Despite promising outcomes in CAR T-cell therapy for relapsed/refractory multiple myeloma (RRMM), nearly all patients eventually relapse. Resistance and relapse may be driven by CAR T-cell and tumor-intrinsic factors. Here, we developed a mechanistic quantitative systems pharmacology (QSP) model of multiple myeloma growth and CAR T-cell therapy using measurable biomarkers to predict and identify factors associated with response and relapse. The model incorporates key components to explore disease dynamics and CAR T-cell expansion. Our model reproduced published pharmacokinetics and biomarker response data from anti-BCMA and anti-GPRC5D CAR T-cell therapies. We then validated the model using clinical biomarker data from a total of 29 real-world RRMM patients treated with commercial anti-BCMA CAR T. Virtual trial simulations, exploring the impact of variable baseline disease and CAR T characteristics on response, predicted that factors associated with worse outcomes are intrinsic to tumor cells (disease burden, low-antigen expression) and CAR T cells (low CAR T-induced killing rate). Interestingly, simulations suggested that a lower baseline percentage of normal plasma cells is associated with higher overall response. The developed model was also used to predict the outcome of BCMA-targeted and GPRC5D-targeted combination CAR T-cell treatment. Sequential combination therapy simulations predicted a better response in scenarios starting with anti-GPRC5D CAR T infusion, followed by anti-BCMA CAR T infusion. Our model can serve as a framework to investigate response mechanisms as well as multi-antigen targeting, and to optimize clinical trial design and dosing regimens.

BCMA and GPRC5D-directed therapies have shown high efficacy in the treatment of relapsed or refractory myeloma with multiple new immune therapies now approved. Preclinical studies have shown that expression of BCMA and GPRC5D are heterogenous in malignant plasma cells. We conducted a phase I dose escalation trial of the BCMA CAR T cell therapy MCARH125 alone or in combination with the GPRC5D CAR T cell therapy MCARH109 in patients with heavily pre-treated relapsed or refractory multiple myeloma. Patients were treated across three dose levels and the primary objective of establishing safety of the concurrent infusion. The trial is registered in ClinTrials.gov, NCT05431608 and has now completed accrual. We treated 15 patients across 3 dose levels; this included 6 patients who received MCARH125 alone and 9 patients treated with concurrent infusion of MCARH125 and MCARH109. 1 patient each with MCARH 125 alone and the co-infusion of MCARH125 and MCARH109 developed immune effector cell associated hemophagocytic syndrome (IEC-HS). There were no instances of grade 3 or higher cytokine release syndrome (CRS) or immune effector cell associated neurologic syndrome (ICANS). The overall response for co-infusion was 78% with a median PFS of 18.2 months. Correlative analysis suggests that antigen loss maybe an important mechanism of resistance even with dual-antigen targeting and we show for the first time that expansion of one CAR population can limit expansion of the second population, as dual-CAR treated patients had significantly less BCMA-CAR expansion than BCMA-CAR alone treated patients, despite equivalent BCMA CAR T cell doses at infusion.

While CAR T has shown superior efficacy in earlier line of therapy [1, 2] for functionally high-risk multiple myeloma (FHRMM), outcomes with its use in later lines (3+) for FHR disease remain unknown. We describe a single-center experience of FHRMM patients (pts), defined as those with progression of disease (POD) < 24 months of frontline therapy, receiving CAR T-cell therapy. Of the 208 pts treated with CAR T, 117 (56%) had FHR disease and had received median of 5 prior lines of therapy (LOT). FHR pts had higher rates of extramedullary disease (EMD) and progression within 12 months of transplant. Median PFS were 11 and 13 months (p = 0.15), and median OS were 34 and 55 months (p = 0.025) in the FHR and non-FHR groups, respectively. On multivariable analyses, EMD and high disease burden were associated with inferior OS. FHRMM pts receiving CAR T as late LOT had inferior survival outcomes compared to those with non-FHR disease, underscoring the poor prognostic impact of POD < 24 months from frontline therapy. This association was largely driven by active EMD and high disease burden at the time of CAR T, highlighting the potential benefit of utilizing CAR T as an early LOT for FHRMM.

Introduction: Ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) are two chimeric antigen receptor (CAR) T-cell products targeting B-cell maturation antigen (BCMA) that have recently been approved for the treatment of relapsed/refractory multiple myeloma (RRMM) with 1-2 prior lines of therapy, based on the results of CARTITUDE-4 and KarMMa-3 trials. While daratumumab (dara) refractoriness is predictive of inferior outcomes with subsequent therapies, not all patients enrolled in these pivotal trials were refractory to this anti-CD38 monoclonal antibody. Therefore, we conducted a single-center retrospective cohort study comparing the clinical outcomes of RRMM patients who received BCMA-directed CAR T-cell therapy based on their dara refractoriness status. Methods: Our analysis included all patients with RRMM who received ide-cel, cilta-cel, or orvacabtagene autoleucel (orva-cel) between April 2018 and November 2023. All patients were dara exposed and divided into two groups according to their dara refractoriness status: dara refractory (DR) and dara non-refractory (DN). Refractory disease was defined according to IMWG criteria as disease that did not respond to therapy (failing to achieve a partial response or better) or as progressive disease within 60 days of the last administered dose. Key outcomes of interest included progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Survival outcomes were calculated from the date of infusion. Response categories were determined per IMWG consensus definitions. CRS/ICANS were graded based on ASTCT criteria. Results: Of 127 patients included (41% female, age range: 37-86 years) in the analysis, 28 (22%) were considered DN at the time of CAR T-cell infusion. In the DR group (n=99), 41.4% patients received cilta-cel, 31.3% patients received ide-cel, and 27.3% patients received orva-cel. In the DN group (n=28), 50% patients received cilta-cel, 32.1% patients received ide-cel, and 17.9% patients received orva-cel. All patients except one in the DN group were triple class exposed. The analyzed groups (DR vs DN) had comparable rates of patients with ECOG performance status >0 (68.7% vs 60.7%) and high-risk cytogenetic abnormalities (70.7% vs 71.4%), including del(17p)/TP53 mutation, t(4;14), t(14;16), t(14;20), 1q gain/amp and/or del(1p) by FISH analysis. In contrast, the DR group had higher rates of extramedullary disease (EMD) (46.5% vs 28.6%), prior BCMA-directed therapy (24.2% vs 7.1%), prior T-cell-redirecting therapy (13.1% vs 3.6%), high tumor burden (defined as ≥50% bone marrow plasma cells) (28.3% vs 14.3%), and a higher median number of prior lines of therapy (6 vs 4). With a median follow-up of 12 months (range: 1-72 months) for the entire population, best ORR was 77.7% (40% sCR/CR, 22% VGPR, 15% PR) in the DR group vs 85.7% (50% sCR/CR, 14% VGPR, 21% PR) in the DN group. The 12-month PFS was 38% (95% CI: 28-not reached [NR]) in the DR group vs 57% (95% CI: 37-NR) in the DN group (HR: 0.6, p=0.08). The 12-month OS was 74% (95% CI: 64-NR) in the DR group and 86% (95% CI: 68-NR) in the DN group (HR: 0.56, p=0.18). CRS and ICANS rates were similar between the two groups: 74.7% (4% grade ≥3) and 13.1% (2% grade ≥3), respectively, in the DR group, and 78.6% (4% grade ≥3) and 21.4% (0% grade ≥3), respectively, in the DN group. Conclusion: A majority of patients treated with BCMA-directed CAR T for RRMM in this single-center experience were dara refractory. Despite more prior lines of therapy and higher rates of EMD, high tumor burden, prior BCMA-directed therapy, and prior T-cell-redirecting therapy; the DR group showed comparable efficacy outcomes to DN group. Longer follow up with more patients, as well as details of efficacy and safety outcomes with univariate and multivariate analysis will be presented at the meeting.

Introduction: Functional high-risk multiple myeloma (FHRMM) is defined through dynamic assessment of disease kinetics after treatment initiation and is generally associated with poor prognosis. When compared to traditional salvage chemotherapy, CAR T has shown superior efficacy as earlier line of therapy (LOT) (1-2) for FHRMM (CARTITUDE-4). However, outcomes with its use in later lines (3+) for FHR disease remain unknown. Here, we describe a single center experience of FHRMM patients (pts) receiving CAR T-cell therapy. Methods: FHRMM was defined as with progressive disease (PD) <24 months of frontline therapy. Primary objective was to determine efficacy outcomes including best overall response (ORR), progression free survival (PFS), and overall survival (OS). Secondary objective was to determine safety outcomes including cytokine release syndrome (CRS), Immune effector associated neurotoxicity syndrome (ICANS), cytopenias, and infection rates within 90 days post CAR T. Cox regression analyses were performed to determine predictors of efficacy in multivariable analyses (MVA). Results: The study included 177 pts treated with CAR T from 3/2018 until 10/2024 with 103 (58%) FHR and 74 (42%) non-FHR pts. Of these 103 FHR pts, 49 (48%) had PD <12 months of frontline therapy. Median pt age was 65 (range 39-86) years with 63 (36%) pts >70 years of age at time of CAR T infusion. A total of 102 (58%), 47 (27%), and 28 (16%) pts had received ciltacabtagene autoleucel (cilta-cel), idecabtagene viculeucel (ide-cel), and investigational B-cell maturation antigen (BCMA) directed autologous CAR T product, respectively. A total of 64 (36%) pts had extramedullary disease (EMD), 34 (19%) had high disease burden (>50% bone marrow involvement), and 94 (54%) had high-risk cytogenetics (HRCG) defined as presence of deletion 17p, t(4;14), t(14;16) on FISH at the time of CAR T. Median prior LOT was 5 (2-14) with 97% of pts having received 3+ LOT, all pts were triple class exposed, 150 (85%) were anti CD38 monoclonal antibody refractory, and 31 (18%) pts had received prior BCMA directed therapy. Baseline characteristics were balanced between the two groups except FHR pts had higher rates of EMD (42% vs 28%) and HRCG (58% vs 47) and shorter median time from autologous transplant to CAR T (31 vs 70 months) compared to the non-FHR pts. With the median follow-up of 16 (95% CI 15-20) months, no differences were seen in the best ORR (84% vs 80%, p=0.4) or CR or better rates (42% vs 47%, p=0.3) between the FHR and non-FHR groups, respectively. The median PFS were 9.2 and 13 months (p=0.3), with 12-month PFS of 42% and 52% in the FHR and non-FHR groups, respectively. Within the FHR group, pts with PD <12 months of frontline therapy had median PFS of 8.3 months vs 12 months in pts with PD 12-24 months post frontline therapy (p=0.5). On MVA stratified by CAR-T product, EMD (HR 2.38, 95% CI 1.52-3.74, p=<.001), high disease burden (HR 2.35, 95% CI 1.47-3.75, p=<.001), and prior BCMA therapy (HR 2.21, 95% CI 1.24-3.95, p=0.008) were associated with inferior PFS. At data cutoff, median OS were 29 and 55 months (p=0.038), with 12-month OS of 78% and 87% in the FHR and non-FHR groups, respectively. Within the FHR group, pts with PD <12 months of frontline therapy had median OS of 29 months vs 26 months in pts with PD 12-24 months post frontline therapy (p=0.1). On MVA stratified by CAR-T product, after adjusting for all significant covariates, only EMD (HR 2.41, 95% CI 1.32-4.42, p=.004) and high disease burden (HR 2.57, 95% CI 1.39-4.74, p=0.003) were associated with inferior OS. There were no significant differences in the rates of CRS (all grade 76% vs 74%, grade 3+ 5% vs 3.6%), ICANS (all grade 12% vs 11%), cytopenias (all grade 51% vs 57%, grade 3+ 26% vs 19%) and infections within 90 days (all grade 43% vs 47%, grade 3+ 16% vs 15%) between FHR and non-FHR pts, respectively. However, patients with FHR disease had higher rates of grade 3 ICANS (5% vs 0%, p=.032). Conclusion: FHRMM pts receiving CAR T as later LOT have inferior survival outcomes compared to those with non-FHR disease, underscoring the poor prognostic impact of PD <24 months from frontline therapy. This association was largely driven by active EMD and high disease burden at the time of CAR T, highlighting the potential benefit of utilizing CAR T as an early LOT for FHRMM. Our findings need to be confirmed with focus on outcomes of FHRMM with CAR T in clinical trials and real-world evidence.

Introduction/Background: Chimeric antigen receptor (CAR)-T cell and bispecific antibody (BsAb) therapies demonstrated high response rates in relapsed/refractory multiple myeloma (RRMM), yet patients often experience significant toxicities. Data on the incidence, risk factors, and outcomes of acute kidney injury (AKI) following CAR T cell and BsAb therapies in RRMM are scarce. Methods: This retrospective study included 205 patients with RRMM who received either first commercial CAR-T cell therapy (n=112) or commercial BsAb therapy (n=93) at our institution between February 2021 and March 2024. Acute kidney injury (AKI) was defined using KDIGO criteria as follows: stage 1 (creatinine rise ≥0.3 mg/dl or 1.5× baseline), stage 2 (2× baseline), and stage 3 (3× baseline). Incidence of AKI occurring up to 90 days post-CAR-T or BsAb therapy was assessed using cumulative incidence following either therapy or death as a competing risk. Univariable cause-specific Cox regression models were constructed to evaluate association with event-free survival (EFS): defined as the time from infusion of BsAb or CAR-T to the date of disease progression, subsequent treatment, or death from any cause: and overall survival (OS). Chronic Kidney Disease (CKD) was defined as eGFR of <60 ml/min/1.73m2 over 3 months using the CKD Epidemiology Collaboration (CKD-EPI) formula. Results: The prevalence of chronic kidney disease (CKD) at baseline was similar in the BsAB and CAR-T groups, 17% vs. 21%, respectively with two patients on maintenance hemodialysis in each group. Compared to the CAR-T cohort, patients treated with BsAb were older (median age: 71 years vs. 67 years) and had a higher proportion with creatinine clearance (CrCl) <60mL/min (44% vs. 26%) at baseline, a higher proportion of albumin <3.5g/dL (47% vs. 21%), a lower proportion of M-spike < 1.5g/dL (73% vs. 97%), and more high-risk cytogenetics (54% vs. 37%). Among patients treated with CAR-T, fludarabine was omitted in 12% due to shortages and reduced in 34% due to CrCl. In the entire cohort at the day 30 timepoint, highest stage I, II & III AKI were seen in 8.3%, 2.1%, 0.53%, respectively. The cumulative incidence of AKI within 90 days was 16% for any stage. There was no significant difference in the incidence of any-stage AKI at 90 days between CAR-T or BsAb treated patients (17% vs. 14%, p=0.5). All patients recovered from post infusion AKI, except for 2 patients treated with BsAb who died of pneumonia within a month without AKI recovery. The median time to recovery from AKI was 3 days (IQR 1-7) in BsAb group and 2 days (IQR (1- 4) in CAR-T group. In univariable Cox regression models, baseline albumin <3.5g/dL (HR: 2.24, 95% CI: 1.10-4.60, p=0.029), M-spike ≥1.5g/dL (HR: 4.03, 95% CI: 1.93-8.40, p<0.001), and ICANS (HR: 2.85, 95% CI: 1.21-6.70, p=0.029), were associated with shorter time-to-AKI, while treatment modality (BsAb vs CAR-T), baseline CKD, and fludarabine use were not. In multivariable analysis, only M-spike ≥1.5g/dL remained significant (HR: 4.11, 95% CI: 1.49-11.3, p=0.009). At a median follow-up of 8.3 months following BsAb and 10 months following CAR-T, AKI was associated with inferior OS by univariable analysis in both BiTE (HR 3.37; 95% CI, 1.68-8.30, p=0.003) and CAR-T (HR 3.49; 95% CI, 1.22-9.98, p=0.035) groups. Patients who developed AKI had significantly lower OS (HR 2.67; 95% CI, 1.25-5.69, p=0.011) in the entire cohort in multivariable analysis, while stratifying by treatment and adjusting for age, cytogenetics, prior lines of therapy, and M-spike. There was no significant association between AKI and EFS. MM and infections are the most frequent primary cause of death. Conclusion: Our study found that in patients with RRMM, higher tumor burden, as indicated by high M-spike, increases the risk of AKI following BsAb and CAR T-cell therapies. The overall incidence of AKI was low, and AKI was reversible in most patients. AKI was associated with inferior survival highlighting that AKI, even if transient, may be a poor prognostic marker. Larger studies can help corroborate these findings which suggest that pts with pre-existing CKD can undergo BsAbs and CAR-T therapy without worsening of their renal function and that AKI in the immediate post therapy setting is usually transient and reversible.

B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio [IRR] = 0.43, 95%CI 0.25−0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31−3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05–3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21−0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17–0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.

Introduction: Infections cause significant morbidity among relapsed refractory multiple myeloma (RRMM) patients receiving chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies (BsAbs). Real-world infection data in patients receiving commercial BsAbs and CAR T-cell therapy as standard of care are lacking and necessary to understand risk factors for serious infections, guiding treatment choices, and management strategies. Methods: This isa retrospective single-center study of infectious complications in RRMM patients during treatment with commercial CAR T-cell therapy, idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel), and BsAbs, including teclistamab, elranatamab, or talquetamab between 8/1/2023-6/1/2024. Infections were graded in accordance with Common Terminology Criteria for Adverse Events v5.0. Patients received antiviral and PJP prophylaxis per standardized institutional guidelines. The primary endpoint was rate of total and serious infections (grade ≥3). Secondary objectives included time to first infection and impact of baseline characteristics on infectious complications. Results: A total of 119 patients (55% Female, 68% Caucasian, 19% Black) were included; 69 treated with BsAbs and 50 treated with CAR T-cells. The BsAb group was older (median age 70 vs 66; p=0.041), had more prior lines of therapy (median 6 vs 5; p=0.01), a greater proportion of high-risk cytogenetics (61% vs 20%; p<0.001), a greater proportion of extramedullary disease (43% vs 12%; p<0.001), a lower baseline median hemoglobin (8.8 vs 11.40 g/dL; p<0.001), and a lower baseline median IgG (432 vs 592 mg/dL; p=0.028). Baseline ECOG, neutrophils, lymphocytes, and platelets were similar. Median follow-up was 3.7m (0.13-11.3m) for BsAbs and 5.3m (1.15-10.25m) for CAR T-cells. Overall, 173 infections were reported with 106 amongst 46 (67%) BsAb patients and 67 amongst 26 (52%) CAR T-cell patients. Upper respiratory tract infections were the most common infections amongst both BsAb and CAR T-cell patients (39% and 49%). The BsAb group had a higher proportion of bacterial infections compared to the CAR T-cell group (49% vs 26%), but a lower proportion of viral infections, (47% vs 60%). Fungal infections were uncommon with 4 reported in the BsAb group and 1 in the CAR T-cell group. Recurrent infections (≥2) were more common in the BsAb group (43% vs 28%). A total of 55 serious infections, not including grade 5, were reported with 43 amongst 28 (41%) BsAb patients and 12 amongst 7 (14%) CAR T-cell patients. Grade 5 infections occurred in 5 BsAb patients and 1 CAR T-cell patient. Recurrent serious infections were more common in the BsAb group (20% vs 6%). In a multivariable analysis, CAR T-cell therapy was associated with a lower rate of serious infections (incidence rate ratio [IRR]: 0.25, 95% CI 0.12-0.51;p<0.001). Male sex (IRR: 3.02 95% CI: 1.70-5.57; p<0.001) was also associated with an increased rate of serious infections. The estimated cumulative incidence of first infection was higher in the BsAb group at day 30 (42% vs 24%) and day 90 (57% vs 40%). Estimated cumulative incidence of first serious infection was also higher in the BsAb group at day 30 (23% vs 6%) and day 90 (31% vs 10%). In a multivariable analysis, CAR T-cell therapy was associated with a longer time to first serious infection (HR 0.33, 95% CI 0.13-0.87; p=0.019). Male sex was associated with a shorter time to first serious infection (HR 2.95, 95% CI 1.40-6.21; p=0.003). There were no differences in infection incidence or time to first infection between ide-cel or cilta-cel nor were there differences seen between BCMA-targeted BsAbs, teclistamab and elranatamab, and GPRC5D-targeted talquetamab. Baseline thrombocytopenia (<100k), neutropenia (ANC<1000), lymphopenia (ALC<500), and hypogammaglobulinemia (IgG<400) were not associated with infection incidence or time to first infection. Conclusion: Infections were common amongst RRMM patients treated with commercial BsAbs and CAR T-cell therapy. In a real-world setting with standardized antimicrobial prophylaxis, BsAbs were associated with a higher incidence of total, serious, and recurrent infections which occurred earlier during treatment. The BsAb group had more high-risk features and more severe anemia at baseline likely contributing to infection incidence. Longer follow-up with more patients and extended analysis will be presented at the meeting.

Despite being the mainstay of management for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), there is limited data regarding the impact of tocilizumab (TCZ) and corticosteroids (CCS) on chimeric antigen receptor (CAR) T-cell efficacy in multiple myeloma (MM). The present study aims to evaluate the prognostic impact of these immunosuppressants in recipients of BCMA- or GPRC5D-directed CAR T cells for relapsed/refractory MM. Our retrospective cohort involved patients treated with commercial or investigational autologous CAR T-cell products at a single institution from March 2017–March 2023. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall response rate (ORR), complete response rate (CRR), and overall survival (OS). In total, 101 patients (91% treated with anti-BCMA CAR T cells and 9% treated with anti-GPRC5D CAR T cells) were analyzed. Within 30 days post-infusion, 34% received CCS and 49% received TCZ for CRS/ICANS management. At a median follow-up of 27.4 months, no significant difference in PFS was observed between CCS and non-CCS groups (log-rank p = 0.35) or between TCZ and non-TCZ groups (log-rank p = 0.69). ORR, CRR, and OS were also comparable between evaluated groups. In our multivariable model, administering CCS with/without TCZ for CRS/ICANS management did not independently influence PFS (HR, 0.74; 95% CI, 0.36–1.51). These findings suggest that, among patients with relapsed/refractory MM, the timely and appropriate use of CCS or TCZ for mitigating immune-mediated toxicities does not appear to impact the antitumor activity and long-term outcomes of CAR T-cell therapy.

Introduction/Background: Chimeric antigen receptor (CAR)-modified T cells targeting BCMA have shown high response rates and durable remissions in patients with relapsed or refractory multiple myeloma (RRMM). Since this innovative therapy leverages the patient's own immune system, T cell fitness prior to CAR-T therapy is increasingly important. Acceptable thresholds for absolute lymphocyte count prior to apheresis which have prognostic impact are not clearly defined. This real-world analysis investigated pre-apheresis (A) and pre-lymphodepletion (LD) ALC, and the ALC reduction between A and LD, on survival outcomes post CAR-T for RRMM. Methods: This was a single center, retrospective analysis of patients with RRMM who received commercial BCMA-directed CAR-T cell therapy, ciltacabtagene autoleucel (cilta-cel) and idecabtagene vicleucel (ide-cel) between August 2021 and May 2023. We assessed the impact of Pre-A and Pre-LD ALC as well as the reduction in ALC (measured as the difference between pre-LD and pre-A ALC) on the progression-free survival (PFS) and overall survival (OS) using the Cox proportional hazard models. Result: Of the 54 patients included, 63% (n=34) received ide-cel and 38% (n=20) received cilta-cel. The median age was 65 years (range, 41-86) and 61% were male. Revised international staging system (R-ISS) stages I/ II/ III were 24% /41% /13%, respectively. 49% (n=26) had extramedullary disease (EMD) present and 56% (n=30) had at least 1 high-risk cytogenetic abnormality by FISH. Patients received a median of 8 (range, 1-20) prior lines of therapy, and 72% (n=38) received bridging therapy. 38% (n=20) had penta-refractory disease. The median pre-A and pre-LD ALC was 0.8×109/L (range, 0.1-2.2) and 0.8×109/L (range, 0.1-3.1), respectively. The median absolute reduction in ALC was 0.1×109/L (range, -2.8-1.0). Using the lowest quartiles as cutoffs, we defined low pre-A ALC as ≤ 0.5 ×109/L, while a high reduction between pre-A and pre-LD ALC was defined as ≥ 0.1 ×109/L based on the highest quartiles. Compared to patients with high pre-A ALC, those with low pre-A ALC received more bridging therapy (87% vs. 66%) and had a higher incidence of high-risk cytogenetics (73% vs. 49%). In contrast, patients with low and high pre-LD ALC were more balanced in terms of bridging therapy (76% vs. 69%) and high-risk cytogenetics (both 56%). The median follow-up time from CAR-T infusion was 18months. Low pre-A ALC was associated with significantly inferior PFS in univariable analysis (HR 2.09, 95% CI 1.04-4.19, p=0.038); this difference remained significant in multivariable analysis (HR 2.10, 95% CI 1.02-4.31, p=0.044) along with 1p deletion (HR 2.54, 95% CI 1.07-6.02, p=0.034) and EMD (HR 2.51, 95% CI 1.19-5.30, p=0.015). Additionally, low pre-A ALC was significantly associated with inferior OS in univariable analysis (HR 6.40, 95% CI 2.48-16.5, p<0.001), and remained a poor prognostic factor for OS in multivariable analysis (HR 6.59, 95% CI 2.44-18.8, p<0.001) along with EMD (HR 4.31, 95% CI 1.28-14.5, p=0.018). Neither pre-LD ALC nor a high absolute reduction in ALC showed significant differences in PFS, while pre-LD ALC was significantly associated with worse OS only in the univariable setting without significance in multivariable analysis. No correlation was observed between pre-A ALC and rates of cytokine release syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), however, CRS was significantly more frequently noted in patients with low pre-LD ALC. Conclusion: In this small real-world analysis, results suggest that the pre-apheresis ALC <0.5 ×109/L may be an independent poor prognostic factor on PFS and OS in RRMM treated with CAR-T cell therapy and low pre-LD ALC may predict higher incidence of CRS after CAR-T infusion. Further investigation is warranted to determine the optimal timing of apheresis in patients with low pre-ALC in a larger cohort.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR T) therapy has demonstrated remarkable efficacy in patients with relapsed/refractory multiple myeloma, and now there are two US Food and Drug Administration-approved BCMA-directed CAR T products. However, despite high initial response rates, most patients eventually relapse. The outcomes of patients with disease recurrence after BCMA-directed CAR T have not been comprehensively studied, and such an analysis would help define optimal treatment strategies. We analyzed the salvage treatments and outcomes of 79 patients with multiple myeloma from two academic institutions, who had progression of disease after treatment with BCMA-directed CAR T. A total of 237 post-CAR T salvage treatment lines were used, and patients received a median of 2 (range, 1-10) treatment lines. The median overall survival from the date of relapse post-CAR T therapy was 17.9 months (95% confidence interval [CI], 14.0 non-estimable). The overall response rate to the first salvage regimen was 43.4%, with a median progression-free survival of 3.5 months (CI, 2.5-4.6). Thirty-five patients (44.3%) received a T-cell-engaging therapy (bispecific antibody or subsequent CAR T) as salvage treatment. The overall survival in patients who received subsequent T-cell-engaging therapy was not reached after a median follow up of 21.3 months. Patients with multiple myeloma who relapse after BCMA-directed CAR T have a limited prognosis but can be potentially treated with multiple lines of salvage therapy. T-cell-engaging therapies appear to maintain pronounced clinical activity in this setting.

Introduction: There is limited data comparing infectious toxicities in patients with relapsed/refractory multiple myeloma (RRMM) treated with T-cell engaging therapies, which include chimeric antigen receptor T-cell therapy (CAR-T) and bispecific antibodies (BsAb). There are now three US FDA approved B-cell maturation antigen (BCMA)-targeting T-cell engagers, and several more in ongoing clinical development. Awareness regarding their infectious toxicities may inform treatment selection and mitigation strategies. Methods: We conducted a single-center, observational study in patients with RRMM comparing infectious complications in patients treated with a commercial or investigational autologous BCMA-targeting CAR-T versus patients treated with a commercial or investigational BCMA-targeting BsAb. The date of CAR infusion (day 0) was between 03/22/2017 - 02/27/2023 for the CAR-T patients. For the BsAb cohort, the date of treatment initiation (day 0) was between 01/21/2020 - 02/07/2023. All infection-specific variables were collected from day 0 until the date of next line of therapy or last follow-up, with a data cut-off of 06/01/23. Infectious events were graded according to CTCAE version 5.0. Prophylactic antimicrobials were administered according to institutional and protocol guidelines. The primary endpoint was the incidence of severe (grade ≥3) infections. Secondary objectives included the time to 1 st infection, infection rate over time, infectious organisms, the impact of prolonged cytopenias, and the utility of intravenous immunoglobulin (IVIg) administration in preventing infections. Results: Of the total 147 patients, there were 92 CAR-T and 55 BsAb treated patients. The median age of the CAR-T and BsAb cohort was 62yrs vs 65yrs, respectively (P=0.043). CAR-T patients had a median of 6.5 prior lines of therapy (IQR 5-8) versus 6.0 (IQR 4-9) in the BsAb cohort (P = 0.7); 97% of CAR-T patients had a prior autologous transplant compared to 75% in the BsAb cohort (P < 0.001). In keeping with current clinical practice, 18 patients (33%) in the BsAb cohort had prior exposure to CAR-T whilst no patients in the CAR-T cohort had prior BsAb exposure. The median follow-up duration for infectious events was similar in both groups at 5.8 months (IQR 3.8-9.2) for CAR-T and 4.3 months (IQR 3.2-9.8) for the BsAb cohort. A total of 209 infections were reported: 115 with CAR-T and 94 with BsAb. In the CAR-T cohort 24/92 patients (26%) experienced ≥1 severe infection, all of which were grade 3 and there were no grade 4 or 5 events. A numerically higher incidence was seen in the BsAb cohort with 21/55 BsAb patients (38%) experiencing ≥1 severe infection (P = 0.14). Nineteen BsAb patients (35%) experienced grade 3 infections, 2 (3.6%) had grade 4 infections and 4 (7.3%) had grade 5 infections. Six CAR-T (6.5%) and 10 BsAb patients (18.2%) had >1 grade 3 infection. The incidence of ≥1 severe infection remained high in the BsAb cohort at 16/37 (43%) even after excluding the 18 BsAb patients with prior CAR-T exposure. The median time from treatment initiation to the first infection of any-grade was 2.5 months (95% CI 1.2 - NR) with CAR-T compared to 3.4 months (95% CI 1.6 - 6.8) with BsAb (P = 0.6). The rate of any-grade infections was similar between the two groups early post-therapy (before day 100). However, there was a significantly higher infection rate of any-grade after day 100 with BsAb compared to CAR-T with a median of 0.24 (IQR 0.18 -0 .34) vs 0.13 (IQR 0.08 - 0.17) infections per 30 days, respectively (P < 0.001) (Figure 1A). Regarding the time to the first grade ≥3 infection, 79% occurred within day 100 for CAR-T patients compared to only 48% in the BsAb cohort (Figure 1B). The proportion of bacterial, viral, fungal, and parasitic infections in the CAR-T group was 49% (n = 56), 48% (n = 55), 4.3% (n = 5) and 0.9% (n = 1) respectively, and in the BsAb group was 51% (n = 48), 44% (n = 41), 3.2% (n = 3), and 0 respectively. Conclusion: Infectious complications were common early after BCMA-targeting BsAb and BCMA CAR-T and declined over time. In this real-world comparison, distinct from their CAR-T counterparts, BsAb recipients appeared to have a more persistent infection risk and higher incidence of severe infections, which included four patients having a grade 5 infection. Further analysis, including the impact of prolonged cytopenias and the utility of IVIg administration will be presented at the meeting.

neutropenia (61%), anemia (21%) and thrombocytopenia (21%).On-target off-tumor TEAEs, all G1, included skin TEAEs (30%), dysgeusia (15%), nail TEAEs (9%) and dysphagia (3%).Doselimiting toxicities of prolonged (out to day 42) G4 neutropenia and/ or thrombocytopenia occurred in 2 pts; MTD was not exceeded.Cytokine release syndrome (CRS) occurred in 21/33 pts (19 G1/2; 2 G3).Immune effector cell-associated neurotoxicity syndrome (ICANS)-type neurotoxicity occurred in 2 pts and was low-grade and reversible with steroid treatment.Overall response rate was 89% (17/19) in efficacy-evaluable pts, including 7/9 pts with prior BCMA-directed therapies including CAR T cells.Median follow-up for treated pts was 3.1 mo (range, 0.1-15.5).At data cutoff, 15/17 pts with a response were ongoing.All 4 pts with available minimal residual disease (MRD) data and best overall response of complete response (CR) were MRD-negative (10 -5 depth) at 3 mo.BMS-986393 reduced soluble BCMA levels across all dose levels; BMS-986393 exposure showed dose-dependence.Conclusions: As of data cutoff, dose escalation of BMS-986393 from 25-450 × 10 6 CAR T cells did not exceed MTD.CRS was mostly G1/2.ICANS-type neurotoxicity was infrequent, low-grade and reversible.A minority of pts had on-target off-tumor TEAEs, all G1.BMS-986393 showed durable responses and efficacy at all tested dose levels, including MRD-negative CRs and in pts previously exposed to BCMA-directed therapies.These preliminary data support GPRC5D-directed CAR T-cell therapy with BMS-986393 for treating RRMM, irrespective of prior BCMA-directed therapy.Part B dose expansion is underway.

BCMA-targeted treatments, including CAR-T therapy and bispecific antibodies (Abs), have established remarkable efficacy for relapsed/refractory multiple myeloma (RRMM). With approval of ide-cel and cilta-cel, CAR-T is quickly becoming more widely used. However, prognosis, clinical outcomes, and treatment approaches of patients with MM with relapse after BCMA CAR-T therapy have not been described comprehensively. We collected disease characteristics and post-study outcomes of MM patients with progression of disease after treatment with BCMA CAR-T at 2 academic centers. We identified 140 patients treated with BCMA CAR-T, of which 79 had relapsed disease with ≥1 salvage therapy and were included in this analysis. Median time between MM diagnosis and relapse after BCMA CAR-T (T0) was 74 months. Patients were highly pretreated with median of 5 prior lines (range 1-18) and 64 patients (81.0%) had high-risk characteristics by FISH. Of the 79 patients, 66 (83.5%) were triple-class refractory and 30 patients (38.0%) were penta-drug refractory. Five patients (6.3%) had received prior treatment with (non-BCMA) bispecific Ab. Patients received a median of 2 (range 1-10) salvage treatments. The objective response rate to the first regimen after T0 was 43.8% with a median progression-free survival (PFS1) of 3.5 months. The most common initial salvage treatments were triplets including approved agents (n=33, 41.8%), combination chemotherapy (bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, etoposide (VD-PACE) or bortezomib, dexamethasone, cyclophosphamide, etoposide, cisplatin ((V)DCEP)) (n=13, 16.5%), or a bispecific Ab trial (n=11, 13.9%). Median overall survival (OS) from T0 for the cohort was 17.9 months (14.0-NE months). In total, 35 patients received T cell-redirecting therapy (CAR-T or bispecific Ab) at any point after CAR-T relapse, including second/subsequent salvage regimens. Of note, OS was significantly longer (median not reached, p<0.001) in the 35 patients that received another T cell-redirecting therapy at any point after BCMA CAR-T relapse. In summary, MM patients with relapse after BCMA CAR-T can be salvaged. The choice for specific salvage therapies should be guided by patient characteristics. Development of novel therapies, including immune-mediated treatments, offers potential for multiple lines of salvage therapy contributing to the observed OS, which compares favorably to previous reports of triple-class refractory MM patients.

BACKGROUND: B-type natriuretic peptide (BNP) is a hormone secreted in response to volume-related ventricular stretch, and as a biomarker is both diagnostic and prognostic in heart failure. Elevation in BNP or its equimolar N-terminal prohormone fragment (NT-proBNP, noteworthy for its longer half-life) qualifies as a criterion in ISBT-IHN-AABB guidelines for the diagnosis of transfusion-associated circulatory overload (TACO). However, real-life range comparisons in TACO vs. non-respiratory transfusion reactions (TR) are lacking. In the Transfusion Associated Dyspnea-Prospective Observation and Laboratory Assessment (TADPOL) study of acute TRs requiring laboratory investigation (cardiorespiratory events +/- fever [CRTR+/-F] vs. standalone high-risk fevers [HRFTR]), patients consented to NT-proBNP testing as part of a multi-dimensional assessment of presentation archetypes and final diagnoses (e.g., TACO, transfusion-associated dyspnea [TAD], febrile non-hemolytic TR [FNHTR]). METHODS: Blood samples were collected within 24h of reaction onset from patients enrolled across 6 centers in the study's first 134 weeks. NT-proBNP (ng/L) was quantified by chemiluminescence immunoassay (Roche Diagnostics) in real-time (3 sites) or by batched testing (3 sites); reference cut-off values to rule in a cardiac cause for dyspnea in the acute care setting were >450 (age <50y), >900 (age 50-75y), and >1800 (age >75y). Summary statistics are reported. Relationships to provisional reaction diagnosis and clinical features were also explored using appropriate tests (Student's t-test, Mann-Whitney U, Pearson's correlation, and/or Fisher's exact test). Discrimination between possible-to-definite TACO and doubtful or ruled-out TACO was assessed using receiver operating characteristic (ROC) curve analysis with logistic regression. RESULTS: At the study mid-point, 1180 TR (604 TADPOL-eligible) occurred, with NT-proBNP tested in 77/100 enrolled patients. NT-proBNP was significantly higher in patients enrolled in the CRTR arms compared to HRFTR (p=0.0009), with no difference between CRTR+F and CRTR-F (p=0.4). NT-proBNP was also significantly higher in patients with dyspnea in the TR (p=0.005). There was no correlation between NT-proBNP and systolic blood pressure change (p=0.1) or at baseline (p=0.1). Provisional reaction diagnoses were available for 55 patients including 32/39 in the CRTR arms: for possible-to-definite TACO (n=14) and TAD (n=19), vs. standalone FNHTR (n=38), the median NT-proBNP (IQR) was 3,439 (1,587-10,668) and 1,893 (674-5,361), vs. 710 (124-10,542), respectively. Transfusion-related acute lung injury was considered possible in 3 cases, all with TACO. Among CRTR, there was a trend towards higher NT-proBNP values in patients with TACO (p=0.05), with no difference in ages (p=0.8). Using the age-adjusted reference cut-off, the sensitivity of high NT-proBNP for TACO was 86%; specificity was 54% when differentiating TACO from all enrolled TR and 38% between TACO and non-TACO CRTR. In ROC curve analysis (Fig. 1), the area under the curve was 72% (95% CI 55-88%) and the threshold value for discriminating TACO from other TR was 1606 with 60% sensitivity and 65% specificity (Fig. 2). CONCLUSIONS: NT-proBNP is strongly correlated with dyspneic TRs compared to isolated febrile TRs. Elevations appeared more marked in TACO, with a sensitivity of 86% using existing laboratory reference values. However, specificity and discrimination within CRTR were poor. These results affirm that NT-proBNP is helpful in ruling out TACO, whereas ruling in TACO continues to demand a more integrated approach. Whether cardiac strain in unclassified CRTR and TAD is evidence of missed TACO or other insults remains to be determined. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal