Ferreri, Christopher J.

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: Cilta-cel is a BCMA-directed CAR T-cell therapy that has shown remarkable efficacy in patients with RRMM. As real-world (RW) experience with cilta-cel continues to expand, and with the recent FDA guidance reducing the recommended proximity to the CAR T center from four to two weeks post-infusion, there is growing interest in identifying patients at low risk for severe early complications who may be safely managed in the outpatient setting and potentially ‘discharged’ home earlier. Methods Data were collected from 769 patients with RRMM treated with cilta-cel at 15 institutions in the U.S. via the Multiple Myeloma Immunotherapy Consortium.Logistic regression was used to identify predictors of patients who could be managed in the outpatient setting (low-risk group). Based on expert consensus within the Consortium, low-risk patients were defined as: grade ≤1 CRS, no ICANS, and no IEC-HS. The remaining patients were categorized as high-risk. We evaluated baseline characteristics with missingness < 20% as predictors, including age, sex, race, and ethnicity, ECOG performance status (PS) at time of lymphodepletion (LD), extramedullary disease, bone marrow plasma cell (BMPC) percentage, high-risk cytogenetics, bridging therapy including response, penta-refractory status, number of prior lines of therapy, prior anti-BCMA therapy, baseline C-reactive protein (CRP), and baseline ferritin. The cohort was restricted to patients with complete data on all predictors (n=455) and split into a training and testing cohort (80/20 split, n=364/91). Bidirectional stepwise regression was used to build the predictive model using variables with significance of p<0.15 selected for entry. The best model was selected based on the AIC (Akaike Information Criterion) and a significance level of p<0.05. Results Among the 455 patients with complete data included in the final model, 290 (64%) were categorized as low-risk and 165 (36%) as high-risk. Compared to the low-risk group, high-risk patients were more likely to have an ECOG PS ≥2 at time of LD (20% vs 9%, p<0.001), high-risk cytogenetics (47% vs 35%, p=0.009), and penta-refractory disease status (34% vs 24%, p=0.031). High-risk patients also had a higher median BMPC percentage (15% vs 5%, p<0.001), and higher baseline pre-LD CRP and ferritin. Overall response rates were high, at 95% vs 90% (p=0.047) for the low vs high risk groups, with complete response or better achieved in 73% vs 66% of patients, respectively (p=0.14). With a median follow-up of approximately 11 months, median progression-free survival was not reached (95% CI: 27-NA) in the low-risk group and 18.2 months (95% CI: 13.1-NA) in the high-risk group. In terms of safety, non-ICANS neurotoxicity (NINT) occurred less frequently in the low-risk group (6.6% vs 13%, p=0.015). Specifically, Parkinsonism was observed in 1.7% vs 6.1% (p=0.013), and cranial nerve palsy in 4.5% vs 5.5% (p=0.7), respectively. Non-relapse mortality (NRM) was lower in the low-risk group (4.2%) compared to the high-risk group (14%; p < 0.001). The most common causes of NRM in the low- and high-risk groups were acute toxicities (0% vs 36%, including CRS, IEC-HS, and ICANS), delayed toxicities (0% vs 8%, including colitis, NINT, and Parkinsonism), infections (50% vs 48%), and other unrelated causes (50% vs 8%). The best model to predict low-risk patients that could be managed in the outpatient settingincluded BMPC percentage and ECOG PS at LD. In the training cohort, patients with a higher pre-LD BMPC percentage and an ECOG PS ³2 were less likely to be in the low-risk group(OR per 1-unit change in BMPC percentage = 0.99, 95% CI=0.98-0.99, p<0.001 and OR for ECOG PS 2-4 = 0.38, 95% CI=0.20-0.72, p=0.003). The AUC for this model was 0.663 in the training cohort and 0.659 in the testing cohort. Conclusion In this large, multi-institutional cohort of patients with RRMM treated with cilta-cel, we identified clinical factors associated with lower risk for early severe toxicities, supporting outpatient administration and the potential for earlier discharge in selected patients, particularly those who are fit and have low disease burden. Our findings provide a practical framework to guide risk stratification and outpatient CAR T management strategies, particularly in light of evolving regulatory guidance and growing RW experience with cilta-cel.

Abstract Introduction: Ciltacabtagene autoleucel (cilta-cel) is a highly effective BCMA-redirected CAR T-cell therapy for RRMM. While the pivotal CARTITUDE-1 trial established a target dose of 0.75 x 10^6 CAR+ viable T-cells/kg, the approved cell dose is 0.5-1.0 x 10^6 and the optimal dosing strategy to balance efficacy and toxicity remains unclear. This question is of interest given that a dose-response association has been demonstrated for idecabtagene vicleucel (a related BCMA-directed CAR T product). It has also been hypothesized that lower doses of cilta-cel may be associated with reduced toxicity. This study aims to evaluate the association between cilta-cel dose and key efficacy and toxicity outcomes using a large, real-world dataset from the US Multiple Myeloma Immunotherapy Consortium. Methods: We conducted a multicenter, retrospective analysis of 751 RRMM patients treated with commercial cilta-cel across 15 US academic centers. The administered cilta-cel dose (million cells/kg) was categorized into four groups: low (<0.5), standard-low (0.5 to <0.6), standard (0.6 to <0.8), and standard-high (0.8 to 1.0). We compared incidence rates of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), delayed neurotoxicity (DNT), and immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) across these dose categories using logistic regression. Best response rates and progression-free survival (PFS), estimated using the Kaplan-Meier method, were also compared, with differences assessed using the log-rank test for the latter. Results presented are derived from multivariable models adjusting for extramedullary disease, ECOG status, penta-refractory disease and receipt of bridging therapy. Results: Among 751 infused patients, the dose distribution was: <0.5 (n=33), 0.5 to <0.6 (n=131), 0.6 to <0.8 (n=550), and 0.8 to 1.0 (n=37). The four dose groups were well-balanced in terms of baseline patient and disease characteristics, including age, high-risk cytogenetics, and extramedullary disease, with the exception of t(14;16), which was more common in the standard-low and standard dose groups (p=0.006). There were no statistically significant differences in the rates of any grade CRS (p=0.11), any grade ICANS (p=0.84), grade ≥3 ICANS (p=0.36), duration of CRS (p=0.18) or ICANS (p=0.64), or IEC-HS (p=0.16) across the four dose categories. Time to onset of CRS was shorter for the standard-high dose compared to the low dose (6 days vs. 8 days; p=0.08). Importantly, there was no significant difference in the rate of DNT (3.0%, 9.2%, 8.8%, 5.4%; p=0.24). Similarly, there was no significant difference in overall response rates (97%, 96%, 96%, 88%; p=0.50) or complete response rates (75%, 65%, 75%, 66%; p=0.10) by dose. The median follow-up was 12.3 months (IQR: 6.9, 20.5). For patients who received a standard-low dose (0.5, 0.6), the median PFS was 17.5 (IQR: 13.5, NR) months. For the standard dose range of (0.6, 0.8), the median PFS was 28.7 (95% CI: 19.8, NR) months, while the median PFS for the standard-high dose (0.8, 1.0) was not reached. For the low dose range of <0.5, the median follow up was only 8.7 months, which did not allow reliable estimation of the median PFS. While the overall difference in PFS among the groups did not reach statistical significance by the log rank test, there was a clear trend toward improved PFS with higher cell doses in the multivariable model, with outcomes clearly ordered in the same direction as the cell dose categories. A similar trend was also evident in the rates of 12-month PFS which showed an improvement with increasing dose (62% ,67%, 73%, 80%). Conclusions: In this large, real-world cohort of RRMM patients treated with cilta-cel, a lower cell dose was not associated with reduced incidence or severity of CRS, ICANS, DNT, or IEC-HS. Conversely, a dose-response correlation with PFS was observed, with higher doses trending toward longer median and 12-month PFS. It remains unknown if a lower cell dose in the commercial setting reflects poor T cell quality, yet these findings suggest that dose reduction of cilta-cel may not be an effective strategy to mitigate toxicities and might be associated with a trend toward lower efficacy. Therefore, the standard target dose should be utilized to maximize patient outcomes and further prospective dose exploration is warranted.

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 Background: Real-world data suggest that safety and efficacy of ide-cel and cilta-cel mirror data from pivotal trials, yet older adults remain underrepresented. We report outcomes of the largest cohort of RRMM patients aged ≥75 years receiving CAR-T and compare them with propensity-matched younger patients. Methods: We retrospectively analyzed RRMM patients receiving standard-of-care BCMA CAR-T at 15 centers from the US Myeloma Immunotherapy Consortium between May 2021 and December 2024. Patients ≥ 75 years were 2:1 propensity-matched to patients < 75 based on CAR-T product, sex, performance status, extramedullary disease, baseline ferritin, penta-refractory status, bridging therapy, prior autologous SCT and lines of therapy. Continuous outcomes were analyzed with multivariable linear regression, binary outcomes with logistic regression, and time-to-event endpoints with Cox proportional-hazards models. We estimated average treatment effects via G-computation, using cluster-robust standard errors to account for the matched sets. Results: After 2:1 propensity matching, the cohort included 194 patients ≥ 75 years (cilta-cel: 64 and ide-cel: 130) and 388 patients < 75 years (cilta-cel: 128, ide-cel: 260). Median ages were 78 (range: 75-90) for the older cohort vs 65 (range: 35-74) for the younger cohort. The older cohort had a higher frequency of t(14;16) (9% vs. 3%, p = 0.005), lower baseline ferritin (151 vs. 196 ng/mL, P = 0.046), and lower likelihood of prior ASCT (57% vs. 71%, P = 0.001). Median prior lines of therapy were 5. Median follow-up time for ≥ 75 and < 75 groups for cilta-cel was 11.5 and 11 months and for ide-cel was 16 and 24.3 months, respectively. ORR did not differ amongst the older vs younger patients: cilta-cel (97% vs. 97%) and ide-cel (90% vs. 88%).For patients ≥ 75 years, median PFS with cilta-cel was 28.7 months (95% CI: 13.3–NR) and with ide-cel was 16.4 months (95% CI: 12.1–22.4). In patients < 75 years, median PFS was not reached for cilta-cel but was 11.5 months (95% CI: 9.6–12.7) for ide-cel, reflecting inferior PFS with ide-cel in the younger group (HR 0.4, 95% CI 0.3–0.6). On sensitivity analysis by Cox proportional hazards model, we did not observe any statistically significant differences in PFS in older vs younger patients receiving cilta-cel, although older patients paradoxically had better PFS with ide-cel compared to their matched younger cohort. In the cilta-cel cohort, HR for PFS for older vs younger patients was 1.48 (95% CI:0.77-2.84; p=0.2) and in the ide-cel cohort it was 0.7 (95% CI: 0.5, 0.98; p=0.04). Median OS was reached only in the < 75-year ide-cel cohort at 40 months (95% CI: 32.5–43.5). Rates of CRS were similar, with any-grade (grade ≥3) CRS seen in 74% vs 78% (0% vs. 0.8%) of cilta-cel recipients and 86% vs. 87% (3.1% vs. 1.5%) of ide-cel recipients in the older vs younger groups, respectively. ICANS rates were 21% vs. 20% for cilta-cel (p = 0.79) and 29% vs 20% for ide-cel (p = 0.07), with similar rates of grade ≥ 3 ICANS. In the cilta-cel cohort, Parkinsonian delayed neurotoxicity (DNT) occurred in 3/62 (4.8%) older patients and 6/128 (4.7%) younger patients. Similarly, other non-Parkinsonian DNT rates were similar across age groups, with 6.4% vs 5.5% in older vs younger cilta-cel cohort and 0% vs 1% in the older vs younger ide-cel cohort. Rates of IEC-HS, and infections were comparable across the cohorts. There was no difference in hospital length of stay and ICU admission rate between products within either age cohort. The overall non-relapse mortality (NRM) was 6.7% for patients ≥ 75 years and 6.2% in patients < 75 years. For cilta-cel, NRM in older vs younger cohort was 9.4% vs 4.7% (p= 0.96) and for ide-cel it was 5.4% vs 6.9%, respectively (p= 0.65). Conclusion: Appropriately selected older adults (≥75 years) receiving CAR-T therapy for RRMM can derive a similar efficacy benefit with CAR-T as a propensity-matched younger cohort, without any increased signal of toxicity including CRS, ICANS or delayed NT. NRM was numerically greater, but not statistically significant, in older adults receiving cilta-cel. Median PFS with cilta-cel and ide-cel in older adults were 28.7 months and 16.4 months with median OS not reached and 40 months, respectively. Older adults, ≥75 years old, should not be excluded from CAR-T therapy solely due to advanced age. Overall, cilta-cel was not associated with worsened toxicities in older adults and may offer better PFS.

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: Prolonged cytopenias are a well-recognized complication following CAR-T therapy, leading to increased morbidity and healthcare utilization. Autologous SCB offers a potential strategy to promote hematologic recovery. We conducted a retrospective multi-institutional analysis across 18 centers comparing outcomes of SCB versus supportive care alone in RRMM patients who experienced prolonged cytopenias >30 days after CAR-T infusion. Methods: Patients were included if they received SCB within 1 year after commercial CAR-T between 6/2021 and 3/2024. To identify matched controls, we reviewed other CAR-T recipients from the same consortium and selected those with an absolute neutrophil count (ANC) of <0.72x109/L and platelet count of <21K at day 30 post-infusion-thresholds representing the 75th percentile of cytopenia severity in the SCB cohort. These criteria ensured control patients had comparable hematologic toxicity but without SCB. Hematologic recovery in the SCB cohort was assessed using the CIBMTR engraftment criteria. For the non-SCB (nSCB) group, cell counts were analyzed cross-sectionally at day 90 post-CAR-T and compared to the SCB cohort with Kruskal Wallis tests. Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan Meier methods. Results: Of the 590 CAR-T recipients, 91 patients (15.4%) developed prolonged cytopenias; 39 patients received SCB and 52 did not. SCB patients more frequently had ISS stage III disease (23.1% vs. 11.5%), exrtamedullary disease (59% vs. 46.2%) and penta-refractory status (43.6% vs. 34.6%). The median number of prior lines of therapy was 6 in both cohorts. Thirteen patients (33.3%) in the SCB and 11 (21.2%) in the nSCB received high intensity infusional chemotherapy (DCEP/PACE/HyperCVAD). Pre-CAR-T cytopenias tended to be less frequent in the SCB vs. nSCB cohort: ANC <1000 in 5.1% vs. 13.5%, Hgb <8 in 23.1% vs. 21.2%, and platelets <50K in 28.2% vs. 40.4%. Median plasmacytosis in the bone marrow prior to CAR-T in the SCB group was 35% and 47.5% in the nSCB group. In the SCB cohort, 2 patients harbored DNMT3A mutations, one of whom had CCUS. Ide-cel was administered in 64.8% and cilta-cel in 35.2% of all patients. The rates and grades of cytokine release syndrome did not differ between groups. Six patients (15.4%) had HLH in the SCB group vs. none in the control group. All (100%) SCB patients received growth factor support; 58% also received TPO agonists. In the nSCB group, 43 patients (82.7%) received growth factor, and 16 patients (30.8%) received TPO agonists. Out of 24 pre-SCB bone marrow biopsies available, only 1 patient had relapsed MM while the remainder had hypocellular marrows. Median CD34+ cell dose was 2.93 million/kg (range: 1.76-23.55) administered at a median of 53 days post-CAR-T (range 24-265). All but one patient (97.4%) in the SCB group achieved hematologic recovery; median time to recovery was 24 days (range 9-87). No new toxicities attributable to SCB were observed. On day 90 post CAR-T infusion, SCB patients had higher median ANC (2.12 vs. 1.59x109/L, p=0.277), Hgb (10.6 vs. 8.7g/dL, p=0.002), and platelet counts (135 vs. 35K/L (p<0.001). Minimal residual disease negativity was achieved in 82.4% (SCB) vs. 83.3% (nSCB). Infections occured in 53.8% and 48.1% of SCB and nSCB cohorts. All serious infections occurred prior to SCB. There were 12 deaths in the SCB group (7 from disease progression, 2 from infection, 1 from neurotoxicity (NT), and 1 unknown) and 27 in the nSCB group (22 from progression, 3 from infection, 1 from HLH, 1 from NT). After a median follow-up period of 12.6 months in the SCB cohort and 11.6 months in the nSCB arm, the mPFS was 11.0 months and 8.2 months, respectively. The mPFS was 10.6 months (SCB) and 5.8 months (nSCB) (p=0.216), and 11.0 months (SCB) and 10.9 months (nSCB), for ide-cel and cilta-cel treated-patients, respectively. Median OS was not reached vs.12.3 months in the SCB vs. nSCB groups, respectively. Conclusion: Overall, SCB was safe and effective in promoting rapid hematologic recovery in nearly all patients. Compared to controls, SCB recipeints had significantly higher Hgb and platelet levels by day 90 post-CAR-T infusion. SCB was associated wih a near doubling of PFS in patients who received ide-cel, though interpretation is limited by non-randomized design and small sample size. Further study is needed to optimize paient selection, timing, and integration of SCB into CAR-T care.

Abstract Introduction Ciltacabtagene autoleucel (cilta-cel) has demonstrated unprecedented response rates and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM), but a proportion of patients experience early relapse. Identifying these patients is essential to guide future therapeutic strategies, such as enhanced bridging therapy or consolidation, while avoiding overtreatment in those likely to achieve durable disease control. Methods We conducted a multi-center study of patients treated with cilta-cel at 15 U.S. academic centers. Outcomes were evaluated based on high-risk (HR) features, including functional HR disease (FHR; relapse within 18 months of first-line therapy initiation), true extramedullary disease (EMD), traditional HR cytogenetics as defined in CARTITUDE-1 [deletion 17p, t(4;14), t(14;16)], and a 2024 IMS-IMWG-adapted HR definition (deletion 17p; t(4;14) or t(14;16) with gain 1q or deletion 1p; and gain 1q with deletion 1p). Multivariable Cox regression was used to examine the association of HR features (FHR, adapted IMS-IMWG HR, and EMD, individually and collectively) with PFS while adjusting for baseline ferritin, prior BCMA, and ECOG performance status (PS ≥2). Among patients with ≥18 months of follow-up, we evaluated predictors of early relapse (≤18 months post infusion) using logistic regression. Results Our cohort included 598 patients treated with cilta-cel between 5/2022 and 12/2024 who had available data on all HR features. The median age was 65 years (range 33-83), and the median prior lines of therapy (pLOT) was 5 (range: 1-18, 84% with >3 pLOT); 8% had received prior BCMA-directed therapy, and 27% were penta-refractory. Most patients (88%) received bridging therapy and 30% achieved ≥ partial response. In our cohort, 33% (n=195) had FHR, 43% (n=258) had traditional HR cytogenetics, 42% (n=253) had adapted IMS-IMWG HR disease, and 11% (n=64) had EMD. Median follow up was 10.6 months (range 0.4-34.1). Overall response rate (ORR) and complete response (CR) rates were lower in patients with vs without HR features: FHR (ORR: 89% vs 94%, CR: 61% vs 75%), traditional HR (ORR: 90% vs 94%, CR: 65% vs 74%), adapted IMS-IMWG HR (ORR: 91% vs 94%, CR: 64% vs 75%) and EMD (ORR: 77% vs 94%, CR: 61% vs 71%). Corresponding 12-month PFS was also lower in patients with vs without HR features: FHR (55% vs 79%), traditional HR (63% vs 78%), adapted IMS-IMWG HR (61% vs 80%) and EMD (59% vs 73%). ORR, CR rate, and 12-month PFS in patients without any HR features compared to those with ≥1 HR feature were 96% vs 90%, 81% vs 64%, and 83% vs 65%, respectively. In multivariable models, each HR feature (FHR, adapted IMS-IMWG HR, and EMD) was independently associated with inferior PFS after adjusting for baseline ferritin, prior BCMA, and ECOG PS ≥ 2. However, because early relapse cannot always be identified a priori based on traditional risk factors, we sought to identify predictors of relapse within 18 months of cilta-cel in a subset of patients with ≥18 months of follow-up (N=247; infused by 12/2023). Notably, while FHR (OR=3.04, 95% CI=1.59-5.89) and adapted IMS-IMWG HR (OR=2.07, 95% CI=1.10-3.89) were independently associated with odds of relapse within 18 months, EMD was not (OR=0.90, 95% CI=0.32, 2.40) when accounting for prior BCMA, ECOG PS ≥ 2, and baseline ferritin. We also used a time-varying Cox model to examine each HR feature associated with PFS at two time periods, <18 and ≥18 months, while adjusting for baseline ferritin, ECOG PS, and prior BCMA. We confirmed that FHR and adapted IMS-IMWG HR were both associated with relapse <18 months (HR=2.05, 95% CI=1.48-2.83 and HR=1.56, 95% CI=1.11-2.19) but not in the ≥18-month time period (HR=0.70, 95% CI=0.19-2.59 and HR=0.76, 95% CI=0.24-2.40). The magnitude of the association for EMD with PFS was similar across both time periods (<18 months HR=1.67, 95% CI=1.09-2.57 and ≥18 months HR=2.17, 95% CI=0.45-10.40). Conclusion While cilta-cel leads to high response rates and durable PFS in RRMM, a subset of patients with FHR and adapted IMS-IMWG HR remains at increased risk for early relapse. In this large multi-center cohort, we describe PFS outcomes across high-risk subgroups and identify key predictors of relapse within 18 months of cilta-cel. These findings inform risk-adapted therapeutic strategies and interventional trials, including bridging, consolidation, or maintenance approaches, to improve outcomes in the highest-risk RRMM patients.