Citations

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

Abstract Teclistamab is an anti-CD3-/B-cell maturation antigen (BCMA) bispecific antibody approved for use in relapsed/refractory multiple myeloma. We undertook a retrospective study of post-approval, real-world outcomes with teclistamab in the US Multiple Myeloma Immunotherapy Consortium. Among 509 patients, 89% would have been ineligible for the MajesTEC-1 trial, primarily due to prior BCMA-directed therapy, cytopenias, or diminished performance status. Cytokine release syndrome occurred in 54% (1.4% grade ≥3) and immune effector cell–associated neurotoxicity syndrome in 11% (2.2% grade ≥3), with no fatal events. Infections occurred in 42% and contributed to death in 5%. Partial response (PR) or better was achieved in 53% and very good PR or better in 45%. With 10.1 months of median follow-up, the estimated median progression-free survival (PFS) was 5.8 months and 12-month overall survival was 61%. Independent predictors of less than very good PR and shorter PFS included BCMA-directed chimeric antigen receptor T-cell therapy in the previous 9 months, high disease burden, lymphopenia, and elevated ferritin. Significance: T cell–engaging bispecific antibodies such as teclistamab represent an important new treatment modality for multiple myeloma and other blood cancers. This study evaluates the real-world safety and efficacy of teclistamab, including its activity in populations not represented in the initial phase I/II study, and identifies clinical variables associated with treatment response. See related commentary by Zweegman et al., p. 542

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

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

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

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

Introduction: Waldenström macroglobulinemia (WM)remains incurable with current therapies. Treatment options for patients beyond initial therapy are limited, underscoring the need for new agents with novel mechanisms of action. Iopofosine I 131 is a novel radiopharmaceutical composed of a lipid raft-targeting phospholipid ether covalently bound to 131I, a beta-emitting radioisotope. Herein, we report the results of the CLOVER-WaM study [NCT02952508] in patients with previously treated WM. Methods: Eligible WM patients had received >2 prior therapies and had symptomatic disease requiring therapy according to consensus recommendations for WM. Treatment consisted of 2 cycles of iopofosine I 131 administered at 15 mCi/m2 on days 1 and 15 of each 57-day cycle. Dose reduction to 10 mCi/m2 was allowed in the second cycle in patients with incomplete hematologic recovery or if the expected total dose exceeded 132 mCi. Supportive care with growth factors and transfusions was permitted per treating physician discretion. The primary endpoint was major response rate (MRR, defined as partial response or better) as determined by the modified VIth International Workshop on Waldenström Macroglobulinemia Response Criteria. Secondary endpoints included overall response rate (ORR), treatment-free survival (TFS), duration of response (DOR), and clinical benefit rate (CBR, defined as stable disease or better). Efficacy endpoints were assessed in the modified intent-to-treat (mITT) population, defined as all patients who received ≥60 mCi total administered dose of iopofosine I 131. MRR was analyzed with a 95% 2-sided confidence interval (CI) using the Clopper-Pearson interval method. In this population, MRR >20% was considered statistically significant. Time-dependent efficacy endpoints were analyzed using the Kaplan-Meier method. Safety was evaluated using CTCAE v4.03 in patients who received >1 dose of iopofosine I 131. The data cut-off for this analysis was May 31, 2024. Results: In 65 patients enrolled (safety population), the median age was 70 (range, 50-88) years; 48 (73.8%) were male, and 17 (26.2%) were female. Sixty-one (93.8%) were White, 1 (1.5%) was Black/African American, and 3 (4.6%) were other or unknown. Fifty-five patients met mITT criteria and were evaluable for efficacy. The median number of prior therapies was 4 (range, 2-15). Bruton's tyrosine kinase inhibitor (BTKi) exposure was noted in 39 (71%) patients, of whom 31 (56%) were BTKi-refractory. Sixteen (29%) patients had MYD88-wild type, and 5 (9%) had CXCR4-mutated disease. The MRR was 56.4% (95% CI, 42.3-69.7). ORR was 80%; among MYD88-wild type patients, ORR was 81%, and among post-BTKi patients, ORR was 72%. CBR was 98%. The median DOR and TFS were not reached at a median follow-up of 8.8 months, with an estimated 72% of responding patients remaining progression-free at 18 months. In the safety population, any-grade adverse events, regardless of causality, were reported in 57 (87%) patients. Grade 3 or higher treatment-emergent adverse events (TEAEs) occurring in >10% of patients included thrombocytopenia (80%), neutropenia (69.2%), anemia (44.6%), lymphopenia (13.8%), infections (12.3%), and febrile neutropenia (10.8%). Adverse event-related death occurred in 1 patient due to bacterial sepsis. Conclusion: Iopofosine I 131 demonstrated durable efficacy in previously treated WM patients, with no current standard of care therapy. The treatment was well-tolerated with a manageable toxicity profile across broad biologic and clinical subgroups, irrespective of risk stratification. Based on the results of this trial, iopofosine I 131 shows promise as a novel treatment for WM patients.

Introduction: Anti-BCMA CAR-T therapies like idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have revolutionized RRMM treatment. However, the 6-8-week manufacturing period often leads to disease progression and/or death in up to 25% of patients (pts), necessitating effective bridging strategies. Talquetamab (talq), a bispecific antibody targeting GPRC5D, is approved for RRMM pts with four prior lines of therapy and offers rapid disease debulking without impacting BCMA. This study assesses the safety and efficacy of a short course of talq as a bridging therapy for pts receiving cilta-cel or ide-cel. Methods: This multicenter retrospective study involved 14 US academic medical centers within the US Multiple Myeloma Immunotherapy Consortium. We included pts with RRMM who underwent leukapheresis and received talq bridging therapy with the intent to proceed to commercial cilta-cel or ide-cel. We assessed the safety, feasibility, and efficacy of talq bridging therapy. Safety outcomes included cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), talq-related unique toxicities, and delayed neurotoxicity (NT). Efficacy outcomes included response rates to talq and CAR-T therapies. Results: Between June 2023 and May 2024, 77 pts received talq bridging therapy after apheresis with the intention to proceed to CAR-T. The median age was 66 years (range, 58-73); 14% were Black and 10% Hispanic. Poor prognostic features, including high-risk cytogenetics, were present in 45%, extramedullary disease (EMD) in 43%, and 72.7% were triple-class refractory. The median number of prior lines of therapy was 5 (range 3-11) and 10 pts (13%) had prior BCMA targeted therapy. Out of 77 pts, 10 pts were pending CAR-T infusion at the time of last follow up; 6 pts could not receive CAR-T infusion due to manufacturing failures. Of the remaining 61 patients who underwent successful CAR-T manufacturing, 58 (95%) pts were successfully infused with CAR-T therapy following talq bridging. Three (5%) pts died due to disease progression prior to CAR-T infusion. Talq was given 0.8 mg/kg biweekly in 59 (76%) pts and the median time on talq was 22 days (IQR: 10-41 days). Following talq bridging, none of the pts had grade >=3 CRS and 2 (2.5%) had grade 3 ICANS. Skin toxicities occurred in 32 (41%), nail toxicities in 19 (25%), and oral toxicities in 43 (56%) pts mainly grade 1. Most oral, skin, and taste changes resolved at the last follow-up (60%). Response to talq was evaluable in 72 out of 77 patients. An overall response was noted in 45/72 (62%) pts including unconfirmed CR in 14, VGPR in 10 and PR in 21 pts. There was no association of AEs and response to talq with high-risk cytogenetics, EMD and high baseline ferritin levels. Out of the 58 patients who went on to receive CAR-T therapy following talq bridging (45 cilta-cel and 13 ide-cel), 38 (65%) experienced CRS, with grade 3 CRS noted in 2 (3%) pts. ICANS occurred in 5 (8.6%) pts, with 1 (1.7%) grade 3 ICANS. Only 1 pt had delayed NT (facial nerve palsy) at the last follow up. No treatment related deaths were observed. Of these 58 pts, response was evaluable in 40 pts and a response at day +30 was noted in 39/40 (97.5%) pts (14 in CR, 10 in VGPR, 15 in PR). The median follow-up from CAR-T was 61 days (28-113). For the 58 pts who received CAR-T, the median time from the last talq dose to CAR-T infusion was 25 days (IQR: 19-36), and to lymphodepletion was 24 days (IQR: 18-33). There was no difference in the CAR-T related AEs by the duration of Talq washout (>4 weeks vs. =< 4 weeks). Conclusions: Talquetamab is an excellent bridging option before BCMA-targeted CAR-T therapy, showing high response rates even with short-term use and enabling most pts to receive CAR-T. Most oral, skin, and taste changes resolved post CAR-T. These findings underscore the effectiveness of a short course of talq bridging to maintain disease control and improve outcomes post CAR-T. Updated data with longer follow-up will be presented at the meeting.

Background: Data on the clinical activity of venetoclax (ven) in lymphoplasmacytic lymphoma (LPL) are primarily limited to a phase 2 trial of ven monotherapy for a 2-year duration in 32 patients (pts) with relapsed/refractory IgM LPL who received a median of 2 prior treatments (tx), including 16 pts with prior BTK inhibitors (BTKi) (Castillo et al, JCO 2021). Overall response rate (ORR) was 84% and median progression-free survival (PFS) was 30 months (mos). We report the clinical activity of ven and prognostic factors associated with outcomes in a larger cohort. Methods: We included pts with LPL treated with ven alone at 9 US centers. The primary outcome was ORR, which included minor response (MR), partial response (PR), very good PR (VGPR), and complete response (CR) per IWWM-7. Secondary outcomes included PFS, overall survival (OS), safety of ven, and predictors of ORR, PFS, and OS. Results: Sixty-two pts were included. Twenty pts (32%) received ven on a clinical trial. At ven initiation, median age was 65 years (range 38 - 87) , 61% were male, serum monoclonal (M) protein was IgM in 50 pts (91%) (IgG/IgA in 3 (5%), absent in 2 (4%), missing n=7), median hemoglobin (Hb) was 10.4 g/dL (range 5.7-16.4), and median serum IgM was 2580 mg/dL (range 5-9300). Mutations of MYD88 and CXCR4 were present in 52 (95%; missing n = 7) and 19 (38%; missing n = 12) pts, respectively. Median lines of tx (LOT) before ven was 3 (range 1-11, 58% ≥3) including antiCD20 monoclonal antibody n=54 (87%), BTKi n=48 (77%), proteasome inhibitor n=40 (65%), and bendamustine n=31 (50%). Pts who received ven on a clinical trial were less heavily pretreated (median prior LOT = 1.5, 20% ≥3) compared with pts treated off trial (median prior LOT = 4, 76% ≥3). ORR to prior BTKi was 71% (CR 4%, VGPR 10%, PR 35%, MR 21%) (missing n=5), with a median duration of tx of 14 mos (range 0.5-119). BTKi was stopped due to progressive disease (PD) in 60% and toxicity in 40%. ORR to most recent tx before ven was 58% (CR 3%, VGPR 8%, PR 32%, MR 15%); 21% SD, 7% PD, and 15% missing. BTKi was the most frequently used tx immediately before ven (48%). Six pts (10%) required plasmapheresis up to 30 days before starting ven. Median time from diagnosis to ven initiation was 5.9 years (range 0.3-23). Ven starting dose was 200 mg in 33 pts (55%), 20 mg in 11 (18%), and 100 mg in 10 (17%) (other n=6, missing n=2). Ten pts (17%) were admitted for ven tx initiation. Maximum ven dose was 400 mg in 16 (27%) and 800 mg in 38 pts (63%) (other n=6, missing n=2). ORR to ven (missing n=3) was 73% (95% confidence interval [CI] 63-86%) (CR 2%, VGPR 21%, PR 44%, MR 7%); 23% were refractory (SD 13%, PD 10%). Median time to best response was 4 mos (range 0.5-30). Median time to peak Hb was 5 mos (range 0.1-24) and to nadir serum M protein level was 8 mos (range 0.5-34). With a median follow-up of 21.9 mos (range 2.3-70.4), the median and 3-year PFS were 30.4 mos (95% CI 11.0-38.6) and 40% (95% CI 25-54%), respectively (Figure). Median and 3-year OS were not reached (NR) (95% CI NR-NR) and 83% (95% CI 70-91%), respectively. Lymphoma was the most common cause of death (n=8/11, 73%). In univariable analyses (UVA), tx with ven on a clinical trial was associated with higher ORR (90% vs 64%; odds ratio = 8.67, 95% CI 1.04-72.16, p=.046) and superior PFS (median 39 mos (95% CI, 28.4-NR) vs 11 mos (95% CI 6.4-NR), p=.028) without a significant difference in OS. Other factors evaluated in UVA to assess association with ORR, PFS and OS were age at ven start, response to last prior tx, prior tx with BTKi, and CXCR4 mutation status. Of these, receipt of prior tx with BTKi was associated with inferior PFS (HR=2.7, 95% CI 1.1-6.5, p=.024), whereas age >65 years at ven start (HR=8.6, 95% 1.1-67.8, p=0.042) and receipt of ≥3 prior tx (HR=12.0, 95% 1.5-95.9, p=.019) were associated with inferior OS. Four pts (7%) developed laboratory tumor lysis syndrome (TLS) including 2 (3%) with clinical TLS. TLS occurred at the 400 or 800 mg dose in 3 pts (missing n=1). Ven dose interruptions and/or reductions occurred in 39%. Three pts (5%) had febrile neutropenia. Ven was stopped due to PD in 21 pts (34%), planned tx completion in 15 (24%) (median tx duration = 25 mos, range 24-28), toxicity 6 (10%), and other 4 (6%); 16 pts (26%) remain on ven. Median duration of tx for those who stopped ven was 12 mos (range 1-33). Conclusion: Ven is an effective tx option for pts with relapsed or refractory LPL. Compared with the phase 2 study, ORR and PFS were lower in this cohort of more heavily pretreated pts.

Abstract Background: New targeted therapies continue to show improved efficacy in various stages of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), sparing patients from chemoimmunotherapy. However, cure remains elusive. Here, we present a front-line alternative based on a combination of high-dose methylprednisolone (HDMP) and ofatumumab, followed by consolidative therapy with lenalidomide plus ofatumumab. Methods: This is a phase II, single-center study in patients with treatment-naive (TN) CLL/SLL. During the first treatment phase (cycles 1-3) patients received HDMP 1000 mg/m2 IV and ofatumumab 2000 mg (300 mg given week 1 then 2000 mg for a total of 12 doses) IV infusions weekly x 4 doses in cycle 1 of a 28 day cycle, then every 2 weeks for cycles 2 and 3. During the second treatment phase (cycles 4-12), patients received renally adjusted lenalidomide 5-10 mg daily and ofatumumab 2000mg IV once every 8 weeks. Growth factor support was permitted at the discretion of treating physician. Prophylactic medications included allopurinol for tumor lysis syndrome (TLS) 3 days before C1D1 through C1; and trimethoprim/sulfamethoxazole and fluconazole through cycle 4, and acyclovir through C12. Patients received aspirin 81 mg/day as thrombosis prophylaxis while on lenalidomide. Patients were assessed for response by iwCLL 2008 criteria (including imaging assessment) after completion of cycles 3 and 12. The study allowed continuation of lenalidomide if patients achieved complete (CR), partial (PR) response or stable disease (SD). Primary endpoints were efficacy, adverse events (AEs) profile, and time-to-treatment failure (TTF). Results: Between January 2012 and September 2015, the study enrolled a total of 45 patients. Median follow-up was 50.4 (5.6-72.8) months. The median age was 62.6 (48.2-86.1) years. Chromosomal analysis by FISH demonstrated Del17p in 8 (17.8%), Del11q (+/- others, except Del17p) in 10 (22.2%), Trisomy 12 (+/- others, except Del17p and Del11q) in 8 (17.8%), Del13q in 10 (22.2%), no mutations in 9 (20%) patients. The IGHV status was unmutated in 34 (75.6%) cases. Indications to start treatment were: symptomatic lymphadenopathy, symptomatic splenomegaly, anemia, and thrombocytopenia in 5 (11.1%), 10 (22.2%), 12 (26.7%), and 18 (40%), respectively. The median duration of treatment was 35.6 (2.7-66.9) months. Reasons for treatment discontinuation were: progressive disease (PD) in 9 (20%), AEs in 15 (33.3%), transplantation in 3 (6.7%), consent withdrawal in 1 (2.2%), and secondary malignancies in 2 (4.4%) cases. The overall response rates (PR+CR) at 3, 12, 24, 36, and 48 months were 75.6%, 77.8%, 66.7%, 44.4%, and 37.8%, respectively. The CR rates at 3, 12, 24, 36, and 48 months were 2.2%, 11.1%, 20%, 17.8%, and 13.3% respectively. Fifteen patients remain in PR/CR and on treatment at the time of this analysis. The intention-to-treat median TTF was 45.2 (2.9-69.7) months, and was not different among high risk groups such as Del17p, Del11q and/or unmutated IgHV. In patients who discontinued for reasons other than PD the median duration of response without treatment was 30.7 (9.8-69.7) months. Three (6.7%) patients underwent allogeneic hematopoietic cell transplantation after a median of 3 (3 - 4) treatment cycles. Treatment was well tolerated with grade 3/4 infusion reaction in 1 (2.2%) patient. Grade 3/4 treatment-related hematological AEs were neutropenia, thrombocytopenia, and anemia in 33 (73.3%), 5 (11.1%), and 1 (2.2%), respectively. Grade 3/4 infections occurred in 6 (13.3%) patients. No grade 3/4 tumor flares were observed, and there were no cases of TLS or thrombosis. Conclusion: The combination of ofatumumab, HDMP and lenalidomide is effective and well tolerated in treatment-naive CLL/SLL, even when poor prognostic features are present. Disclosures Komrokji: Novartis: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Speakers Bureau. Locke:Novartis Pharmaceuticals: Other: Scientific Advisor; Cellular BioMedicine Group Inc.: Consultancy; Kite Pharma: Other: Scientific Advisor. Kharfan-Dabaja:Seattle Genetics: Speakers Bureau; Incyte Corp: Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau. Sokol:Spectrum Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Mallinckrodt Pharmaceuticals: Consultancy.