Citations

Abstract Background Secondary central nervous system lymphoma (SCNSL) is a rare but significant complication, affecting approximately 2–10% of patients with diffuse large B-cell lymphoma (DLBCL), often leading to poor outcomes. The CNS-International Prognostic Index (CNS-IPI) remains a widely adopted tool for estimating CNS relapse risk; however, recent advances in molecular profiling and evolving treatment paradigms have challenged the adequacy of CNS-IPI alone in guiding risk assessment. This study evaluates the prognostic relevance of CNS-IPI in conjunction with molecular and clinical factors, specifically cell-of-origin (COO), gene expression, and frontline treatment regimens. The aim is to refine risk stratification and identify patients at highest risk for SCNSL. Method Building on our previous study, we analyzed data from patients with newly diagnosed DLBCL between 2002 and 2023, enrolled in the Mayo Clinic/University of Iowa Lymphoma Molecular Epidemiology Resource. Patients with primary CNS lymphoma, CNS involvement at diagnosis, or who received CNS-directed therapy were excluded. COO was determined using the Hans algorithm and/or Nanostring profiling. Multivariate cause-specific Cox regression models were used to estimate hazard ratios (HR) and 95% confidence intervals (CIs) for predictors of CNS relapse that were measured at the time of initial DLBCL diagnosis. Cumulative incidence with competing risks and cause-specific Cox models were used to analyze relapse risk. Result We included 2137 patients in our analysis, median age at diagnosis was 63 (IQR 53-72), with 41.6% (n=890) females. The albumin level was below normal in 32.5% (n=350), 64.0% (n=1367) had CNS-IPI of intermediate/high, 37.5% (n=586) had non-germinal center B-cell (GCB) COO, and 14.5% (n=309) were double expressor positive. At a median follow-up of 83 months (IQR 42 -143), 82 (3.8%) SCNSL relapses were observed; the 3 and 5 yrs cumulative incidence for SCNSL from time of DLBCL diagnosis were 3.7% (95% CI 3.0-4.7) and 3.8% (95% CI 3.1-4.8) respectively. In models accounting for death as a competing risk, the 5-year cumulative SCNSL incidence estimate for patients with a CNS-IPI low was 1.5% (95% CI 0.8-2.7), Intermediate was 4.9% (95% CI 3.7-6.4), and high was 6.1% (95% CI 3.8-9.6). The 5-year cumulative SCNSL incidence estimate for patients with non-GCB COO was 5.2% (95% CI 3.6-7.4) compared to 2.4% (95% CI 1.6-3.6; p=0.001) for GCB patients, and the 5-year cumulative SCNSL incidence for double expressor positive patients was 8.6% (95% 5.8-12.6) compared to 1.5% (95% CI 0.8-2.7; p<0.001) for double expressor negative patients. In a multivariable model (including CNS-IPI, COO, double expressor, treatment group, extranodal involvement, and albumin group), CNS-IPI intermediate (HR 2.85 [1.58-5.14]; p<0.001) and high (HR 4.31 [2.15-8.65]; p<0.001), non-GCB COO (HR 2.36 [1.37-4.06]; p=0.002], double expressor (HR 5.56 [2.88-10.73]; p<0.001), and below normal albumin (HR 1.89 [1.02-3.50]; p=0.042) were independently associated with increased risk of SCNSL. The majority of the SCNSL relapse occurred within the first 2 years after DLBCL diagnosis; 81.7% (n=67), with only 6.1% (n=5) occurring after 5 years. For patients who developed SCNSL, the median OS from the time of SCNSL diagnosis was 24 months (95% CI 17-34), with 5 years OS of 31% (95% CI 22-43). These findings are being validated using an external, international cohort, and final analysis will be presented at the time of presentation at ASH. Conclusion In this large, prospectively followed cohort with long-term follow-up data, SCNSL remains a rare but devastating complication of DLBCL, with a 5-year cumulative incidence of 3.8% and it is associated with very poor long-term survival. While CNS-IPI remains a strong predictor of SCNSL risk, our study identifies non-GCB COO and double expressor phenotype as independent, additive molecular risk factors. These findings suggest that current risk stratification tools may underestimate the risk of CNS relapse in molecularly defined high-risk subgroups. Considering the poor outcomes linked to SCNSL and the absence of a connection with frontline treatment types, future research should aim to enhance risk prediction models through molecular profiling and explore prophylactic strategies to reduce the likelihood of SCNSL.

Abstract Introduction Nearly 60% of pts with diffuse large B-cell lymphoma (DLBCL) are cured with first-line chemoimmunotherapy; ~40% will relapse or have refractory disease, mostly pts with high International Prognostic Index (IPI) scores of 3–5. Pts with IPI scores of 1–2 with bulky disease and/or very high LDH levels have also been identified as a high risk (HR) population (Maurer et al, ASH 2023, #4512). GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment (Tx) of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin [COO]) and immunomodulatory activity. CC-220-DLBCL-001 (NCT04884035) is an ongoing Phase 1b, open-label, multicenter trial to assess safety and preliminary efficacy of GOLCA+R-CHOP in previously untreated a-BCL. GOLCA+R-CHOP demonstrated a manageable safety profile and encouraging efficacy with high end of Tx (EOT) complete metabolic response (CMR) and minimal residual disease (MRD) negativity rates (Amzallag et al, ASH 2024, #579). We report efficacy results with median follow-up (f/u) of 24 mos, including 24-mo progression-free survival (PFS) rates. Methods Pts aged ≥18 years with ECOG PS ≤2, IPI 0–5 (Part 1) and IPI 2–5 (Part 2), and previously untreated a-BCL with measurable disease were included. Pts were treated with GOLCA+R-CHOP for 6 cycles of 21 days (D) or until disease progression/unacceptable toxicity/study withdrawal. In dose escalation, GOLCA dose levels were 0.2mg D1–7, 0.4mg D1–7 (recommended Ph 2 dose), or 0.4mg D1–10. In dose expansion, pts were randomized 1:1 to R-CHOP+GOLCA 0.2 or 0.4mg. Primary endpoint was safety of GOLCA at 0.4mg (cutoff 23 Sep 2024); efficacy (cutoff 12 May 2025) was a secondary endpoint. HR pts were defined as: IPI 1-2 with HR features (≥1 lesion with maximum diameter ≥7 cm and/or screening LDH >1.3×ULN) or IPI 3–5. Results At cutoff, 78 pts were treated with GOLCA+R-CHOP (n=35 at 0.2mg D1–7, n=37 at 0.4mg D1–7, n=6 at 0.4mg D1–10). Baseline characteristics were described previously. Sixty-five pts (83%) completed Tx, and 72 (92%) entered the f/u period (61 [78%] ongoing). Tx was discontinued in 17% of pts, primarily due to progressive disease (3%) and adverse events (AEs; 6%). Median relative dose intensity for GOLCA and CHO components was high (97%–99%), indicating uncompromised delivery of curative standard-of-care (SOC) Tx. Seventy-two pts were efficacy evaluable (n=34 at 0.2mg D1–7, n=33 at 0.4mg D1–7). At 0.4mg, EOT CMR rate was 88% (29/33); all 29 pts were alive and progression free at cutoff. In HR pts at 0.4mg, EOT CMR rate was 89% (25/28) and was similar in pts with GCB (16/17 [94%]) and non-GCB/ABC (9/11 [82%]) phenotypes. Of pts treated with 0.4mg with available ctDNA data, 90% achieved MRD negativity (undetectable ctDNA by PhasED-Seq assay) at EOT. All pts still in f/u at time of data cutoff had reached the 24-mo efficacy assessment. At median f/u of 24 mos (range, 0.7–34.4), the 24-mo PFS rate was 79% in both 0.4mg and HR 0.4mg pts and consistent in pts with GCB (88%) and non-GCB/ABC (73%) phenotypes. The 24-mo OS at 0.4mg was 85.3% overall and 86.2% in HR pts. Pts treated at 0.4mg D1–7 and D1–10 had comparable exposure to GOLCA (no pt completed the 10-day schedule). In pooled D1–7 and D1–10 schedules, 24-mo PFS was 82% in overall and HR populations. Grade 3/4 Tx-emergent AEs (TEAEs) in the safety population were mainly hematologic and occurred in 91% of pts (neutropenia [87%], an on-target side effect of GOLCA; thrombocytopenia [42%]; anemia [36%]; febrile neutropenia [22%]); neutrophil nadir and recovery occurred in a predictable fashion. Serious TEAEs occurred in 36 pts (46%). Non-hematologic AEs (fatigue, rash, GI disorders) were infrequent and mostly low grade. Conclusions GOLCA (0.4mg) +R-CHOP resulted in a high rate of durable CMRs, irrespective of COO, and promising 24-mo PFS in the overall and HR populations. GOLCA+R-CHOP demonstrated a predictable and manageable safety profile with low rates of non-hematologic AEs; addition of GOLCA to R-CHOP did not compromise SOC delivery. These data continue to show that GOLCA 0.4mg, when added to SOC Tx, has a potential to cure more previously untreated pts with HR LBCL and support the ongoing Phase 3 trial, GOLSEEK-1, in this population (NCT06356129).

Abstract Introduction Approximately 40% of patients with DLBCL will experience relapse after initial treatment with standard-of-care chemo-immunotherapy. Effective treatment options are limited for patients who experience first-line treatment failure, particularly for those with R/R disease following CAR T-cell therapy or those not able to receive CAR T-cell therapy (Sehn et al, N Engl J Med. 2021). GOLCA is a potential, first-in-class, oral CELMoD agent designed for the treatment of lymphoma, with preferential distribution to lymphoid organs and enhanced activity in lymphoma cell lines. GOLCA drives the closed, active conformation of cereblon to induce rapid and deep degradation of Ikaros and Aiolos, leading to direct cell killing (agnostic of cell of origin) and immunomodulatory activity. In the two-part, multicenter, first-in-human Phase 1/2 study (CC-99282-NHL-001; NCT03930953), GOLCA was well tolerated and effective in patients with R/R DLBCL (Bachy et al, ICML 2025, #148). Here, we provide longer follow-up in patients with R/R DLBCL from Part B of the study. Methods Patients with R/R DLBCL and disease progression after ≥ 2 lines of therapy or transplant-ineligible patients after ≥ 1 line of therapy were included in the study. Patients received GOLCA monotherapy orally, once daily at different dosing schedules in Part A. In Part B, GOLCA was dosed at 0.2 or 0.4 mg (14 days on/14 days off) ± R. Total GOLCA treatment duration was up to 2 years or until progressive disease (PD)/unacceptable toxicity. Primary objectives included safety and recommended Phase 2 dose determination. Results As of April 3, 2025, a total of 77 patients with R/R DLBCL were enrolled in Part B Cohort C (GOLCA 0.2 mg + R, n = 39; GOLCA 0.4 mg + R, n = 38). Median age was 66 years (range, 20–86). Patients were heavily pre-treated; median number of prior treatments was 4 (range, 1–11), 55% of pts had prior CAR T-cell therapy, 38% had prior bispecific antibody treatment, and 44% were refractory to last treatment. Ten patients (13%) were ongoing, 4 completed 2 y of treatment, and 63 (82%) had discontinued treatment, mostly due to PD (n = 48 [62%]). The most common any-grade (G) treatment-emergent adverse events (AEs) in the 0.2- and 0.4-mg cohorts, respectively, were neutropenia (54% and 84%), an on-target side effect of GOLCA, and anemia (44% and 45%). G3/4 neutropenia was reported in 49% of patients with 0.2 mg and 79% with 0.4 mg, and febrile neutropenia (FN) in 5% and 16%, respectively. Granulocyte colony-stimulating factor was used in 81% and 88% of patients with neutropenia and 50% and 100% of patients with FN in the 0.2-mg and 0.4-mg cohorts. Dose interruptions (mainly due to infections/neutropenia) occurred in 49% and 53% of patients and discontinuations due to AEs occurred in 10% and 3% with 0.2 and 0.4 mg. One G5 pneumonia was considered related to study treatment (0.2 mg). The median follow-up was 11.8 months (range, 3.1–35.1) with 0.2 mg and 16.2 months (range, 3.8–31.4) with 0.4 mg. The overall response rate (ORR) in efficacy evaluable patients was 34% (complete response rate [CRR], 20%) with 0.2 mg (n = 35) and 58% with 0.4 mg (n = 36), including a CRR of 44% with this dose. In patients with prior T-cell–redirecting treatment, the ORR was 33% (CRR, 22%) with 0.2 mg (n = 18) and 56% (CRR, 38%) with 0.4 mg (n = 16). Seven of 35 (0.2 mg) and 14 of 36 (0.4 mg) patients experienced durable response > 12 months. The median time to response with both 0.2 and 0.4 mg was 1.8 months. In patients with durable responses (remained in response [CR or partial response] for more than two consecutive efficacy assessments) to GOLCA, circulating tumor DNA reduction from baseline continues to deepen over time. Response was similar across clones/tumor variants. Conclusions With additional follow-up, GOLCA + R continued to demonstrate a predictable and manageable safety profile, with no new safety signals observed at longer follow-up. Durable responses were shown in heavily pretreated patients with R/R DLBCL, including those with prior T-cell–redirecting therapy. GOLCA + R induced a decrease in circulating tumor DNA across tumor variants. These data support the ongoing development of GOLCA + R in patients with R/R non-Hodgkin lymphoma.

Abstract Introduction Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) for which the only approved therapies are JAK inhibitors which improve splenomegaly and disease-related symptoms. Inflammatory pathways beyond JAK-STAT are critical in the pathobiology of MF and contribute to patients' clinical manifestations. IL-1β is a master regulator of inflammation which is overexpressed in MPNs, preferentially supports the MPN mutant stem cell, and interacts with key cytokines that are implicated in fibrogenesis, inflammatory symptoms, and disease progression. Knockout of IL-1β in MPN mouse models led to an abrogated clinical phenotype, while pharmacologic inhibition of IL-1β resulted in reduction of reticulin fibrosis and osteosclerosis. Canakinumab is a fully human monoclonal antibody that binds to and neutralizes IL-1β. It is approved for rare inflammatory disorders with a safety profile that has been extensively studied in the CANTOS trial that assessed cardiovascular outcomes in high-risk patients (pts). Based upon these data, we designed a phase 2 study of canakinumab in pts with MF. Methods NCT05467800 is a Myeloproliferative Neoplasm Research Consortium (MPN-RC) ongoing open-label, 2-part, phase 2 study of canakinumab in pts with MF. Part 1 enrolled pts with MF previously treated with or ineligible to receive a JAK inhibitor. Canakinumab was given subcutaneously at a dose of 200mg on day 1 of 21-day cycles. Primary response assessment occurred at week 24 following cycle 8. Responding pts could continue to receive canakinumab. Eligible pts had platelets >25 x109/L and a need for MF-directed therapy defined as ≥ 1 of the following: hemoglobin <10 g/dL, transfusion dependency, splenomegaly palpated ≥ 5cm below left costal margin, and/or MPN-SAF version 4.0 TSS ≥ 10. The primary endpoint was overall response rate (ORR) including CR, PR, or CI after 8 cycles (24 weeks). A Bayesian optimal phase 2 (BOP2) design was used with an interim analysis performed after 10 pts. Results In part 1, 14 pts were enrolled and 13 were treated. One pt discontinued prior to starting treatment due to rapidly progressive disease. Enrollment onto part 1 has closed with 2 pts remaining on treatment. Median age was 70 y (range: 55-83). Eleven (84.6%) pts had received prior ruxolitinib. Median hemoglobin was 8.2 g/dL (range: 5.7-13.2), median platelet count was 114 x 109/L (range: 21-484), and median WBC was 9.7 x 109/L (range: 2.4-71.4). Five (38.5%) pts were transfusion dependent. Median MF-SAF TSS at baseline was 15 (range: 4-46). Median spleen volume at baseline was 1522 cm3 (range: 362cm3-2997cm3). Pts received a median of 9 cycles (range: 2-19). Three (23%) pts responded at week 24, achieving a CI-symptom response (TSS50). Six (46%) pts experienced progression of disease due to spleen volume increase. Median hemoglobin was 8.2 g/dL at baseline, 7.9 g/dL at week 12, and 9.0 g/dL at week 24. Median platelet count was 114 x 109/L at baseline, 98 x 109/L at week 12, and 183 x 109/L at week 24. Median MF-SAF TSS declined from 15 at baseline to 10 at week 12 and 9 at week 24. Eleven (85%) pts exhibited symptom improvement during treatment (MF-SAF TSS percent change from baseline range -20% to -85%). In pts with baseline hsCRP ≥ 1.0 (n = 8), canakinumab led to a reduction at week 24 (or EOT if prior to week 24) in 5/8 (62.5%) with a median decrease in CRP of 37%. The most common adverse events (AEs) were anemia and thrombocytopenia and often attributed to underlying disease. Non-hematologic grade ≥ 3 AEs occurred in 3 pts and were deemed unrelated to canakinumab, except for one grade 3 increase in bilirubin that was possibly related per the treating physician. Conclusion The IL-1β inhibitor, canakinumab, resulted in consistent symptom improvement and exhibited beneficial impact on cytopenias in pts with R/R MF while demonstrating a manageable toxicity profile. Consistent with pre-clinical data, inhibition of IL-1β had little impact on splenomegaly, an observation that was likely enhanced by frequent JAK inhibitor discontinuation prior to study start. Given the encouraging impact on MF symptoms, blood counts and reassuring safety profile, the study was amended to enroll pts on a stable dose of a JAK inhibitor (ruxolitinib, fedratinib, momelotinib, or pacritinib) who have the potential to benefit from additional therapy. Part 2 is currently enrolling at multiple sites and updated clinical and correlative data will be presented at the meeting.

Abstract Background Patients (pts) with plasma cell leukemia (PCL) were excluded from key trials, so we assessed their outcomes with standard of care bispecific antibodies (BsAbs). Methods Our multicenter retrospective US Myeloma consortium study included PCL pts treated with BsAbs. PCL was defined as ≥5% circulating plasma cells, including primary PCL, secondary PCL, historical PCL, and active PCL within 30 days of BsAb initiation. Endpoints were toxicity rates, overall response (ORR), progression-free survival (PFS), and overall survival (OS). Results Our study involved 122 PCL pts from 15 US centers with: 27% primary PCL, 65% secondary PCL, 51% active PCL, 53% women, median age of 65 years (range 31-83), 77% white, 15% black, 60% high-risk cytogenetics, 45% high bone marrow burden (≥50% plasma cells), 5% CNS myelomatosis, and 20% EMD. Median prior lines of therapy (tx) were 6 (IQR 5-9), 94% triple-refractory, 57% penta-refractory, 73% prior transplant, and 57% prior BCMA tx (70% in talquetamab group, 41% in BCMA BsAb group). Treatments included 4 cohorts: 37% teclistamab, 11% elranatamab, 42% talquetamab definitive tx, and 11% talquetamab bridge to CAR-T. BsAb was used either as monotherapy (94%) or in combination (6%) with other agents. CRS grade (G) 1 was 41%, G2 14.8%, G3 2.5%, and G4 1.6%, while ICANS G1 was 8.2%, G2 7.4%, G3 3.3%, and G4 1.6%. Infections occurred in 34% and median hospitalization was 10 days (IQR 8-15). Of 110 evaluable pts, ORR was 54.5%, with 24.5% CR, 13.6% VGPR, and 16.4% PR. The ORR was 60.8% for talquetamab definitive tx (21.6% CR, 23.5% VGPR, 15.7% PR), 46.2% for elranatamab (38.5% CR, 7.7% PR), and 33.3% for teclistamab (20% CR, 4.4% VGPR, 8.9% PR). Talquetamab bridge to CAR-T in 12 evaluable pts had a pre-CAR-T day 30 ORR of 58.3% (16.7% CR, 8.3% VGPR, 33.3% PR). With a median follow-up of 8.3 months (mo), the median (m) PFS was 3.2 mo, and mOS was 9.2 mo, with similar outcomes between primary vs. secondary PCL (p=0.37 for PFS, p=0.18 for OS). Talquetamab definitive tx had better outcomes with a mPFS of 5.5 mo, mOS of 11.5 mo, 10-mo PFS of 31.2%, and 10-mo OS of 55.7%, and further improved when used as a bridge to CAR-T, with unreached mPFS, unreached mOS, 10-mo PFS of 53.8%, and 10-mo OS of 62.7%. BCMA BsAbs had inferior outcomes, with teclistamab yielding a mPFS of 1.2 mo, mOS of 8.1 mo, 10-mo PFS of 15.3%, and 10-mo OS of 44.3%, while elranatamab showed a mPFS of 1.6 mo and mOS of 3.6 mo (p=0.007 for PFS, p=0.023 for OS). In BCMA naive pts, BCMA BsAbs' outcomes remained inferior to talquetamab with a mPFS of 1.2 mo and mOS of 3.4 mo (p=0.003, 0.001). Sixty pts with active PCL had a poor mPFS (1.6 vs. 4.4 mo, p=0.036) and mOS (5.3 vs. 10.7 mo, p=0.004) compared to pts with only historical PCL. However, in active PCL, talquetamab definitive tx (n=29) showed superior outcomes with a mPFS of 6.9 mo and mOS of 12.2 mo (p=0.003, 0.012). Talquetamab bridge to CAR-T (n=3) showed a mPFS of 3.2 mo and mOS of 5.2 mo. BCMA BsAbs had inferior outcomes: teclistamab with a mPFS of 0.7 mo and mOS of 1.4 mo, while elranatamab showed a mPFS of 1.0 mo and mOS of 3.1 mo (p=0.003, 0.012). In BCMA naive pts, BCMA BsAbs' efficacy remained poor with a mPFS of 0.7 mo and mOS of 1.4 mo (p=0.006, 0.002). While in pts with only historical PCL (without active PCL), BCMA BsAbs in BCMA naive pts led to similar outcomes with a mPFS of 5.2 mo and mOS of 8.5 mo, compared to a mPFS of 3.7 mo and mOS of 10.4 mo with talquetamab (p=0.90, 0.86). Multivariable analysis (MVA) associated active PCL with worse PFS (p=0.035, HR=1.93, CI 1.05-3.55) and OS (p=0.017, HR=2.3, CI 1.16-4.60), talquetamab with improved PFS (p=0.009, HR=0.41, CI 0.21-0.81) and OS (p=0.012, HR=0.40, CI 0.19-0.82), and talquetamab bridge to CAR-T with improved PFS (p=0.042, HR 0.28, CI 0.08-0.95) without reaching statistical significance for OS (p=0.11, HR 0.29, HR 0.07-1.3). MVA results remained similar when the talquetamab bridge to CAR-T cohort was excluded. Conclusions Despite PCL's poor prognosis, talquetamab was superior to BCMA BsAbs in active PCL, with a mPFS of 6.9 mo and mOS of 12.2 mo, aligning with the broader cohort. BCMA BsAbs had poor efficacy in active PCL, even in BCMA naive pts, with a mPFS of 0.7 mo and mOS of 1.4 mo. In historical PCL without active PCL, BCMA BsAbs in BCMA-naive pts showed comparable outcomes to talquetamab. In the overall cohort, talquetamab bridge to CAR-T improved PFS without reaching significance for OS benefit in MVA.

Abstract Background: Talquetamab (Talq), a GPRC5D-targeting bispecific antibody, shows promising activity in relapsed/refractory multiple myeloma (RRMM). However, outcomes in patients (pts) with soft tissue plasmacytoma (STP) remain poorly characterized. Method: We retrospectively analyzed 463 RRMM pts treated with Talq at 15 U.S. centers by Dec 2024. Pts were grouped by presence of STP at Talq start: (1) extramedullary disease (EMD; lesions not contiguous with bone), (2) paraskeletal disease (PSK; bone-contiguous), (3) EMD + PSK, and (4) No-STP. Those receiving Talq as a bridge-to-CAR T (n=103, 22%) were censored at CAR T infusion if progression had not occurred. Time-to-event endpoints were calculated from Talq step-up, using Kaplan-Meier/Cox models. Result: Median age was 66 years (y) (35–89); 54 (11.7%) had EMD, 26 (5.6%) PSK, 60 (13%) EMD+PSK, and 320 (69%) No-STP. EMD pts were younger than No-STP (62 vs 66 y, p=.009), while PSK (66.5) and EMD+PSK (64.5) were similar to No-STP. Median prior lines were higher in PSK (7) vs EMD (5), EMD+PSK (6) and No-STP (6) (p=.035). Median time from diagnosis to Talq was shortest in EMD (3.8 y), followed by EMD+PSK (4.6 y), vs PSK (6.4 y), and No-STP (5.9 y) (p=.015). Among pts with any EMD (EMD or EMD+PSK), 81 (69%) had visceral involvement and 85 (73%) had multiple lesions. Rates of prior BCMA- or GPRC5D-directed therapy, plasma cell leukemia (≥5% circulating plasma cells at the time of Talq), and penta-refractoriness were similar across groups. ECOG ≥ 2 at Talq was more common in EMD (42%), PSK (39%), EMD+ PSK (37%) than in No-STP (23%) (p = .002). Other baseline features were similar. Cytokine release syndrome (CRS) rate/severity were similar across groups. The immune effector cell–associated neurotoxicity syndrome (ICANS) was more frequent in PSK (38%) vs EMD (11%), EMD + PSK (18%), and No-STP (11%), with the most PSK cases (60%, 6/10) being grade ≥2 (p=.006). No difference in CRS/ICANS onset or duration. Infection rates were lower in No-STP (36%) vs EMD (55%), PSK (46%), and EMD+ PSK (48%) (p=.025). Best overall response rates (ORR) were 71% in EMD, 68% in PSK, 67% in EMD+PSK, and 71% in No-STP (p=.9). Complete response (CR) rates were 14% in EMD, 20% in PSK, 13% in EMD+ PSK, and 25% in No-STP (p=.1) [CRs were not required to be confirmatory, which may not meet full IMWG criteria]. Radiographic response was evaluable in 41 EMD (86%), 16 PSK (61.5%), and 48 EMD+PSK (80%) pts, with partial response (PR) or better observed in 48%, 27%, and 38%, respectively. Among pts with any STP, 34% received radiation (XRT) (4 as bridge-to-CAR T), 24 (51%) were evaluable, and 71% (n=17) achieved ≥PR. The median follow-up from Talq initiation was 10.1 months (mo) (95% CI: 8.8–11.4) and was longest in EMD (13.9 mo) compared with PSK (10.8 mo), EMD+PSK (12.4 mo), and No-STP (9.8 mo) (p = .040). Median progression-free survival (PFS) was 4.3 mo (95% CI: 3.6–5.06) in EMD, 4.8 mo (95% CI: 2.2–7.3) in PSK, 3.8 mo (95% CI: 3.1-4.5) in EMD+ PSK, and 8.3 mo (95% CI: 7.0–9.6) in No-STP (p <.001). Among pts receiving XRT for any STP (within 4 weeks prior to or during Talq), responders had longer PFS vs non-responders (15.4 vs. 2.4 mo; p=.009). Multivariable analysis (MVA) showed inferior PFS with EMD (Hazard Ratio (HR) 1.58; 95% CI, 1.04-2.3; p=.029), EMD+PSK (HR 1.91; 95% CI, 1.2–2.8; p = .001), ECOG ≥ 2 (HR 1.4; 95% CI, 1.04–1.9; p = .024), and del(17p) at any timepoint (HR 1.99; 95% CI, 1.1–3.5; p=.017), while longer time from diagnosis to Talq was modestly protective (HR 0.95 per year; p = .016), likely reflecting less aggressive biology in those reaching 5th+ line later. PSK alone showed a non-significant trend toward inferior PFS (HR 1.5; p = .1). Median overall survival (OS) was 13.0 mo (95% CI: not reached [NR]–NR) in EMD, 12.9 mo (95% CI: 6.9–18.9) in PSK, 10.9 mo (95% CI: NR–NR) in EMD+PSK, and NR (95% CI: NR–NR) in No-STP (p = .017). The primary cause of death was disease-related across all groups (p = .6). MVA for OS showed worse outcomes with EMD+PSK (HR 1.7; p=.033), ECOG ≥ 2 (HR 1.98; p <.001), and active PCL at Talq (HR 2.1; p =.010). Conclusion: Soft tissue plasmacytoma, particularly EMD and EMD+PSK, remain strong adverse prognostic factors in Talq-treated patients, with significantly shorter PFS and OS despite similar response rates. Radiation to STP sites was associated with improved outcomes in select cases. Prospective strategies are needed to optimize management for this high-risk population.

Abstract Background Patients (pts) with multiple myeloma and CNS involvement (CNS MM) have poor outcomes, and we recently showed that CAR-T has activity and is reasonable in this population (Gaballa et al., 2025). We sought to evaluate the safety and efficacy of Bispecific T-cell engagers (BsAbs) in CNS MM pts, with specific interest in evaluating ICANS. Methods We conducted a retrospective study of CNS MM pts treated with BsAbs via the MM immunotherapy consortium. Primary endpoints were toxicity rates, with a specific focus on ICANS. Secondary endpoints were systemic responses, CNS responses, and survival outcomes. CNS MM was defined as involvement of the brain parenchyma, spinal cord tissue, leptomeningeal disease, or CSF positivity. CNS response was determined based on CSF and imaging, as complete CNS response, partial CNS response, and non-response/progression. Results The study included 24 pts from 13 US institutions treated with teclistamab (33%), talquetamab (50%), elranatamab (17%), and were used as monotherapy in 83% while 17% received them in combination with either daratumumab or IMiDs. The median age was 64.5 (range 41-82), 50% female, 79% white, and 17% black. High-risk cytogenetics were identified in 39%, 4% had prior primary PCL, and 21% had secondary PCL (2 active within 30 days of BsAb initiation). All pts were triple-refractory, 33% were penta-refractory, and 39% had non-CNS EMD. Pts received a median of 5 prior lines of therapy (IQR 4-7), 71% prior transplant, and 21% prior CAR-T. Prior BCMA therapy was received in 83% of the talquetamab group and 17% of the BCMA BsAbs group (teclistamab and elranatamab). CNS disease was determined based on both imaging and CSF findings in 58%, imaging only in 33%, and CSF only in 8%. Site of CNS disease included 42% brain/cranial nerves, 13% spinal cord, or 46% with both. CNS disease was diagnosed prior to BsAb in 19 pts, with a median interval of 46 days (IQR 7-234), and 3 pts were identified within 2 weeks after BsAb initiation. Two pts identified at days 68 and 121 were included in the safety evaluation but excluded from the efficacy assessments. One pt received teclistamab and intrathecal chemotherapy (IT chemo) as a bridge to CAR-T and achieved a complete CNS response before CAR-T. CNS-directed therapy consisted of: 30% radiotherapy (RT), 30% IT chemo, 13% RT + IT chemo, 9% RT + surgery, and 4% steroids. CRS grade (G) 1-2 occurred in 50%, with no G3-4 CRS. ICANS G 1, 2, and 3 occurred in 13%, 21%, and 4%, respectively, with no G 4 ICANS. One pt developed delayed parkinsonism, and another developed leukoencephalopathy; both had CNS MM diagnosed pre-BsAbs and achieved a CNS response (1 complete, 1 partial). Infections occurred in 67% of pts, with 42% being severe, and 1 infection-related death. The systemic ORR of 18 evaluable pts was 67%, including 22% CR, 17% VGPR, and 28% PR. The overall CNS response of 19 evaluable pts was 58%, including 37% complete CNS response and 21% partial CNS response. Of 11 pts achieving a CNS response, 82% didn't have subsequent CNS progression. In 9 pts achieving CNS response after BsAb initiation, the median time to CNS response was 0.9 months (range 0.03-2.8), with an unreached median duration of CNS response. With a median follow-up of 11 months, the median PFS was 5.0 months (95% CI 2.5-NA) and OS was 12.2 months (95% CI 7.7-NA). No significant difference in median PFS (10.6 vs 4.6 months, p=0.11) or OS (20.2 vs 9.3 months, p=0.37) was observed between BCMA BsAbs (n=11) and talquetamab (n=11). Due to small sample limitation, no significant difference was observed in the median PFS (4.6 vs 8.2 months, p=0.48) or OS (20.2 vs 9.9 months, p=0.73) between BsAb monotherapy (n=19) and BsAb combination therapy (n=3). One pt who received teclistamab as a bridge to CAR-T achieved a complete CNS response and remains progression-free to date, demonstrating the best long-term outcome with a PFS of 674 days. Conclusions Our study demonstrates that BsAb use in pts with CNS MM is safe without increased incidence of ICANS. The use of BsAbs in combination with a multimodal CNS-directed approach led to an overall CNS response rate of 58% and an unreached median duration of CNS response. Previous studies (Gaballa et al., 2025) reported a 100% CNS response rate with CAR-T. In this study, 1 pt treated with BsAb as a bridge to CAR-T had the longest PFS, warranting further research to evaluate this combination's efficacy in this very high-risk population.

Abstract Background Talquetamab (talq) is a GPRC5D-directed bispecific antibody (BsAb) approved for the treatment of relapsed and refractory multiple myeloma (RRMM). The pivotal monumenTAL-1 clinical trial did not include patients with renal impairment (RI, creatinine clearance<40 mL/min) and therefore, data for the use of this agent in RI is lacking. Methods We examined the outcomes of patients with RRMM treated with standard of care (SOC) talq in a multicenter, retrospective cohort study. RI was defined as creatinine clearance (CrCl) <40 mL/min. For each patient we recorded demographics, disease characteristics, prior therapies, incidence and severity of adverse events of special interest, namely cytokine release syndrome (CRS) and immune-cell associated neurotoxicity syndrome (ICANS), along with response, progression-free (PFS) and overall survival (OS). We compared binary variables between different groups using Chi-squared test and assessed progression free survival (PFS) and overall survival (OS) using Kaplan Meier and Cox proportional hazards models. Patients who received talq as a bridge therapy prior to chimeric antigen receptor T-cells (CART cells) were censored for PFS analysis at the time of subsequent therapy. Results We included 417 patients who received SOC Talq and had complete datasets. 91 (22%) had RI, including 20 (5%) on dialysis. The median age was 68 and 65 years for patients with and without RI. Patients with RI were more likely to be female (64% vs. 51%), less likely to have prior CART cells (35% vs. 48%). There were no differences in performance status, race, presence of high-risk cytogenetic abnormalities [del17p, t(4;14), t(14;16), gain/amplification 1q], lines of prior therapy (median 6 vs. 6), prior ASCT (68% vs. 72%), presence of CNS disease (4% vs. 4%), prior plasma cell leukemia (8% vs 9%), prior BCMA therapy (54% vs. 61%) and triple class refractory disease (90% vs. 94%) among patients with and without RI. Rates of CRS (63% vs. 56%, P=0.21) were similar in the two groups, while severe CRS (grade ≥3: 6% vs 2%, P=0.02) was more common in patients with RI. Any grade (20% vs 14%, P=0.21) and high grade ICANS (grade ≥3: 4% vs 4%, P=0.97) were similar in patients with and without RI. There was no difference between groups on risk of infection (P=0.65) with cumulative risk at 6 months of 39% vs. 40%. With 11.1 months of median follow up, the overall response rate (60% vs 67%; P = 0.12), and progression-free survival (median 7.3 vs. 6.5 mo.; P = 0.9) were comparable between the two groups. There was no difference in outcomes according to RI in both patients previously treated with BCMA-directed therapy and BCMA-naïve. Conversely, among patients with RI, median PFS was 4.6 and 8.5 mo. for patients with and without prior BCMA therapy. Similarly, among patients without RI, median PFS was 6.5 and 6.2 mo, respectively. Among BCMA-naïve patients, there was no difference in OS between patients with and without RI (median not reached, 12 mo. OS rate 71% vs. 73%, P=0.53), while among patients with prior BCMA-directed therapy there was a trend towards better OS for patients without RI (median 8.9 vs. 13.8 mo; 12 mo. OS rate 43% vs 59%, P=0.06). Five patients (25%) became dialysis independent following talq therapy. On multivariable analysis, ECOG >1 (HR 1.62, 95% C.I. 1.25-2.10, P<0.001) and deletion of 17p (HR 1.55, 95% C.I. 1.17-2.06, P=0.003) but not RI or prior BCMA-directed therapy affected PFS. OS was affected by ECOG >1 (HR 2.37, 95% C.I 1.71-3.30, P<0.001), triple-class refractoriness (HR 3.03, 95% C.I. 1.12-8.21, P=0.03) and prior BCMA-directed therapy (HR 1.79, 95% C.I. 1.24-2.59, P=0.002) but not by RI. Conclusion Our findings support the feasibility of talq in patients with RI, including those on dialysis, with similar safety and efficacy profile to patients without RI. While neither prior BCMA-directed therapy nor RI affect PFS, refractoriness to conventional agents and prior exposure to BCMA-directed therapy adversely affects OS. This observation likely reflects better post progression survival following talq due to the availability of efficacious therapeutic options, including those directed at BCMA.

Abstract Introduction: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an aggressive auto-inflammatory disorder defined by somatic UBA1 mutations. UBA1 mutations arise in hematopoietic stem cells and bias differentiation toward myeloid lineages. Clonal involvement of monocytes and neutrophils in VEXAS is frequent. Recently, natural killer (NK) cells have been recognized within the UBA1 mutant clone; mutated NK cells have an exhausted phenotype and impaired cytotoxicity (Ganesan BioRxiv 2025; Breillat et al, Blood 2025). A unique NK-like T cell type (CD3+CD16+[CD56-] T cells) has a role in the immunopathogenesis of severe COVID-19, resulting in heightened cytotoxicity and tissue damage (Georg et all, Cell 2022). As NK cells do not typically express CD3, and as the activation of inflammatory pathways is not restricted to myeloid cells in VEXAS, (Mizumaki et al, Nat Comm 2025) we sought to assess the CD3+ cell populations for co-expression of CD16 using single-cell (sc) multiomic data from VEXAS patients. Methods: After IRB approval, we performed sc-proteogenomic sequencing using a custom-made gene panel (Tapestri, MissionBio) in 2 VEXAS patients. Libraries were sequenced on an Illumina NovaSeq instrument. In one case, we performed in parallel CITE-Seq in parallel and used canonical correlation analysis (CCA) to integrate these immunophenotypic and transcriptomic data with matching cell populations identified from proteogenomic sequencing. We used pathway analysis (IPA) and gene ontology enrichment (gProfiler), as well as differential gene expression (RNA-seq) to identify significant gene signatures. T-tests with Welch's correction were performed for statistical significance on surface markers from proteogenomic data which were transformed by center log ratio. Our observations were then validated in sc-proteogenomic data from two additional VEXAS patients profiled at the NIH. Results: We used a sc-multiomic strategy to study CD3+ T cell subsets in VEXAS patients. In the first UBA1 mutant (mt) sample, using clusters defined by UMAP overlay of CITE-Seq/proteogenomic data, we defined positive expression of CD3 expression in the non-UBA1mt T cell cluster. We then examined the proteogenomic data (n=700 cells) to identify CD3+ cells (n=89 UBA1mt, n=42 UBA1wt). We then divided the CD3+ fraction into CD56+ vs CD56- to obtain CD3+CD56+ (n=25 UBA1mt, n=12 UBA1wt) and CD3+CD56- (n=64 UBA1mt, n=0 UBA1wt) cells. The CD3+CD56- cells were not only entirely UBA1mt, but also co-expressed CD16, significantly elevated from CD3+CD56+ UBA1wt cells (p<0.0001; and no significance from granulocyte populations): 10% of UBA1mt cells were CD3+CD16+CD56-. This cell subset was detected in an additional 3 VEXAS samples, and, in each case, there was no significant difference between UBA1mt/UBA1wt CD3 expression (both were T cell subsets) and no significant difference in CD56 expression. There was a significant increase in CD16+ expression in UBA1mt over UBA1wt (p<0.0001) cells, but not between UBA1mt cells and other granulocytes. Finally, we assessed the CITEseq data from the first UBA1mt case and focussed on gene expression and pathway differences between CD3+ and CD3+CD16+(CD56-) cell populations. Using IPA, we found top differentially expressed pathways included neutrophil degranulation, inflammation, cell killing, and IL-8 activity. Differentially expressed genes included FCGR3B, TLR2, IL1R2, FCGR2A, CCR1, CXCL8, and CXCR1, some of these overlapping with what was reported in similar cells (CD3+CD16+) detected in COVID-19 (Georg et all, Cell 2022). Conclusion: We identify a unique NK-T cell like [CD3+CD16+(CD56] subset of cells within UBA1mt cells in patients with VEXAS. This cell type has been reported in patients with severe COVID-19 as having increased cytotoxic functions and associated with fatal outcomes. Rare or aberrant cell clusters defined by standard clustering analysis may mis-identify some cell types, especially if they aberrantly express CD3+CD16+, as either marker could be used to pre-gate cells into larger clusters of lymphoid or myeloid cells. Prospective and functional profiling of this cell type in VEXAS patients is ongoing.

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.