Fogel, Lindsay

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 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<40, 65% had HRCA and 29% had >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<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<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<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<0.001) and OS (0.13, 0.05-2.56; p<0.001). Ultra high-risk MM (1.40, 1.06-1.84; p=0.02) and baseline albumin <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<50K (2.14, 1.48-3.10; p<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 >70% of patients developing dysgeusia.

Abstract Introduction: Elranatamab, a BCMA-CD3 bispecific antibody, has shown efficacy in relapsed multiple myeloma (MM), but real-world data on its safety and effectiveness are limited. Methods: We conducted a retrospective, multi-center study of patients (pts) treated with commercial elranatamab from 8/2023–3/2025 at 9 U.S. academic centers. Logistic and Cox regression were used for binary and time-to-event outcomes, respectively. Multivariable analysis (MVA) adjusted for prior lines of therapy (LOTs), baseline Hgb (per g/dL), and LDH (per 100 U/L) as continuous variables; and for BCMA exposure, extramedullary disease (EMD; extraosseous soft tissue lesions), and ECOG ≥2 as binary variables. Results: Of 130 pts, median age was 71 yrs (range 39–95); 57% were female, 82% white, 13% black, and 35% had ECOG ≥2 (11% ≥3). Median LOTs was 6; 91% were triple-class refractory, 49% penta-refractory, 49% BCMA-exposed (median 15.5 mo [IQR 11.8–20.5] since last exposure), and 49% had prior anti-BCMA CAR-T. Most recent BCMA exposures included: CAR-T (84%), TCE (9.4%), and ADC (6.3%). Only 22% met MagnetisMM-3 cohort A eligibility (which excluded BCMA-exposed pts). High-risk cytogenetics (del(17p), t(4;14), t(14;16), or amp(1q)) were present in 44% (25%, 13%, 6.3%, and 7.9%, respectively). EMD was seen in 22%. Median treatment duration was 4.0 mo (95% CI 2.93–6.3) overall and 7.9 mo (95% CI 5.83–NA) with ≥VGPR. Discontinuation due to toxicity or non-relapse mortality occurred in 12% but was significantly lower among those receiving IVIg (5% vs. 17%, p=0.031); IVIg was given in 47%. The overall response rate (ORR) was 65%, including ≥VGPR in 46% and ≥CR in 36%, consistent with MagnetisMM-3 (ORR 61%, ≥CR 35%; Lesokhin et al. Nat Med. 2023). After median follow-up of 7.5 mo, median PFS was 4.3 mo (95% CI 3.4–11.3), OS was 14.6 mo (95% CI 8.6–NA), and DOR was 12.2 mo (95% CI 6.1–NA). In contrast, MagnetisMM-3 (Prince et al., ASH 2024) reported median PFS and OS of 17.2 and 24.6 mo, respectively, with DOR not reached despite 28.4 mo of follow-up. In univariate analysis, ECOG ≥2 was associated with lower ORR (45% vs. 71%; OR 0.34, 95% CI 0.16–0.73, p=0.006), shorter OS (4.3 mo vs. NA; HR 2.41, 95% CI 1.33–4.35, p=0.004), and shorter PFS (1.7 vs. 6.5 mo; HR 1.77, 95% CI 1.09–2.87, p=0.020). Prior BCMA-directed therapy was linked to reduced odds of ≥VGPR (OR 0.38, 95% CI 0.19–0.77, p=0.008) and ≥CR (OR 0.43, 95% CI 0.20–0.89, p=0.025). Higher baseline LDH was linked to shorter OS (HR 1.37, 95% CI 1.23–1.53, p<0.001) and PFS (HR 1.31, 95% CI 1.18–1.44, p<0.001). Higher baseline Hgb was associated with higher ORR (OR 1.46, 95% CI 1.20–1.81, p<0.001) and ≥CR (OR 1.54, 95% CI 1.26–1.92, p<0.001). Among BCMA-exposed pts, recent exposure (<1 [n=15] vs. ≥1 yr [n=32]) was associated with shorter OS (4.1 mo vs. NA; HR 3.66, 95% CI 1.26–10.6, p=0.017). In MVA, higher baseline LDH remained independently associated with shorter OS (aHR 1.36, 95% CI 1.19–1.54, p<0.001) and PFS (aHR 1.27, 95% CI 1.13–1.43, p<0.001); higher Hgb with greater odds of ≥CR (aOR 1.44, 95% CI 1.14–1.85, p=0.003) and longer PFS (aHR 0.84, 95% CI 0.72–0.99, p=0.034); and BCMA exposure with lower odds of ≥CR (aOR 0.32, 95% CI 0.10–0.91, p=0.037). CRS occurred in 40% (grade ≥2 in 12.3%, grade 3 in 2.3%), and ICANS in 17% (grade ≥2 in 7.7%). These rates contrast with MagnetisMM-3 (no grade ≥3 CRS, 3.4% ICANS). ICANS risk was lower in BCMA-exposed pts (9.4% vs. 24%; OR 0.32, 95% CI 0.11–0.85, p=0.029), and decreased with more LOTs (OR 0.73, 95% CI 0.55–0.92, p=0.016) and higher Hgb (OR 0.71, 95% CI 0.52–0.94, p=0.023). Tocilizumab and steroids were used in 36% (treatment 28%, prophylaxis 9.2%) and 23%, respectively. Steroid use was less common in BCMA-exposed pts (11% vs. 34%; OR 0.23, 95% CI 0.08–0.60, p=0.004) and declined with more LOTs (OR 0.68, 95% CI 0.52–0.85, p=0.002). Infections occurred in 40% of the cohort, more common in pts with CrCl <40 mL/min (59% vs. 36%; HR 2.58, 95% CI 1.02–6.80, p=0.049). IVIg was linked to improved infection-free survival (HR 0.59, 95% CI 0.37–0.93, p=0.023). Conclusions: Elranatamab demonstrated meaningful activity in real-world relapsed MM, though PFS and OS were shorter than in MagnetisMM-3, likely reflecting an older, frailer population with higher disease burden. ICANS was more frequent than in MagnetisMM-3. Baseline anemia and elevated LDH, markers of poor marrow reserve and higher disease burden, were strongly linked to worse outcomes.