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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

Background: Anti-BCMA CAR T cells are a new standard of care for the treatment of RRMM patients. Hence, it is paramount to identify determinants of response and resistance for individualized approaches. There is emerging data about the importance of depth of response in prolonged progression-free survival (PFS) and of genetic antigen escape in treatment resistance. By contrast, there is limited understanding of how patient' outcomes are shaped by immune fitness prior aphaeresis, and virtually no data about CAR T and endogenous profiles post infusion. Aim: Characterize immune dynamics and investigate its prognostic value in RRMM patients treated with CAR T cells. Methods: Immune profiling was performed using multidimensional and computational flow cytometry in 285 bone marrow aspirates from 120 RRMM patients enrolled in the KarMMa phase 2 trial. In total, 170 immune clusters were identified and systematically quantified in a pileup analysis of samples collected before and at months 1, 3, 6 and 12 after CAR T infusion. Immune scores were developed using cox regression with 10-fold cross-validation. Results: At baseline (n = 63), there were significant associations between the bone marrow immune composition and the number of prior lines of treatment, prior autologous transplant and staging. Namely, there were higher proportions of ICOS, PD1, TIGIT and TIM3 positive cells within the CD4+ and CD8+ T cell compartments from heavily pretreated patients and those with R-ISS 3. A baseline immune score defined by the percentages of GrzmB+HLADR+ cytotoxic NK cells, TIGIT+ Tregs, CD4+CD127+ICOS+ and CD4+CD25+CD127+TIGIT+, CD8+TIGIT+, CD8+GrzmB+HLADR+ and CD8+CD27+CD95+CD45RAloCD197lo T cells was associated with PFS. Patients with low vs high risk immune score at baseline had median PFS of 25 vs 6 months, respectively (p < .001). Interestingly, there were no significant associations between the baseline risk score and treatment or staging, suggesting potential complementarity of immune profiling with other prognostic factors. At month 1 after infusion (n = 55), the presence of >1% vs <1% CAR T cells was associated with longer PFS (medians of 20 vs 8 months, p = .002). In addition to the magnitude of CAR T persistence, it was interesting to observe increased percentages of CD8+ CAR T cells in patients with <5 prior lines of therapy, of CD4+HLADR+ and CD8+TEMRA CAR T cells in patients with R-ISS 1/2, as well as of PD1+TIM3+ CD4+ and CD8+ CAR T cells in patients with R-ISS 3. Moreover, the phenotype of CAR T cells was associated with PFS. Patients with low vs high risk immune score (ie, based on the percentages of CD4+CD57+, CD8+CD27-EM, CD8+PD1+TIM3+ and CD4+CD8+ CAR T cells) had median PFS not reached vs 11 months, respectively (p < .0001). Similarly to the above, there were no significant associations between the CAR T immune risk score and treatment or staging, suggesting potential complementarity of CAR T quantification and phenotyping post-infusion with other patient' characteristics. Next, we investigated endogenous T cell dynamics in 51 RRMM patients with paired samples prior and after CAR T infusion. There were significant differences in the frequencies of 30 immune clusters, including CD27+ naïve and EM CD4+ and CD8+ T cells, ICOS+ and TIGIT+ Tregs, CD4+ and CD8+ T cells, as well as of CD25+CD127+ CD4+ and CD8+ T cells. Furthermore, an immune risk score defined at the latest available time point (n = 95) was associated with PFS (p < .0001). Patients with lower levels of GrzmB+ cytotoxic NK cells and of immunoregulatory HLADR- NK cells, as well as of CD4+CD27+CD95+CM, CD4+HLADR+, CD8+PD1+ and CD8+CD27-CD95+EM T cells showed a high risk score and a median PFS of 6 vs 20 months in patients with low risk immune score. Conclusions: This is one of the largest dynamic studies of immune profiling in a clinical trial investigating anti-BCMA CAR T cells in RRMM. Our results uncovered that patient' immune status is shaped by prior treatment and staging, and that the distribution of different NK, Treg, CD4+ and CD8+ T cells prior aphaeresis is associated with PFS. Furthermore, the phenotype of CAR T cells at month 1 after infusion may be as prognostic as its percentage. We also showed how treatment with CAR T cells modulates the bone marrow immune composition and how it may contribute to immune escape vs surveillance. Altogether, this study supports immune profiling for improved understanding of response and resistance to CAR T cells in RRMM.

Introduction: Health disparities negatively impact outcomes of patients (pts) with hematologic malignancies. Limited retrospective data correlating health disparities with lymphoma outcomes prohibit proper identification of reversible causes and elaboration of potential interventions. We present data from a coordinated effort between the National Clinical Trials Network (NCTN) cooperative groups (Alliance for Clinical Trials in Oncology [Alliance], Eastern Cooperative Oncology Group [ECOG], and the Southwest Oncology Group [SWOG]) to catalog the racial, ethnic, and socioeconomic characteristics of pts with lymphoma to better understand the quality of data collected, analyze selected health disparity indicators, and develop a prospective data collection tool. Methods: We conducted a retrospective analysis of demographic data from pts with lymphoma enrolled on 32 cooperative group therapeutic trials between 2005 and 2020. Special focus was placed on data regarding race, ethnicity, and proxies that help identify socioeconomic status (health insurance, residential zip code, Social Deprivation Index [SDI]). These were evaluated in relation to histology-based metrics from the Surveillance, Epidemiology, and End Results Program (SEER) Program with reported data through 2022. Here, our focus is to characterize baseline demographic and disparities data on the collection of these 32 NCTN lymphoma trials. Results: A total of 3,897 pts were included, with 3,406 non-Hodgkin lymphoma (87.4%) - 1,644 diffuse large B-cell (DLBCL, 48.3%), 905 follicular (26.6%), 669 mantle cell (19.6%), 113 primary central nervous system (3.3%), 75 T-cell (2.2%) - and 491 Hodgkin lymphoma (12.6%). Age at registration was available for 3,891 pts with median age 57.1 years (range: 18-92). The majority of patients were male (58.8%; one pt missing biological sex data). Race data were available for all but one patient, where most pts were white (W, 86.6%), followed by 246 African American (AA, 6.3%), 99 Asian (A, 2.5%), 13 American Indian or Alaska Native (AI, 0.3%), 8 Native Hawaiian or Pacific Islander (PI, 0.2%), 11 with more than 1 race reported (0.3%), and 145 with unknown/not reported race. Ethnicity data were unknown for 327 pts (8.4%) with 179 Hispanic or Latino (Hisp, 4.6%). Combined race/ethnicity data showed 3,010 non-Hisp white (NHW, 77.2%) and 219 non-Hisp black (NHB, 5.6%). For comparison, in the SEER database, 84.7% of all lymphoma cases were W, with 8.6% AA, 5.2% A/PI, 0.4% AI, and 1.1% unknown race, and with 13.9% of pts reported as Hisp. When focusing on the 804 pts enrolled on Alliance CALGB 50303 and ECOG-ACRIN 1412 studies, two randomized DLBCL studies, there was a more proportional representation of W and AA pts with DLBCL - 82.1% and 9.8% compared 84.6% and 7.7%, respectively, at SEER database, with 5.3% Hisp (with another 5.3% unknown) compared to 14.9% at SEER. Insurance information was missing in 113 pts. Of the remainder, 2,102 pts had private insurance only (55.6%), 549 with a mix of private and public (14.5%), 701 public only (18.5%, including 11.4% Medicare, 4.5% Medicaid, 0.8% both), and 166 self-pay (4.4%). Year-matched SDI score was available in 2,885 pts, where higher SDI scores = higher social deprivation. The total mean SDI score for the overall cohort was 42.5 with significant differences observed based on race/ethnicity and insurance type. Specifically, NHW were from less deprived areas (mean SDI=38.8) than NHB (66.4) or Hisp (65.5) (p<0.0001). Those without insurance (mean SDI=52.6) or only public insurance (48.9) were located in areas associated with greater deprivation compared to pts with private (40.1) or public+private (38.8) insurance (p<0.0001). Conclusion: To our knowledge, this is the largest retrospective catalog of racial, ethnic, and socioeconomic characteristics of pts with lymphoma enrolled on cooperative group therapeutic trials. The scope of NCTN cooperative group lymphoma studies provides a unique opportunity to assess novel therapeutic outcomes for patients representing racial, ethnic and socioeconomic subgroups with both common and rare lymphoma subtypes. From this resource, additional analyses on relationships between SDI, race/ethnicity, insurance coverage, disease subtype, and temporal trends will be presented. Support: U10CA180821, U10CA180882, UG1CA189823

Introduction QUADs with an anti-CD38 mAb, an IMiD, a proteasome inhibitor and dexamethasone followed by autologous stem cell transplantation (ASCT) in the treatment of newly diagnosed multiple myeloma (NDMM) led to substantial improvements in depth of response, including minimal residual disease (MRD) negativity, and progression-free survival. The therapeutic success of QUAD + ASCT has reinvigorated an interest in fixed-duration therapy, yet optimal short term efficacy endpoint for treatment cessation is unknown. We used a large dataset of patients (pts) treated with QUAD + ASCT, monitored with serial MRD assessment and managed with MRD-adapted treatment duration to determine the best short term efficacy endpoint to identify pts at low risk of treatment failure. Methods We analyzed 221 pts with NDMM treated with QUAD + ASCT and monitored with serial marrow-based MRD by next-generation sequencing. Based on trial design (N=116) and institutional practice (N=105) most pts received post ASCT QUAD consolidation followed by treatment cessation if MRD<10-5 in two consecutive datapoints. Pts were monitored with MRD post induction, ASCT and consolidation, and at least yearly thereafter. We utilized Cox regression to build parallel models of predictors of disease progression or MRD resurgence utilizing the same patient and disease features and one distinct short term efficacy endpoint per model, inputted as time-varying covariate. Efficacy endpoints tested were IMWG-defined stringent complete response (sCR), MRD<10-5 (single datapoint), MRD<10-6, sustained MRD (S-MRD, two consecutive assessments at least 1 year apart) <10-5and S-MRD<10-6. Best fitting models were determined using Akaike's information criterion (AIC, lower value indicates better fitting model), an information theory approach, and Heagerty & Zheng C index. Results Median age of the 221 pts. was 61 years (IQR 55-68), 21% age 70 or older, 37% had MM with 1 high risk chromosome abnormality [HRCA, gain/amp 1q, t(4;14), t(14:16), del(17p)], 16% had 2+HRCA, 30% were non-White and 58% male. We followed pts for a median of 40.6 mo. and performed 979 MRD assessments. One hundred and eighty-three pts (83%) achieved sCR, 170(77%) MRD<10-5, 146 (66%) MRD<10-6 , 110 (50%) S-MRD<10-5 and 90 (41%) S-MRD<10-6. Average time to achieve the endpoint was 7.8 mo for sCR, 7.1 mo. for MRD <10-5, 9.4 mo. for MRD<10-6, 19.3 mo. for S-MRD<10-5 and 20.5 mo. for S-MRD<10-6. We first tested models to predict PFS among all 221 pts. Predictive models included same covariates (ISS, high LDH and number of HRCA) other than the efficacy endpoint. The best fitting model (AIC 417.2, C-stat 0.757) was based on S-MRD<10-5 (HR=0.23, 95% C.I. 0.11-0.47) and included presence of 1 HRCA (HR=2.93, 95% C.I. 1.31-6.52), 2+ HRCA (HR=7.60, 95% C.I. 3.31-17.43), high LDH (HR=1.64, 95% C.I. 0.81-3.33), ISS2 (HR 1.31, 95% C.I. 0.62-2.77) and ISS3 (HR 1.96, 95% C.I. 0.90-4.28). The model with S-MRD<10-6 had similar, but not better performance (AIC 419.4, C-stats 0.752). We subsequently analyzed the 121 (55%) pts who reached MRD-guided treatment cessation for the best fitting model to predict progression or MRD resurgence in absence of continuous therapy. Among these pts, 117(97%) achieved sCR, all (by definition) MRD<10-5, 116 (96%) MRD<10-6 , 95 (79%) S-MRD<10-5 and 81 (67%) S-MRD<10-6. The best fitting model (AIC 197.2, C-stat 0.766) was based on S-MRD<10-5 (HR 0.01, 95% C.I. 0.002-0.05) and included presence of 1 HRCA (HR=1.41, 95% C.I. 0.49-4.07), 2+ HRCA (HR=5.43, 95% C.I. 1.75-16.84), high LDH (HR=3.19, 95% C.I. 0.98-10.40), ISS2 (HR 1.25, 95% C.I. 0.53-2.96) and ISS3 (HR 0.73, 95% C.I. 0.23-2.37). The model with S-MRD<10-6 did not perform better (AIC 232.4, C-stat 0.727). Among the 94 pts who achieved S-MRD<10-5 and were monitored off therapy, the risk of MRD resurgence or progression 2.5 years after cessation of therapy was 6.1%, 15.0% and 22.2% and risk of progression was 3.0 %, 12.0% and 11.1% for patients with 0, 1 and 2+ HRCA, respectively Conclusion In the setting of QUAD therapy + ASCT, no short term conventional or MRD-based efficacy parameter negates the cumulative impact of HRCA on prognosis. S-MRD<10-5 is the best predictor of PFS and yields the best predictive models for risk of MRD resurgence or progression in the setting of fixed duration therapy. This analysis validates S-MRD<10-5 as efficacy parameter for treatment cessation in trials exploring fixed duration therapy in NDMM.

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: Bruton tyrosine kinase (BTK) inhibitors are highly effective against Waldenström macroglobulinemia (WM). Their effectiveness can be limited by resistance caused by BTK mutations and intolerance. BGB-16673 is a bivalent small molecule that induces BTK degradation by binding specifically to BTK and the E3 ligase. The E3 ligase catalyzes the transfer of ubiquitin molecules to BTK, which marks BTK for destruction by the proteasome. Preclinically, BGB-16673 degraded wild-type and mutant BTK associated with covalentand noncovalent BTK inhibitors (ncBTKis), leading to tumor suppression. CaDAnCe-101 (BGB-16673-101; NCT05006716) is an ongoing, open-label, first-in-human, phase 1/2 study evaluating BGB-16673 monotherapy in patients with a range of B-cell malignancies. Here, early results in patients with WM enrolled in the phase 1 portion are presented. Methods: Eligiblepatients must have confirmed R/R WM (≥2 prior therapies), an ECOG performance status of 0-2, and adequate organ function. Patients must have previously received an anti-CD20 antibody and, in the US and EU, a covalent BTK inhibitor (cBTKi). BGB-16673 was orally dosed once daily in 28-day cycles. Dose escalation used a Bayesian optimal interval design (6 planned dose levels, 50-600 mg once daily). Primary objectives were to evaluate safety/tolerability (CTCAE v5.0) and to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks (cycle 1). A secondary objective was to evaluate the overall response rate (ORR, IWWM-6 consensus criteria), with the first assessment occurring after 4 weeks of treatment. Results: As of May 24, 2024, 22 patients with WM were enrolled and treated (100 mg, n=4; 200 mg, n=10; 350 mg, n=8). The median age was 73.0 (range, 56-81) years, and the median number of prior therapies was 3.5 (range, 2-11), including prior cBTKis (n=22 [100%]), BCL2 inhibitors (n=4 [18%]), and ncBTKis (n=3 [14%]). Twenty patients (91%) had previously received chemotherapy. According to the International Prognostic Scoring System for WM, 6 patients (27%) had low-risk disease, 7 (32%) had intermediate-risk disease, and 8 (36%) had high-risk disease (missing/unknown data, n=1). Five patients (23%) had BTK mutations, 20 (91%) had MYD88 mutations, and 8 (36%) had CXCR4 mutations. The median follow-up was 4.3 (range, 0.3-21.3) months. Ninety-five percent of patients reported any-grade treatment-emergent adverse events (TEAEs; grade ≥3, 45%; serious, 23%), the most common (≥20%) of which were neutropenia/neutrophil count decreased (32%; grade ≥3, 23%), contusion (23%; no grade ≥3), and diarrhea (23%; no grade ≥3). The most common grade ≥3 TEAE (≥20%) was neutropenia/neutrophil count decreased. No atrial fibrillation, hypertension, febrile neutropenia, or major hemorrhage occurred. Three patients (14%) had a grade ≥3 infection (bronchopulmonary/cerebral aspergillosis, septic shock, and pseudomonal bacteremia/sinusitis). No patients had a TEAE that led to treatment discontinuation or dose reduction. No DLTs occurred, and the MTD was not reached. One patient (5%) died due to a TEAE (septic shock, considered related to disease progression). One patient died due to disease progression. In 21 response-evaluable patients (1 too early), the ORR (minor response or better) was 90%, the major response rate (partial response [PR] or better) was 81%, and the very good PR or better rate was 14%. Median time to first response was 0.95 (range, 0.9-3.7) months, with responses deepening over time. Seventeen patients remain on treatment and have ongoing responses. Responses were seen at the lowest dose (100 mg, 4/4), in patients previously treated with a cBTKi (19/21) and an ncBTKi (3/3), and in patients discontinued from prior BTKi due to disease progression (15/17). In addition, responses were observed in patients with and without mutations in BTK (with, 5/5; without, 6/8; unknown, 8/8), MYD88 (with, 18/20; without, 1/1), and CXCR4 (with, 8/8; without, 11/13). One patient had IgM flare at initial response assessment and went on to develop PR. Conclusions: Early data from this ongoing, first-in-human study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows promising antitumor activity in heavily pretreated patients with BTK inhibitor-exposed R/R WM, including those with BTK and CXCR4 mutations.

Introduction CD19-directed CAR T-cell therapies are an important option for the management of relapsed/refractory (R/R) DLBCL. Studies suggest that ~50% of pts receiving CAR T-cell therapies will relapse within 6 months, with an estimated overall survival (OS) of only 5 months. Additionally, 25-35% of pts do not receive subsequent treatment, indicating a high unmet need. CD19 loss is a potential mechanism of resistance to CAR T-cell therapies; thus, treatments that target alternate B-cell antigens are an attractive option. Here, we report for the first time the primary analysis of the ELM-1 expansion cohort investigating the efficacy and safety of odronextamab, a CD20×CD3 bispecific antibody, in pts with R/R DLBCL progressing after CAR T-cell therapy (NCT02290951). Methods Pts aged ≥18 with DLBCL and disease progression after CAR T-cell therapy received intravenous odronextamab weekly in 21-day (D) cycles during Cycles (C) 1-4, with steroid prophylaxis and step-up dosing in C1 (described previously), followed by 160 mg on D 1, 8, and 15 of C2-4. After C4, odronextamab maintenance treatment continued at 320 mg Q2W until disease progression or unacceptable toxicity. Pts with complete response (CR) for ≥9 months transitioned to Q4W dosing. All pts received infection prophylaxis. The primary analysis was conducted when all pts had completed ≥9 months of follow-up. Primary endpoint was objective response rate (ORR), as assessed by independent central review (ICR) according to the Lugano classification. Key secondary endpoints included duration of response (DOR), progression-free survival (PFS), and OS. Exploratory endpoints included immune biomarker assessment. Results As of January 22, 2024, 60 pts were treated and evaluable for efficacy and safety, with median follow-up of 16.2 months. Prior CAR T-cell therapies were axi-cel (50%), tisa-cel (12%), liso-cel (10%), and not specified (28%). Median time since prior CAR T-cell therapy was 6.5 months (range 1.2-46.2). Median age was 63 years (range 27-82; aged ≥75 years: 10%), and 65% were male. Pts had received a median of 3 prior lines of therapies (range 2-9); 77% of pts were refractory to their last therapy, 77% were double refractory, and 72% were refractory to prior CAR T-cell therapy. 48% of pts relapsed within 90 D of CAR T-cell therapy, and 67% relapsed within 180 D. Of the 20 pts with available tumor biopsies at baseline, 10 were CD19(-) and only 2 were CD20(-). 92% of pts completed C1 and 52% completed ≥4 C of treatment. The median duration of treatment was 12 weeks (range 0.7-154.1). The ORR and CR rate by ICR were 48% and 32%, respectively, and were consistent across pts with high-risk features and across prior CAR T products. ORR in pts relapsing in ≤90 D was 21% (6/29) and in pts relapsing in ≤180 D was 33% (13/40). ORR was observed even in pts with low CD20. Median DOR was 14.8 months (95% CI 2.8-not estimable [NE]) and median duration of CR was not reached (NR) (95% CI 3.3-NE); the probability of maintaining CR for 24 months was 68%. Median PFS was 4.8 months (95% CI 2.6-5.4) and median OS was 10.2 months (95% CI 4.6-15.8). Median PFS and OS in complete responders was NR. T-cell counts increased at Week 14 and demonstrated a functional phenotype (CD69 expression and TEMRA count), which was confirmed by ex vivo stimulation. T-cell expansion was observed regardless of CAR T product or time from CAR T administration. The most common TEAE was CRS (any grade [G]: 48%; G1: 25%; G2: 23%; G≥3: 0%). G≥3 TEAEs occurred in 77% of pts (most common: neutropenia 17%, anemia 13%, and neutrophil and white blood cell count decrease 10% each). Five pts (8%) permanently discontinued odronextamab due to AEs (COVID-19, pneumonia, encephalopathy, epilepsy, and gait disturbance [n=1 each]). There was one treatment-related death (COVID-19 pneumonia). No cases of ICANS were reported. G≥3 infections occurred in 12 pts (20%); 2 were due to COVID-19. No cases of tumor flare or TLS were reported. Conclusions ELM-1 is the only study to prospectively evaluate efficacy and safety of a CD20×CD3 bispecific antibody in pts with R/R DLBCL progressing after CAR T-cell therapy. Odronextamab monotherapy was associated with encouraging efficacy and generally manageable safety in a setting with limited treatment options and historically dismal outcomes. Efficacy was observed even in pts relapsing in ≤90 D, supporting the potential of odronextamab as an accessible, off-the-shelf option in the post-CAR T setting.

Background: C10603/RATFIY was the first AML trial to show the benefit of adding a targeted agent to intensive chemotherapy for a specific genetically determined subset (Stone R et al, NEJM 2017). The addition of the multi-kinase inhibitor midostaurin (M) to chemotherapy in previously untreated adults with FLT3-mutant AML resulted in superior event-free (EFS) and overall survival (OS) compared to placebo (P) and led to the approval of this agent in combination therapy. Subsequently, additional targeted drugs including gilteritinib for relapsed/refractory FLT3-mutant AML and quizartinib plus chemotherapy in untreated adults with AML with FLT3-ITD disease have gained approval. Long-term follow-up after reporting of the primary endpoint, especially if met, is important in oncology. Objective: We report the EFS and OS data from C10603 using 10 years of follow up to determine the persistence of a midostaurin benefit and to assess the nature of late relapses or toxicity. Methods: C10603 enrolled 717 pts (360 on the M and 357 on the P arm; median age 47.8 years (range 18-61), 398 women (55.5%) of whom 51.7% were randomized to M and 59.4% to P (p=0.04), and 89% white) from 2011-2015 with previously untreated AML who had either a FLT3-TKD or ITD mutation with allelic ratio of >0.05 to receive daunorubicin/cytarabine (3+7) induction (one reinduction permitted) followed by up to 4 consolidation cycles with cytarabine 3 g/m2 every 12h on days 1, 3 and 5. M (50 mg bid) or P was given orally on days 8-22 of each chemotherapy cycle as well as daily during one year of single-agent maintenance. Allogeneic transplantation (alloHCT) was employed at investigator's discretion; study drug was not continued post-HCT. Pts stayed on their randomized arm and were not re-randomized prior to maintenance. Pts were followed for relapse and survival after the end of protocol therapy, regardless of subsequent therapy, for 10 years. Log-rank tests, Kaplan-Meier methods, and Cox proportional hazard models were used to evaluate the treatment effect in EFS and OS, as well as the alloHCT effect. All p values are two-sided. Results: We have completed the 10-year FU on this trial and data collection has concluded. The median EFS was 8.2 months (95% CI, 5.5-11.4) on the M arm compared with 3.0 months for P (95% CI, 1.9-6.0) with a HR of 0.79 (95% CI 0.67-0.94, p=0.0067). Among the 420 CR pts who achieved complete remission (CR) by the protocol specified time of 60 days, 253 have had an event (death in 69 and relapse in 184); these events were relatively equal on each arm. OS, the co-primary endpoint, remained marginally superior for those randomized to M compared to P; the 10-year OS estimate was 43.7% (95% CI, 38.7-49.3%) vs 38.6% (95% CI, 33.6-44.4%) (p= 0.0485). The hazard ratios for OS favored randomization to M in each key biological subgroup (FLT3-ITD low or high allelic ratio or FLT3-TKD), but smaller subsets precluded statistical significance. There was a 10-year OS benefit in favor of M in men (p=0.005), but not women (p=0.9). A total of 414 transplants were performed: only 5 in the latter half of the follow-up period. Transplantation in CR1 was highly beneficial overall (10-year OS, 56% vs 35.8% without transplantation, p=0.001). Among those transplanted in CR1, randomization to M was marginally better than P (61.5% vs 49%, p=.064). After censoring for alloHCT in CR1, there was an OS trend in favor of M (51.8% v 48.0%, p=0.102). In CR1 patients who were randomized to maintenance therapy, M reduced the cumulative incidence of relapse in ELN 2017 favorable and intermediate risk pts, but not in those with adverse risk disease (HR 0.71, 0.47, and 1.01, respectively); maintenance M had no effect on OS. Only 3 pts relapsed after 5 years (all randomized to M). 25 pts randomized to M vs 13 P pts died after 5 years of follow-up. 5 pts on each arm died of a new primary cancer whereas 17 M and 5 P pts were coded as having died from treatment-related causes. None of the 3 pts who relapsed after 4 years had spliceosome mutations at diagnosis; whereas 18% (21/117) patients pts who had relapsed earlier had spliceosome mutations at diagnosis (p=0.419). Conclusions: The EFS benefit of randomization to midostaurin vs placebo when added to chemotherapy was maintained over time, although the benefit for OS was diminished, likely due in part to aging. Patient and disease factors differed between early vs late relapses, which could suggest the use of alternative therapies during distinct therapeutic stages.

Abstract Aims Cardiogenic shock (CS) is a critical manifestation of severe cardiac dysfunction, necessitating precise evaluation of left ventricular (LV) function by transthoracic echocardiography. The prognostic value of global longitudinal strain (GLS) has not been examined in patients with CS. Therefore, we aimed to assess the prognostic significance of GLS in patients with CS. Methods and results This was a retrospective study of patients with CS from 2007 to 2018 who had a transthoracic echocardiography performed within 24 h of admission. GLS was measured, and conventional parameters were obtained. LV dysfunction was categorized by GLS: > 9.7% (Quartile 1), 7.0% < GLS ≤ 9.7% (Quartile 2), 5.0% < GLS ≤ 7.0% (Quartile 3), and ≤5.0% (Quartile 4). Outcomes included in-hospital and 1-year all-cause mortality. Among 623 patients with CS with the median LVEF of 31% [inter-quartile range (IQR): 24–41%] and the median GLS of 7.0% (IQR: 5.0–9.7%), in-hospital mortality was 29%. Mortality increased across GLS quartiles: Quartile 1: 17%; Quartile 2: 22%; Quartile 3: 35%; and Quartile 4: 42%. GLS remained the only independent echocardiographic predictor of in-hospital mortality after adjusting for clinical covariates (adjusted odds ratio: 1.23 per 1% decrease, 95% confidence interval: 1.04–1.46, P = 0.015). GLS independently predicted 1-year all-cause mortality (P < 0.001). The prognostic value of GLS was superior in cases with acute coronary syndrome. A classification and regression tree analysis identified GLS as the most important echocardiographic variable for predicting in-hospital mortality. Conclusion GLS independently predicted short- and long-term mortality in patients with CS, surpassing conventional echocardiographic parameters in prognostic value, supporting its potential role in risk stratification in this population.

Background: Monoclonal B-cell lymphocytosis (MBL) is a common premalignant condition that can be classified into chronic lymphocytic leukemia (CLL)-type (CD5, CD23, and CD20 co-expression), and non-CLL-type (CD5-negative) based on flow cytometry immunophenotypes. CLL-type MBL is relatively well characterized with increased risk of hematologic (especially lymphoid) malignancies, serious infections, and decreased response to vaccinations. However, the prevalence, genetic predispositions, and clinical consequences of non-CLL-type MBL remain to be fully elucidated. Herein, we report findings in non-CLL-type MBL in a large screening cohort. Methods: We screened 10,330 individuals (40 years or older with no prior history of hematologic cancers) for MBL with highly sensitive flow cytometry, in the Mayo Clinic Biobank, with patients recruited from primary care-based clinics. Individuals were genotyped by Regeneron Genetics. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Among those individuals residing in the 27 counties surrounding Rochester, Minnesota, we identified incident hematologic malignancies and melanomas using ICD codes and the Rochester Epidemiology Project, a population based medical records linkage system. All diagnoses were manually reviewed for confirmation. Cox regression was used to calculate hazard ratios (HR) and 95% CIs, adjusted for age and sex. Results: We identified 1,736 individuals with MBL and 8,341 individuals without MBL. Among those with MBL, 246 (14.2%) had non-CLL-type MBL as the major clone. The median age of non-CLL-type MBL was 77 years (range, 47-95). The prevalence of non-CLL-type MBL significantly increased with age, with 0.5% prevalence among those between 40 to 59 years of age, 2.3% prevalence among those between 60 and 79 years, and 7.8% prevalence in those 80 years of age or older. The prevalence of non-CLL-type MBL was significantly higher (P < .001) among males (3.1%) than females (2.0%). Using the genome-wide complex trait analysis tool, the heritability of non-CLL-type MBL was estimated to be ~26%, suggesting inherited genetics plays a role in etiology. To identify common inherited variants, we first evaluated the known CLL susceptibility variants, many of which also associated with CLL-type MBL. Among the 42 variants, none were statistically associated (all P > .05) with non-CLL-type MBL. We next conducted a genome-wide association study to identify novel variants, and the most significant variant resided in 10q26.3 (minor allele frequency [MAF]control = 0.7%, MAFMBL = 3.5%, OR = 6.4, 95% CI 3.6-11.3, P = 5.7 * 10-8). Among the 6,478 individuals (192 with non-CLL-type MBL and 6,286 without MBL) followed for incident hematologic malignancies, 36 developed lymphoid and 23 developed myeloid malignancies after a median of 4.2 years of follow up. Similar to CLL-type MBL, non-CLL-type MBL was associated with a 5.2-fold risk for lymphoid malignancies (95% CI 2.0-13.0, P < .001). Elevated but not significant risks were observed for myeloid malignancies (HR = 2.3, 95% CI 0.5-10.3, P = 0.27). The lymphoid malignancies developed by individuals with non-CLL-type MBL included diffuse large B-cell lymphoma, multiple myeloma, marginal zone lymphoma, and other low-grade lymphomas. We recently reported that individuals with CLL-type MBL are at higher risk for developing melanoma (HR = 1.9, 95% CI 1.3-2.8). Interestingly, non-CLL-type MBL had no evidence of an association with melanoma risk (HR = 0.4, 95% CI 0.1-1.8). We did not observe a significant difference in overall survival between individuals with non-CLL-type MBL vs those without MBL. Conclusions: In the largest screening cohort to date, we evaluated the etiology and clinical outcomes of non-CLL-type MBL, an understudied yet common condition that occurs in ~4 million adults in the United States. Non-CLL-type MBL is more common in men and older individuals, and evidence supports that inherited genetics plays an etiological role with 10q26.3 locus identified as a novel susceptibility locus. Individuals with non-CLL-type MBL had significantly increased risk of lymphoid malignancies, similar to CLL-type MBL, but, distinct from CLL-type MBL, no evidence of an increased risk of melanoma. Our study provides insights into the prevalence, genetic predispositions and clinical consequences of non-CLL-type MBL and how it differs from the classic CLL-type MBL.