Median Prior Lines Of Therapy Research Articles

Outcomes Multiple Myeloma Patients Progressing after BCMA-Directed Chimeric Antigen Receptor T Cell (CART) Therapy

Background: Chimeric Antigen Receptor T Cell Therapy (CART) targeting B-cell Maturation Antigen (BCMA) has gained approval for Relapsed/Refractory Multiple Myeloma (RRMM) following a minimum of four prior lines of therapy (LOT). Despite the significant improvement in outcomes with a remarkable progression-free survival (PFS) reported in pivotal trials, a substantial proportion of patients (pts) eventually experience disease progression. The available treatment options thereafter are currently limited, and the outcomes in this specific cohort of pts have not been extensively characterized. This study aimed to investigate the clinical outcomes of pts with RRMM who failed BCMA CART therapy, either as standard of care (SOC) or as part of a clinical trial. Methods: We conducted a retrospective analysis as of 7/10/2023 of RRMM pts progressing after BCMA CART and receiving the next LOT at the University of Kansas Medical Center in collaboration with US Myeloma Research Innovations Research Collaborative (USMIRC). Those who received therapy on clinical trial as the next LOT were included. Baseline demographic data were described, and outcomes were evaluated for two subgroups: “early” relapse pts (progression ≤ 6 months) and “later relapse”, those progressing after 6 months. Baseline pt characteristics were outlined by descriptive analyses. Responses including overall response rate (ORR), and complete response or better (>CR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Statistical analysis was done with the use of Fisher's exact test and the Kaplan-Meier method for progression-free (PFS) and overall survival (OS) calculations. OS was calculated from relapse after CAR-T till the last office visit/death. Regression models for univariate and multivariate analysis were performed. Results: Thirty pts were included in the analysis. Baseline demographics is summarized in Table 1. The majority (57%) had extramedullary disease (EMD) and 90% had an ECOG performance status of 0-1. The mean age of the pts was 61.3 years (SD=9.6), with 73% male and 80% White. Pts had 5 median prior LOT. All pts were refractory to PI, IMid, Daratumumab, double-refractory and-triple refractory. 63% were penta-refractory. Sixteen (53%) pts relapsed ≤ 6 mo after CART infusion and 14 (47%) relapsed after 6 months, with median follow-up of 21.73 Months (25-75 IQR: 13.87-40.17 mo). Baseline demographics were similar. The presence of 1p genetic mutation was significantly associated with lower incidence of early progression (early: 0% vs later: 36%, p=0.014). Also, pts with 2 autologous stem cell transplants (ASCT) had later relapses (early: 0% vs later: 43%, p=0.009). Outcomes with next LOT: Of these 30 pts, 10 received BCMA-directed therapies (3 got belantamab mefodotin and 7 received bispecifics (BCMA on Harpoon trial and teclistamab, 2 received GPRC5D targeting bispecific, talquetamab. The rest 18 (60%) got chemo immunotherapies including 1 ASCT and 5 VD-PACE/KD-PACE. 70% of pts progressed on the next LOT. Overall response rate (ORR) was 30%. (Figure 2a). There were 14 deaths, all related to myeloma progression. The median OS was 8.53 months (4.9-NR). Figure 2b summarizes the LOT and OS outcomes. In univariate analysis (UVA), EMD was associated with a significantly higher risk of death (HR=4.15, 95% CI=1.12-15.3, p=0.019), but this was not significant after adjusting in the multivariate analysis (MVA) (HR=2.74, 95% CI=0.63-11.8, p=0.2). Male gender was associated with worse survival in UVA. However, no factors were associated with a higher risk of death in a multivariate analysis. Conclusion: This study describes outcomes for post-CART relapse in RRMM. Most pts do not respond to the first LOT post-BCMA CART relapse. The survival was less than a year, suggesting need for further studies with a longer follow-up and larger sample size to establish the best regimen for CART failure and characterize prognostic factors associated with poor outcomes for CART relapses.

Evaluating the Safety of HCAR19 (Now Actalycabtagene Autoleucel- Actaly-Cel™), a Novel Humanized CD19-Directed Chimeric Antigen Receptor T-Cells in Pediatric, Adolescents, and Young Adults with Relapsed/ Refractory B- Acute Lymphoblastic Leukemia (ESHA) - Report of Phase-1B

Background and aims Chimeric Antigen Receptor (CAR) T-cell therapies for relapsed-refractory Pediatric B-cell Acute Lymphoblastic Leukemia (r/r-B-ALL) show remarkable success but remain prohibitively expensive. We developed and reported a Humanized CD19-directed novel CAR T-cell- HCAR19 (now -Actalycabtagene autoleucel- Actaly-cel™) with robust activity and low toxicity in pre-clinical studies. This led to regulatory approval for the first CART-cell trial in India as a Pilot Phase-1 study (CTRI/2021/05/033348), and it's encouraging safety profile and responses led to approval for a roll-on Phase 1b/2 Trial (CTRI/2023/03/050689) to monitor safety, identify Phase-2 Dose (P2D) and assess efficacy. Trial design permitted pooling of data of both trials for all objectives. We report here the Phase-1b analysis of Actaly-cel in r/r-B-ALL in Pediatric, Adolescents and Young Adults 3-25 years of age. Methods Patients with r/r B-ALL not in remission after 2 or more lines of therapy ineligible for Allogenic-Stem Cell Transplant (Allo-SCT) were included if no CD19-negative blasts population were detected on flow-cytometry records. Those with isolated extra-medullary disease, active neurological involvement/ sequelae, genetic syndromes/prior malignancy, or prior CD19-directed therapy were excluded. Bridging therapy was at physician discretion. Lymphodepletion was with Fludarabine (30mg/m 2) x 3-days and cyclophosphamide (500 mg/m 2) x 2-days. There were 3 Target Doses, TD-1, 2 & 3 CART-cells at 1 x10 6, 3-5 x10 6 and 10-15 x10 6/kg recipient weight respectively. Escalation and de-escalation followed 3+3 design with Coherence-guided dose-decision for bivariates- efficacy and toxicity, allowing all patients to be evaluable. Primary end-point was Overall Response Rates (ORR) at Day-30 on bone-marrow flow-cytometry. Patients were monitored for toxicities, in-vivo dynamics of Actaly-cel, and cytokine profiles. Results Of 12 patients enrolled Actaly-cel was infused in 9 at time of analysis as 2 were withdrawn prior to apheresis (1-progression, 1-withdrawl of consent) while 1 is awaiting infusion. Three patients were assigned TD-1 and 6, TD-2. In TD-2 group, 1 received lower dose (2.13x10 6/kg) due to obesity and weight gain from severe-Covid19 prior to infusion. Median age was 16-yrs (range:8-24), M:F-3:2, median prior lines of therapy were 3 (range:2-5), 6 had high-risk cytogenetics, and median pre-infusion bone-marrow blasts were 19.5%(range:0-88%). Eight patients were evaluable for response and toxicities. All had Grade 3 leukopenia and thrombocytopenia. Peak cytokine release syndrome (CRS) was Grade-3 in 1(12.5%), Grade-2 in 2(25%), and Grade-1 in 5(62.5%). Those with ≥ Grade-2 CRS received tocilizumab with full recovery. Only 1 patient had Immune effector cell associated neurotoxicity syndrome (ICANS) peak-Grade 3, and was also the only one with Grade-3 CRS and had severe-Covid19 prior to infusion. ICANS resolved with steroids in 4 weeks, but recurred in the second month post-infusion, this time associated with leukemia-progression. Toxicities corroborated with IL-6 (median peak: 25pg/ml, range:2.8-3604), but not with Ifn-γ, which remained low (median peak:6.25pg/ml, range:0-68.1) (Fig-1). ORR was 87.5% (1 no-response-NR), 3 Morphological Remission with MRD-positive (Partial Response-PR), and 4 MRD-negative (Complete Response-CR). Responses correlated with Actaly-cel expansion dynamics (Fig-2) the only non-response being in a patient with poor expansion. At median follow-up of 3 months (range:1-15) 3 patients with no or partial Day-30 response expired from progression within few weeks. All 4 with CR had B-cell aplasia needing intravenous immunoglobulin. Two of them underwent subsequent Allo-SCT, 1 relapsed post-transplant and died from disease progression 15 months later, while the other is alive in remission at 15 months. Two patients remain in CR at 3 and 12 months without further therapy, while 1 with PR is on follow-up. Patients receiving TD-2 had ORR of 100% (CR-3, PR-1) with peak toxicity of Grade-2 CRS in only 1. Conclusion In a Phase-1/1b trial, Actaly-cel had good safety profile with low toxicity and robust activity resulting in high ORR that improved at higher doses. In-vivo dynamics and toxicity profile of Actaly-cel showed robust activity and low cytokines corroborating with pre-clinical studies. A median dose of 5x10 6/kg Actaly-cel is proposed as the P2D.

Longitudinal Patient-Reported Outcomes (PROs) in a Prospective Registry of CAR T-Cell Therapy Recipients

Background Chimeric antigen receptor T-cell therapies (CAR-T) significantly improve survival and health-related quality of life (HRQoL) in clinical trials of relapsed hematologic malignancies. However, the impact of CAR-T on real-world longitudinal patient-reported outcomes (PROs), particularly in the immediate post-CAR-T period during which patients are hospitalized and at risk for acute CAR-T-related toxicities, has not been studied. Further, few CAR-T studies have utilized Patient-Reported Outcomes Measurement Information System (PROMIS) survey instruments, which are recommended to enable comparison of PROs across various CAR-T products and disease types. To characterize real-world HRQoL and symptom burden in patients receiving CAR-T, we integrated PROMIS PRO instruments into a prospective cellular therapy registry. Methods The University of Chicago Cellular Therapy Biobank prospectively administers the PROMIS v1.2 Global Health and PROMIS-29 Profile v2.1 instruments to CAR-T recipients. PRO instruments are administered at the following timepoints, anchored to the day (D) of CAR-T receipt: baseline (at time of apheresis), D+1, D+15, D+28, D+90, D+180, and then every 3 months until the 2-year timepoint. The Biobank was queried for all patients who completed a baseline and at least one post-CAR-T survey. PROMIS T-scores were analyzed by one-way repeated measures ANOVA up to the 12-month timepoint. PROMIS T-scores were longitudinally visualized as mean change from baseline. Minimally important differences (MID) that were clinically significant were defined as T-score changes of at least 2. Statistical analyses were performed in STATA, version 17.0. Results There were 68 patients available for PRO analysis. Median age was 65 years (range, 24-80) and 63% were male. Most patients had large B-cell lymphomas (n = 27, 40%) or multiple myeloma (n = 27, 40%). Median prior lines of therapy were 4 (range, 1-12), with only 3 patients receiving 1 prior therapy. The majority of patients received CD19-targeted products (n = 35, 51%), followed by BCMA-targeted products (n = 27, 40%). Patients lived a median of 36 miles from the CAR-T center (range, 2-544), with 65% living over 30 miles away. Survey completion rates at timepoints were as follows: 73% at D+15, 82% at D+28, 84% at D+90, 76% at D+180, and 95% at 12 months. For PROMIS Global Health, there was a significant longitudinal change in Global Physical Health (p = .002), with a clinically meaningful improvement by D+28 which was no longer observed by D+90 ( Figure 1), but no significant change in Global Mental Health (p = .09). For PROMIS-29 Profile, there were significant longitudinal changes in physical function (p = .0001), fatigue (p = .001), and social role functioning (p = .002), but not anxiety (p = .08), depression (p = .45), sleep (p = .92), or pain (p = .27). There were clinically meaningful improvements in both physical and social role functioning in the first 28 days after CAR-T which were no longer observed by D+90 ( Figure 1). Fatigue significantly worsened in the first 28 days after CAR-T to a clinically meaningful degree, but subsequently improved to better than baseline after D+90 ( Figure 2). With a median follow-up of 9 months (range, 1-28), 40% of patients had post-CAR-T disease progression. Relapses occurred a median of 4.9 months after CAR-T, with 31% of relapses (n = 8) occurring before D+90. There were 10 deaths (15%) at a median of 6.7 months after CAR-T. Conclusions In this real-world prospective PRO analysis, there were clinically meaningful improvements in several HRQoL domains in the first month after CAR-T, namely physical and social functioning, despite significantly worsening fatigue during the same time period. However, these HRQoL improvements diminished after D+28, concurrent with the transition of patients from the CAR-T center to home. These results suggest that intensive support by the inpatient and outpatient care teams may improve physical HRQoL during the immediate post-CAR-T period. In addition, given the low rate of relapses before D+90 in this cohort, worsening patient-reported functioning after D+28 may be driven by changes in care support after discharge to home. Interventions to optimize the post-CAR-T transition to home are warranted, as well as studies utilizing PROMIS PROs to identify patients with deteriorating HRQoL who may benefit from augmented support and/or closer surveillance for relapsed disease.

FLT3 Inhibitors in Combination with FLAG-IDA in Relapsed or Refractory Acute Myeloid Leukemia

1. Introduction The addition of a FLT3 inhibitor improves overall survival in combination with front-line intensive chemotherapy in acute myeloid leukemia (AML). In the ADMIRAL trial, gilteritinib - a second-generation, type I FLT3 inhibitor - improved survival in relapsed or refractory AML compared to intensive chemotherapy. However, it is unknown whether the combination of a FLT3 inhibitor and intensive chemotherapy improves survival in the relapsed or refractory setting compared with intensive chemotherapy alone or intensive chemotherapy with venetoclax in FLT3 mut AML. 2. Methods We analyzed 27 patients with FLT3 mut AML treated with FLAG-IDA for relapsed or refractory disease from January 1, 2013 to April 18, 2023 at VCU Massey Comprehensive Cancer Center. Baseline disease characteristics were obtained, including molecular profiling either through PCR, NGS, or both, alongside cytogenetic risk, doses of induction regimens, response, and survival. We separated patients that underwent treatment with FLAG-IDA and a FLT3 inhibitor (gilteritinib, midostaurin, or sorafenib), venetoclax, or FLAG-IDA alone. Measurable residual disease (MRD) assays were PCR-based when available; otherwise, MRD was assessed through multiparameter flow cytometry. We used the D'Agostino & Pearson method for normality testing and the Kruskal-Wallis test for between-group comparisons. We applied the Bonferroni correction if multiple comparisons were made. We analyzed survival by the Kaplan-Meier method with significance determined by the log-rank test. The event for calculating the overall survival (OS) was the date of death. Patients were otherwise censored at the date of last contact. 3. Results All 27 patients treated with FLAG-IDA harbored mutations in FLT3-ITD (70.3%) or FLT3-TKD (29.6%). Twelve (44.4%) patients received FLT3 inhibitors with FLAG-IDA: eight (66.7%) with midostaurin, three (25.0%) with gilteritinib, and one (8.3%) with sorafenib. Five (41.6%) patients received a FLT3 inhibitor (FLT3i) for previously untreated disease, then subsequently received a FLT3i at disease progression. Ten (37.0%) patients received FLAG-IDA without a FLT3i, and five (18.5%) received FLAG-IDA and venetoclax. The median FLT3 variant allele frequency was 33.96% (95% CI, 5.1-63.9) in the FLT3i cohort, 18.0% (95% CI, 8.0-27.0) in the FLAG-IDA cohort, and 5.0% (95% CI, 3.0-29.0) in the venetoclax cohort. The median prior lines of therapy were as follows: three for the FLT3i cohort, two for the FLAG-IDA cohort, and three for the venetoclax cohort (p = 0.137). There was no difference in the achievement of CRc between the FLT3i and FLAG-IDA groups (27.3% vs 33.3%, p > 0.999) or between the FLT3i and venetoclax groups (27.3% vs 50.0%, p = 0.560). The proportion of responders that achieved MRD negativity was nonsignificantly higher in the FLT3i cohort (75.0% vs 20.0%, p = 0.206). The median overall survival nonsignificantly favored the FLT3i cohort compared to the FLAG-IDA cohort (7.7 months vs 4.1 months, p = 0.992) and the venetoclax cohort (7.7 months vs 6.3 months, p = 0.902). 4. Discussion The addition of a FLT3 inhibitor resulted in nonsignificantly higher rates of MRD negativity and prolonged overall survival when compared to FLAG-IDA alone or FLAG-IDA and venetoclax. The optimal combination regimen for relapsed or refractory FLT3 mut AML is unknown, but likely should include a FLT3 inhibitor. The limitations of our study include its retrospective nature; subsequent FLT3 inhibitor combinations or maintenance strategies may have provided a survival benefit the FLT3i cohort. Therefore, prospective clinical trial designs are needed to further confirm these findings.

Seven-Day Vein-to-Vein Point-of-Care Manufactured CD19 CAR T Cells (GLPG5201) in Relapsed/Refractory CLL/SLL Including Richter's Transformation: Results from the Phase 1 Euplagia-1 Trial

Background Despite treatment advances, chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) remain incurable. Patients (pts) with concurrent Richter's transformation (RT) have poor prognoses with limited treatment options. Chimeric antigen receptor (CAR) T-cell products targeting CD19 have shown activity in pts with CLL/SLL or RT, yet data are limited and no therapies are approved. Due to limited treatment options and short survival of pts with RT, rapid treatment delivery is essential. A novel decentralized and automated point-of-care (PoC) manufacturing model was developed to administer fresh, autologous CAR-T treatments within 7 days of apheresis. An update on the Phase (Ph) 1 Euplagia-1 trial of PoC manufactured GLPG5201 is presented. Methods Euplagia-1 (CTIS: 2022-501686-47-00) is a Ph1/2 study of PoC-manufactured GLPG5201 in pts with R/R CLL or SLL, including pts with RT. Pts with CD19+ R/R CLL/SLL with ≥2 prior therapy lines are eligible. Pts with RT are eligible regardless of prior therapy. GLPG5201, an anti-CD19/41BB CAR-T therapy, is administered as a fresh product following fludarabine/cyclophosphamide lymphodepleting chemotherapy. Upon screening, pts receive daily ibrutinib until leukapheresis. The primary objectives are safety and determining a recommended Ph2 dose (Ph1), and objective response rate (ORR; Ph2). Secondary objectives include additional efficacy measures, pharmacokinetics and feasibility of PoC manufacturing. Results As of April 26, 2023, 12 pts were enrolled in Ph1 at dose level (DL) 1 (35×10 6 CAR+ T cells, n=6) or DL2 (100×10 6 CAR+ T cells, n=6) at a single institution. All pts were diagnosed with R/R CLL, 7/12 with concurrent RT. Median age was 66 years (range 58-71); 8/12 pts were male. Median prior lines of therapy were 4 (range 2-10); 10/12 pts received a BTK inhibitor, 9/12 pts venetoclax, and 1 pt an allogeneic stem-cell transplant. Five of 7 pts with RT relapsed after, or were refractory to, R-CHOP. Six of 12 pts had a TP53 mutation, 1 pt had a 17p deletion; 11 pts had an unmutated IGHV status and 2 had a complex karyotype reported. GLPG5201 was manufactured for all pts and administered as a fresh infusion. Median vein-to-vein time was 7 days (range 7-14). Due to lower manufactured CAR+ T cell yield, 3 pts received DL1 instead of the intended DL2. A preserved early memory phenotype for CD4+ and CD8+ CAR T cells was observed in the final product, compared with apheresis starting material ( Figure). Most treatment emergent adverse events (TEAEs) were Grade 1-2; most Grade ≥3 events were hematological ( Table). Six (50%) pts had Grade 1-2 cytokine release syndrome (CRS), with no CRS Grade ≥3. No neurotoxicity was reported. A dose limiting toxicity occurred in 1 pt (Grade 4 neutropenia, DL2), which was manageable and within expectations in this pt population. No unexpected GLPG5201-related toxicities were observed; no deaths occurred while pts were on study. Eleven pts responded to treatment (best ORR 92%). Complete response (CR) was observed for 9 pts (CR rate [CRR] 75%). ORR and CRR were 83% and 67% at DL1, and 100% and 83% at DL2, respectively. All but 1 pt with RT responded (ORR 86%); CR was achieved by 5/7 pts with RT (CRR 71%). One pt with RT was refractory with CD19-negative disease. At the time of analysis, 9/11 (82%) pts had ongoing responses; duration was up to 9 months post-infusion (median follow-up 3.2 months; range 1-9). Two pts progressed after an initial response, 1 pt with CD19-negative disease. Robust CAR T-cell expansion was observed in all pts by qPCR, with a median maximum expansion of 4.4×10 5 copies/µg DNA (C max). Median T max was 14 days (range 9-20 days). Median AUC 0-28d was 5.3×10 6 copies/µg DNA × days. GLPG5201 could be detected in peripheral blood up to 9 months post-infusion. Conclusion Data from 12 pts enrolled in the Ph1 Euplagia-1 study demonstrate that PoC CAR-T manufacturing with a short vein-to-vein time is feasible. GLPG5201 is administered as a fresh product; median vein-to-vein time is 7 days. There are no unexpected safety findings, and no CRS Grade ≥3 or any ICANS are reported. Efficacy data are encouraging, with a 92% best ORR and 75% CRR; 6/7 pts with RT responded. With this novel PoC manufacturing model, an early phenotype of less differentiated CAR T cells is preserved in the final product. GLPG5201 demonstrates rapid in vivo expansion and durable persistence post-infusion . Euplagia-1 is ongoing, and updated data will be presented.

Tolerability and Clinical Activity of Novel First in Class Oral Agent, Inobrodib (CCS1477), in Combination with Pomalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma

Background Inobrodib (CCS1477) is a first in class potent, selective, and orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyltransferases with oncogenic roles in hematological malignancies. Inobrodib exhibits potent anti-tumor cell activity in a range of hematological cell lines, including multiple myeloma, and demonstrates additive/synergistic activity with pomalidomide. Aims: We report preliminary safety (primary objective) and efficacy (secondary) data for inobrodib in combination with pomalidomide (pom) and dexamethasone (dex) from relapsed/refractory multiple myeloma (RRMM) patients treated in the Phase I/IIa trial (NCT04068597). Methods : Eligible patients (pts) had confirmed RRMM and had exhausted available or suitable standard of care treatment options. Two dose escalation combination cohorts were completed; pts received inobrodib at doses of 25 mg or 35 mg bidaily on a 4 days on/3 days off intermittent schedule, as well as standard dosing of pom and dex in 28-day cycles. Adverse events were graded by CTCAE v5.0. Responses were investigator assessed per IMWG. Results: Initial dose escalation cohorts enrolled 15 RRMM pts with a median age of 71 yrs (range 41-80). Median prior lines of therapy was 5 (range 3-9). Median follow-up was 56 days (range 13-189), with a median number of 3 cycles received (range 1-7). Almost all patients were pomalidomide-refractory (13/15, 87%), 13/13 (100%, 2 pts data missing) were triple class refractory and 3 pts (20%) received prior BCMA therapy. At the data cut-off (5 th June 2023), Grade (gr) 3 /4 treatment-emergent adverse events (TEAEs) were reported in 11 of 15 (73%) pts. Over half of the patients remain on treatment and all but three remain in follow-up for survival analysis. Of these three patients, two died due to disease progression and one due to an unrelated cardiac event at the end of cycle 2. The most frequent gr 3/4 events were infections (41.1%). The majority of the other gr 3/4 TEAE were hematological and seen in 5 of 13 (38.5%) pts; neutropenia (23.5%) thrombocytopenia (5.9%, all gr 3) and anemia (11.8%, all gr 3). Seven of 15 (47%) pts experienced TEAEs considered related to inobrodib; all events were gr 1/2 apart from a single patient with gr 3 electrolyte abnormalities. No DLTs were noted; two pts (13%) discontinued due to related events. The majority of patients 13/15 (87%) showed signs of activity with disease markers decreasing over time. At the point of data cut off, 7/15 (47%) heavily pre-treated patients achieved confirmed responses (MR or better) per IMWG criteria; 2 VGPR, 3 PR and 2 MR. Of note, two further patients, who initially received inobrodib monotherapy but progressed were transferred into the pom-dex combination cohort and subsequently achieved objective responses (VGPR and PR). Summary: The first in class agent inobrodib in combination with pom-dex shows promising early efficacy in heavily pre-treated, including pom-refractory, RRMM patients. The combination is tolerable, with the most common events being infections, as expected in this patient population. Dose optimisation continues as part of this study with expansion arms in an earlier setting planned.

Fixed-Duration Pirtobrutinib Combined with Venetoclax ± Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia: Updated Results, Including MRD Data, from the BRUIN Phase 1b Study

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia (CLL). Recent clinical studies have evaluated the safety and efficacy of fixed-duration regimens with venetoclax and cBTKi. While these combinations are effective, their use may be limited by toxicity. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, has shown promising safety and efficacy in heavily pretreated relapsed or refractory (R/R) CLL patients (pts). Here, we report the safety and efficacy of fixed-duration pirtobrutinib combined with venetoclax ± rituximab in pts with R/R CLL. Methods: Pts with R/R CLL were eligible for pirtobrutinib combined with venetoclax ± rituximab in the phase 1b portion of the multicenter phase 1/2 BRUIN study (NCT03740529). Prior cBTKi therapy was allowed, but not prior venetoclax. Pts were enrolled into sequential cohorts, first in the pirtobrutinib + venetoclax (PV) cohort and then the PV + rituximab (PVR) cohort. Pirtobrutinib 200 mg QD was started on cycle 1 day 1, and venetoclax was started on cycle 2 day 1 with the standard 5-week dose ramp to 400 mg QD target dose. PV was given for up to 24 cycles; each cycle was 28 days. For the PVR cohort, rituximab was given at 375 mg/m 2 on cycle 1 day 1 and then 500 mg/m 2 on day 1 of cycles 2-6. The primary endpoint was safety as assessed by treatment-emergent adverse events (TEAEs) graded according to CTCAE v5.0. Other key endpoints included overall response rate (ORR), progression-free survival (PFS), and minimal residual disease (MRD). Undetectable MRD (uMRD) was defined as less than 1 CLL cell/10,000 nucleated cells (<1x10 -4) in peripheral blood by ClonoSEQ® assay (Adaptive Biotechnologies, Seattle, WA). A data cut of May 5, 2023, was utilized. Results: Fifteen pts received PV, and 10 received PVR. Median age was 66 years (range, 49-77) for those who received PV and 69 (range, 39-78) for those who received PVR. Median prior lines of therapy was 1 (range, 1-2) for the PV cohort and 2 (range 1-4) for the PVR cohort. Most pts had received prior chemotherapy (PV=53%; PVR=60%), CD20 monoclonal antibody (73%; 70%), and cBTKi (73%; 60%). The majority of pts had IGHV unmutated CLL (PV=73%; PVR=89%). ORR was 93.3% (95% CI, 68.1-99.8) for the 15 pts receiving PV and 100% (95% CI, 69.2-100.0) for the 10 pts receiving PVR, with 10 complete responses (PV=7; PVR=3). Median duration of follow-up for PFS was 22.1 months (IQR, 20.1-25.7) for PV and 22.1 months (IQR, 20.7-22.1) for PVR; PFS at 18 months was 92.9% (95% CI, 59.1-99.0) for the 15 pts receiving PV and 80.0% (95% CI, 40.9-94.6) for the 10 pts receiving PVR. The overall uMRD rate at cycle 13 was 70.8% (PV=10; PVR=7) for the 24 evaluable pts, with 87.5% (PV=12; PVR=9) of pts achieving uMRD at some time during the trial and all but one pt sustaining uMRD during subsequent MRD assessments ( Figure). Twenty-two pts discontinued treatment (PV=14; PVR=8); of these, 14 completed all 24 cycles of therapy (PV=9; PVR=5) and 8 discontinued early because of progressive disease (PV=2), adverse events (PVR=2), protocol noncompliance (PV=1), death unrelated to treatment (PVR=1), or other reasons (PV=2). Three pts (PV=1; PVR=2) continue to receive treatment. The median relative dose intensity was similar in both cohorts (PV=97.9%; PVR=98.6%). The most common TEAE of any grade included nausea (PV=60.0%; PVR=40.0%), fatigue (53.3%; 50.0%), and diarrhea (46.7%; 60.0%). The most common grade ≥3 TEAE was neutropenia/neutrophil count decreased (PV=46.7%; PVR=60.0%). Grade ≥3 clinical tumor lysis syndrome occurred during venetoclax dose escalation (PV=2), including a grade 3 case that resolved spontaneously after 24 hours and a grade 4 case that resolved after short-term intravenous fluids. Treatment-related adverse events led to dose reductions in three pts (PV=1; PVR=2) and treatment discontinuation in two pts (PVR=2). Conclusions: Fixed-duration pirtobrutinib combined with venetoclax ± rituximab was well tolerated and demonstrated sufficiently promising efficacy to warrant further investigation in pts with R/R CLL. The BRUIN CLL-322 phase 3 trial comparing PVR vs VR in previously treated CLL is currently enrolling pts (NCT04965493).

Sonrotoclax (BGB-11417) in Combination with Dexamethasone for the Treatment of Relapsed/Refractory Multiple Myeloma with t(11;14): Safety, Efficacy, and Determination of Recommended Phase 2 Dose

Background: B-cell lymphoma-2 (BCL2) family proteins represent attractive therapeutic targets as they play an important role in MM cell survival. In patients with relapsed/refractory (R/R) MM harboring t(11;14) for whom multiple prior lines of therapy failed, single-agent venetoclax, a first generation BCL2 inhibitor, demonstrated antimyeloma activity (Kumar S, et al. Blood. 2017). Dexamethasone, a long-standing mainstay of treatment for MM, increases the expression of both BCL2 and Bim. This results in a greater dependency on BCL2 for tumor survival, ultimately increasing the sensitivity to a BCL2 inhibitor. Sonrotoclax (BGB-11417) is a BH3 mimetic that binds and inhibits BCL2 with potency >10x that of venetoclax in biochemical assays. BGB-11417-105 (NCT04973605) is an ongoing phase 1b/2 trial designed to evaluate safety and efficacy of sonrotoclax as monotherapy, in combination with dexamethasone, or in combination with dexamethasone plus carfilzomib in patients with R/R MM harboring the t(11;14). Here, we report preliminary data from the sonrotoclax plus dexamethasone dose-escalation (DE) cohorts. Methods: Eligible patients have R/R MM that is t(11;14) positive by fluorescence in situ hybridization (per central assessment) who have received 1-7 prior lines of therapy for MM with previous exposure to a proteasome inhibitor and an IMiD agent. In dose escalation, patients received 80, 160, 320, or 640 mg of sonrotoclax daily with 40 mg of dexamethasone weekly until intolerability, disease progression, or death. The primary objectives in the DE cohorts were to assess the overall safety/tolerability profile as well as determine the maximum tolerated dose (MTD)/maximum assessed dose (MAD) and establish the recommended phase 2 dose (RP2D). AEs were reported per CTCAEs v5.0; safety was assessed by a safety monitoring committee (SMC) after a 21-day dose-limiting toxicity (DLT) window for each cohort and was guided by a modified toxicity probability interval method (mTPI-2). Disease responses were assessed per International Myeloma Working Group 2016 criteria. Results: As of May 26, 2023, 19 patients have been enrolled in the 80-, 160-, and 320-mg (n=3 each) and 640-mg (n=10 patients) dose-escalation cohorts. The median age was 68 years (range, 52-81 years). The median prior lines of therapy was 4 (range, 1-12) and 11 patients (58%) failed on a prior anti-CD38 antibody. The most common AEs (>20% of all patients) were insomnia (n=9; 47%), fatigue (n=6; 32%), nausea (n=5; 26%), and arthralgia (n=4; 21%); none of which were severity grade ≥3. Three patients (16%) experienced grade ≥3 treatment-emergent AEs (TEAEs). One patient (33%) in the 160-mg cohort had grade 3 increases in liver enzymes and diarrhea; one patient (10%) in the 640-mg cohort had a grade 3 decrease lymphocyte count and hypokalemia; and one patient (10%) in the 640-mg cohort had grade 3 cataracts and retinal detachment. Three patients experienced COVID-19 (grade 1-2, n=2; grade ≥3, n=1). Three patients experienced TEAEs that led to treatment discontinuation (COVID-19, cancer pain, hematuria; n=1 each). No patient, across all dose levels tested, experienced a DLTs; thus, sonrotoclax 640 mg daily was the determined to be the MAD and the RP2D in combination with dexamethasone. Four patients (21%) died while on study; however, no deaths were determined by the investigators to be associated with study treatment. One patient died from COVID-19 while receiving study therapy; three additional patients died ≥50 days after treatment discontinuation (COVID, progressive disease, and unknown causes, n=1 each). With a median treatment duration of 120 days (range, 30-526), ORR was 58%; 11 patients had a PR or better (n=6, PR; n=2, very good PR; n=2, CR; n=1, stringent CR [sCR]; Figure). The ORR for the 640-mg cohort was 70% (n=3, PR; n=2 VGPR; n=1, CR; n=1, sCR). Nine patients remained on treatment; the longest duration of response was 483 days (20 cycles) which, at data cutoff, was still ongoing. Conclusion: Sonrotoclax plus dexamethasone was generally well tolerated in patients with R/R MM harboring t(11;14) at doses up to 640 mg, and initial safety and efficacy results are promising. The SMC has recommended 640 mg in combination with dexamethasone as the RP2D. Recruitment is ongoing for the sonrotoclax in combination with dexamethasone and carfilzomib dose-finding arms and the sonrotoclax plus dexamethasone indication expansion cohort.

Outpatient Management of CAR-T and Teclistamab for Patients with Lymphoma and Multiple Myeloma

Background: Patients (pts) receiving FDA-approved chimeric antigen receptor T-cell (CAR-T) therapy or Bispecific antibody Teclistamab (Tec) are commonly managed in the inpatient setting given the common adverse events such as cytokine release syndrome (CRS) and immune cell-associated neurotoxicity syndrome ICANS. We have previously reported that hospital-based outpatient (HBO) management of pts receiving CAR-T is feasible and safe (Bansal et al, ASH2022). In 2023, HBO management at our institution began incorporating home health visits and management of grade 1 CRS in outpatient setting for select pts receiving standard of care (SOC) CAR-T. Here, we report outcomes of our updated practice. Methods: We retrospectively analyzed medical records and remote monitoring data of adult pts who received SOC CAR-T or Tec between 10/2020 and 7/2023 at Mayo Clinic, Rochester under an IRB approved protocol. Results: In 3/2023, pts deemed to be low risk for severe CRS (fever onset >= 3 days from infusion, CRP<100) received HBO management for grade 1 CRS, including outpatient administration of tocilizumab. If CRS improved or resolved, outpatient monitoring was continued. If CRS persisted within the observation period on HBO, pts were admitted. Recurrent CRS after the first episode were all managed inpatient. Nine pts met these criteria for HBO CRS management and their outcomes were compared to those who received initial inpatient (INPT) CRS management (INPT, n=17) during the same timeframe, as well as the outcome of 164 pts who had CRS management INPT prior to our practice change (Table 1). Two-third of the pts with initial management of CRS outpatient did not require hospitalization. Median time to hospitalization trended later than those managed inpatient at the onset of CRS. The duration of hospitalization was comparable for all pts admitted between initial HBO and INPT CRS management. However with fewer admissions in the initial CRS HBO group, the average hospitalization days (LOS) per patient treated for that group was lower compared to initial INPT CRS management. Data on additional pts will be presented at ASH. In 1/2023, pts on RPM with no ongoing CRS symptoms, no language barriers, and no compliance concerns received home health visits during weeks 3 and 4 post CAR-T infusion in place of clinic visits on HBO. Home health visit team communicated with HBO staff to review assessment and plan. Changes in HBO utilization will be presented. Finally, 24 pts received 223 Tec infusions on HBO. Median age was 66 years, 15 (61%) were males, 9 (38%) had high risk cytogenetics. The median prior lines of therapy was 5. Among these pts, 220/223 (99%) doses were performed on HBO and 204/220 (93%) infusions never required admission for management. Twenty pts enrolled in RPM (Figure 1). An average of 2 alerts were generated per patient during the 2 week period and median time from infusion to alert was 1.5 days. Majority of alerts were resolved over a phone call and only 13/114 (11%) alerts required a physician visit/hospital admission. Of the 16 Tec infusions resulting in admission, 4/16 (25%) required re-admission resulting in a total of 20 hospitalizations. Admissions mostly occurred during step-up dosing (18/20; 90%). Most common reason for first admission was fever (13/16, 85%) and median time to admission was 1 day from infusion. Median LOS was 1.5 days (range, 0-12). In terms of CRS, majority were Grade 1 (12/13, 93%) which were managed with steroids (dexamethasone/ prednisone) alone. One patient had CRS grade 4 event, in the setting of concurrent decompensation during dialysis, and was treated with steroids, tocilizumab, vasopressor, CRRT, thoracentesis, intubation and mechanical ventilation. The rate of second CRS event after management of first CRS with steroid (dexamethasone/ prednisone) was 15% (2/13). These second CRS episodes also resolved with steroid alone. Data on additional pts receiving Tec will be presented at ASH. Conclusion: Our data showed that additional advances in outpatient practice, including initial outpatient management of CRS and outpatient administration of Tec step up dosing are feasible, safe and reduce hospital resource utilization.

A Phase IB/II Study of Blinatumomab in Patients with B-Cell Acute Lymphoblastic Leukemia (ALL) and B-Cell Non-Hodgkin Lymphoma (NHL) As Post-Allogeneic Blood or Marrow Transplant (alloBMT) Remission Maintenance

Background: AlloBMT can be curative as consolidation for high risk B ALL and NHL. However, transplant-related toxicity and disease relapse limit survival. Post-transplantation cyclophosphamide (PTCy) as graft-versus-host disease (GVHD) prophylaxis limits GVHD and facilitates alternative allograft sources. Following PTCy, cellular immune reconstitution is favorable for strategies to augment anti-tumor immunity. Blinatumomab (blina) is effective in the treatment of CD19+ ALL and NHL. Blina leads to T cell activation that may enhance post-transplant tumor-specific T cell responses, leading to a more potent graft-versus-tumor effect. A study of 21 B ALL pts demonstrated the feasibility of post-transplant blina but did not improve survival when pts universally remained on immunosuppression for at least 1 cycle of treatment (Gaballa. Blood. 2022). We present results of a phase Ib/II trial to assess the tolerability and preliminary efficacy of blina as post-alloBMT remission maintenance in B-cell ALL and NHL in pts off immunosuppression. Methods: Pts ≥1 month-old with high risk CD19+ B ALL or ≥18 years-old with NHL who underwent alloBMT with PTCy were eligible. Pts had to be 60-180 days post-transplant with count recovery and in remission. Pts had to be off immunosuppression for ≥4 weeks prior to treatment, and without a history of grade ≥3 acute GVHD or severe chronic GVHD. Pts could receive 2 cycles of blina if they had evidence of disease (including MRD) at their pre- and/or post-transplant evaluations but otherwise received 1 cycle. Blina was given as a continuous infusion at 9 mcg/day on C1D1-7 and 28 mcg/day on C1D8-28 and C2D1-28. Results: The study closed to accrual on January 31, 2023 following enrollment of 42 pts (26 male/16 female) with a median age of 54 (Range 30-73). Among enrolled pts, 19 had Ph-negative B ALL and 23 had B-cell NHL. All pts underwent reduced-intensity conditioning alloBMT using a regimen of fludarabine, cyclophosphamide, and total body irradiation. Median prior lines of therapy were 2 (range 1-6). Additional transplant details are presented in Table 1. All B ALL pts were in an MRD-negative CR by flow cytometry at a sensitivity of 0.01% at alloBMT. All pts received a single cycle of therapy. Pts started blina a median of 137 days post-transplant (range, 90-182). Four pts failed to complete a full cycle due to G4 transaminitis (1), G4 neutropenia (1), relapse (1), and patient preference in the setting of tremors (1). Grade 3 or 4 adverse events felt to be at least possibly related to the study drug included G3 neutropenia (7%), G4 neutropenia (19%), anemia (5%), G3 ALT (5%), G4 AST (2%), G3 AST (2%), and neurotoxicity (7%). Two pts (5%) developed chronic GVHD following blina requiring the resumption of immunosuppression. At a median follow-up of 40 months post-alloBMT, the 3-year relapse-free survival is 73% (95% CI 54-85%) due to a 24% (95% CI 12-39%) incidence of relapse and a 4% (95% CI 0-17%) incidence of non-relapse mortality, as shown in Figure 2. All 3 (100%) relapsed B ALL pts and 2/6 (33%) relapsed B NHL pts presented with CNS involvement. Four pts with CNS relapse (80%) had CNS involvement prior to alloBMT. Among 2 pts who died without relapse, 1 was unrelated to alloBMT, while the other died of therapy-related myeloid neoplasm. Data on biomarkers including changes in T cell subpopulations in both BM and PB, and co-signaling molecule expression will be presented. Conclusions: Post-alloBMT maintenance therapy with blina is feasible with minimal toxicity in pts off immunosuppression. Initial survival outcomes are promising with the majority of relapses involving the CNS. A randomized trial of maintenance with blina after alloBMT with PTCy is needed to confirm efficacy in this high-risk population.

Double Step-up Dosing (2SUD) Regimen Mitigates Severe Icans and CRS While Maintaining High Efficacy in Subjects with Relapsed/Refractory (R/R) B-Cell Non-Hodgkin Lymphoma (NHL) Treated with AZD0486, a Novel CD19xCD3 T-Cell Engager (TCE): Updated Safety and Efficacy Data from the Ongoing First-in-Human (FIH) Phase 1 Trial

Background: AZD0486 (formerly TNB-486) is a novel, IgG4 fully human CD19xCD3 bispecific TCE incorporating a unique low affinity anti-CD3 moiety designed to reduce cytokine release while retaining potent T-cell mediated cytotoxicity of malignant B cells. A silenced Fc prevents nonspecific binding, antibody-dependent cellular cytotoxicity, and confers a long half-life suitable for intermittent administration. Preliminary clinical activity in Diffuse Large B-cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) was reported [ Hou et al, Blood 2022; Jacobs et al, HemaSphere 2023] following fixed and single step-up dosing (1SUD). We now present focused updated safety data following implementation of 2SUD in the ongoing FIH phase 1 study (NCT04594642). Methods: Patients with R/R CD19+ B-NHL failing ≥2 prior lines of therapy, including prior CD19 CART and/or CD20 TCE, were enrolled. AZD0486 was administered in escalating doses in either no SUD (Day (D)1, D15 0.03-2.4mg), 1SUD (D1 0.27-1 mg, D15 2.4-10 mg), or 2SUD (D1 0.27 mg, D8 1 mg, D15 2.4-7.2 mg, FL/DLBCL only) schedules. AZD0486 was given IV every 2 weeks in 28D Cycles (C) up to 2 years. Monthly dosing was considered for patients in complete response (CR) at C6. Responses were assessed by RECIL 2017 by Central Imaging Review, AEs by CTCAE v5.0, and CRS/ICANS by 2019 ASTCT criteria. Results: As of 03 July 2023, 62 patients (27 DLBCL, 25 FL, 5 mantle cell lymphoma, 4 marginal zone lymphoma, 1 other) received AZD0486 and were evaluable for safety. Median age was 68 (range 22-86), with 58% male, 81% stage III/IV. Median prior lines of therapy was 3 (range 2-16) including 23 (37%) failing CART and 3 (4.8%) failing CD20 TCE. Fifteen (24%) were CD20 negative at study entry. The complete response (CR) rate was 91% (10/11) in patients with FL treated in 2.4 mg dose cohorts and for all FL efficacy evaluable subjects dosed at 2.4mg or above, CR was achieved in 14/17 (83%) with an overall response rate (ORR) of 88%. Median duration of response (DOR) has not beenreached. With the implementation of 2SUD regimen, no Grade 3+ CRS or ICANS events were observed (Table 1). Grade 1-2 CRS events decreased from 62.5% to 22.2% (fixed/1SUD, 15/24 and 2SUD, 4/18). Grade 1-2 ICANS events decreased from 20% (5/24) to 5.6% (1/18), presented mainly as confusion, and typically resolved in 1-2 days. The most common AEs (occurring in >20%) of any grade and regardless of drug causality were CRS (48%), anemia (34%), neutropenia (32%), lymphopenia (29%), ICANS (27%) and decreased WBC (20.9%). Treatment-related events of Grade ≥3 included lymphopenia (24%), neutropenia (15%), ICANS (9.7%) and anemia (3.2%). No treatment related deaths were reported (1 death due to COVID19, unrelated) and no treatment-related AEs lead to discontinuation (1 patient discontinued due to COVID-19, unrelated). Preliminary analysis (TNF-a, IL-6, IL-8, IL-10) suggests a decrease in cytokine levels after target dose with 2 SUD compared to fixed dosing and 1SUD, regardless of target dose. Conclusions: AZD0486 (formerly TNB-486) is an active treatment in patients with advanced R/R B-NHL and has a predictable safety profile characterized by mainly low-grade AEs and fully transient and reversible CRS/ICANS events. The 2 SUD schedule reduced the overall rate of low grade CRS and ICANS (Grade 1-2) and abrogated Grade 3 events further improving the risk/benefit profile of AZD0486. Dose escalation is ongoing to identify the RP2D.

Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma

Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma

A Phase 2 Study of the Fully Oral Combination of ASTX727 (Decitabine/Cedazuridine) Plus Venetoclax for Older and/or Unfit Patients with Acute Myeloid Leukemia

Background: The combination of a hypomethylating agent (HMA) plus venetoclax is the standard of care for patients (pts) with acute myeloid leukemia (AML) who are older (age ≥ 75 yrs) and/or unfit for intensive chemotherapy. ASTX727 (oral decitabine/cedazuridine) is an oral formulation of decitabine with pharmacokinetic AUC equivalent exposures to IV decitabine. We performed a phase 2 study to evaluate the efficacy and safety of ASTX727 plus venetoclax in the frontline (FL) and relapsed-refractory (R/R) settings. Methods: Pts ≥ 18 yrs with WHO 2016-defined AML were eligible. The FL cohort enrolled newly diagnosed pts with ECOG ≤ 3 who were either ≥ 75 yrs or ineligible for intensive chemotherapy due to comorbidities. Pts ≥ 18 yrs and ECOG ≤ 2 were eligible for the R/R cohort. Pts with a history of myelodysplastic syndrome (MDS), including previously treated MDS, were eligible. Treatment consisted of ASTX727 (decitabine/cedazuridine) 35/100 mg PO daily x 5 days and venetoclax 400 mg PO daily (adjusted for azoles) for 28 days during induction (held if blast clearance on day 21 bone marrow examination) and 21 days in consolidation. Dose reductions were permitted for toxicity/tolerability. Therapy was administered in 28-day cycles for up to 24 cycles. Risk stratification and responses were determined per ELN 2022. This study was registered on ClinicalTrials.gov (NCT04746235). Results: 52 pts have been enrolled (42 in the FL and 10 in the R/R cohorts). In the FL cohort, the median age was 79 yrs (range 50-92). 17/42 (40%) pts had antecedent MDS (including 8 [19%] with treated secondary AML) and 6/42 (14%) had therapy-related AML (t-AML). By ELN 2022, 6 (14%) were favorable, 3 (7%) were intermediate, and 33 (79%) were adverse. 9/42 (21%) had complex cytogenetics and 6 (14%) had TP53 mutations. In the R/R cohort (n=10), the median age was 71 yrs (46-75). 2 (20%) pts had antecedent MDS and 2 (20%) had t-AML. By ELN 2022, 3 (30%) were intermediate and 7 (70%) were adverse. 5/10 (50%) had complex cytogenetics and 2/10 (20%) had TP53 mutations. The median prior lines of therapy in the R/R cohort was 2 (1-4), with 5 (50%) pts with 2 or more prior lines of therapy. The median number of cycles given was 3 (1-12). In the FL cohort, the ORR was 67% (28/42 pts: 15 [36%] CR, 11 [26%] CRi, 2 [5%] MLFS). In responding FL pts, measurable residual disease (MRD) by flow cytometry became undetectable in 7/22 (32%) pts with adequate samples. In the R/R cohort, the ORR was 50% (5/10 pts: 3 [30%] CR, 2 [20%] CRi). The median number of cycles to first and best response were 1 (1-4) and 1 (1-7), respectively. At a median follow-up of 12.8 months, the median OS was 12.7 months in the FL cohort and 7.6 months in the R/R cohort (figure A). In pts achieving CR/CRi (n=26 FL and 5 RR), the median RFS was 9.8 months in the FL and 4.6 months in the R/R cohort (figure B). The median DOR was 13.2 and 4.6 months the FL and R/R settings, respectively. 2 (4%) pts (1 FL and 1 R/R) went off protocol to undergo stem cell transplantation. We then stratified the FL pts into 3 genetic groups (group 1: TP53 wt, K/NRAS wt, no FLT3-ITD; group 2: TP53 wt, K/NRAS mut or FLT3-ITD positive; group 3: TP53 mut) as previously described (Döhner, ASH 2022). The median OS in group 1 (n=24), group 2 (n=12), and group 3 (n=6) was 16.2, 9.1, and 1.4 months, respectively. In FL pts achieving CR/CRi, the median RFS in group 1 (n=17), group 2 (n=7), and group 3 (n=2) was 13.2, 8.1, and 9.8 months, respectively. OS in the FL cohort was similar between the pts under 80 yrs (n=21, median 12.7 months) vs those 80+ yrs (n=21, median 14.8 months), p=0.98. The most common grade 3/4 adverse events were neutropenic fever (23%), pneumonia (13%), bacteremia (8%), cellulitis (6%), sepsis (6%), and respiratory failure (6%). 4-wk and 8-wk mortality were 10% and 15%, respectively. The median time to cycle 2 was 38 days (26-70). In pts who experienced count recovery during cycle 1, the median time to platelets > 50 x 10 9/L and absolute neutrophil count > 1.0 x 10 9/L was 23 (18-55) and 42 (28-69) days, respectively. Cycle 2 dose reductions occurred in 27/42 (64%) pts (21 venetoclax dose reductions, 6 both drugs reduced). Of the 29 observed deaths, 15 (52%) occurred in non-responders, 11 (38%) following AML relapse, and only 3 (10%) in pts with ongoing response (1 sepsis, 1 GI hemorrhage, and 1 electing to pursue hospice). Conclusions: In this older and very high-risk population of pts with AML, an entirely oral regimen consisting of ASTX727 and venetoclax was effective and tolerable.

Phase 2 Study of CD19 CAR T Cells with a Fully Human Binder for Large B-Cell Lymphoma in Relapse or Progression after a Murine Binder-Bearing CD19 CAR T-Cell Therapy

BACKGROUND T cells engineered with a CD19-targeted chimeric antigen receptor (CD19 CAR T cells) have revolutionized the treatment of high-risk, relapsed, or refractory large B-cell lymphoma (LBCL), but durable responses are only achieved in 30-40% of patients (pts). Outcomes are dismal in case of disease recurrence after CD19 CAR T-therapy; in this situation we have previously reported low efficacy and limited duration of response after a second infusion of the same CD19 CAR T-cell product (Gauthier, Blood, 2022). We observed that repeat CD19 CAR T-cell infusions were impaired by CD8+ T-cell responses against murine amino acid sequences located in the single chain variable fragment (scFv) of the CAR, which led to rapid immune rejection of CAR T cells. We hypothesized that CAR T cells engineered with a fully human scFv could circumvent anti-murine scFv immune responses in pts previously exposed to murine scFv-bearing CAR T cells. We report our phase 2 clinical trial results investigating treatment with fully human scFv-bearing CD19 CAR T cells (JCAR021) in R/R LBCL pts with relapsed or progressive disease after murine scFv-bearing CD19 CAR T-cell therapy. METHODS Pts with R/R LBCL were enrolled at the Fred Hutchinson Cancer Center on a phase II study (NCT03103971). Key eligibility criteria included: i) relapsed disease after complete response (CR) to prior CD19-targeted non-JCAR021 CAR T-cell therapy or persistent disease after partial response to prior CD19-targeted non-JCAR021 CAR T-cell therapy; ii) CD19-positive disease since completing the prior CD19-targeted CAR T-cell therapy. Pts received lymphodepletion (LD) with cyclophosphamide 300 mg/m2/d and fludarabine 30 mg/m2/d for 3 days. Cytokine release syndrome (CRS) and neurotoxicity (NT) were graded according to the Lee 2014 criteria and CTCAE v4.03 criteria, respectively. Disease response was evaluated at day +28 after JCAR021 infusion per PET-CT Lugano criteria. The planned sample size and CAR T-cell dose were n=27 and 7x10 6 CAR T cells/kg, respectively. RESULTS Pt characteristics, and outcomes are shown in the Table. All eight screened pts were enrolled, received LD, and JCAR021 infusion. Median age at enrollment was 63 (range: 41-77). Prior to lymphodepletion, 4 pts (50%) had bulky disease (largest lesion ≥5cm). All pts had extranodal disease. We observed elevated LDH prior to lymphodepletion in 6 pts (75%). Median prior lines of therapy was 5 (range: 3-7). Prior CD19 CAR T-cell product type was lisocabtagene maraleucel, n=4 (50%); axicabtagene ciloleucel, n= 3 (37%); or tisagenlecleucel, n=1. Response to the prior CD19 CAR T-cell therapy was CR in 5 pts (62%) and PR in 3 pts (38%). Median time from the first CAR T-cell infusion to relapse or progression was 165 days (range 49-434). Median time from the first CAR T-cell infusion to JCAR021 infusion was 304 days (range: 202-603). JCAR021 was administered at the dose of 7x10 6 (n=6, 75%) or 2x10 6 CAR T-cells/kg (n=2, 25%; dose reduction due to grade 5 NT in subject #6). We observed all-grade CRS in 4 pts (50%; grade 1, n=2; grade 2, n=2 not requiring vasopressors) and NT in 1 patient (dose limiting toxicity, grade 5 NT from intracerebral hemorrhage with concurrent acute kidney injury and toxic encephalopathy). At day+28 responses were seen in 3 of 8 pts (37%; CR, n=2; PR, n=1), all of whom received 7x10 6 CAR T-cells/kg. Two pts in CR after JCAR021 had bulky disease and elevated LDH prior to LD. In both pts, the prior CD19 CAR T-cell therapy had induced CR lasting ≥ 6 months. In the two evaluable responders (death in CR, n=1), we observed disease relapse or progression within 3 months. Median overall survival was 105 days (95%CI, 92-NA). We measured expansion of JCAR021 CAR T-cells in all pts. Exploratory analyses showed lower in vitro CAR T-cell expansion during manufacturing (fold expansion of CD8+ CAR T-cells, p<0.001) and lower in vivo CAR T-cell expansion (peak CD8+ CAR-T, p=0.002; AUC day0-28, p=0.01; JCAR021 dose, 7x10 6/kg) compared to pts receiving JCAR021 as their first CD19 CAR-T product (CAR-naïve cohort). CONCLUSION In LBCL pts with disease relapse or progression after a first CD19 CAR T-cell therapy, we observed low response rates and lack of durable responses after treatment with the fully human scFv-bearing product JCAR021, prompting early study termination. Lower CAR T-cell expansion during manufacturing in CAR-exposed pts suggest pre-existing T-cell dysfunction as a potential mechanism of failure.

The Effect of Stem Cell Infusion on Immune Effector Cell Associated Hematotoxicity with BCMA CAR T in Multiple Myeloma

Introduction: In recent pivotal clinical trials and real-world studies of patients undergoing BCMA CAR-therapy for multiple myeloma (MM), a significant percentage have exhibited persistent Immune Effector Cell Associated Hematotoxicity (ICAHT). The resulting, sometimes profound and long lasting cytopenias, are associated with increased morbidity, such as high rates of infections and bleeding and complicate further anti-MM therapy once the patient relapses post CAR-T cell therapy. While growth factor support is widely applied in patients with ICAHT, the effects are usually short lived. Consequently, the use of CD34 selected stem cell boost in ICAHT as a more permanent solution has been described, however studies have been limited by small patient numbers and short follow up. Herein, we report on our multi-institutional experience at ICAHT in patients who received autologous BCMA CAR T therapy both in commercial and clinical trial settings. Methods: We included recipients of autologous BCMA CAR T therapy at 2 large academic centers between 2020 and 2023. For this study, neutropenia was defined as an absolute neutrophil count (ANC) of ≤ 1000, thrombocytopenia as platelet counts ≤ 70,000 and anemia as hemoglobin ≤9 g/dL. ICAHT was characterized by the presence of any of these hematological abnormalities. The variables were assessed at 21 days, 3 months, and 6 months post CAR-T infusion. Median follow up time was 23 months. Results : A total of 108 patients received BCMA CAR T therapy, 42 (39%) were treated on a clinical trial, 52 (48%) received commercial Idecabtagene vicleucel and 14/108 (13%) commercial Ciltacabtagene autoleucel. Baseline characteristics of the whole patient cohort are shown in table 1. The median age was 68 (range 57-69) years, with 63/107 (60%) being male. About 11% (n=12) patients were Black. 97/108 (90%) received at least one prior ASCT and the median prior lines of therapy was 5 (range 4-6). At D+21, ICAHT was observed in 68% (n=69/102) of patients, which reduced to 35% (n=30/86) and 27% (n=21/78) at the 3-month and 6-month assessments, respectively. Risk factors for ICAHT were the following: history of a prior ASCT, higher number of prior lines of therapy, a decreased platelet count prior to lymphodepletion and history of ICANS, which interestingly occurred in 11/69 (16%) patients who developed ICAHT but was not seen in those without ICAHT. About 97%(n=67/69) of patients with ICAHT had stem cells in storage and 26% (n=17/69) received a stem cell boost. The median time to stem cell boost following CAR T infusion was 116 (range 49-166) days. The median dose of stem cell infused was 3.91 (range 2.11-5.12) x10 6 CD34/kg cells. Unsurprisingly, patients with ICAHT who received a stem cell boost had significantly worse cytopenias prior to stem cell boost compared to those ICAHT patients without stem cell infusions at 120 days. Hgb was 8.4g/dL vs 10.2g/dL, p=0.02, and mean platelet levels were 30x10 9/L vs 54x10 9/L, p=0.01, compared to ICAHT patients without stem cell support. ANC levels were not significantly different between those two ICAHT groups (1700/mL vs 1500/mL), likely due to a higher use G-CSF support in ICAHT patients who received stem cell support (75% vs 55%, NS). Stem cell infusion significantly improved Hgb levels at 3 and 6 months follow up with an increase to 10.6g/dL, p=0.002, and 10.5g/dl, p=0.02, respectively. Similarly, platelet counts at 3- and 6-months post stem cell boost improved significantly to 131x10 9/L, p=<0.001, and 150x10 9/L, p=<0.001, respectively. ANC levels showed a nonsignificant increase to 2.8/mL and 3.9/mL at 3 and 6 months, yet, G-CSF support was no longer required. We further investigated whether the occurrence of secondary AML/MDS was associated with ICAHT, however these events were rare and developed in only 2 patients, one who had no ICAHT and the other one who had ICAHT without stem cell boost. Conclusion: Nearly one-third of the patients who underwent BCMA CAR T therapy continued to experience ICAHT even at the 6-month post-infusion period. The utilization of a stem cell boost for managing ICAHT lead to significantly improved Hgb and platelet counts at 3 and 6 months follow up with also substantial improvement in ANC without further G-CSF requirements. These results suggest that the use of stem cell infusions in CAR-T cell induced ICAHT can improve cytopenia associated morbidities and facilitate further anti MM therapy post CAR-T relapse.

Efficacy of Chimeric Antigen Receptor T-Cell Therapy Is Not Impaired By Previous Bispecific Antibody Treatment in Patients with Large B-Cell Lymphoma

Introduction: Potential T-cell exhaustion after bispecific antibody (BsAb) treatment remains an open question, raising the theoretical concern that prior BsAb exposure could affect subsequent chimeric antigen receptor (CAR) T-cell efficacy. Clinical data on CAR T-cell outcomes after prior BsAb treatment in the setting of large B-cell lymphoma (LBCL) are scarce and highly awaited to better define treatment sequencing in relapsed/refractory (R/R) patients. Methods: We conducted a retrospective, international study including R/R LBCL patients treated with CD19-targeted CAR T-cells at 15 centers between July 2018 and January 2023 who had been exposed to BsAbs prior to apheresis. Then, we identified a control cohort from patients included in the DESCAR-T Registry (n=764). We carried out a 1:1 propensity score matching (PSM) to achieve balance between cohorts; 13 baseline covariates were included in the PSM. We compared response rates, survival outcomes and toxicity after CAR T-cell therapy, according to previous BsAb exposure. Results: We identified 47 LBCL patients who received BsAb therapy prior to CAR T-cell apheresis. Median age was 65 years (range 31-82), with a male predominance (66%), and median prior lines of therapy before BsAb were 2 (IQR 2-3) (Table). The BsAbs targeted CD20/CD3 (91%) or CD22/CD3 (9%), either in monotherapy (n=41, 87%) or in combination with other agents (n=6, 13%) (lenalidomide [n=2], polatuzumab [n=1], chemotherapy [n=2], missing [n=1]). The median time on BsAb treatment was 98 days (IQR 56-160) with a best overall (complete) response rate (ORR [CRR]) of 47% (19%). Median progression-free survival (PFS) and duration of response (DOR) were 3.1 months (95% CI 2.7-4.4 months) and 8.8 months (95% CI 2.2-NR), respectively. Cytokine release syndrome (CRS) occurred in 59% of patients (grade 3 in 4%). No neurologic toxicity (NT) was reported. In 26 (55%) patients, bispecific antibody was the last line before CAR T-cell therapy. Median washout between the last BsAb dose and lymphocyte apheresis for CAR T-cell manufacturing was 43 days (range 34-103 days). In terms of the subsequent CAR T-cell therapy, patients received axi-cel (n=22, 47%), tisa-cel (n=20, 43%) or liso-cel (n=5, 11%). Most patients developed CRS after infusion (79%, 6% grade >2), with a low rate of NT (23%, 2% grade >2). Neutropenia and thrombocytopenia grade >2 were reported in 66% and 45% of patients, respectively. Regarding efficacy, ORR after infusion was 83% (CR 43%). Median PFS and overall survival (OS) were 6.6 months (95% CI 2.6-not reached [NR]) and NR (95% CI 9.0-NR), respectively. The rate of overall (complete) response was similar between patients who had previously responded (CR or PR) or not (SD or PD) to BsAb therapy (82% [41%] vs 84% [44%], respectively, p=0.64). However, all 9 patients achieving CR after BsAb achieved subsequent response to CAR T-cells. Given the wide variability in the washout between last BsAb dose and lymphocyte apheresis, we evaluated the impact of this interval on CAR T-cell efficacy. The 6-month PFS and OS of patients previously exposed to BsAb within 45 days of lymphocyte apheresis was similar to patients who had a longer washout (59% vs 47% [p=0.25] and 83% vs 67% [p=0.21], respectively). In the second part of the analysis, we matched our cohort with a control group of CAR T-cell recipients not previously exposed to BsAbs. The final analysis included 2 sets of 42 patients with comparable characteristics. Median follow-up from CAR T-cell infusion was 11.5 months for the BsAb cohort (CI 95% 6.4-19.0 months) and 18.8 months for the control cohort (CI 95% 10.9-23.0 months). Patients with previous BsAb exposure showed a similar PFS (p=0.10, Figure) and OS (p=0.08) after CAR T-cell infusion in comparison to the control group. In terms of toxicity, there were no differences in the incidence of CRS (p=0.41) or NT (p=1.0) after infusion. Conclusions: Previous exposure to bispecific antibody treatment targeting different antigens does not have a negative impact on survival outcomes after CAR T-cell therapy. Lack of response to a previous BsAb does not predict for lower response rates after CAR T-cell infusion.

A First-in-Human Phase 1 Trial of NX-2127, a First-in-Class Bruton's Tyrosine Kinase (BTK) Dual-Targeted Protein Degrader with Immunomodulatory Activity, in Patients with Relapsed/Refractory B Cell Malignancies

Introduction: Although BTK inhibitors (BTKi) are effective therapeutics in the treatment of B cell malignancies, emerging BTK resistance mutations in chronic lymphocytic leukemia (CLL), as well as potential growth-promoting kinase-independent scaffolding function of BTK, present a need for improved or new approaches. Additionally, preclinical and clinical data in non-Hodgkin's lymphoma (NHL) suggest that drugs modulating cereblon may synergize with BTKi to provide a therapeutic effect. NX-2127 is an oral, first-in-class, dual-function small molecule degrader that combines BTK degradation with the immunomodulatory activity of an Ikaros and Aiolos degrader. Preliminary safety of NX-2127 in patients across B cell malignancies and efficacy in patients with CLL have been presented previously [Mato et al. 2022; Danilov et al. 2023]. Here we report further safety and efficacy follow-up in patients with CLL and efficacy data in patients with NHL enrolled to date. Methods: NX-2127-001 (NCT04830137) is a first-in-human, multicenter, open-label, dose-escalation (Phase 1a) and cohort-expansion (Phase 1b) trial evaluating the safety and preliminary efficacy of NX-2127 in adults with relapsed/refractory B cell malignancies, including CLL, diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and Waldenstrom's macroglobulinemia (WM). NX-2127 is administered orally once daily in 28-day cycles. Results: As of 9 June 2023, 47 patients were enrolled and treated with NX-2127 at once-daily doses of 100 mg (n=28), 200 mg (n=10), and 300 mg (n=9). Patients were predominantly male (66%), with a median age of 74 (range 50-92) years. Twenty-nine patients were treated for CLL/small lymphocytic lymphoma, 5 DLBCL (2 GCB [Germinal-center B-cell-like], 3 non-GCB), 5 MCL, 3 MZL, 3 WM, and 2 FL. Patients enrolled were heavily pretreated with median prior lines of therapy of 4 (range 2-10) in NHL and 5 (range 2-11) in CLL. Prior treatments in patients with CLL comprised: BTKi 100% (including covalent [cBTKi] and non-covalent [ncBTKi] inhibitors); BCL2 inhibitor 76%, with a large proportion of CLL patients exhibiting BTKi resistance mutations at baseline. Prior treatments in patients with NHL included: BTKi 72% (cBTKi and ncBTKi); bispecific antibody 1/18; bispecific antibody and CAR-T 1/18. There were two reported dose-limiting toxicities: one previously reported cognitive disturbance in a patient with CLL treated at 300 mg; and neutropenia in a patient with MZL treated at 300 mg. The most common any grade treatment-emergent adverse events (TEAEs) were fatigue (48.9%), neutropenia (42.6%) and hypertension (36.2%, see Table). The most common grade ≥3 TEAEs were neutropenia (38.3%), hypertension (14.9%) and anemia (12.8%). Contusion was reported in 27.7% of patients (all below grade 3), atrial fibrillation in 12.8% of patients (6.4% grade ≥3). Most common reasons for treatment discontinuation were progressive disease (PD, 25.5%) and AE (21.3%). Median follow-up for the study was 9.5 (range 0.1-24.3) months. NX-2127 exhibited dose-dependent pharmacokinetics (PK) with a mean half-life of 2-4 days across cohorts. Rapid, robust and sustained BTK degradation was observed in all patients, regardless of their absolute BTK starting level, tumor type, or dose level of NX-2127 (Figure). In addition, degradation of the cereblon neo-substrate Ikaros was observed. Among the efficacy evaluable patients with CLL, there were 9 PRs/PR with rebound lymphocytosis; additionally, 11 patients had SD at the time of data cut-off and 4 had PD. Two patients with WM were treated and efficacy evaluable (1 SD, 1 PD). Among the efficacy evaluable patients with NHL, there were 2 CRs and 1 PR; additionally, 3 patients had SD, and 5 had PD. Two CRs are ongoing with 9.2 and 11.8 months of duration. Conclusion: This first-in-human study of NX-2127 is actively enrolling and dose-expansion cohorts in DLBCL and MCL have been initiated at the 300 mg daily dose. Findings include dose-dependent PK accompanied by degradation of BTK and Ikaros. Encouraging and persistent responses were observed in heavily pretreated patients with relapsed/refractory CLL and NHL with a manageable safety profile. These data support the treatment concept of combining immunomodulatory activity and BTK degradation in a single molecule and support further development of NX-2127 in B cell malignancies.

Clinical Outcomes of Subsequent Therapies in Patients with Relapsed/Refractory Multiple Myeloma Following Talquetamab Treatment: Analyses from the Phase 1/2 MonumenTAL-1 Study

Introduction: Talquetamab (tal) is an off-the-shelf, T-cell redirecting bispecific antibody (BsAb) targeting G protein-coupled receptor family C group 5 member D. Results from the phase 1/2 MonumenTAL-1 (NCT03399799/NCT04634552) trial showed overall response rates (ORRs) of >71%, which were durable, and a manageable safety profile with the recommended phase 2 doses (RP2Ds) of subcutaneous (SC) tal, 0.4 mg/kg weekly (QW) or 0.8 mg/kg every other week (Q2W), in patients (pts) with relapsed/refractory multiple myeloma. Data with tal also demonstrated preservation of B cells throughout treatment, contributing to relatively few severe infections. To date, there is a paucity of data describing pt outcomes after T-cell redirection therapies. Here, we report outcomes for pts who received subsequent antimyeloma therapies (SATs) after discontinuing tal in MonumenTAL-1, including pts who went on to receive subsequent T-cell redirection therapies. Methods: Pts eligible for MonumenTAL-1 were intolerant to or progressed on established therapies (phase 1) or had ≥3 prior lines of therapy (LOT), including ≥1 proteasome inhibitor (PI), ≥1 immunomodulatory drug (IMiD), and ≥1 anti-CD38 monoclonal antibody (mAb) (phase 2). Pts received step-up doses and the QW or Q2W RP2Ds of SC tal until progressive disease (PD), unacceptable toxicity, withdrawal of consent, or death. Following tal discontinuation, SAT, start/end date of SAT, best response to SAT, and date of PD on SAT were recorded, if available. Data are pooled for the QW and Q2W RP2D cohorts. Response to SAT is based on investigator-reported assessment. Efficacy is presented for first SAT received post tal discontinuation. Results: As of 17 Jan, 2023, 288 pts with no prior exposure to T-cell redirection therapies received tal at the RP2Ds (0.4 mg/kg QW [n=143] or 0.8 mg/kg Q2W [n=145]). Median prior LOT was 5. In the QW and Q2W cohorts, respectively, 74.1% and 69.0% were triple-class refractory, 29.4% and 23.4% were penta-drug refractory, and 15.4% and 11.0% had prior belantamab mafodotin exposure. Overall, 135 pts received ≥1 SAT post tal discontinuation: chemotherapy-based regimens (n=60 [44.4%]), a PI-, IMiD-, or other anti-neoplastic-containing regimen (n=40 [29.6%]), anti-CD38 mAb-containing regimens (n=36 [26.7%]), BsAbs (mostly monotherapy, n=23 [17.1%]: n=18 [13.3%] anti-B-cell maturation antigen [BCMA]; n=5 [3.7%] anti-Fc receptor-like protein 5 [FcRH5]), chimeric antigen receptor T-cell (CAR-T) therapy (n=20 [14.8%]; of whom n=18 [13.3%] were reported as receiving anti-BCMA-targeting CAR-T therapy), or anti-BCMA antibody-drug conjugates (n=13 [9.6%]). Time from tal discontinuation to the start of first SAT was generally similar across all drug classes (median, 1.1 months [range, 0.1-7.4]), including T-cell redirection therapies and bridging therapy in pts receiving CAR-T therapy: 1.5 months (range, 0.1-7.4) with CAR-T, 1.7 months (range, 1.0-3.5) with anti-BCMA BsAbs, and 1.0 month (range, 1.0-2.3) with anti-FcRH5 BsAbs. Best responses for each treatment class are shown in the Table. Pts had deep responses to CAR-T therapy as the first SAT post tal discontinuation with an ORR of 66.7% (8/12) (Table). ORR was 33.3% (2/6) in pts treated with anti-BCMA BsAbs as the first SAT post tal and 66.6% (2/3) with subsequent anti-FcRH5 BsAb therapy. Conclusions: Pts from MonumenTAL-1 who discontinued tal were effectively treated with several classes of therapy. Subsequent treatment with T-cell redirection therapies appears feasible, with 25.0% of pts achieving a complete response or better with CAR-T therapy post tal. Further investigation in larger pt populations is warranted to better understand the sequencing of T-cell redirecting therapies after tal to optimize outcomes.

Identifying Causes of Unscheduled Healthcare Interactions and Changes to Patient Disposition in Individuals Receiving Outpatient Commercial Bispecific Antibody Therapy in Relapsed/Refractory Multiple Myeloma (RRMM)

Introduction: Teclistamab is a BCMA targeting bispecific antibody that was FDA approved for treating relapsed/refractory multiple myeloma (RRMM) based off the results of the MajesTEC-1 trial (Usmani S, et al. Lancet 2021, Moreau P, et al. N Engl J Med 2022), and is the first bispecific antibody approved for myeloma treatment. While patients included in the MajesTEC-1 study were monitored closely per trial protocols, little is known about what patient-reported care concerns and education gaps may exist outside of a trial setting with standard of care teclistamab and whether these gaps lead to a high number of unscheduled healthcare interactions. Methods: We retrospectively analyzed patient reported symptom concerns for commercial teclistamab patients at Memorial Sloan Kettering Cancer Center (MSKCC) via review of the electronic health record for a 4-month observation period following treatment initiation. Patients were included in the study if they had a response to teclistamab (per IMWG criteria), remained on treatment for at least 4 months as of our data cut-off (07/20/2023), and did not have evidence of disease progression during the observation period. Collected data included all unscheduled healthcare visits, including urgent care visits, emergency room visits, and hospital admissions. We also evaluated all outpatient communications, including telephone calls to physicians' offices and messages sent to physicians' offices through MSKCC's online patient portal. The total observation period included the first 4 months of therapy, during which patients were scheduled to receive treatment weekly and be seen by their physicians at regular 4-week intervals. Results: We identified 52 patients treated with teclistamab at our center as of the data cut-off, 19 of which met our inclusion criteria. Of note, this population had poorer performance status (89% vs 67% ECOG ≥1) and had more heavily pretreated disease (6 vs 5 median prior lines of therapy) when compared to the MajesTEC-1 population, with the majority not being eligible for MajesTEC-1 per its criteria. Within this population, 79% of patients communicated with their physicians' offices outside of their scheduled monthly appointments, with an average of 2.3 (0-8) communications sent per patient during the 4-month observation period. The most common reason for communication was upper respiratory tract infection (URI) symptoms, accounting for 24% of all communications. Other notable reasons included gastrointestinal (GI) symptoms (20%), disease related pain (13%), injection site reactions (9%) and symptoms of volume overload (9%). Unscheduled visits included 8 urgent care (UC) visits, and 20 emergency department (ED) visits involving 11/19 patients. The 20 ED visits led to 16 inpatient admissions, not including planned admissions for step-up dosing (data summarized in Figure 1), with a median length of stay of 4 days (2-24 days). URI symptoms triggered 50% of UC visits and 40% of the ED visits not leading to inpatient admission, but only accounted for 6% of hospital admissions. The most common cause of hospital admission was a non-URI acute infection (29%). Conclusions: Our data suggest that RRMM patients being treated with outpatient teclistamab have frequent unscheduled healthcare interactions. The high prevalence of URIs in our population indicates that infection rates in this frequently hypogammaglobulinemic patient population may be underreported. However, these do not frequently lead to inpatient admissions or to significant morbidity/mortality. Overall, teclistamab patients would likely benefit from improved patient education with regards to expected side effects of therapy, with pre-existing management plans in place for URIs, GI symptoms, and injection site reactions. Applying these principles may limit excessive healthcare visits for patients, particularly in those with heavily relapsed/refractory myeloma with poor disease prognosis. Data from additional patients, including patients receiving step-up dosing as outpatients as part of a pilot study, will be presented at the meeting.

Teclistamab in Relapsed Refractory Multiple Myeloma: Multi-Institutional Real-World Study

Introduction: Teclistamab is the first BCMA-targeting bispecific antibody (bsAb) that has received FDA approval in RRMM based on the MajesTEC-1 study, which showed a single-agent ORR of 63%. In this report, we present the safety and efficacy of teclistamab since its approval in a real-world multi-institutional cohort. Methods: All consecutive patients with RRMM treated with at least one dose of standard-of-care teclistamab at 5 academic centers in the US were included in this study. Data including patient demographics, disease, and treatment characteristics at the most recent assessment before starting treatment were retrospectively collected. Results: A total of 89 patients were treated across 5 academic institutions. The median age was 68 years (range: 37-89), with 48% (n=43) females. Among the patients, 30% (n=27) were Black, 2.2% (n=2) Asian and 12% (n=11) were other minorities. High-risk cytogenetic profile was observed in 65% (n=49/75) of the patients. About 48% (n=39) of the patients exhibited EMD on PET-CT. Four patients had CNS involvement, 1 had pPCL, and 3 had concomitant AL amyloidosis. Furthermore, 98% (n=87) of the patients had triple-class refractory MM, while 85% (n=76) had penta-refractory MM. The median prior lines of therapy were 6 ( range: 3-13) and 80% (n=71) of patients received a prior ASCT. About 37% (n=33) had received prior BCMA-directed therapy, which included BCMA CAR-T in 17, BCMA BsAb in 5, and Belantamab mafadotin in 11 patients . Table 1 compares this patient cohort with the MajesTEC-1 study population. Grade 1/2 CRS was observed in 48% (n=43) of patients, while 3% (n=3) experienced grade 4 CRS. Grade 1/2 ICANS was noted in 7% (n=6) of patients, grade 3/4 in 4.4% (n=4), and grade 5 in 1 patient. Steroids were utilized in 22% (n=16) of patients, while tocilizumab was administered in 44% (n=32) of patients. Notably, step-up dosing of teclistamab was administered entirely in the outpatient setting in 9% (n=8) of patients. For the remaining, inpatient step-up dosing was administered, and the median hospitalization duration was 10 days. At a median follow-up of 1.35 months (range: 0.16-4.38), the ORR among the evaluable patients was 55%, with rates of ≥ VGPR and PR at 37% (n=28) and 18% (n=13), respectively. The 3-month PFS rate was 54% (95% CI: 43%, 69%), while the 3-month OS rate was 80% (95% CI: 71%, 90%). Multivariate analysis did not reveal any significant associations between disease response and the following factors: number of prior lines of therapy (HR 1.03, 95% CI 0.76-1.42), baseline lymphocyte counts (HR 0.98, 95% CI 0.47-2.02), high-risk cytogenetics (HR 0.38, 95% CI 0.09-1.39) and the presence of extramedullary disease (HR 0.56, 95% CI 0.15-1.93). There was a trend towards worse ORR in patients with prior exposure to BCMA targeting agents, albeit not quite significant (HR 0.28, 95% CI 0.07-1.04, p=0.065). There were 61 infectious events with 50%, 45% and 5% of these being viral, bacterial, and fungal infections, respectively. The most common sources of infections were upper respiratory tract infections/pneumonias (33%), blood borne infections including bacteremia and viremia (27%) and urinary tract infections (11%). The cumulative incidence of any infection at 3 months was 55% and grade 3/4 infections were seen in 55% (n= 54) of cases. There was one grade 5 infection noted in this study due to COVID 19 pneumonia. Primary IVIG and PJP prophylaxis were used in 40% (n=34) and 51% (n=43) of patients, respectively and the use of such was associated with a significant reduction of infectious events (26/51 [51%] of any infectious event for no IVIG use vs 13/34 [38%] for IVIG use, p= 0.015). The results will be updated with longer follow-up at the meeting. Conclusion : In this large real-world, multi-institutional study including a diverse cohort of heavily pretreated patients with triple-class and penta-refractory MM, including approximately 40% with prior BCMA exposure, teclistamab demonstrated a respectable ORR of 55% with ≥ VGPR in 37% of cases. The incidence of Grade 3 or higher infections at 3 months remained high at 56%, however the use of prophylactic measures, including primary IVIG prophylaxis was associated with a significant reduction of all infections and should be strongly considered in patients receiving teclistamab.