Citations

Abstract Background The prognostic relevance of fluorescence in-situ hybridization (FISH) abnormalities is well-established in multiple myeloma (MM), where high-risk (HR) abnormalities are associated with poor survival. In AL amyloidosis, however, the cytogenetic landscape and its implications might be different. For example, t(11;14), common in AL amyloidosis, has historically been linked to inferior outcomes in the pre-daratumumab era. HR FISH abnormalities are less common and less well-defined in this setting, underscoring the need to evaluate their significance in this disease. Methods We retrospectively analyzed 698 newly diagnosed AL amyloidosis patients seen at Mayo Clinic, Rochester, between 2012–2021 who had baseline FISH testing. HR FISH was defined as del(17p)/monosomy 17, t(4;14), t(14;16) or t(14;20). Baseline characteristics and treatment patterns were compared between the HR and the standard-risk (SR) groups. Staging used the Mayo 2004 system with European modification. Hematologic responses were assessed at 2 and 6 months, and cardiac/renal responses at 3, 6, 12, and 24 months per consensus criteria. Overall response rate (ORR) for hematologic and organ responses included patients who achieved partial response (PR), very good partial response (VGPR), and complete response (CR). Overall survival (OS) was estimated via Kaplan-Meier; comparisons used log-rank testing. Cox regression was used for univariate and multivariable analyses. Results Among 698 patients, 73 (10.4%) had HR FISH. The most common HR abnormality was t(14;16) (n=34, 4.9%), followed by del(17p)/monosomy 17 (n=21, 3%), and t(4;14)/t(14;20) (n=12 each, 1.7%). Across the cohort, t(11;14) was most frequent (51.3%), followed by del(13q) (36.2%), hyperdiploidy/tetraploidy (26.3%), and 1q gain/amp (23.6%). Compared to SR group, HR FISH group had fewer males (43% vs. 69%, p<0.0001), with no difference in age (62.5 vs. 65, p=0.44), cardiac (73% each, p=1) or renal involvement (52% vs. 54%, p=0.71). More HR patients had early cardiac stage (69% vs. 55.9%, p=0.04). Both groups were predominantly lambda isotype (82% vs. 74%, p=0.15), with similar baseline dFLC (21.6 vs. 28.4 mg/dL; p=0.81). Intact immunoglobulin secretion was more common in the HR group (68% vs. 45%, p=0.004). The HR group more often underwent advanced bone imaging (44% vs. 29%, p = 0.015) and had a higher incidence of lytic lesions or fractures (27% vs. 15%, p = 0.046). Use of bortezomib-based therapy, primarily CyBorD, was similar between the groups (67% each). Daratumumab-based therapy (16% vs. 11%, p=0.25) and autologous stem cell transplantation (ASCT) (33% vs. 25%, p=0.16) were numerically higher in the HR group, though not statistically significant. Post-ASCT maintenance was more frequent in the HR group (17% vs. 7%, p=0.006). At 2 months, hematologic ORR was higher in the HR group (90% vs. 72%, p=0.007), with higher ≥VGPR (67% vs. 32%, p<0.0001) and CR rates (24% vs. 8%, p=0.0004). At 6 months, the HR group maintained higher ≥VGPR (89% vs. 71%, p=0.008) and CR rates (41% vs. 26%, p=0.04), with no difference in ORR (98% vs. 92%, p=0.18). Cardiac responses at 6 months favored the HR group (VGPR or better: 29% vs. 12%, p=0.013; CR: 13% vs. 3%, p=0.007). At 12 months, cardiac ≥VGPR remained higher (50% vs. 29%, p=0.01), though CR was not significantly different (18% vs. 9%, p=0.1). Renal ≥VGPR at 6 months was more common in the HR group (47% vs. 22%, p=0.004), but not renal CR (9% vs. 7%, p=0.95). At 12 months, renal ≥VGPR remained higher in HR (61% vs. 40%, p=0.004). With a median follow-up of 87 months, median OS was not reached in HR (95% CI: 72.6–NR) vs. 88.9 months (95% CI: 72.8–110.5) in SR (p=0.03). In multivariable analysis, age ≥65 (HR 1.56, p=0.0001) and >2 organ involvement (HR 1.46, p=0.002) were associated with worse OS, while ASCT (HR 0.35, p<0.0001) and cardiac stage I/II (HR 0.48, p<0.0001) predicted better OS. HR FISH was not independently associated with OS (HR 0.74, p=0.14). Conclusions HR FISH abnormalities in AL amyloidosis are not independently associated with OS, unlike in MM. Patients with HR FISH abnormalities more often presented with earlier cardiac stage and demonstrated deeper hematologic and organ responses than patients with SR FISH abnormalities. This study underscores how clonal characteristics can potentially aid in more personalized treatment approaches for patients.

Abstract Background Multiple myeloma, the second most common hematologic malignancy, has witnessed incremental progress in its management over the past decade underscored by substantial improvement in patient outcomes, although it remains largely incurable. Due to its relapsing-remitting course with current therapies, patients experience considerable burden, particularly with the use of parenteral regimens that are administered on a continuous basis. As such, exploration of newer oral, finite-duration therapeutic options may be of benefit. Selinexor, an oral selective exportin (XPO)-1 inhibitor has an established synergistic activity with other antimyeloma therapies, including immunomodulatory drugs and proteasome inhibitors. In combination with dexamethasone, selinexor is currently approved at 80 mg twice a week dose, and in combination with bortezomib plus dexamethasone, it is approved at 100 mg once weekly dose for patients with relapsed and/or refractory multiple myeloma (RRMM). Herein, we present the results of Arm B of the 2-arm SCOPE trial that examined an all-oral regimen of selinexor, pomalidomide and low-dose dexamethasone (SPd) regimen for RRMM. Methods The SCOPE trial is an investigator-initiated, single arm, phase 2 study that assessed the efficacy and safety of selinexor (S), 60 mg orally (PO) weekly, pomalidomide (P), 4 mg PO, days 1-21 and dexamethasone (d), 40 mg PO, weekly in 28-day cycles given for a fixed duration (total 18 cycles ) in patients who were exposed to up to 2 prior lines of antimyeloma therapy, at least one of which included both a proteasome inhibitor and the immunomodulatory agent, lenalidomide. Olanzapine, along with a 5-HT3 antagonist comprised the mandatory anti-emetic prophylactic regimen. The trial's primary endpoint was overall response rate (ORR), based on confirmed response, and the key secondary endpoints were progression-free survival (PFS), duration of response (DOR), overall survival (OS), and safety of SPd. The International Myeloma Working Group (IMWG) 2016 criteria were used for response assessment in addition to reporting of the minor response. The distribution of PFS and OS was estimated using the Kaplan Meier method. Toxicity was graded using the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Results At the data cutoff date (May 28, 2025), 28 of 29 enrolled patients with RRMM were evaluable. The median age at study entry was 67.5 years (range: 65-72 years). SPd was used as the first salvage regimen in 21% of patients, and the remaining 79% of patients had previously received 2 lines of therapy at study entry. All patients had previously been exposed to a proteasome inhibitor and an immunomodulatory agent, and 32% were dual refractory. Notably, 64% of patients had previously been exposed to the anti-CD38 monoclonal antibody, daratumumab, and 11% of patients were daratumumab-refractory. The median follow-up was 23.9 months (range: 2.9-38.8 months). The patients had received a median of 9 cycles of SPd (range:1-18 cycles), and at data cutoff, 36% of patients had completed all the planned 18 cycles of SPd. The ORR was 61% (95% CI:41-78) and the rate of measurable residual disease (MRD)-negative complete response (CR) was 21%, CR 11%, very good partial response (VGPR) 18%, partial response (PR) 11% as the best response achieved. Additionally, 7% and 25% of patients had attained a minor response (MR) and stable disease (SD), respectively. The median PFS was 24 months [95% CI: 7.1– not-estimable (NE)] months, and the median DOR was not reached (NR). 2-year OS rate was 93%. The toxicity associated discontinuation rate was 7%, and no grade (Gd) 5 events or unexpected toxicities were encountered during treatment. Gd 3 or higher hematologic toxicities occurred in 43% [Gd 3/4 anemia (11%/0%), thrombocytopenia (14%/0%), neutropenia (25%/7%), lymphopenia (4%/4%)]. Gd 3+ non-hematologic toxicities occurred in 46% [Gd 3 /4 (%) infections (21%/0%), fatigue (4%/0%), nausea (7%/0%) and anorexia (0%/7%). No patients experienced Gd 3 or 4 diarrhea, vomiting or weight loss. Additional data will be presented at the meeting. Conclusion Weekly selinexor in combination with pomalidomide and dexamethasone is an effective and safe, all-oral regimen for patients with RRMM who are previously exposed to a proteasome inhibitor and lenalidomide. SPd regimen is currently being examined in an ongoing phase 3 randomized controlled trial.

Abstract Background Paroxysmal nocturnal hemoglobinuria (PNH) is an ultra-rare blood disease characterized by uncontrolled complement activation with potentially life-threatening complications. Therapeutic options comprise both terminal complement inhibition, targeting C5 to prevent intravascular hemolysis (IVH), and proximal complement inhibition, intervening upstream within the complement cascade to address IVH and extravascular hemolysis (EVH). Pegcetacoplan, the first C3 and C3b inhibitor, demonstrated efficacy and safety in complement inhibitor (CI)–experienced (CIexp) and –naïve (CInaive) patients in two phase 3 studies with a three year follow up (PEGASUS [NCT03500549] and PRINCE [NCT04085601]). The aim of this study was to describe real world clinical and treatment outcomes in CIexp and CInaive PNH patients prescribed pegcetacoplan. Methods Data were drawn from the Adelphi PNH II Disease Specific Programme™, a real-world cross-sectional survey of hematologists and their consulting PNH patients. Data were collected from November 2023–January 2025 in Canada, France, Germany, Italy, Spain, the UK, and the US. Patients prescribed pegcetacoplan for ≥3 months were included and described as CIexp if they had previously been treated with CI, or CInaive if patients had never been prescribed CI therapy. Physicians reported patient demographics, clinical characteristics, and treatment outcomes. Patients provided data on patient-reported outcomes, including the EQ-5D-5L and Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue. Response to pegcetacoplan was categorized as no, minor, partial, good, major or complete response per SAAWP-response criteria (Risitano et al, 2019). Analyses were descriptive. Results Overall, 54 physicians provided data for 77 patients prescribed pegcetacoplan (54 CIexp patients and 23 CInaive patients). Median (interquartile range [IQR]) age was 45.0 (33.5–55.0) years (CIexp, 47.0 [37.0–60.8]; CInaive, 39.0 [30.0–45.0]), 63.6% (Cexp, 64.8%; Cnaive, 60.9%) were male, 57.9% (CIexp, 50.9%; CInaive, 73.9%) were in employment. Median (IQR) time since diagnosis was 2.4 (1.3–4.9) years (Cexp, 3.1 [2.0–5.5]; Cnaive, 1.3 [0.8–2.3]) with median (IQR) time since start of pegcetacoplan initiation being 0.6 (0.4–1.0) year (CIexp, 0.6 [0.4–0.9]; CInaive, 0.6 [0.5–1.2]). Clinical outcomes were measured at treatment initiation and the time of survey, and reported as median (IQR). Hemoglobin levels increased from 9.0 (8.0–9.2) to 11.0 (10.3–12.1) g/dL, and 9.0 (7.0–10.5) to 11.5 (10.6–12.0) g/dL, for Cexp (n=52) and Cnaive (n=21), respectively. Lactate dehydrogenase levels decreased from 490 (295–594) to 260 (189–377) U/L for Cexp (n=53), and 275 (214–775) to 220 (187–278) U/L for Cnaive (n=18). Absolute reticulocyte counts decreased from 200 (135–275) to 113 (105–217) x109/L for Cexp (n=19) and 160 (113–250) to 110 (100–134) x109/L for CInaive (n=7). Positive movement by at least one response category since pegcetacoplan initiation were observed in 85.2% CIexp (n=27) and 61.5% CInaive (n=13); with patients classified as having a ‘good’, ‘major’ or ‘complete’ response increasing from 3.7% to 74.1% for CIexp and 23.1% to 69.2% for CInaive. Perceived severity of PNH improved after pegcetacoplan initiation, with ‘mild’ severity increasing from 13.0% to 68.5% and 34.8% to 87.0%; patients experiencing no fatigue increased from 5.6% to 57.4% and 8.7% to 65.2%, for CIexp and CInaive, respectively. For both CIexp and CInaive, complete treatment adherence was reported for 87.0% of patients. Since pegcetacoplan initiation, proportion of ‘well’ or ‘very well’ controlled PNH patients increased from 14.8% to 96.3% for CIexp and 52.2% to 100.0% for CInaive. Overall, 25 patients self-reported data (n=14 CIexp; n=11 CInaive). Patients reported a mean (Standard Deviation [SD]): EQ-5D VAS score of 66.8 (16.0) and 76.7 (18.7); EQ-5D utility score of 0.86 (0.16) and 0.91 (0.13); FACIT-Fatigue 41.1 (9.5; n=13)and 37.1 (12.2; n=11) for CIexp and CInaive, respectively. Conclusion Improvements in clinical values, perceived PNH severity, control of PNH, and both physician and patient-reported fatigue were observed in CIexp and CInaive patients. These data suggest that pegcetacoplan has positive outcomes regardless of prior CI exposure. These findings indicate that the efficacy of pegcetacoplan in a real-world clinical practice is consistent with results from clinical trials and other real-world evidence for both CIexp and CInaive patients.

Abstract Introduction: Inherited & acquired bone marrow failure syndromes (BMFS) have “stress erythropoiesis” with macrocytic anemia, elevated fetal hemoglobin (HbF) & erythropoietin (EPO) levels. The degree of HbF elevation & its capacity to discriminate between patients with inherited & acquired BMFS needs to be systemically studied. Genetic testing is often delayed & it is important to establish an early clinical diagnosis to make clinical decisions such as initiation of immunosuppressive therapy. Methods: After institutional review board approval, we compiled a clinically & genetically well-annotated cohort of patients with BMFS evaluated at Mayo Clinic. All patients were required to have at least cytopenia(s) & evidence of low or variable bone marrow cellularity upon a bone marrow evaluation. Patients with pre-clonal or malignant disorders were excluded. Clinical diagnoses were independently verified for accuracy. Detailed clinical & laboratory features were recorded. Germline genetic testing was performed as clinically appropriate on peripheral blood or bone marrow samples through targeted panels. Distribution of continuous variables was statistically compared using nonparametric (Mann-Whitney or Kruskal-Wallis) tests, while nominal variables were compared using the Chi-Square test. Kaplan-Meier estimate of overall survival (OS) was computed from the date of diagnosis to date of death or last follow-up (also censored at the time of allogeneic hematopoietic stem cell transplant). Results: Between years 1998 - 2023, 129 patients met criteria for inclusion in the study. Among these, clinical diagnoses included immune-mediated aplastic anemia (AA, n=56, 43%, 21% severe or very severe as per the Camitta criteria), telomere biology disorders (TBD, n=37, 29%), Fanconi anemia (n=10, 8%), GATA2 haploinsufficiency (n=8, 6%), Diamond-Blackfan anemia (DBA, n=2, 2%), deficiency of adenosine deaminase-2 (DADA2, n=2, 2%), congenital dyserythropoietic anemia (CDA, n=1, 1%), congential amegakaryocytic thrombocytopenia (CAMT, n=1, 1%), Schwachman-Diamond syndrome (n=1, 1%) & undefined (n=11, 9%). Among the inherited group, 63% had an identifiable germline pathogenic variant (most commonly, TERT/TERC 30%, FANC group 25% & GATA2 15%) with the rest diagnosed on a clinical basis. Elevated HbF >1% was noted in 79% of all BMFS patients; 83% AA, 70% TBD, 50% in DADA2 & 67% in undefined patients (no data was available for other inherited subtypes). In patients with an elevated HbF, absolute monocyte count (p=0.04) was significantly higher; however, there were no other significant associations with variables at diagnosis such as hemoglobin (p=0.5), white blood cell count (WBC, p=0.14), absolute neutrophil count (p=0.5), platelet count (p=0.7), mean corpuscular volume (MCV, p=0.2), absolute lymphocyte count (p=0.1), absolute reticulocyte count (p=0.4), EPO level (p=0.3), presence of a PNH clone (p=0.2), or presence of a germline variant (p=0.3). When diseases were grouped into inherited & acquired (AA) subgroups, median HbF was not significantly different (median%, 4.5 versus 2.3, p=0.4), with elevated HbF (>1%) in 75% versus 83% (p=0.6) patients respectively. On the other hand, minor PNH clone (>0.1% in at least two cell types) was detectable in the acquired group only (0 versus 55%, p<0.0001). Similarly, acquired group had a shorter (<3 months) onset of cytopenias preceding diagnosis (P<0.0001), with no significant differences in MCV (p=0.2), marrow dysplasia (p=0.09) or atypia (p=0.6), & splenomegaly (p=0.9). At median follow-up of 7 years, Kaplan-Meier estimate of transplant-censored median OS was lower in inherited versus acquired group (16 years versus median not reached, p=0.02). Elevated HbF did not significantly predict adverse OS in either group. Conclusions: Fetal hemoglobin is elevated in both patients with inherited & acquired (aplastic anemia) BMFS. When compared to established variables, elevated HbF has neither diagnostic utility nor prognostic relevance in predicting adverse outcomes. On the other hand, onset of cytopenias and presence of a minor PNH clone are both useful clinical variables in differentiating patients with inherited from acquired BMFS. Our data offers practical clinical utility in making early treatment decisions for patients with BMFS.

Abstract Background Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder characterized by uncontrolled terminal complement activation leading to intravascular hemolysis (IVH), thrombosis, and premature mortality. The complement C5 inhibitor (C5i) ravulizumab provides immediate, complete, and sustained inhibition of terminal complement activity through an 8-weekly weight-based dosing interval, resulting in control of IVH, reduced morbidity (thrombosis rate) and mortality (improved survival). Pivotal trials of ravulizumab have shown durable efficacy and safety (Kulasekararaj et al. Ann Hematol 2025). While real-world evidence supporting its use is accumulating, further data are needed to more comprehensively characterize its effectiveness and safety in routine clinical practice.Aims To evaluate the real-world effectiveness and safety of ravulizumab among US patients with PNH over 1 year, based on physician chart review data. Methods Medical chart data from 127 US patients with PNH who started ravulizumab between June 1, 2021 and May 31, 2023 were randomly selected and abstracted by 50 hematologists/oncologists from academic (n=25) or community (n=25) settings. Included patients were aged ≥18 years on the date of ravulizumab initiation (index), had ≥12 months of medical data pre- and post-index, and continued ravulizumab for ≥12 months, unless the patient died. Complement inhibitor (Ci)-experienced patients had previous eculizumab or pegcetacoplan use pre-index; Ci-naive patients had no previous use of any Ci pre-index. Outcomes included changes in lactate dehydrogenase (LDH), hemoglobin (Hb), and absolute reticulocyte count (ARC) up to 12 months post-index. Breakthrough IVH (BT-IVH) events (defined as LDH ≥2 × upper limit of normal [ULN; 246 U/L] and ≥1 of the following: anemia, dyspnea, hemoglobinuria, or fatigue) were assessed from index to earliest of death, loss to follow-up, ravulizumab discontinuation, or chart abstraction. Event rate was calculated per 10 person-years (PY).Results The sample included 69 Ci-naive (mean [standard deviation; SD] age: 51.4 [14.1] years; 59.4% male) and 58 Ci-experienced patients (mean [SD] age: 45.0 [14.7] years; 51.7% male; previous eculizumab: n=52; previous pegcetacoplan: n=6). In both respective cohorts, ravulizumab was associated with significant reductions in mean (SD) LDH level at month 12 (−348 [424] U/L and −20 [75] U/L; p<0.001 and p<0.05), with improvements observed from 1-month post-index. Similarly, mean (SD) Hb levels significantly increased over 12 months (2.2 [1.8] g/dL and 1.3 [1.5] g/dL, respectively; p<0.001 for both), with improvements seen as early as 1-month post-index. Significant reductions in mean (SD) ARC were observed 1-month post-index and were maintained for up to 12 months in Ci-naive patients (−45 [52] × 103/μL; p<0.001). This effect was not observed in Ci-experienced patients (−7 [85] × 103/μL; p=0.536). Over a median follow-up of 1.8 years (Ci-naive) and 1.6 years (Ci-experienced), 4 BT-IVH events occurred in 4 Ci-naive patients (5.8%; event rate: 0.30 per 10 PY), and 7 events occurred in 5 Ci-experienced patients (8.6%; event rate: 0.69 per 10 PY). All events were resolved without transfusion, dose modification, or discontinuation of ravulizumab, and no events resulted in thrombosis. Summary/Conclusion These real-world data from US adults with PNH showed that ravulizumab was associated with early and sustained significant and clinically meaningful improvements in hematological markers for PNH, in both Ci-naive patients and those with prior eculizumab or pegcetacoplan use. Ravulizumab treatment was associated with a low incidence of BT-IVH events, and all events were resolved without the need for transfusion, dose adjustment, or treatment discontinuation. Importantly, no thrombotic events occurred during these events. Despite the known differences in data collection between clinical trial and real-world populations, these findings align with an analysis of long-term clinical trial data from Kulasekararaj et al. (2025), which reported BT-IVH in 14.8% of C5i-naive (event rate: 1.0 per 10 PY) and 7.8% of eculizumab-experienced patients (event rate: 0.33 per 10 PY) with PNH over a follow-up period of up to 6 years (median: 3.9 and 2.7 years, respectively). Overall, this analysis supports the use of ravulizumab, with only 6–7 infusions per year, as an effective treatment for patients with PNH in the real-world setting.

Abstract Background Central nervous system involvement in multiple myeloma (CNS-MM) is a rare but highly aggressive manifestation. Limited data exists regarding its incidence, biology, treatment patterns, and outcomes. A deeper understanding of the features unique to CNS-MM will help inform risk stratification and management strategies. Methods We conducted a retrospective study of CNS-MM patients at our institution between January 2000 and December 2023. We identified 305 MM patients with pathology-proven extramedullary disease (EMD). CNS involvement was defined as the presence of parenchymal (brain or spine) or leptomeningeal involvement by MM. Univariate analysis was performed to compare the clinical characteristics between EMD patients with and without CNS-MM. Results Out of 305 patients with EMD, we identified 22 patients with CNS-MM. Common symptoms prompting evaluation of CNS-MM were headaches (32%), numbness or tingling (32%), weakness (27%), confusion (23%), falls (23%), and visual disturbances (14%). Among these patients, 17 (77%) had detectable disease in cerebrospinal fluid (CSF), 12 (55%) in the brain parenchyma, 4 (18%) in the spinal cord parenchyma and 6 (27%) in the leptomeninges. Of the CNS-MM patients, the median age at diagnosis of MM was 58.3 years and the median time to CNS-MM involvement was 16.2 months, with 3 (14%) patients having CNS involvement at diagnosis. The predictors of CNS-MM development were high-risk cytogenetics (OR 2.9, p=0.04) and presence of additional visceral organ involvement outside of the CNS (OR 3.4, p=0.03). EMD was multifocal in 20 CNS-MM patients (83%) and visceral organ involvement [most commonly lymphadenopathy (27%), solid organ (18%) and pleural fluid (14%)] was present in 14 (64%) of these patients, compared to 54% in EMD patients without CNS-MM. High-risk cytogenetics [del(17p), 1q gain/amplification, t(4;14), t(14;16), t(14;20)] were seen in 16 (73%) patients, most commonly 1q gain or amplification (40%), t(4;14) (23%), and del(17p) (18%). Five (23%) exhibited a double-hit profile. In comparison, 113 (40%) EMD patients without CNS-MM had high risk cytogenetics. The median overall survival (OS) from diagnosis of CNS-MM was 6 months (95%CI:1.26-36) compared to 15.6 months (95%CI: 12-18) from diagnosis of EMD in EMD patients without CNS-MM (p=0.05). Median OS from diagnosis of MM in the CNS-MM cohort was 36 months (95%CI: 22.8-NA) compared to 55.2 months (95%CI: 45.6-68.4) in EMD patients without CNS-MM (P=0.11). When excluding CAR-T or bispecific therapy recipients, median OS from diagnosis of MM for CNS-MM was 22 months versus 48 months in EMD patients without CNS-MM (P=0.02). Overall response rate in our CNS-MM cohort with first treatment for EMD was 32% compared to 48% in EMD patients without CNS-MM (p=0.04). In patients with CNS-MM, median progression-free survival (PFS) from CNS-MM diagnosis was 3.3 months (95%CI: 0.8-12) versus 3.9 months (95%CI: 3-5.1) in EMD patients without CNS involvement (p=0.2). Six (27%) CNS-MM patients received CAR-T; 3 received cilta-cel, 2 received ide-cel and one received a BCMA CAR-T on trial. Bispecific therapy was used in 4 (18%) patients, with 2 receiving Teclistamab and 2 Talquetamab. Three (14%) CNS-MM patients received both CAR-T and bispecific therapy. The median PFS on CAR-T therapy was 10.5 (95%CI: 5.6-NA) months and 12.7 (95%CI: 10.2-NA) months on bispecific therapy. The median OS from diagnosis of CNS-MM for patients who received CAR-T or bispecific therapy was 36 months (95%CI: 14.0-NA), compared to 1.2 months (95%CI: 0-14.4) for those who did not (p=0.002). Six (27%) patients with CNS-MM, all of whom had CSF involvement of disease, received intrathecal therapy; methotrexate in 3, cytarabine in 2, and one receiving both. Two of these patients demonstrated improvement in cerebrospinal fluid findings following intrathecal chemotherapy, in conjunction with other therapies. Patients who received intrathecal chemotherapy had a median OS measured from development of EMD of 10.8 (95%CI: 3.6-NA) months, compared to 15 months (95%CI: 4.8-NA) in those without IT chemotherapy (p=0.59). Conclusion Central nervous system involvement in MM is relatively uncommon and associated with dismal outcomes. High-risk cytogenetics and involvement of other visceral sites are associated with a higher risk of CNS involvement. Intrathecal therapy offers limited value and immune effector therapies represent efficacious options for treatment.

Abstract Background Measurable residual disease (MRD) negativity post- autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma (MM) is associated with favorable outcomes and may overcome the adverse impact of high-risk cytogenetic abnormalities (HRCAs). However, as the definition of high risk evolves and MRD emerges as a key endpoint, understanding its prognostic value within individual HRCAs is critical for treatment guidance. Methods We retrospectively included patients with NDMM that underwent an ASCT between September 19, 2016, and October 19, 2023, and achieved MRD negativity on Day 100 post ASCT. The MRD testing was conducted using multiparameter flow cytometry with a sensitivity of 2x10. HRCAs were defined as del(17p), 1q21+ gain or amplification (1q21+), t(4;14), t(14;16), t(14;20) and del(1p) and rest were considered standard risk (SRCA). Patients were grouped by the number of HRCAs (0, 1, ≥2). An adaptation of the recently proposed International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) classification for high-risk disease (TP53 mutation unavailable) was also used. Progression-free survival (PFS), measured from stem-cell infusion to progression or death, was estimated using Kaplan–Meier methodology and compared using log-rank test. Results We identified 386 patients with MRD negativity post ASCT, of which 381 had cytogenetic data available for analysis. The median follow-up for the study cohort was 47.3 months (95% CI: 43.2-50). The median age at the time of ASCT was 65.7 (25.4-79.2) years and 58.3% patients were males. A total of 49% (n=189) patients had standard-risk cytogenetics, 31.4 % (n=121) harbored 1 HRCA, 15.3% (n=59) patients had two HRCAs and 3.1% (n=12) had 3 HRCAs. The individual HRCA by their prevalence were: 1q21+ in 35.5%(n=137), del(17p) in 14.3% (n=55), t(4;14) in 10.9% (n=42), t(14;16) in 5.4% (n=21), del(1p) in 4.2% (n=16), and t(14;20) in 1.04% (n=4) of patients. The most common double-hit lesions were1q21+ gain and/or amplification co-occurring with t(4;14) (33.9%, n=20) and del(17p) with 1q21+ (18.6%, n=11). Despite universal MRD negativity at Day 100, several HRCAs remained prognostically significant for PFS. Patients with del(17p) had worse 3-year PFS (71%) than those without (81%) [hazard ratio (HR)=1.85, 95% CI 1.11–3.07, p = 0.0172], though 3-year OS did not significantly differ at data cutoff (80% vs. 92%, p=0.1176). Presence of 1q21+ was associated with an inferior 3-year PFS (73%) compared to those without [84%, HR: 1.96 (95% CI: 1.25–3.06), p=0.0026], while 3-year OS was similar (88% vs. 91%, HR:1.33 p=0.36). Isolated 1q21+ had inferior PFS with comparable OS when compared to SRCA [3-year PFS of 82% vs. 88% respectively (HR:1.97, p=0.0177)]; 3-year OS was 91% vs. 94% (HR:1.38, p=0.44)]. Among 1q21+ patients, those with co-occurring HRCAs had a 3-year PFS of 66% vs. 81% for isolated 1q21+ (HR: 1.47, p=0.21). Patients with t(4;14) had worse 3-year PFS (64%) vs. 82% in non t(4;14) [HR 2.11(95% CI: 1.21-3.67) p=0.0064], and 3-year OS of 82% compared to 91% [HR 2.14 (95% CI: 1.02–4.49), p=0.038]. Isolated t(4;14) showed a 3-year PFS of 59% vs. 87% in standard-risk (p=0.06), and 3-year OS of 90% vs. 93% [HR 3.29, 95% CI 0.95–11.33, p = 0.06]. The presence of t(14;16), t(14;20), and del(1p) did not significantly affect 3-year PFS (all p>0.1), likely due to small subsets. When patients were grouped by the number of HRCAs, PFS declined with increasing cytogenetic complexity. Compared to standard risk, the 3-year PFS was 77% for 1 HRCA vs [HR = 2.11 (95% CI: 1.29–3.46), p = 0.0027], 67% for ≥2 HRCA [HR = 2.64 (95% CI: 1.53–4.57), p = 0.0005]. Maintenance therapy was used in 98% of patients. Patients with HRCAs received a doublet maintenance compared to SRCA (p<0.0001), even in MRD negative disease post ASCT. Conclusion In patients with certain HRCA, achievement of MRD negativity post-ASCT does not overcome the adverse impact of HRCA on PFS. In our cohort, patients with del(17p), t(4;14), or 1q21+ continued to exhibit significantly shorter PFS despite achieving MRD-negative status. These findings underscore the need for ongoing risk-adapted strategies even in patients with MM who attain MRD-negative state. The OS estimates are immature at this time.

Abstract Background Primary plasma cell leukemia (pPCL) is a rare and aggressive variant of multiple myeloma (MM), characterized by the presence of more than 5% circulating plasma cells on a peripheral blood smear. Despite advancements in therapy, including novel agents and autologous stem cell transplantation (ASCT), pPCL remains associated with markedly poorer survival outcomes compared to newly diagnosed MM. Although disease progression is common in pPCL, individual courses vary widely upon relapse and thereafter. We aim to describe the natural history of pPCL, focusing on clinical features and survival outcomes at the time of relapse or disease progression. Methods Patients with pPCL who were followed at our institution's cancer center between 2006-2024 were included for retrospective analysis. The electronic health record was reviewed to provide detailed information on patient demographics, disease characteristics, treatment regimens, and clinical outcomes. Time to next treatment (TTNT) and overall survival (OS) analysis were performed using the Kaplan-Meier method. Statistical analyses were performed using the SAS biostatistical software JMP 17.0.1 (SAS Institute Inc). Results We analyzed a cohort of 106 patients with relapsed pPCL after first-line therapy, all of whom received induction with novel agents. To date, 64 patients (60%) have died. Across the entire cohort, median OS is 39 months (mos) (95% CI: 25-68). 59 patients (56%) were diagnosed after 2015. Baseline FISH cytogenetics were available for 100 patients; 57 (57%) had one or more high-risk cytogenetic abnormality. Nearly all patients (96%) had ≥50% clonal plasma cells on initial bone marrow biopsy. While most patients (n = 61; 58%) were planned to undergo upfront ASCT, 20 (33%) experienced disease progression during induction therapy and required a more intensive salvage regimen (often infusional chemotherapy) prior to ASCT. The median TTNT after first-line therapy (TTNT#1) for the entire cohort was 10.4 mos (95% CI: 8–14). The median TTNT after second-line therapy (TTNT#2) for the entire cohort was 5.7 mos (95% CI: 4.3–7.1). Clinical details at first relapse, prompting initiation of second-line therapy, were available for 91 patients. Of these, 26 patients (29%) had symptomatic relapses—due to CRAB features or extramedullary disease—while 65 patients (71%) experienced asymptomatic biochemical progression. Symptomatic relapses were followed by significantly shorter TTNT#2 (3.9 vs. 7.0 mos; p = 0.039) and inferior OS from the start of second-line therapy (7.5 vs. 31.2 mos; p <0.0001) compared to asymptomatic relapses. The median TTNT#2 for patients who relapsed during induction and received salvage ASCT was 6.9 mos (n=20). In contrast, those treated after relapse with non-ASCT regimens (n = 86) fared worse; those receiving novel agent-based combinations, including doublets, triplets, or quadruplets (n=64) had respective median TTNT#2 of 3.3, 6.0, and 3.3 mos. Patients treated with infusional chemotherapy (n = 9) had the poorest outcomes, with a median TTNT#2 of just 1.4 mos. The median TTNT diminished with each subsequent line of therapy: TTNT#3 (n = 73) was 5.8 mos, TTNT#4 (n = 53) was 4.0 mos, and TTNT#5 (n = 35) was 2.6 mos. Patients with pPCL harboring the t(11;14) cytogenetic abnormality who were treated with venetoclax-based regimens (n = 8) during any line of therapy had a longer corresponding median TTNT of 15.0 mos. Additionally, 23 patients received anti-BCMA CAR-T cell therapy as a post-relapse line of therapy. At last follow-up, 15 of these patients (65%) had not relapsed, and after a median 20.7 mos of follow-up, the median TTNT following CAR-T cell therapy had not yet been reached. Patients who received CAR-T after 1-3 prior lines (n=15) had a median TTNT that was not reached; those who had received 4 or more prior lines (n=8) had a median TTNT of 20 mos. ConclusionsDespite the use of novel agent-based combination regimens and ASCT as first-line therapy, most patients with pPCL eventually experience disease progression. Consistent with MM, symptomatic relapse in pPCL is associated with poorer outcomes compared to asymptomatic biochemical progression. Additionally, the duration of response shortens with each successive line of therapy. Notable exceptions include venetoclax-based regimens in patients with t(11;14), and anti-BCMA CAR-T cell therapies: each appear to confer more durable responses than historical treatments in patients with relapsed pPCL.

Abstract Introduction: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, life-threatening hematological disorder affecting ≈24 per 1,000,000 people in the US. Iptacopan, the first orally administered monotherapy for PNH, received US Food and Drug Administration approval in December 2023. APPRISE-PNH is a data platform designed to capture comprehensive real-world information on iptacopan-treated patients with PNH. The aim of this study was to describe patient profiles and assess treatment patterns and clinical outcomes among iptacopan-treated patients (age ≥18 years) with PNH in the US real-world setting. Methods: The present interim analysis of APPRISE-PNH includes data from patients enrolled between July 2, 2024, and June 13, 2025, with additional data collection expected through 2025. Duration of therapy was measured from the date of iptacopan initiation (index) until discontinuation or data cutoff, whichever occurred first. Treatment adherence was measured using the medication possession ratio (MPR; ratio of the total days' supply to days covered) and the proportion of days covered (PDC; ratio of days with supply to days covered). Clinical outcomes were assessed during follow-up including hemoglobin (Hb; change from pre-index to highest level post index, proportion of patients with Hb increase ≥2 g/dL, and proportion of patients with Hb normalization to ≥12 g/dL), lactate dehydrogenase (LDH) (change from pre-index to lowest level post index and proportion of patients with LDH reduction <1.5× upper limit of normal [ULN]), and number of red blood cell (RBC) transfusions. Results: Among 52 patients enrolled as of June 13, 2025, the median age was 53.7 years, 38% were male, and 60% were covered by commercial insurance. Overall, 25% of patients (n=13) were complement inhibitor (CI) naive at the time of iptacopan initiation, while 75% (n=39) were treatment experienced and had received ≥1 prior CI therapy for PNH (77% ravulizumab, 46% eculizumab, 26% pegcetacoplan). All patients received iptacopan 200 mg twice daily, per the product label; the median (IQR) duration of iptacopan therapy was 9.8 (5.0-12.8) months. At the time of data cutoff, 2 patients discontinued therapy (1 due to provider decision, 1 due to death). The median (IQR) MPR and PDC were 105.2% (100.6%-110.7%) and 97.3% (92.7%-99.5%), respectively. Among the 52 patients enrolled in APPRISE-PNH, 42 patients had medical records available at the time of data cutoff. Of the 23 of 42 patients (55%) with Hb values available pre- and post index at the time of data cutoff, 4 were CI treatment naive (median [IQR] pre-index Hb, 9.9 [9.1-10.2] g/dL) and 19 were CI treatment experienced (median [IQR] pre-index Hg, 10.7 [8.9-12.2] g/dL). The median (IQR) change from pre-index to highest value post-index was similar for both groups (1.6 [0.8-2.3] g/dL and 1.6 [0.6-3.4] g/dL, respectively). However, among the CI treatment–experienced patients, those with pre-index Hb <12 g/dL (n=11) experienced a greater improvement than those with pre-index Hb ≥12 g/dL (n=8), with median (IQR) of 3.3 (2.2-4.5) g/dL vs 0.4 (0.1-1.3) g/dL, respectively. Overall, 12 of 23 patients (52%) achieved a Hb increase ≥2 g/dL, and 17 of 23 (74%) achieved Hb normalization to ≥12 g/dL. Among the 18 of 42 patients (43%) with LDH values available pre- and post index, the median (IQR) change from pre-index to lowest post-index value was −41.5 (−155.8 to 2.5) U/L. Among those with clinical data, most patients (38 of 42; 90%) did not require RBC transfusions during follow-up and 4 had evidence of an RBC transfusion over the follow-up period; 2 of 4 patients requiring transfusions had aplastic anemia and/or myelodysplastic syndrome. At the time of data cutoff, no patients with clinical data available had evidence of a major adverse vascular event (including thrombosis, transient ischemic attack, stroke, and major bleeding) over the follow-up period. Conclusions: These data represent early insights into the real-world use of iptacopan and related Hb response in US patients with PNH. Adherence to iptacopan was high, and iptacopan treatment improved Hb and LDH parameters, providing comprehensive hemolysis control. Enrollment is currently ongoing; data on additional patients with longer follow-up are forthcoming.

Abstract Introduction: Iptacopan, the first oral complement inhibitor, offers an attractive alternative to parenteral complement blockers in paroxysmal nocturnal hemoglobinuria (PNH). While clinical trials have confirmed its efficacy vs terminal C5 inhibition, real-world data on breakthrough hemolysis (BTH), complement-activating conditions (CACs), and switching patients with satisfactory response to prior therapy (hemoglobin [Hgb] ≥10 g/dL) are limited. We studied a large multi-institutional PNH cohort treated with iptacopan. Methods: We performed a retrospective analysis of 62 patients with PNH who received iptacopan for ≥3 months between FDA approval in December 2023 and April 2025 (mean exposure, 1.01 years; 62 patient-years). Patients from the Cleveland Clinic network and Mayo Clinic were analyzed. Demographics, prior therapies, reasons for transition, Hgb, lactate dehydrogenase (LDH), platelet counts, thrombotic events, CACs, BTH, and adverse events were extracted. Efficacy was assessed separately for treatment-naive patients and treatment-experienced patients (sub-optimal responders [Hgb <10 g/dL] and optimal responders to prior therapy). Results: Overall, 12 of 62 patients were treatment naive and 50 switched from prior therapy (of whom 21 had sub-optimal responses and 29 had optimal responses). In the 50 patients who switched, 60% transitioned from ravulizumab, 30% from pegcetacoplan, 8% from eculizumab, and 2% from ravulizumab and danicopan. The primary reasons for switching were the convenience of oral medications (n=17), extravascular hemolysis or BTH (n=10), prior medication side effects (n=5), desire to further improve Hgb (n=6), and not documented (n=12). A total of 4 patients discontinued iptacopan (2 pregnancies, 1 insurance reversal, 1 intolerable gastrointestinal toxicity). Three patients reported headaches, and 1 reported abdominal pain; all resolved within 1 week from treatment start. Across the 62 patient-years, no thrombotic events occurred, 18 CAC episodes were managed with iptacopan 200 mg BID (10 infections, 1 heart-failure exacerbation, 2 minor surgeries, 1 traumatic brain injury, 2 pancreatitis, 2 pregnancies), and none triggered BTH. Overall, 3 clinically significant BTH events (in 3 patients; 4.8% annualized) were recorded: 2 infection-related (managed outpatient) and 1 alcoholic pancreatitis; all resolved with a 1- to 2-day increase to iptacopan 400 mg BID ± single-dose eculizumab. Two hemolytic events secondary to non-adherence were reported (4 days after stopping iptacopan). These resolved after resuming iptacopan 200 mg BID without need for hospitalization. In treatment-naive patients, mean Hgb increased significantly by 1.87 g/dL from iptacopan initiation (baseline) to 3 months (9.9±1.9 to 11.8±1.3 g/dL; P=.005), sustained until last follow-up at 12 months. LDH decreased by 369 U/L at 3 months (P=.058), sustained through 12 months. No significant change was seen in platelets, absolute neutrophil count (ANC), or white blood cell (WBC) count. In treatment-experienced sub-optimal responders, mean Hgb increased significantly by 2.16 g/dL from baseline to 3 months (8.6±.89 to 10.8±2.1; P<0.001). At 12 months, 85% of patients had increased Hgb compared with baseline (median increase: 3.31±1.62 g/dL). LDH decreased significantly from baseline to 3 months by 229 U/L (P=.03), with no significant changes noted in LDH from 3 to 12 months or in platelets, ANC, or WBC counts. In previously treated complement inhibitor responders, mean Hgb increased significantly by 0.75 g/dL from baseline to 3 months (12.0±1.3 to 12.8±1.7 g/dL; P=.004), with 79% showing improvements from baseline at 12-month follow-up (median increase: 1.16±0.82 g/dL). LDH decreased significantly by 45 U/L from baseline to 3 months (P=.03), with no further significant changes from 3 to 12 months. Conclusions: In this real-world cohort, iptacopan provided substantial and durable hemoglobin improvement across naive and previously treated patients with PNH, with meaningful reduction in hemolytic parameters, absence of thrombosis, and low BTH rate predominantly linked to infection. Patients with previous satisfactory responses also showed improved Hgb levels. The favorable safety profile and high treatment persistence underscore iptacopan's role as an effective first-line or switch therapy and support its incorporation into evidence-based sequencing algorithms in the evolving PNH treatment landscape.