomes 4 and 14 (t(4;14)) results in overexpression of MMSET and has been associated with poor clinical outcomes in patients (pts) with multiple myeloma (MM). KTX-1001 is a first-in-class, potent, and selective oral inhibitor of MMSET (also known as NSD2) developed as the first investigational therapy to directly target the high-risk t(4;14) translocation, a key molecular driver in MM. KTX-1001 binds to and inhibits the catalytic SET domain of MMSET, thereby suppressing the deposition of dimethylated histone H3 lysine 36 (H3K36me2), leading to downregulation of oncogenic histone modifications and epigenetic reprogramming of malignant plasma cells. Preclinically, KTX-1001 synergistically inhibited cell viability in MM cell lines when combined with a proteasome inhibitor (PI), immunomodulatory drug (IMiD), or cereblon E3 ligase modulator (CELMoD™). Preliminary findings were previously reported from the initial cohort of 18 pts enrolled in a first-in-human phase 1 trial evaluating KTX-1001 in relapsed/refractory multiple myeloma (RRMM; NCT05651932; Bories et al. Blood. 2024;144[Suppl 1]:3370). Here, we present updated results from this study. Methods RRMM pts who received ≥3 prior therapies, including PI, IMiD and anti-CD38 monoclonal antibody (anti-CD38 mAb), received oral KTX-1001 across 9 dose levels using a 3+3 dose-escalation design. Primary objective was to determine the recommended Phase 2 dose (RP2D) and the maximum tolerated dose (MTD). Secondary objectives included pharmacokinetics, pharmacodynamics (PD), and primary efficacy. The dose expansion phase has been initiated to evaluate KTX-1001 in combination with either carfilzomib or the investigational CELMoD™ mezigdomide in t(4;14) RRMM pts. Results As of 13 June 2025, 40 pts have been treated in the monotherapy dose-escalation phase. The maximum tolerated dose (MTD) was exceeded due to dose-limiting toxicities (DLTs) in 2 pts: two Grade (Gr) 4 thrombocytopenia and one Gr 3 epistaxis. Backfill at selected dose levels is ongoing to further characterize safety profile and refine dose optimization. The median time from initial MM diagnosis was 8 years (range:2-20) with a median of 6.5 prior lines of therapy (range: 3-25). This included stem cell transplant (70%), BCMA CAR-T (42.5%), and non-CAR-T BCMA targeted drugs such as antibody-drug conjugates and bispecific antibodies (57.5%). The median age was69 years (range:50-83); 21 were female and 19 were male. Extra-medullary disease was present in 13 (32.5%) pts. Nineteen (47.5%) pts had t(4;14) translocation, 5 (12.5%) had 1q21 gain and 4 (10%) had deletion 17p. A total of 16 (40%) pts have shown a treatment response according to IMWG criteria or have achieved stable disease: 1 VGPR (10+ months), 1 PR (4+ months), 2 MR (3+ and 12 months), 12 SD (2-20+ months). KTX-1001 has demonstrated a favorable tolerability profile. Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 31 (77.5%) pts. The most frequent (≥20% pts) Gr 3/4 TEAEs were thrombocytopenia in 12 pts (30%; grade 4 in 8 [20%]), neutropenia in 12 pts (30%; febrile neutropenia in 2 [5%]), anemia in 10 (25%) pts. Gr 3 infections were observed in 5 (12.5%) pts and fatigue in 5 (10%) pts. The main reason for treatment discontinuation was progressive disease (57.5%), other pts discontinued due to physician decision (5%), consent withdrawal (5%), and one pt due to adverse event. Twelve (30%) pts remain on treatment. At Cycle 1 Day 15, drug exposure and steady-state concentrations of KTX-1001 increased with dose. A dose-dependent reduction in H3K36me2, the primary PD marker of KTX-1001 activity, was observed in peripheral blood at Cycle 2 Day 1 and beyond, which plateaued above dose-level 4. Paired bone marrow samples further confirmed on-target PD effects, with a marked reduction in H3K36me2 levels in MM cells at Cycle 2 Day 1 with observed anti-MM effect of reduced proliferation of MM cells with concomitant increased proliferation in immune cells in pts achieving clinical benefit. ConclusionsKTX-1001 is a novel agent showing tolerable safety profile in RRMM and demonstrating promising single agent activity in heavily pretreated, triple class refractory RRMM including those with high-risk features. KTX is currently evaluated in ongoing study in combination with carfilzomib and the investigational CELMoD™ mezigdomide in t(4;14) RRMM pts.

Abstract Cardiac involvement in AL amyloidosis significantly impacts both short and long-term survival. Achieving cardiac complete response (CarCR) is linked to excellent survival, comparable to that of the general population. We undertook this study to characterize patients with AL amyloidosis who achieved CarCR. Methods: A single-center retrospective study of patients diagnosed with cardiac AL amyloidosis between 2004 and 2023 and achieved a documented CarCR for at least 12 months. Patients were included if they had evidence of cardiac involvement confirmed by cardiac imaging (transthoracic echocardiogram or cardiac magnetic resonance) and Congo red–positive tissue (non-cardiac or heart biopsy), and were evaluable for cardiac response based on baseline NT-proBNP > 650 pg/mL or BNP > 150 pg/mL. CarCR was defined as a reduction in NT-proBNP to less than 350 pg/mL (or BNP less than 80 pg/mL). Heart transplant patients were excluded. Results: Sixty-three patients were included, representing 4.6% of the cardiac evaluable population in the study period. This proportion increased in the second period compared to the first period (7.5% vs 3.2%, P<0.001). The median age at diagnosis of 57 years (ranging from 29 to 79); 63% were male. Lambda light chain disease was evident in 63% of patients. The median difference between the involved and uninvolved light chain (dFLC) at baseline was 429 mg/L (interquartile range [IQR] 143-708). While all patients had cardiac involvement, 63% also presented with extra-cardiac involvement [kidneys (52%), liver (16%), autonomic nerves (14%), luminal gastrointestinal tract (11%), and peripheral nerves (10%)]. The median baseline NT-proBNP for the entire cohort was 1977 pg/mL (IQR 1393-3026). The median troponin T (n=43) was 0.02 ng/mL (IQR <0.01-0.05) and the median high-sensitivity troponin T (n=19) was 49 ng/L (IQR 38-79 ng/L). Cardiac stage distribution, according to the European modification of the Mayo 2004 staging model, was as follows: 59% stage II, 39% stage IIIa, and 2% stage IIIb. At baseline, echocardiogram features included a median left ventricular (LV) ejection fraction of 63%, a median intraventricular septum thickness of 14 mm, and a median average LV longitudinal strain of -12%. The most common first-line therapies were autologous stem cell transplantation (ASCT; with or without induction, 54%), bortezomib-containing therapy (22%), and daratumumab-containing therapy (13%). Hematological complete response rates at 3-month, 6-month, and best response prior to CarCR were 32%, 49% and 76%, respectively. At CarCR, the median NT-proBNP was 265 pg/mL (IQR 220-307) with a median time from treatment onset to CarCR achievement of 20.6 months. At CarCR, 33% of patients were on loop diuretics. The CarCR rate at 6, 12, 24, 36, 48 and 60 months from treatment onset was 10%, 39%, 81%, 90%, 95% and 96%, respectively. Temporary increase of NT-proBNP above 350 pg/mL with return to CarCR was documented in 46% of patients. Echocardiogram parameters also improved significantly at the time of CarCR, with average left ventricular longitudinal strain showing the greatest median improvement in relation to baseline (from -12% to -17%, p<0.001). However, echocardiographic parameters did not fully normalize in all patients. Cardiac progression was seen in 14% of patients, at a median of 7.6 years from the initial time of CarCR. In addition, subsequent clone-directed therapy was given in 44% of patients at a median of 4.6 years from the initial treatment. With a median follow-up of 9.5 years, eight patients (13%) died, 4 due to causes unrelated to AL. We compared the survival of patients who achieved CarCR to the general U.S. population, matching for age, sex, and the year treatment. The observed survival of CarCR patients was similar to that of the general population (p=0.35). Conclusion: Patients with persistent CarCR >12 months in AL amyloidosis are uncommon and demonstrate excellent outcomes. The achievement of hematological CR was required in 3 out of 4 patients reaching a CarCR. Echocardiographic changes of amyloid infiltration may still persist in this highly favorable cohort, indicating that “complete” response refers primarily to functional and prognostic improvement, not necessarily a full restoration to pre-disease cardiac morphology and function. Achieving CarCR is associated with a low risk of cardiac progression, but the need for subsequent clone-directed therapy remains elevated.

Abstract Background: Gastrointestinal (GI) symptoms are frequent in patients (pts) with systemic light chain amyloidosis (AL), yet their clinical significance remains poorly defined. We investigated the role of symptomatic GI involvement in disease burden, survival, and organ-specific outcomes in a large single-center cohort. Methods From 2010–2025, 4,396 AL pts were evaluated at our center; 560 pts (13%) had provider-attributed symptomatic GI AL. Pts with localized AL or positive biopsy without GI symptoms were excluded (n=38). We analyzed relationships between GI symptoms, anatomic/histologic involvement, laboratory parameters, survival, and need for nutritional support using Wilcoxon rank-sum, Chi-square, Kaplan-Meier, and logistic regression tests. Results GI symptoms included early satiety (n=320/57%), diarrhea (n=189/34%), nausea (n=184/33%), abdominal pain (n=148/26%), dysphagia (n=119/21%), vomiting (n=75/13%), GI bleeding (n=74/13%), and heartburn (n=71/13%). Only nausea and GI bleeding were not associated with cardiac (n=366/65%) renal (n=274/49%) or hepatic (n=84/15%) AL, whereas dysphagia, early satiety and heartburn were more frequent with cardiac (all OR=1.7), abdominal pain and diarrhea with hepatic (OR=2 and 1.6, respectively), and vomiting with renal involvement (OR=2; all p<0.04). Autonomic involvement impacted GI symptoms, often without proof of parenchymal GI amyloid. Of the 124 pts with formal autonomic testing, only 44 (35%) had positive GI biopsies as compared to AL GI pts without proven autonomic involvement (240/436, 55%). Pts with autonomic involvement were more symptomatic than pts with positive GI biopsies, suffering more often from dysphagia (29% vs 19%), diarrhea (41% vs 32%), and gastroparesis (34% vs 9%, all p<0.001). We screened changes in body weight, calcium, VitB12, Hb, PO4, and albumin at diagnosis. Of the 175 pts with documented weight loss in this cohort, pts with GI AL lost more weight compared to those with other organ involvement (21% vs 14% of weight, p=0.002), and had lower phosphate (3.7 vs 4.0 mg/dL, p=0.06). In our cohort of pts with GI symptoms, 298 (53%) had a positive GI biopsy. Biopsy-proven anatomic involvement dictated symptoms (all p<0.05): Of the 20 pts with positive esophageal biopsy, dysphagia was present in 45%; only 33% of the pts without an esophageal biopsy had dysphagia. Similar patterns were seen for the 170 pts with a positive gastric biopsy (n=170) in terms of heartburn (21% vs 11%), for the 165 pts with positive small bowel biopsies in terms of abdominal pain (68% vs 32%), and for the 130 pts with positive colon biopsies and diarrhea (46% vs 33%). Specific histopathological patterns were prognostic. Mucosal involvement (n=161) was an independent risk factor for survival compared to submucosal (n=64) and vascular (n=102) involvement throughout the GI tract (HR 1.83; p=0.03). Three-layer GI infiltration was associated with inferior mOS (2.4 vs 5.1 vs 7.8 y for 3 vs 2 vs 1-layer involvement, HR 3.19/1.56/1; p<0.05). Counterintuitively, vascular involvement had the lowest risk of bleeding in all GI anatomic sites (p=0.02). In the colon, only mucosal involvement was associated with a higher risk of bleeding (OR=5; p=0.04). GI involvement in AL pts did not worsen prognosis (mOS 10.0/6.3y, p=0.02), and pts with isolated GI AL (n=74/13%) had an even better survival (55% surviving at 10 y). Cachexia (n=120; mOS 3.5 vs 7.8 y, p<0.001), need for nutritional support (n=36; mOS 0.9 vs 7.0 y, p<0.001), and diarrhea (mOS 5.8 vs 6.9 y, p=0.06) were risk factors for death. In pts with hematologic response (≥PR), bleeding did not recur within 3 y (n=27), but even with response, diarrhea (n=160) persisted in 39%. Resolution was less frequent without hematologic response (persistence in 69%, OR=3.5). Improvement was most often due to treatment of bacterial overgrowth (11/35 pts; 68%) and loperamide (54/59 pts; 91%). Conclusion In AL, meaningful GI involvement is defined by nausea, diarrhea, occurrence of bleeding, and malnutrition. These are primarily associated with mucosal infiltration. GI symptoms can occur in the face of autonomic involvement. While long-term persistence of GI bleeding is rare after serologic response, cachexia and persistent diarrhea drive morbidity, need for nutritional support, and poor survival.

ABSTRACT Light chain multiple myeloma (LCMM) is a subtype of multiple myeloma (MM) characterized by the exclusive production of immunoglobulin light chains and accounts for 15%–20% of newly diagnosed MM. A comprehensive comparison of LCMM with MM producing intact immunoglobulin (non‐LCMM) remains limited. In this retrospective study, we described distinct clinical and cytogenetic features and assessed long‐term outcomes in 852 LCMM patients diagnosed between 01/01/2004 and 12/31/2022, compared with non‐LCMM controls matched for age, sex, and year of diagnosis. On univariable analysis, LCMM patients were more likely to present with elevated creatinine (> 2 mg/dL), beta‐2‐microglobulin ≥ 5.5 mg/L, elevated LDH, hypercalcemia, t(11;14), del(13q), and t(6;14). Conversely, IMS‐IMWG high‐risk disease, hyperdiploidy, t(4;14), and serum albumin < 3.5 g/dL were less common. On multivariable analysis, elevated creatinine (OR: 5.1, 95% CI: 1.2–27, p = 0.04), t(11;14) (OR: 2.6, 95% CI: 1.3–5.2, p = 0.006), and del(13q) (OR: 4.1, 95% CI: 2.1–8.2, p < 0.001) were independently associated with LCMM, while IMS‐IMWG high‐risk disease (OR: 0.3, 95% CI: 0.1–0.8, p = 0.02) and hyperdiploidy (OR: 0.3, 95% CI: 0.1–0.7, p = 0.002) were less frequent. Despite these differences, progression‐free survival with frontline treatment (HR: 0.97, 95% CI: 0.84–1.11, p = 0.63) and overall survival (HR: 0.99, 95% CI: 0.87–1.13, p = 0.94) were similar between LCMM and non‐LCMM patients. This study highlights the distinct clinical and cytogenetic features of LCMM, marked by higher rates of renal failure, t(11;14), and del(13q), lower prevalence of IMS‐IMWG high‐risk disease, and comparable survival outcomes.

Abstract This retrospective analysis examined 15 years of autologous stem cell transplantation (ASCT) for light chain (AL) amyloidosis at the Mayo Clinic (2010-2024). We aimed to assess ASCT utilization trends, factors influencing practice changes, and current indications amid newer therapies. Four hundred and forty-one ASCTs were divided into cohort 1 (2010-2019) and cohort 2 (2020-2024), revealing a significant ASCT reduction in cohort 2 (385 vs 56, average 71% annual decrease). Cohort 2 patients were older, more likely to have relapsed/refractory disease, and had higher baseline bone marrow plasma cell burden compared to cohort 1. Pre-ASCT induction was more frequent in cohort 2 (89.3% vs 56.4%), with daratumumab (Dara)–cyclophosphamide-bortezomib-dexamethasone (CyBorD) replacing CyBorD as the predominant induction regimen. Lymphoma-based regimens were also more common in cohort 2 (15.1% vs 5.3%, P = .02). Day-100 satisfactory hematological response improved in cohort 2 (91.1% vs 72.7%, P = .001), although hematological complete response rates did not significantly differ (50.9% vs 38.8%, P = .09). In summary, there is a decrease in the utilization of ASCT in AL amyloidosis. This procedure is primarily reserved for patients with suboptimal responses, relapsed/refractory disease, lymphoplasmacytic clones (predominantly immunoglobulin M amyloidosis), or high bone marrow plasma cell burden (myeloma phenotype). This study underscores a significant shift in ASCT practice, driven by novel therapies, emphasizing more personalized management in AL amyloidosis.