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Patients with plasma cell leukemia (PCL) are generally excluded from pivotal T-cell redirecting bispecific antibody (BsAb) trials. We evaluated real-world outcomes in a multicenter retrospective study of 122 patients with primary or secondary PCL across 15 academic centers, categorized as 'active' (≥5% circulating plasma cells within 30 days of BsAb initiation) or 'historical'. In a heavily pretreated population, patients received teclistamab (37%), elranatamab (11%), talquetamab as a line of therapy (Tal LOT, 42%), or talquetamab as bridging therapy to CAR-T (Tal Bridge, 11%). Cytokine release syndrome (CRS) was grade 1-2 in 56% and grade 3-4 in 4%, whereas neurotoxicity was grade 1-2 in 16% and grade 3-4 in 5%. Among 110 evaluable patients, the overall response rate (ORR) was 55%, including 61% with Tal LOT, 58% with Tal Bridge, 46% with elranatamab, and 33% with teclistamab. With a median follow-up of 8.3 months, talquetamab demonstrated superior survival. Tal LOT showed a median progression-free survival (mPFS) of 5.5 months and a median overall survival (mOS) of 11.5 months, and both were unreached in the Tal Bridge cohort. In contrast, teclistamab and elranatamab showed a mPFS of 1.2 and 1.6 months and mOS of 8.1 and 3.6 months, respectively (P=0.007, P=0.023). In active PCL, Tal LOT achieved mPFS/mOS of 6.9/12.2 months versus 0.7/1.4 months with teclistamab and 1.0/3.1 months with elranatamab, respectively (P<0.001, P=0.002). Multivariable analysis associated active PCL with worse survival and Tal LOT with improved outcomes. BsAbs were safe in PCL, with talquetamab showing superior outcomes compared with BCMA-directed BsAbs.

ABSTRACT Talquetamab is a GPRC5D × CD3 bispecific antibody approved for relapsed/refractory multiple myeloma (RRMM). This is the first real‐world study to comprehensively report muco‐cutaneous toxicities, infections, and efficacy of talquetamab in 151 patients across five countries with the longest follow‐up reported enabling better efficacy and toxicity estimates. The median age was 64 years; high‐risk cytogenetics were present in 42%; ECOG ≥ 2 in 22%; 12% had creatinine clearance < 30; and 55% would not have met MonumenTAL‐1 eligibility. Patients received a median of 6 prior lines of therapy, 53% were penta‐refractory, and 75% received prior BCMA therapy. Talquetamab was associated with skin toxicity in 39.7%, nail toxicity in 75.5%, dysgeusia in 60.4%, and oral toxicities in 62.9%, with grade ≥ 3 events uncommon (≤ 4%) and dose interruptions infrequent (9.6% for skin toxicity, 6.9% for dysgeusia, and 4.0% for oral toxicities). These findings underscore the need for improved supportive care for muco‐cutaneous toxicities. In multivariate analysis, only platelet count < 50 (HR 1.8, 95% CI 1.15–2.83) was associated with inferior PFS, while penta‐refractory status, absolute lymphocyte count < 0.4, and prior BCMA‐targeted therapy were not statistically significant. With a median follow‐up of 12.7 months, the overall response rate was 67.6%, median progression‐free survival was 7 months, and 12‐month overall survival was 65%. This study shows that talquetamab efficacy is maintained in a heavily pretreated real‐world population with high prior BCMA exposure and notable comorbidity burden.

Abstract Recent therapeutic advances, including bispecific antibodies (bsAbs), have improved outcomes for patients with relapsed/refractory multiple myeloma (RRMM). However, early mortality (EM) remains a significant challenge, even in the era of novel immunotherapies. We conducted a multicenter, retrospective analysis of real-world patients with RRMM treated with commercial bsAbs to evaluate the incidence and causes of EM. Between May 2022 and June 2025, a total of 441 patients were treated across 7 countries. EM, defined as death within 12 months of therapy initiation, occurred in 148 patients (34%), with a median time from bsAb initiation to death of 2.87 months (interquartile range, 1.38-6.85). The leading cause of EM was progressive disease (72%), followed by infection (13%); regardless of the cause of death, 82% had active disease at the time of death. Our findings highlight that despite encouraging efficacy, EM remains high among real-world bsAb recipients, emphasizing the need for improved disease control strategies and supportive care interventions.

Abstract Introduction: The GPRC5D-directed bispecific antibody (BsAb) Talquetamab (Talq) has shown promising results for patients (pts) with relapsed/refractory multiple myeloma (RRMM) in the MonumenTAL-1 clinical trial (Chari et al. NEJM 2022). However, there are limited data on the use of Talq in the real-world setting. Methods: All pts with RRMM who started Talq between 8/2023-3/2025 across 15 US academic centers were included. High-risk cytogenetic abnormalities (HRCA) were defined as del(17p), t(4;14), t(14;16) and/or gain/amplification 1q21. Time-to-event analyses were estimated using the Kaplan-Meier method. Toxicities including CRS and ICANS were graded using CTCAE v5.0 or ASTCT criteria. Results: A total of 484 pts were included, with a median age of 65 years (range 35-89), and 83 pts (17%) were aged ≥75 years. 20% of pts were black. 21% had baseline CrCl&lt;40, 65% had HRCA and 29% had &gt;1 HRCA (i.e Ultra high-risk MM). The median number of prior lines of therapy was 6 (IQR 4, 8). 50% were penta-refractory, 69% received at least one prior BCMA-directed therapy (46% CART; 32% BsAb). Prior to initiation of Talq, 11 pts (2%) had CNS MM, 29 (6%) had PCL and 126 (26%) had true extramedullary disease (EMD). 70% would have been ineligible for the MonumenTAL-1 trial. For most pts (n=405; 84%) the dosing strategy from Cycle 2 was 0.8 mg/kg every 2 weeks. and the 0.4 mg/Kg weekly dosing was used in 28 patients (6%). In 6% of pts, an additional drug was added to Talq, mostly pomalidomide (n=20) or daratumumab (n=10). 101 pts (21%) received Talq as bridging for CART. Median duration of Talq treatment was 102 days. 62% developed CRS (Grade ≥3, 2%; including one Grade 5 event). 15% developed ICANS (Grades 3-4, 4%). Steroids were used in 213 patients (44%), tocilizumab in 145 (30%) and anakinra in 9 (2%). 22 patients (5%) required ICU stay during the first cycle, for a median of 6 days (range 1-31). A total of 200 pts (41%) had infections (median 1 infection each, range 1-6), including 99 (20%) with bacterial infections, 113 (23%) viral infections and 21 (4%) fungal infections. IVIG was used in 261 pts (54%). 79% of patients (n=384) developed Talq-related oral toxicity, 55% (n=269) skin toxicity and 199 (41%) nail toxicity. 157 patients died after a median follow up of 11.5 months (mos), and the leading causes of death were MM progression (n=120) and infection (n=10). 8 pts (1.7%) developed invasive second primary malignancies. The ORR was 73%, including 46% ≥VGPR. The median PFS (mPFS) for the entire cohort was 7.8 mos (95% CI 6.9-9.4) and the 12 months PFS rate was 39%. The median OS had not been reached and the 12 months OS rate was 63%. For pts who would have been eligible for MonumenTAL-1, the mPFS was 12.2 mos (95% CI 9.7 – not reached (NR); for trial-ineligible pts, the mPFS was 6.9 mos (5.8 – 8.0; p=0.003). For BCMA-naive pts, the mPFS was 15.7 mos (11.8-NR); for BCMA-exposed pts, the mPFS was 6.8 mos (6.0-7.8; p=0.0002). For patients who received Talq as bridging prior to CART, the median PFS was NR (14.1 – NR); for those who did not receive Talq as bridging the mPFS was 6.5 mos (5.3-7.6; p&lt;0.0001). In multivariable analyses, worse OS and PFS were associated with trial ineligibility [(HR 1.38, 95% CI 1.03-1.86; p=0.03) and (2.33, 1.31-4.14; p=0.004)], BMI&lt;30 [(1.42,1.06-1.89; p=0.02) and (1.50, 1.01-2.22; p=0.045)] and true EMD at baseline [(1.95, 1.49-2.56; p&lt;0.001) and (1.65, 1.16-2.36; p=0.005). On the other hand, use of Talq as bridging to CART was associated with better PFS (0.27, 0.17-0.43; p&lt;0.001) and OS (0.13, 0.05-2.56; p&lt;0.001). Ultra high-risk MM (1.40, 1.06-1.84; p=0.02) and baseline albumin &lt;3 (1.68, 1.18-2.37; p=0.004) were associated with worse PFS; ECOG ≥2 (1.68, 1.18-2.40; p=0.004), and baseline Plt&lt;50K (2.14, 1.48-3.10; p&lt;0.0001) was associated with worse OS. Conclusions: In this large real-world analysis of 484 Talq recipients, the ORR was comparable to MonumenTAL-1 but the median PFS was shorter. This likely reflects differences in patient selection, with 70% of patients in our cohort being trial-ineligible. Patients who received Talq as pre-CAR-T bridging had superior survival outcomes. Rates of toxicities were similar to MonumenTAL-1, including &gt;70% of patients developing dysgeusia.

Abstract Introduction: The CARTITUDE-4 (NCT04181827) trial compared cilta-cel, a chimeric antigen receptor (CAR)-T cell treatment (tx) targeting B-cell maturation antigen (BCMA), with 2 standard-of-care regimens in patients (pts) with RRMM and 1–3 prior lines of therapy (LOT). Cilta-cel significantly improved overall survival (hazard ratio [HR] 0.55) and progression-free survival (PFS; HR 0.29). The DREAMM-7 (NCT04246047) and DREAMM-8 (NCT04484623) trials evaluated belamaf, an anti-BCMA antibody-drug conjugate (ADC), in combination with bortezomib and dexamethasone (BVd) and with pomalidomide and dexamethasone (BPd), respectively. Both trials demonstrated improved survival and response rates with belamaf in pts with ≥1 prior LOT. International Myeloma Working Group (IMWG) guidance for RRMM tx recommends using anti-BCMA T-cell redirecting therapy (TCRT), such as CAR-T (eg, cilta-cel), before anti-BCMA ADCs (eg, belamaf). As cilta-cel and belamaf have not been compared head to head, we conducted unanchored matching-adjusted indirect comparisons (MAICs) to estimate relative efficacies using CARTITUDE-4 study individual patient data (IPD) and published data from DREAMM-7 and DREAMM-8. Methods: Unanchored MAICs were performed using IPD from apheresed pts in the CARTITUDE-4 cilta-cel arm. Eligibility criteriafrom DREAMM-7 and DREAMM-8 were applied to the cilta-cel cohort. Further adjustments were made by weighting cilta-cel IPDto match reported baseline characteristics (including refractory status [for DREAMM-8], cytogenetic risk, International Staging System stage, and presence of extramedullary disease) from DREAMM-7 and DREAMM-8. Outcomes were compared using weighted IPD for cilta-cel and reported response rates and simulated IPD based on published Kaplan–Meier PFS curves for BVd and BPd. For each matched population, we compared PFS, ORR, and very good partial response or better (≥VGPR) and complete response or better (≥CR) rates. A weighted Cox proportional hazards model was used to estimate PFS HRs and 95% CIs. A weighted logistic regression analysis was used to derive relative response ratios (RRs) with 95% CIs to compare relative tx effects. Results: The MAICs included 208 apheresed pts from CARTITUDE-4 (cilta-cel), 243 pts from DREAMM-7 (BVd), and 155 pts from DREAMM-8 (BPd). To form comparable cohorts, we excluded cilta-cel pts who would not have been eligible for DREAMM-7 (n=87) or DREAMM-8 (n=55). Cilta-cel pts were most commonly excluded from the DREAMM-7 MAIC due to bortezomib refractoriness or anti-CD38 refractoriness (n=55 and n=50, respectively), and from the DREAMM-8 MAIC due to bortezomib refractoriness (n=55). After exclusions, 121 and 153 cilta-cel pts remained in the MAICs with BVd and BPd, respectively. After adjustment, cilta-cel was associated with significantly lower risk of progression or death compared with BVd (HR 0.46 [95% CI 0.28–0.75]; P=0.0020) and BPd (HR 0.61 [95% CI 0.39–0.96]; P=0.0320). ORR was significantly higher with cilta-cel vs BVd (92.9% vs 82.7%; RR 1.12 [95% CI 1.03–1.22]; P=0.0087) and vs BPd (89.3% vs 77.4%; RR 1.15 [95% CI 1.04–1.29]; P=0.0100). Rates of ≥VGPR and ≥CR were also higher with cilta-cel vs BVd (≥VGPR: 89.7% vs 65.8%; RR 1.36 [95% CI 1.21–1.53]; ≥CR: 86.0% vs 34.6%; RR 2.49 [95% CI 2.04–3.03]; both P&lt;0.0001) and vs BPd (≥VGPR: 86.6% vs 63.9%; RR 1.36 [95% CI 1.18–1.56]; ≥CR: 81.8% vs 40.0%; RR 2.05 [95% CI 1.65–2.53]; both P&lt;0.0001). Sensitivity analyses were consistent with the adjusted comparisons and showed statistically significant PFS and tx response benefits with cilta-cel vs BVd and BPd. Conclusions: These MAICs demonstrated superior PFS and response rates with cilta-cel compared with 2 belamaf-containing regimens (BVd and BPd). Results should be interpreted with caution as there were substantial differences in the pt populations of CARTITUDE-4 vs DREAMM-7 and DREAMM-8. However, adjusted cilta-cel cohort sizes remained large enough for robust comparisons that showed statistically significant differences across efficacy outcomes. Another limitation is the remaining potential unmeasured residual confounding differences. Nonetheless, these findings support IMWG guidance recommending anti-BCMA TCRTs prior to ADCs and provide valuable comparative evidence in the absence of head-to-head trials.

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 &lt;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&lt;0.0001) and 45% had prior CAR-T in 45% (57% in Talq vs. 37% in BCMA TCE, p&lt;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&lt;0.01. Apart from HRCAs, adverse disease characteristics included FHRMM (HR 1.20) and EMD (HR 1.46); all p&lt;0.05. Among laboratory markers, hemoglobin &lt;9 g/dL (HR 2.10), platelet count &lt;75 ×10⁹/L (HR 1.96), and elevated ferritin (≥600 ng/mL; HR 2.17) (all p&lt;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&lt;0.001) were also associated with inferior PFS. In a multivariable analysis (MVA), prior BCMA therapy (HR 1.72, p&lt;0.0001), ferritin &gt;600 ng/mL (HR 1.68, p&lt;0.0001), hemoglobin &lt;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 &gt;600 (HR 1.88), hemoglobin &lt;9 g/dL (HR 1.6), platelet count &lt;75 ×10⁹/L (HR 1.36) and leukopenia &lt;0.25 x 10⁹/L (HR 1.52) were adverse prognostic markers on UVA. A MVA confirmed the independent impact of ferritin &gt;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 &gt;600 (HR 1.79), ECOG ≥2 (HR 1.55), Hb &lt;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: BCMA- and GPRC5D-targeting immunotherapies including CART cell therapy and Bispecific antibodies are currently approved for the treatment of multiple myeloma. However, clinical outcomes after dual antigenic exposure remain undefined. Herein we report the first report of BCMA-GPRC5D dual targeted multiple myeloma (DEMM). Methods: We conducted a retrospective multi-center study of RRMM patients treated with both BCMA- and GPRC5D-targeted treatments (TT) (CAR T, bispecific antibodies, ADCs) between November 1, 2022, and July 1, 2025. Outcomes included PFS1 (post-dual exposure), and overall survival (OS). Kaplan-Meier estimates and event-free probabilities were calculated. Results: One hundred and fifty patients who underwent TCE treatments were included and 49 patients met the criteria for inclusion. Median age was 65 years, 22.4% had creatinine clearance &lt;=30 and ECOG 2 or greater was present in 22.2%; 57% had high-risk cytogenetics (IMWG 2016), and 60.5% were penta-refractory. Patients received a median of 6 prior lines of therapy (LOT) before 1st TCE and 9 prior LOT before DEMM. 65.3% received 1 TCE, 30.6% received 2 TCE and 4.1% received 3 TCE before DEMM. Similarly, 67.3% received 1 BCMA, 24.5% received 2 BCMA TT and 4.1% received 3 BCMA TT before DEMM. Prior TT included- BCMA CART (57.1%), BCMA Bispecific (57.1%), BCMA ADC (18.4%), other TCE (10.2%). The last dual exposure was GPRC5D Bispecific in 91.8%, BCMA Bispecific in 6.1% and BCMA CART in 2%. The median followup post relapse was 3.4 months (range 0.0-16 mos). The median PFS during the last dual exposure TT was 3.98 months (95% CI: 2.96–6.70). 32.7% did not receive any subsequent LOT and died due to progressive disease. 67.3% of patients had progressive MM and received next LOT. Median PFS1 was 1.77 months (95% CI: 1.28–6.21) with 3-, 6-, and 12-month event-free probabilities of 44%%, 19% and 0% respectively. Median OS was 5.7 months (95% CI: 2.53-12.16) for DEMM from the time of refractoriness to dual antigenic targets. Conclusions: Patients dual-exposed to BCMA- and GPRC5D-directed therapies have a poor prognosis, 32.7% had not received further treatment and in those who received treatment the PFS1 was less than 2 months and an OS of 5.7 months from progression. This reflects an area of high unmet need for the patients that are dual-exposed to BCMA- and GPRC5D-directed therapies. Further data on the cohort will be updated at the meeting. Acknowledgements include, the International Myeloma Foundation, IMWG.

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 &lt;.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 &lt;.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.