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Abstract Introduction: Teclistamab is the first FDA approved BCMA-directed bispecific antibody for the treatment of relapsed and refractory multiple myeloma (RRMM). With BCMA-targeting CAR-T therapies, cytokine release syndrome (CRS) is a risk factor for cardiotoxicity. Teclistamab was associated with fatal cardiovascular adverse events (CVAEs) in a recent US pharmacovigilance database analysis, but this analysis was limited by reporting bias. Therefore, the aim of our study is to conduct a multicenter study to define the real-world incidence of CVAEs in RRMM patients treated with teclistamab. Method We performed a retrospective multi-center cohort study of patients receiving teclistamab at 5 medical centers. Baseline oncologic and cardiovascular characteristics (including vital sign and echocardiographic data) were collected. Baseline cardiovascular disease (CVD) was defined as presence of coronary artery disease, congestive heart failure, severe or symptomatic valvular heart disease, or stroke at baseline. CVAE was collected and categorized based on CTCAE v5.0 by each institution. Major adverse cardiovascular event (MACE) was a composite outcome with any of the following: congestive heart failure, asymptomatic cardiomyopathy (interval LVEF drop >10% to resultant LVEF less than 50%), coronary artery disease requiring intervention, stroke or cardiovascular death. Arrhythmia was a composite outcome with any of the following: atrial tachyarrhythmia, ventricular tachyarrhythmia or bradyarrhythmia. Median follow-up was calculated through reverse Kaplan-Meier method. Multivariable Cox regression analysis was used to define the relation between MACE and survival. Cause of death was categorized as myeloma-related death or non-myeloma-related deaths (i.e. CRS, infection or cardiovascular death). Cause-specific Cox regression was performed to define relationship between MACE and cause of death. Results In a cohort of 219 patients treated with teclistamab with median follow-up of 20.1 months, 7.3% (N=16) developed MACE, 7.3% (N=16) developed arrhythmia and 12.8% (N=28) developing any MACE or arrhythmia. MACE occurred at a median of 4.5 days (IQR 2.25-15.75 days) after teclistamab step-up. The incidence of MACE was 16.4% in patients with baseline CVD versus 2.7% in those without baseline CVD (p<0.001). Patients who developed MACE had inferior ECOG performance status (PS) (PS >=2: 62.5% vs. 27.7%; p=0.008). Additionally, baseline hemoglobin level (9 vs 10g/dL; p=0.072) was numerically lower in MACE, compared to no MACE. There was no difference in age, sex, bone marrow (BM) plasma cell burden, ferritin, C-reactive protein or LDH levels between MACE vs. no MACE group. Patients who developed MACE had lower baseline diastolic blood pressure (67.7 vs 73.8mmHg; p=0.041) and numerically lower LVEF (51.4 vs 59.3%; p=0.059; baseline echocardiogram performed in 86% of all cohort). Patients who developed MACE had similar incidences of CRS (Grade >=2: 25.0 vs 16.7%; p=0.620) and immune effector cell-associated neurotoxicity (ICANS) grade 2 or higher (12.5 vs 7.5%; p=0.812). In multivariable Cox regression analysis, MACE was independently associated with inferior overall survival (HR 2.72; 95% CI 1.41-5.25; p=0.003), after adjusting for baseline CVD, age, high BM burden, extramedullary disease, and plasma cell leukemia. In cause-specific multivariable Cox regression analysis, MACE was independently associated with non-myeloma-related death (HR: 10.77 95% CI 4.39- 26.41; p<0.001) but not with myeloma-related death (1.54; 95% CI 0.64- 3.70; p=0.336). Conclusion In conclusion, in this large, real-world multicenter study, we observed that MACE occurred in over 7% of patients following teclistamab for RRMM, typically within 2 weeks of initiation. MACE was significantly associated with increased non-myeloma-related mortality. In contrast to CAR-T therapy, CRS or ICANS were not associated with MACE, whereas majority of patients who developed MACE had ECOG PS >=2 or baseline cardiovascular disease. More studies are necessary to define mechanisms and strategies to reduce these MACE and improve survival. Patients with baseline cardiovascular disease or poor performance status may benefit from cardiovascular optimization before and during teclistamab therapy.

Abstract Introduction: Bispecific T-cell engagers (TCE) targeting BCMA (teclistamab, elranatamab) and GPRC5D (talquetamab) are important therapeutic options in relapsed/refractory MM (RRMM). However, data on the independent prognostic impact of individual cytogenetic abnormalities and functional high-risk MM on outcomes with TCEs remains limited. Methods We included RRMM patients treated with BCMA TCEs (teclistamab, elranatamab) and talquetamab across 15 centers in the US. Patients where TCEs were used only as bridging therapy to CAR-T were excluded. High-risk cytogenetic abnormalities (HRCA) included del(17p), t(4;14), t(14;16), 1q gain/amplification (1q21+), del(1p) before initiation of TCE. Functional high-risk disease (FHRMM) was defined as PFS <18 months with frontline therapy. Extramedullary disease (EMD) included visceral or soft tissue disease and excluded paraskeletal disease. Progression-free survival (PFS) was estimated from TCE initiation using the Kaplan–Meier method and compared using the log-rank test. Univariate and multivariable Cox proportional hazards models were used to identify predictors of PFS in the entire cohort and the subcohorts of BCMA TCEs and talquetamab (Talq). Results We analyzed 943 treatment initiations with TCEs in RRMM, comprising 577 BCMA-directed TCEs [teclistamab (n=436) and elranatamab (n=141)] and 366 talquetamab initiations. The median follow-up from TCE initiation was 13.4 months (95% CI: 12.5–14.2) and median age was 68 years (interquartile range 61-75 years). Two ore more HRCAs were noted in 30% of the cohort (34% in Talq vs. 28% in BCMA TCEs, p=0.04), EMD was present in 21% of patients (26% in Talq vs. 18% in BCMA TCEs, p=0.002), and 45.5% of patients had FHRMM (47% in Talq vs. 45% in BCMA TCE, p=0.54). The median prior lines of therapy was 6 (interquartile range: 5-8), with 92% being triple-class refractory (TCR); 60% received prior BCMA-directed therapy (85% in Talq vs. 45% in BCMA TCE, p<0.0001) and 45% had prior CAR-T in 45% (57% in Talq vs. 37% in BCMA TCE, p<0.001). The best overall response rate (ORR) was 67.1 % for the entire cohort (66.4% for BCMA cohort and 68.2% for Talq), with 32.5% patients achieving a ≥ complete response. The median PFS was 7.7 months (95% CI: 6.7–8.6) for the entire cohort, with a median PFS of 10.1 months (95% CI: 7.5-13.4) for teclistamab and 10.1 months (95% CI: 3.9-NR) for elranatamab. In the more heavily pretreated talq cohort, the median PFS was 6.4 months (95% CI: 5.1-7.5). In a univariate analysis (UVA), several HRCAs were associated with inferior PFS−del(17p) (HR 1.59), t(4;14) (HR 1.43), del(1p) (HR 1.54), and ≥2 HRCAs (HR 1.64), all p<0.01. Apart from HRCAs, adverse disease characteristics included FHRMM (HR 1.20) and EMD (HR 1.46); all p<0.05. Among laboratory markers, hemoglobin <9 g/dL (HR 2.10), platelet count <75 ×10⁹/L (HR 1.96), and elevated ferritin (≥600 ng/mL; HR 2.17) (all p<0.01) were prognostic for PFS. ECOG ≥2 (HR 1.62), prior BCMA-directed therapy (HR 1.56), and prior CAR-T (HR 1.44) (all p<0.001) were also associated with inferior PFS. In a multivariable analysis (MVA), prior BCMA therapy (HR 1.72, p<0.0001), ferritin >600 ng/mL (HR 1.68, p<0.0001), hemoglobin <9 g/dL (HR 1.53, p=0.001), ECOG PS ≥2 (HR 1.52, p=0.0009), del(17p) (HR 1.44, p=0.0034) and FHRMM (HR 1.26, p=0.047), were associated with inferior PFS. Within the talq cohort (n=366), EMD (HR 1.64), del(17p) (HR 1.42), del(1p) (HR 1.54), FHRMM (HR 1.34), ECOG ≥2 (HR 1.56), ferritin >600 (HR 1.88), hemoglobin <9 g/dL (HR 1.6), platelet count <75 ×10⁹/L (HR 1.36) and leukopenia <0.25 x 10⁹/L (HR 1.52) were adverse prognostic markers on UVA. A MVA confirmed the independent impact of ferritin >600 ng/mL (HR: 1.77), ECOG ≥2 (HR 1.61) and functional high-risk status (HR 1.52) on PFS, whereas del(17p) and EMD were trending toward significance. Within the BCMA TCE cohort (n=577), prior BCMA therapy (HR 1.9), ferritin >600 (HR 1.79), ECOG ≥2 (HR 1.55), Hb <9 g/dL (HR 1.54), and del(17p) (HR 1.52) were independently associated with inferior PFS on a MVA.Conclusions: In this large real-world cohort of TCE, outcomes varied by fitness, disease biology, and treatment history. The ECOG PS, elevated ferritin, functional high-risk status and del(17p) were consistently associated with inferior PFS. Prior BCMA exposure was an independent risk factor for inferior PFS in the BCMA TCE cohort, but not with talquetamab.

Abstract Background: Systemic AL amyloidosis is an incurable disorder caused by misfolded light chain fibrils. Survival is determined by the extent of cardiac involvement and response to therapy. Mayo 2012 (stage I-IV) and European modified Mayo 2004 (stage I-IIIB) prognostic scores were developed in a historic treatment era, prior to widespread bortezomib and daratumumab use. These no longer discriminate those with the poorest outcomes. We presented a new model sub-stratifying IIIB into a high risk, ‘IIIC’ group, incorporating longitudinal strain (LS) to the European modified score (IIIC: LS >-9% + NT-proBNP >8500ng/L + high-sensitivity troponin T [hs-TnT] >50ng/L) in the bortezomib-era (2015-2019) last year (Khwaja et al, ASH 2024). Here, we present an independent external validation of the IIIC model in the modern treatment era. Methods: The ‘IIIC model’ was derived from a large real-world cohort of adults from the UK National Amyloidosis Centre (2015-2019). Performance was externally validated across Europe (Greece, Italy, Netherlands, Switzerland), USA (2015-2024) and UK (2020-2024). Survival estimates were generated from diagnosis to death or last follow-up using the Kaplan-Meier method and groups compared using Cox regression (using Stata v18). Stage IIIB and IIIC were defined as follows IIIB: LS <-9%, NT-proBNP >8500ng/L, hs-TnT >50ng/L and IIIC: LS >-9%, NT-proBNP >8500ng/L, hs-TnT >50ng/L, respectively. Stage I, II and IIIa were defined as previously described in the European modification of Mayo 2004 staging system. Results: 2493 patients were analysed from 2015-2024 (derivation, n=573; validation: Europe, n=374, USA n=458, UK, n=1088). In the derivation cohort, LS ≥-9% and standard cardiac biomarkers (NT-proBNP 332ng/L and 8500ng/L and hs-TnT>50ng/L) were selected as independent prognostic factors in a multivariable model. In the European and UK validation cohort (n=1462), median age at diagnosis was 67 years (range 35-95) with 1014 (69%) cardiac and 869 (60%) renal involvement. Median difference in involved and uninvolved free light chain (dFLC) was 181 mg/L (range 0-24933), NT-proBNP 1911ng/L (range 42-70000), hs-TnT 45ng/L (range 3-1221) and LS -14.7% (range -3- -28). In the US cohort median NT-proBNP was 1764 (range 13-71000) and hs-TnT 44 (6-687). Applying the new model staging, the patient stages were across Europe and UK were stage I: 224 (15%), II: 627 (43%), IIIA: 396 (27%), IIIB: 139 (10%) and IIIC: 76 (5%), respectively. 592 (41%) were treated with first-line daratumumab-based regimens. In the US dataset stage I: 103 (22%), II: 176 (38%), IIIA: 131 (29%), IIIB: 48 (10%) and IIIC: 16 (3%), respectively. 234 (51%) were treated with first-line daratumumab-based regimens. At a median follow-up of 30 months (95% CI 28-32) in the European and UK validation cohort, estimated median overall survival (OS) was not reached and 2-year OS was 74% (95% CI 72-77). Median survival for stages I-II, IIIA, IIIB and IIIC were not reached (NR), 67, 31 and 10 months, respectively (p<0.001). Hazard ratios for stage II, IIIA, IIIB, IIIC were 2.01 (95% CI 1.32-3.07), 3.51 (95% CI 2.31-5.35), 5.67 (95% CI 3.60-8.91) and 11.12 (95% CI 6.93-17.87), respectively (p<0.001). This was confirmed in the US cohort with a median survival for respective stages were NR, NR, NR, 8 and 2 months (p<0.001). External validation in the European and UK cohorts exhibited good predictive performance: 12-month calibration slope was 1.00 (95% CI 0.81-1.20, p=0.98), Harrel's C was 0.90 (95% CI 0.76-1.00), Royston's D 1.07, R2D 0.21 (95% CI 0.15-0.28). In 1462 patients with dataset available, stage IIIC discriminated the poorest outcome despite a greater proportion treated with first-line daratumumab v IIIB in the validation cohort (59% v 40%, p=0.008). 12-month OS for IIIC v IIIB was 44% (95% CI 32-55) v 69% (95% CI 60-76), specificity for 12-month OS 97% v 92% and diagnostic odds ratio 6.62 v 2.36. Conclusions: This study validates the new staging system from stage I-IIIC with robust identification of an ultra-poor prognostic group (Stage IIIC) in a contemporarily treated patient cohort. Despite novel therapies, the OS remains <12 month in the IIIC group and also poor in stage IIIB with median OS 31 months compared to a median of >5 years for all other stages. This staging system can be considered as a new standard of care for risk stratification of AL amyloidosis. Novel approaches are required for patients with advanced risk.

Abstract Introduction Detecting genetic abnormalities is mandatory during diagnostic workup and for potential individualization of therapy selection in multiple myeloma (MM) and its precursor conditions. At present, this requires invasive bone marrow (BM) biopsies, severely limiting early detection, patient monitoring, and the precise selection of therapy. The current standard for detecting genetic alterations in MM is fluorescence in situ hybridization (FISH), which cannot detect point mutations and other clinically relevant alterations. Consequently, the IMS-IMWG guidelines were recently updated to require next-generation sequencing for the classification of high-risk MM. Moreover, the importance of identifying alterations in therapeutic targets (e.g., BCMA, GPRC5D) for guiding immunotherapies is becoming increasingly recognized. To address this need, we recently launched GenoPredicta, a CLIA-approved Laboratory Developed Test that enables routine monitoring, informing diagnosis, and treatment selection by comprehensively and robustly characterizing MM genomes with whole genome sequencing (WGS) from a minimum of ~50 circulating tumor cells (CTCs) isolated from peripheral blood (PB) or tumor cells from BM. Here, we describe the characterization of clinical and research samples with GenoPredicta, highlighting resistance-conferring genetic alterations that can only be detected by sequencing and that are consistent with patients' clinical histories, while further demonstrating the complete concordance of GenoPredicta with prior FISH results. Methods Tumor cells were isolated from BM and/or PB samples using fluorescence-activated cell sorting (FACS) (after CD138+ enrichment for PB) and subjected to whole genome sequencing (WGS), from which we identified copy number alterations, structural variants, and single nucleotide variants and indels. For a subset of samples, the BM was also characterized by FISH, using a standard clinical panel for characterizing MM; for other samples prior FISH results were available from patients' clinical records. Results The analytical validation of GenoPredicta, conducted on a retrospective cohort of >60 viably frozen samples from >30 patients, showed complete concordance between BM and PB for detected genomic abnormalities, with all clinically relevant events (11 translocations and 125 CNVs) observed in BM recapitulated in PB (100% recall). All events identified by FISH in 14 samples (8 translocations and 30 CNVs) were also identified in the BM (100% recall), with 50 translocations and 30 CNVs not detected by FISH also absent in the WGS data (100% precision). The abnormalities detected in these samples also included multiple high-risk events not assayed by FISH, including biallelic TP53 loss (Del 17p coupled with a deleterious TP53 mutation, observed in 4 patients) and MYC::IGL translocations (2 patients). Moreover, for all fresh peripheral blood clinical samples with FISH results available from patients' histories, GenoPredicta recalled 100% of reported events. Among these clinical samples, we notably observed a case with both a biallelic GPRC5D deletion and a TNFRSF17 (BCMA) deletion combined with a truncating mutation on the remaining allele. This was consistent with the patient's clinical history showing progression after therapy with talquetamab (anti-GPRC5D bispecific), and previous nonresponse to teclistamab (anti-BCMA bispecific) after prior therapy with Cilta-cel (BCMA-directed CAR T). GenoPredicta also detected other mutations likely to confer resistance to immunotherapies, including loss-of-function mutations in IKZF3 and deletions of FCRL5 in frozen peripheral blood research samples. Conclusion We demonstrate that WGS-based characterization of MM from BM or CTCs is a viable replacement for FISH for clinical diagnosis and monitoring, with blood-based measurements enabling comprehensive profiling of the myeloma cancer genome. Importantly, this includes genetic alterations that confer resistance to therapy, allowing for both early detection of such alterations and more precise selection of therapy.

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.

Context.— Optical genome mapping (OGM) represents a promising cytogenomic technology that detects structural variants, including fusions, rearrangements, copy number variants, and loss of heterozygosity, in a single assay. Unlike karyotyping, fluorescence in situ hybridization, or chromosomal microarray, OGM leverages long-molecule imaging to map the whole genome with high resolution. This positions OGM as a novel tool for constitutional and somatic/cancer genomics. However, its current and planned utilization in clinical and research settings remains unknown, necessitating further investigation. Objective.— To investigate the current utilization of OGM in clinical and research laboratories, assess its applications, and evaluate future utilization strategies. Design.— In 2024, a supplemental questionnaire was incorporated into 6 College of American Pathologists proficiency testing programs to evaluate OGM’s utilization. Results.— Of 921 returned questionnaires, 712 were analyzed after duplicates were removed. Sixty-seven (9.4%) currently offered OGM testing: 5.2% (37) for research only, 1.8% (13) for only clinical use, and 2.4% (17) for both. Future adoption plans showed 7.6% (53 of 700 laboratories) and 7.9% (55 of 700 laboratories) aiming to implement OGM clinically within 12 and 24 months, respectively. The most common applications included hematologic malignancies and constitutional/germline postnatal disorders, followed by prenatal testing. International laboratories demonstrated statistically higher utilization rates than domestic laboratories ( P = .001). Conclusions.— This first survey on OGM clinical utilization reveals its status as a niche technology, with 67 laboratories currently using it. Its primary clinical applications are in constitutional/germline analysis and hematologic malignancies. Although international laboratories led in 2024, 108 laboratories (domestic and international) plan clinical adoption within 24 months, signaling OGM’s potential for broader integration.

Abstract Deep brain stimulation (DBS) of the subthalamic nucleus improves motor symptoms in patients with Parkinson’s disease. Using functional MRI, optimal DBS response networks have been characterized. However, neural activity associated with Parkinsonian symptoms is magnitudes faster than what can be resolved by this method. Although both spatial and temporal domains of these networks appear crucial, no single study has yet investigated both domains simultaneously. Here, we aimed at closing this gap by analysing electrophysiological data from a total of n = 127 hemispheres. Using subthalamic local field potentials that were recorded concurrently alongside whole-brain magnetoencephalography in a multi-centre cohort of patients who underwent subthalamic DBS for the treatment of Parkinson’s disease (n = 100 hemispheres), we analysed the DBS response network in both spatial and temporal domains. In every cortical vertex, cortico-subthalamic coupling was correlated with stimulation outcomes. This network spatially resembled functional MRI-based findings (R = 0.40, P = 0.039) and explained significant amounts of variance in clinical outcomes (βstd = 0.30, P = 0.002), whereas theta–alpha and low beta coupling did not show significant associations with DBS response (theta–alpha: βstd = −0.02, P = 0.805; low beta: βstd = −0.08, P = 0.426). The ‘optimal’ high beta coupling map was robust when subjected to various cross-validation designs (10-fold cross-validation: R = 0.29, P = 0.009; split-half design: R = 0.31, P = 0.026) and was able to predict outcomes across DBS centres [R = 0.74; P(1) = 8.9 × 10−5]. We identified a DBS response network that resembles the previously defined MRI network and operates in the high beta band. Maximal connectivity to this network was associated with optimal DBS outcomes and was able to cross-predict clinical improvements across DBS surgeons and centres.