Citations

Abstract Despite significant therapeutic advances in multiple myeloma (MM), outcomes in patients with plasma cell leukemia (PCL) remain dismal. We conducted a multicenter retrospective analysis of patients with PCL who were treated with the B-cell maturation antigen–directed chimeric antigen receptor T-cell (CAR-T) products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). We identified 34 patients; 19 patients received ide-cel and 15 received cilta-cel. With a median follow-up of 11.9 months, the overall median progression-free survival (mPFS) was 9.0 months (95% confidence interval [CI], 4-15) and the median overall survival (mOS) was 13.0 months (95% CI, 8 to not estimable [NE]). The 1-year cumulative incidence of progression or death was 72%, and the 1-year cumulative incidence of death was 47%. Patients who received cilta-cel had a longer mPFS (19.0 months vs 6.0 months) and mOS (>23 months [NE] vs 9.0 months) when compared with those treated with ide-cel. Similarly, the 1-year cumulative incidence of disease progression or death was 37.5% (95% CI, 17.4-68.5) with cilta-cel, whereas all patients treated with ide-cel progressed or died within 12 months of infusion. The rates of hematologic and nonhematologic toxicities were similar between patients treated with cilta-cel and those treated with ide-cel and were consistent with those reported in patients with MM. In this first multicenter study that evaluated patients with PCL who were treated with standard-of-care CAR-T products, we show that CAR-T is safe, feasible, and associated with improved outcomes when compared with historic standards.

Abstract Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), 2 B-cell maturation antigen (BCMA)–directed chimeric antigen receptor T-cell (CAR-T) therapies, have transformed outcomes for relapsed/refractory multiple myeloma; however, the 6 to 8 weeks manufacturing time risks disease progression or death in up to 10% of patients. Talquetamab, a G-protein–coupled receptor, family C, group 5, member D (GPRC5D)–targeting bispecific antibody, represents a promising option. We performed a multi-institutional retrospective analysis across 20 centers (18 United States, 2 Germany) evaluating talquetamab as a bridging therapy prior to cilta-cel or ide-cel. Among 134 patients receiving talquetamab, 119 proceeded to CAR-T (n = 98 cilta-cel, n = 21 ide-cel). Reasons for not proceeding (n = 15) included progression (n = 7), manufacturing failure (n = 6), or patient decision (n = 2). Median age was 65 years and had median 5 prior lines of therapy. Notably, 85% would not have met CARTITUDE-1/KarMMa eligibility criteria. Talquetamab was administered for a median 23 days. Toxicity was manageable: no grade ≥3 cytokine release syndrome (CRS), 2% grade 3 immune effector cell–associated neurotoxicity syndrome (ICANS) and grade 1 to 2 talquetamab unique toxicities (70% oral, 38% skin, and 17% nail; 60% resolved). Talquetamab achieved 71% response rate. After CAR-T, 88% responded (54% complete response), with low-grade toxicities (2 grade ≥3 CRS, 1 grade 3 ICANS, and 5% grade ≥3 infections). Two cases of facial palsy and 1 acute myeloid leukemia occurred. Talquetamab correlated with sustained soluble BCMA decline and peak CAR-T expansion around day 14. Talquetamab bridging appears safe, enabling the majority of difficult-to-treat patients to successfully proceed to BCMA CAR-T therapy.

Abstract Outcomes of bispecific antibodies in patients with renal impairment (RI) are not well characterized, given the exclusion of these patients from clinical trials. Herein, we evaluated patients with relapsed/refractory multiple myeloma and RI treated with standard-of-care teclistamab. RI was defined as creatinine clearance (CrCl) <40 mL/min. CrCl <30 mL/min or dialysis dependence was defined as severe RI. Of the 384 included patients, 81 (21%) had RI, including 45 (18%) with severe RI, and 18 (5%) on dialysis. Patients with RI were more likely to be older (median age, 71 vs 67 years; P = .002) and have a higher median number of previous lines of therapy (7 vs 6; P = .04). Rates and severity of cytokine release syndrome (51% vs 59%; grade ≥3: 1.2% vs 1%) and immune effector cell–associated neurotoxicity syndrome (16% vs 13%; grade ≥3: 2.5% vs 2.6%) were similar in patients with and without RI, respectively. Patients with RI had higher baseline and day 30 post-teclistamab grade ≥3 anemia and grade ≥3 thrombocytopenia. Renal function did not worsen after teclistamab initiation in most patients with RI outside of the context of disease progression. Overall response rate (52% vs 56%; P = .61) and survival outcomes (median progression-free survival, 4.6 vs 6.5 months; P = .62) were comparable in patients with and without RI, respectively, after a median follow-up of 9.9 months. No differences in overall survival or non-relapse mortality were noted. Our findings suggest that treatment with teclistamab is feasible in patients with RI, including those on dialysis, with a similar safety and efficacy profile to patients without RI.

PURPOSE Idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), two B-cell maturation antigen–directed chimeric antigen receptor (CAR) T-cell therapies have demonstrated remarkable efficacy in relapsed/refractory multiple myeloma (RRMM). We compare safety, efficacy, and survival among patients with RRMM treated with standard-of-care (SOC) ide-cel or cilta-cel. METHODS Data were from a retrospective chart review of patients with RRMM leukapheresed by December 31, 2022, with the intent to receive SOC ide-cel or cilta-cel at 19 institutions. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type. RESULTS A total of 641 patients were leukapheresed by December 31, 2022, with ide-cel (n = 386) and cilta-cel (n = 255). Five hundred eighty-six patients were infused (n = 350 for ide-cel; n = 236 for cilta-cel) with a median follow-up of 12.6 and 13.0 months for ide-cel and cilta-cel, respectively. After IPTW, patient characteristics were well balanced. Cilta-cel was associated with higher likelihood of grade ≥3 cytokine release syndrome (CRS; odds ratio [OR], 6.80 [95% CI, 2.28 to 20.33]), infections (OR, 2.03 [95% CI, 1.41 to 2.92]), second primary malignancies (OR, 1.77 [95% CI, 0.89 to 3.56]), and delayed neurotoxicity (OR, 20.07 [95% CI, 4.46 to 90.20]). Cilta-cel was also associated with better treatment responses (≥complete response: OR, 2.42 [95% CI, 1.63 to 3.60]), longer progression-free survival (hazard ratio [HR], 0.48 [95% CI, 0.36 to 0.63]), and longer overall survival (HR, 0.67 [95% CI, 0.46 to 0.97]). No associations were observed between therapy type and immune effector cell–associated neurotoxicity syndrome, any CRS, severe cytopenia at days 30 and 90, or nonrelapse mortality. We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time period as Food and Drug Administration approval for cilta-cel (≥March 2022). CONCLUSION Cilta-cel demonstrated superior efficacy and survival, with higher incidence of certain toxicities, compared with ide-cel.

Background: Teclistamab (Tec) received regulatory approval for the treatment of relapsed refractory multiple myeloma (RRMM) based on the MajesTEC-1 study. The risk of CRS and ICANS with Tec is well established with a manufacturer's recommendation of inpatient observation for 48-hours for CRS/ICANS monitoring after the initial 3 step up doses. There are limited real-world data on the characteristics of and risk factors for CRS and ICANS with Tec. Such data could inform management of Tec patients (pts), including patient selection for inpatient or outpatient step-up dosing. Methods: RRMM pts treated with standard-of-care Tec across 13 U.S. academic institutions were included in this analysis. The follow-up data cutoff was 30 April 2024. CRS and ICANS classification was based on the American Society for Transplantation and Cellular Therapy consensus grading criteria. Multivariable logistic regression models were fitted to estimate the effects of covariates on CRS and ICANS events, with a particular focus on grade ≥2 CRS, any-grade ICANS, and the combination of CRS grade ≥2 and/or any-grade ICANS. Results: 385 pts were included in the analysis, with a median of 6 lines of prior therapy. Median age was 68 years (range 31-92), 88 patients (25% of pts with available data) had ECOG ≥2, and 301 pts (78%) would have been ineligible for MajesTEC-1. 48 (33%) of 145 evaluable pts with a baseline bone marrow (BM) prior to Tec had >50% BM plasma cells, 139 pts (36%) had extramedullary disease (EMD) (either paraskeletal or true-EMD) and 5 pts (1%) had plasma cell leukemia prior to start of Tec. 224 pts (59%) received Tec with an accelerated step-up dosing regimen, defined as having at least one step-up dose interval of ≥ 2 days. 220 pts (57%) developed any-grade CRS [Grade 1: 46% (N=179), grade 2: 10% (N=37), grade 3: 0.8% (N=3), grade 4: 0.3% (N=1)]. Median time to CRS from start of Tec was 3 days (range, 0-15). Fifty-four pts (14%) developed any-grade ICANS [Grade 1: 7% (N=26), Grade 2: 5% (N=18), grade 3: 3% (N=10), grade 4: none]. There were no grade 5 CRS or ICANS events. Median time to onset of ICANS from start of Tec was 4 days (range, 0-25). There was one case of hemophagocytic lymphohistiocytosis in the entire cohort. 38% of pts received tocilizumab and 17% of pts received corticosteroids. In univariate analysis (UVA), baseline platelet <50, triple-class refractory, penta-refractory status, and EMD prior to start of Tec were associated with increased risk for CRS grade ≥2 (p-values <0.1) and incorporated in MVA. Baseline platelet <50, age >60, ECOG ≥2, Hgb <8 g/dL, BM plasma cells >50%, and ferritin or CRP in the upper quartile were associated with increased risk for any-grade ICANS in UVA (p-values <0.1). Baseline platelet <50, ECOG ≥2, Hgb <8 g/dL, BM plasma cells >50%, ferritin or CRP in the upper quartile, and prior BCMA exposure were associated with increased risk of CRS grade ≥2 and/or any-grade ICANS in UVA (p-values <0.1). Accelerated step-up dosing, renal impairment (CrCl < 30 mL/min) and baseline LDH in the upper quartile were not associated with an increased risk of either CRS or ICANS in UVA. Baseline BM plasma cells >50% was excluded from multivariable analysis (MVA) due to high number of missing data, since most pts (62%) did not undergo BM biopsy prior to start of Tec. In MVA, risk factors for CRS grade ≥2 included baseline platelet <50 at the start of Tec treatment (OR: 2.35, 95% CI 1.08-5.08; p=0.03) and penta-refractory disease (OR: 2.48, 95% CI 1.13-5.45; p=0.02). Risk factors for any-grade ICANS included platelet <50 (OR: 4.18, 95% CI 1.88-9.28; p=0.0004), age >60 (OR: 7.54, 95% CI 1.63-34.89; p=0.01) and CRP in the upper quartile (OR: 2.51, 95% CI 1.16-5.43; p=0.02). Risk factors for CRS grade ≥2 and/or any-grade ICANS included platelet <50 (OR: 2.65, 95% CI 1.42-4.94; p=0.002) and ECOG ≥2 (OR: 2.07, 95% CI 1.19-3.61; p=0.01). Conclusions: This real-world analysis of RRMM pts treated with Tec revealed comparable rates CRS and ICANS relative to the MajesTEC-1 study, and these were mostly limited to grade 1/2. MVA demonstrated a significantly higher risk of CRS grade ≥2 and/or any-grade ICANS in pts with baseline platelet <50 and/or ECOG ≥2, the former may reflect BM disease burden. These results may help identify pts who are at higher risk for IEC related toxicities with Tec that would warrant inpatient monitoring during initial step-up dosing. OP, AA, & LF: co-first authors. AG, HCL & JK: co-senior authors

*Authors contributed equally. Introduction. Two chimeric antigen receptor (CAR) T-cell therapies have been FDA approved for patients with relapsed/refractory multiple myeloma (RRMM): idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). Prior work from our consortium identified racial and ethnic differences in safety and response to ide-cel among patients treated in the standard of care (SOC) setting; despite these differences, survival was similar across race and ethnicity. Here, we extend this work to investigate racial and ethnic differences in safety, efficacy, and outcomes in a larger cohort of patients treated with SOC ide-cel with longer follow-up and patients treated with SOC cilta-cel. Methods. Data for RRMM patients who underwent leukapheresis by 12/31/2022 and were treated with SOC ide-cel or cilta-cel were pooled across 19 institutions in the U.S. Multiple Myeloma Immunotherapy Consortium. We compared Non-Hispanic White, Non-Hispanic Black, and Hispanic (any race) patients, excluding other racial and ethnic groups due to small sample sizes that precluded sub-group investigations. Separately for each CAR T-cell therapy, racial and ethnic differences in baseline patient characteristics, safety, and treatment responses were examined using chi-square and Kruskal-Wallis rank sum tests. Kaplan-Meier survival curves and log-rank tests were used to examine progression-free survival (PFS) and overall survival (OS) by race and ethnicity. Results. Among 332 RRMM patients treated with ide-cel, Non-Hispanic Black and Hispanic patients comprised 17% and 10% of the cohort, respectively. Hispanic patients were younger at infusion compared to Non-Hispanic Black and Non-Hispanic White patients (55.5 vs. 63 vs. 66 years, p<0.001). Non-Hispanic Black patients had a higher disease burden (≥ 50% bone marrow plasma cell percentage) compared to Non-Hispanic White and Hispanic patients (35% vs. 20% vs. 19%, p=0.05), while a higher proportion of Non-Hispanic White patients had high-risk cytogenetics compared to Non-Hispanic Black and Hispanic patients (37% vs. 23% vs. 10%, p=0.003). Non-Hispanic Black patients were more likely to develop severe (≥ grade 3) cytopenia at day 30 (p<0.001) and day 90 (p=0.01) post-infusion, and these differences were particularly driven by higher rates of severe neutropenia among Non-Hispanic Black patients at these time points. Non-Hispanic White patients were more likely to achieve a best response of partial response (PR) or better (82%) compared to Non-Hispanic Black (75%) and Hispanic patients (63%, p=0.02). No other racial and ethnic differences in baseline patient characteristics (including cytopenias), safety, PFS, and OS were observed (p>0.05). Among 222 RRMM patients treated with cilta-cel, Non-Hispanic Black and Hispanic patients comprised 12% and 9% of the cohort, respectively. At baseline, Non-Hispanic Black and Hispanic patients were more likely to have anemia (p=0.01), and Non-Hispanic Black patients were more likely to have thrombocytopenia (p=0.02) and neutropenia (p=0.06) compared to Non-Hispanic White patients. No other differences in baseline patient characteristics were observed by race and ethnicity. While not statistically significant, a higher rate of severe (≥ grade 3) cytopenia at day 90 post-infusion was observed among Non-Hispanic Black and Hispanic patients compared to Non-Hispanic White patients (33% vs. 44% vs. 21%, p=0.07), similar to the ide-cel cohort. This finding was primarily driven by higher rates of severe neutropenia among Non-Hispanic Black patients and higher rates of anemia among Hispanic patients. No other racial and ethnic differences in safety, responses to cilta-cel, PFS, or OS were not observed in the cilta-cel cohort (p>0.05). Conclusion. In a large cohort of RRMM patients treated with SOC ide-cel or cilta-cel, we observed a higher rate of cytopenias post-infusion and inferior ide-cel responses among racial and ethnic minority patients compared to Non-Hispanic White patients. Despite these differences, survival was similar across race and ethnicity, suggesting that both available CAR T-cell therapies for RRMM patients can be utilized across all populations. Future studies that include larger patient cohorts of racially and ethnically diverse patients should be conducted to confirm these findings and additionally evaluate long-term outcomes.

Background: Teclistamab (Tec), a first-in-class BCMA bispecific T-cell antibody, received regulatory approval for the treatment of RRMM based on the MajesTEC-1 study [Moreau et al, NEJM, 2022] which demonstrated an overall response rate (ORR) of 63% and median progression free survival (PFS) of 11.3 months. However, less than 15% (N=24) of patients (pts) enrolled in MajestTEC-1 were ≥75 years, an age cohort that is often underrepresented in clinical trials and comprises approximately one third of MM pts at diagnosis [SEER 22 2017-2021]. In this multicenter retrospective study, we report the real-world safety and efficacy of a large cohort of elderly (≥75 years) RRMM pts treated with Tec. Methods: Pts with RRMM who received standard-of-care Tec across 13 U.S. academic institutions were included in the study. The follow-up data cutoff was 30 April 2024. Pts were divided by age into two groups: age <75 years (<75 group) and age ≥75 years (≥75 group). High-risk cytogenetic abnormalities (HRCA) were defined as the presence of del(17p), t(4;14), t(14;16) and/or gain or amplification of 1q21. Disease response and progression was evaluated using IMWG criteria. Time-to-event analyses were evaluated using the Kaplan-Meier method. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) assessment was based on the American Society for Transplantation and Cellular Therapy consensus grading. Results: Among 385 pts, 83 (22%) were in the ≥75 group (median age 78, range 75-92) and 302 (78%) in the <75 group (median age 65, range 31-74). Compared to pts in the <75 group, those in the ≥75 group were more often white (78% vs. 63%, p=0.009). Both the ≥75 and <75 age groups had a median of 6 prior lines of therapy, a similar proportion with ECOG ≥2 at start of Tec (29% vs. 24%, respectively; p=0.37), and a high proportion of pts with triple-class-refractory disease (77% vs. 85%, p=0.06) and pts who would have been ineligible MajesTEC-1 (73% vs. 80%, p=0.20). In contrast, pts in the ≥75 group had a lower incidence of adverse MM risk factors compared to the <75 group, including HRCA (44.6% vs. 57.9%, p=0.03), ultra high-risk (≥2 HRCA) MM (12% vs. 24%, p=0.02), extramedullary disease (22% vs. 40%, p=0.02), hemoglobin <8 g/dL (10% vs. 21%, p=0.02) or albumin <3 g/dL (6% vs. 19%, p=0.04) at the time of starting Tec. Moreover, a lower proportion of pts in the ≥75 group had prior autologous stem cell transplantation (43% vs. 72%, p<0.0001) or prior BCMA-directed therapy (33% vs. 55%, p=0.0003). The median time from diagnosis to start of Tec was longer for pts in the ≥75 group (7.21 years vs. 5.81 years, p=0.02). There was no significant difference in rates of any-grade CRS (52% vs. 59%, p=0.27), CRS grade 2-4 (10% vs. 11%, p=0.74) or any-grade ICANS (19% vs. 13%, p=0.12) between the ≥75 and <75 age groups, respectively. Four pts in the entire cohort developed CRS grade 3-4, one of whom was in the ≥75 group. Ten pts developed grade 3 ICANS (none grade 4), three of whom were in the ≥75 group. There was no significant difference between the ≥75 group and <75 group in ORR (62% vs. 53%, p=0.17) and ≥very good partial response (VGPR) rate (53% vs. 44%, p=0.14). After a median follow-up period of 9.9 months (95% CI 9.6-10.6 months), the median PFS in the ≥75 group was 10.7 months (95% CI 6.6-NR) vs. 5.2 months (95% CI 6.6-NR) in the <75 group (p=0.005). At the time of data cut-off, the median overall survival (OS) for pts in the ≥75 group had not been reached (95% CI NR - NR) compared to 16.1 months (95% CI 14.0 - NR) in the <75 group (p=0.048). In multivariable analysis for the entire cohort, age ≥75 was not significantly associated with either PFS (HR 0.87, 95% CI 0.54-1.39; p=0.55) or OS (HR 0.60, 95% CI 0.30-1.19; p=0.15). Conclusions: This analysis of a large cohort of RRMM pts treated with Tec in the real-world setting demonstrates comparable efficacy and safety outcomes in elderly (aged ≥75 years) pts to those reported in the overall study population of MajesTEC-1. The adverse baseline disease characteristics and inferior efficacy in pts <75 years age compared to ≥75 years likely reflect patient selection and prescribing patterns in the early era of access to commercial BCMA bispecific therapy with Tec. In multivariable analysis there was no significant impact of age ≥75 on survival outcomes. OP, DD & LF: co-first authors. KKP, HCL & AGC: co-senior authors

Introduction. Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel), two anti-B-cell maturation antigen (BCMA) CAR T therapies, have demonstrated remarkable responses and improved survival among patients with relapsed/refractory multiple myeloma (RRMM) in the clinical trials and standard of care (SOC) setting. Here, we compare safety, efficacy, and survival for patients treated with SOC ide-cel and cilta-cel. Methods. Data were from a retrospective chart review of RRMM patients leukapheresed by 12/31/2022 with the intent to receive SOC ide- or cilta-cel at 19 institutions in the US Multiple Myeloma Immunotherapy Consortium. An inverse probability of treatment weighting (IPTW) approach was used to compare outcomes by therapy type (cilta- vs. ide-cel), balancing on age, sex, race and ethnicity, performance status, extramedullary disease, high-risk cytogenetics, prior BCMA therapy, bone marrow plasma cells, penta-refractory status, lymphodepleting chemotherapy, baseline ferritin, low cell dose, and bridging therapy response. Logistic regression and Cox proportional hazard models were used to examine the association of treatment type with safety, efficacy, and survival accordingly, while adjusting for IPTW weights. We employed propensity score matching utilizing the same covariates to identify the association of treatment type with progression-free survival (PFS) within relevant patient sub-groups. Results. A total of 641 patients were leukapheresed by 12/31/2022 with ide-cel (n=386) and cilta-cel (n=255). 586 patients were infused (n=350 for ide-cel; n=236 for cilta-cel) with a median follow-up of 13.0 and 12.6 months, respectively. After IPTW, patient characteristics were well-balanced. Patients treated with cilta-cel were more likely to have grade ≥ 3 cytokine release syndrome (CRS) (OR=5.52, 95% CI=1.76-17.30, p=0.004), infections (OR=2.07, 95% CI=1.44-2.97, p<0.001), and delayed neurotoxicity (NT) (OR=20.97, 95% CI=4.75-92.42, p<0.001) compared to patients treated with ide-cel. In the cilta-cel cohort, 24 patients (10%) experienced delayed NT compared to 2 patients (1%) in the ide-cel cohort. Although not statistically significant, patients treated with cilta-cel were more likely to have any second primary malignancies (SPMs) (OR=1.87, 95% CI=0.94-3.71, p=0.08) and any SPMs excluding non-melanoma skin cancers (OR=1.78, 95% CI=0.78-4.10, p=0.2) but no association was observed for odds of hematologic SPMs (OR=0.98, 95% CI=0.26-3.61). No association was observed for therapy type with any or severe immune effector cell-associated neurotoxicity syndrome, any CRS, severe cytopenias, and non-relapse mortality. Compared to ide-cel, cilta-cel was associated with better treatment responses of ≥ complete response (OR=2.38, 95% CI=1.61-3.51, p<0.001) and ≥ partial response (OR=1.74, 95% CI=0.99-3.05, p=0.06). Patients treated with cilta-cel had a longer PFS and overall survival (OS) than ide-cel (HR=0.47, 95% CI=0.35-0.62, p<0.001 and HR=0.63, 95% CI=0.42-0.93, p=0.02, respectively), and these findings were similar in the intention to treat cohort (PFS: HR=0.44, 95% CI=0.34-0.55, p<0.001; OS: HR=0.55, 95% CI=0.41-0.73, p<0.001, respectively). We observed consistent findings when repeating the analyses restricting the ide-cel cohort to patients infused during the same time-period as FDA approval for cilta-cel (≥ March 2022), restricting to patients with data on all covariates, and restricting to sites that contributed data for both products. In a propensity matched population, (n=380; n=190 for cilta-cel and n=190 for ide-cel), patients treated with cilta-cel had superior PFS compared to those treated with ide-cel in most subgroups with respect to age and disease characteristics including extramedullary disease, high-risk cytogenetics, and elevated baseline ferritin (p<0.05). Conclusion. Our results suggest superior efficacy of cilta-cel with a higher incidence of certain toxicities compared to ide-cel in the SOC setting. This study provides valuable information for patient counseling and guiding the selection of CAR T-cell therapy for specific patient populations. Further validation through similar large-scale real-world experiences or prospective studies is needed to confirm our results and enhance applicability in the clinical setting. *DH, LP, & DD are co-first authors * YL, KP, & SS are co-last authors

Introduction: Recent efforts have shed light on the clinical and laboratory factors associated with toxicity and response to BCMA-directed CAR-T therapy in patients with relapsed/refractory multiple myeloma (RRMM). However, a major limitation of current scoring systems lies in their assessment at time of lymphodepletion. Because they are not determined before apheresis, they are ill-equipped to guide patient selection, anticipate level-of-care, or plan pre-emptive toxicity management strategies. We therefore aimed to characterize early predictors of CAR-T toxicity and response. Study Design: In this multicenter observational study, we examined demographic, clinical, and laboratory data across three distinct timepoints: indication (e.g., treatment decision), apheresis, and pre-lymphodepletion (LD). CRS and ICANS were graded according to ASTCT criteria. Hematotoxicity (ICAHT) was graded using EHA/EBMT criteria. Early infections (day 0-100) were defined based on microbiologic data or as a clinical infection syndrome, and graded per Hill et al, Blood 2018. Kaplan-Meier estimates of progression-free (PFS) and overall survival (OS) were compared by log-rank test. Cox proportional hazard models were applied to explore associations between pre-apheresis risk factors and key toxicity and survival outcomes. The CAR-HEMATOTOX (HT) score - encompassing markers of inflammation (e.g., CRP, ferritin) and marrow reserve (e.g., hemoglobin, ANC, platelet count) - was determined at each timepoint (Rejeski et al, Blood 2021). Results: We included 530 RRMM patients treated with standard-of-care cilta-cel (n=184) or ide-cel (n=346) across nine centers. Median age was 65 (range 31-88), median ECOG was 1 (IQR 0-1), and patients received a median of 5 prior lines of therapy (IQR 4-7). The median time from indication to apheresis was 16 days (IQR 7-52), while the median time from apheresis to infusion was 56 days (IQR 46-69). The proportion of high-risk patients by HT score did not change between the pre-apheresis and LD timepoints (19% vs. 20%, p=0.82). Most patients stayed either low-risk (n=388, 73.2%) or high-risk (n=68, 12.8%). However, 35 patients (6.6%) shifted from high-to-low risk, while 39 patients (7.4%) progressed from low-to-high risk - reflecting their response to bridging therapies. We noted considerable differences in morbidity and mortality based on the pre-apheresis HT score. Compared to their low-risk counterparts (score 0-2, n=427), high-risk patients (score ≥3, n=103) were hospitalized longer (12 vs. 15 days, p=0.009) and required more frequent ICU admissions (6% vs. 12%, p=0.05). They exhibited more severe early cytopenias (G3+: 8% vs. 25%, p<0.001) and late cytopenias (G3+: 7% vs. 21%, p<0.001), resulting in increased use of TPO agonists and stem cell boosts. Grade 3 or higher ICANS was also more common in HThigh patients (3% vs. 11%, p=0.006), as were severe infections (14% vs. 27%, p=0.007). We found increased non-relapsed mortality in HThigh patients (1-yr NRM 4.6% vs. 16.1%, p<0.001), but no significant difference in the occurrence of secondary malignancies (p>0.9). With a median follow-up of 12.4 months, HThigh patients showed inferior PFS (1-yr PFS 29% vs. 63%, p<0.0001) and OS (1-yr OS 49% vs. 83%, p<0.0001). Transitioning from a low-to-high score was linked to poor survival (1-yr PFS 26%), while the shift from high-to-low risk was associated with favorable outcomes (1-yr PFS 51%). In a multivariable Cox regression model of pre-apheresis features, a high HT score (aHR 2.52, p<0.0001), prior anti-BCMA therapy (aHR 1.55, p=0.04), history of extramedullary disease (aHR 1.42, p=0.02), and penta-refractoriness (aHR 1.45, p=0.02) were independently associated with PFS. Notably, the presence of more than 3 of these high-risk features defined an ultra-high-risk cohort of 28 patients (5.3%) with particularly dismal survival (1-year PFS 15%). Conclusions: Leveraging granular pre-apheresis data from a large international cohort, we identify early markers of toxicity and response in CAR-T-treated RRMM patients. The HT score - reflecting baseline inflammation and hematopoietic reserve - identified high-risk patients likely to benefit from pre-emptive toxicity mitigation strategies such as prophylactic stem cell collection. Most importantly, we characterize a small yet ultra-high-risk group of RRMM patients in need of more effective bridging and therapeutic options.

Background: Tec is a BCMA-directed bispecific antibody (BsAb) approved for RRMM after ≥4 prior lines of therapy (LOT) based on the MajesTEC-1 trial. However, patients who had previously received a BCMA-DT were excluded from MajesTEC-1. Herein, we evaluated outcomes of RRMM patients with prior exposure to BCMA-DT treated with standard-of-care Tec. Methods: This was a multicenter retrospective cohort study. We compared variables between different groups using Chi-squared and Kruskal-Wallis tests, and assessed progression free survival (PFS) and overall survival (OS) using Kaplan Meier and Cox proportional hazards model. We used the maximally selected rank statistics method to determine the optimal cut-off point for continuous variables to find the most significant difference in PFS among different groups. Results: A total of 385 patients were included in this study. 193 patients had received a prior BCMA-DT, of whom 77%, 22%, and 1% had received 1, 2, and 3 prior anti-BCMA agents, respectively. In patients who had received a prior BCMA-DT, 35% were aged ≥70 years, 24% had ECOG performance status (PS) ≥2, 61% had high-risk FISH, 32% had extramedullary disease (EMD) at Tec initiation, and 42% were penta-refractory. Compared to the cohort without prior BCMA-DT (n=192), patients who were treated with prior BCMA-DT were more likely to have high risk FISH (61% vs 49%, p=0.02), and higher median number of prior LOT (7 vs 5, p <0.001). The specific types of prior BCMA-DTs with the respective overall response rate (ORR) to the most recent prior BCMA-DT were: antibody drug conjugate only (ADC, n=47, ORR 43%), chimeric antigen receptor T-cell therapy only (CAR T, n=99, ORR 86%), BsAb only (n=6, ORR 100%), ADC + CAR T (n=36, ORR 56%), and other ADC/CAR T/BsAb combinations (n=5, ORR 60%). Median follow up was 9.9 (95% CI:9.5-10.6) months. Patients with prior receipt of BCMA-DT had a lower ORR (51.4% vs 61.5%; p=0.012) and ≥very good partial response rate (39.4% vs 52.6%, p=0.009), but similar ≥complete response rate (22.3% vs 24%; p=0.78) to Tec compared to those without prior BCMA-DT. Moreover, patients with prior BCMA-DT had worse median PFS compared to patients without prior BCMA-DT (prior BCMA-DT: 4.6 months, 95% CI: 2.7-7.5; without prior BCMA-DT: 8.2 months, 95% CI: 5.7-12.2; p=0.017). On multivariable analysis incorporating prior BCMA-DT, age, cytogenetics, EMD, and ECOG PS, receipt of prior BCMA-DT was not independently associated with PFS (HR 1.25, 95% CI 0.95-1.64, p=0.1). The estimated 1-year OS rate was 58.9% (95% CI: 51.64-67.2) for the prior BCMA-DT group vs 65.1% (95% CI: 58.1-73.1) for the group without prior BCMA-DT, p=0.16. For the prior BCMA-DT cohort, response rates to Tec were numerically higher in patients who received CAR T (ORR 51.2%) followed by ADC (ORR 45.5%), and bispecific (ORR 30%) as their most recent prior BCMA-DT (p=0.39). No significant difference in PFS was noted when stratifying patients by number of prior BCMA-DTs, types of all prior BCMA-DTs received, type of most recent prior BCMA-DT, or depth of response to most recent BCMA-DT. Patients who responded to Tec had a numerically longer median time from most recent BCMA-DT exposure to Tec initiation compared to non-responders: 10.5 vs 7.5 months, p=0.48. We found that the optimal cut-off for time from last BCMA-DT exposure to Tec initiation was 8.7 months. Patients with > 8.7 months between last exposure to prior BCMA-DT and Tec initiation had a superior median PFS with Tec (8.1 months, 95% CI: 4.6-11.7) compared to patients with < 8.7 months from last exposure to prior BCMA-DT (2.5 months, 95% CI: 1.1-5.7), p=0.001. The toxicity profile for patients with prior BCMA-DT was similar to those who had not received a prior BCMA-DT. Grade ≥2 CRS occurred in 8.7% vs 13% (p=0.18), and grade ≥2 ICANS in 7.7% vs 6.7%, (p=0.85) of patients with and without prior BCMA-DT, respectively. Patients in the prior BCMA-DT cohort were more likely to have grade 3 thrombocytopenia in the first 30 days after Tec initiation (10.7% vs 6.6%; p=0.08). Conclusion: This is the largest study to date of any BCMA-directed BsAb among BCMA-exposed patients. Receipt of prior BCMA-DT was associated with a trend toward worse PFS, although not statistically significant, and lower likelihood of attaining an overall response. Waiting >9 months between sequencing BCMA therapies may be associated with improved PFS. D.D., M.A.V.M., J.A.D: co first authors; F.A., C.F., L.S.: co senior authors