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Background: Mutations of isocitrate dehydrogenase (IDH) are recurrent in acute myeloid leukemia (AML) and the prevalence increases with age. The prognostic impact of IDH1 and IDH2 mutations remains controversial. IDH inhibitors are small molecules that bind within the IDH enzymatic active site, blocking aberrant 2-hydroxyglutarate production and inducing myeloid differentiation. While they can lead to differentiation syndrome, they generally have a more favorable side-effect profile, making them an attractive option for older patients. We aimed to describe the prevalence and prognostic impact of IDH mutations in newly diagnosed (ND) AML patients ≥ 60 years in a large cohort of patients treated on a Leukemia and Lymphoma Society-sponsored trial. Methods: We performed a retrospective observational analysis including patients ≥ 60 years with ND AML who were enrolled on the Beat AML clinical trial (NCT03013998) before May 10, 2023. Patients were treated with a variety of treatment regimens. Cytogenetic analysis and next-generation sequencing (FoundationOne®Heme) were obtained. Mutations were considered present at any detectable VAF. Cox proportional hazard models were used to describe the relative risk of each variable on death over time from the date of trial inclusion. Results: A total of 1023 patients with ND AML were identified. Patients had a median age of 72 (range 60-92) years and the majority were non-Hispanic White (83.2%), and male (57.6%). Ninety-nine (9.7%) patients were IDH1MUT, 193 (18.9%) patients were IDH2MUT including 10 (1.0%) patients with a co-occurring IDH1 and IDH2 gene mutations. Both IDH1MUT and IDH2MUT were associated with 2022 ELN favorable-risk (26.3% and 22.3% for IDH1 and IDH2 respectively, vs 15.5% overall (P<0.001)). IDH1MUT significantly co-occurred with DNMT3AMUT (42.4%), NPM1MUT (44.4%) and less frequently with TP53MUT (10.1%) (P<0.001 for all). IDH2MUT was associated with DNMT3AMUT (35.8%), NPM1MUT (31.1%), SRSF2MUT (38.3%), and less frequently with TET2MUT (6.7%) and TP53MUT (9.3%) (P<0.001 for all). Normal karyotype was higher in IDH1MUT (P<0.001) and IDH2MUT (P<0.001), whereas complex karyotype (P<0.001 for both) and core-binding factor AML (P=0.047, P=0.015) were lower in IDH1MUT and IDH2MUT. To evaluate the impact of IDH mutations in patients ≥ 60 years, we focused on patients evaluable for outcome treated with lower-intensity therapy (LIT) (N=674), and intensive chemotherapy (IC) (N=178), separately. Among the LIT treated patients, 96 patients received treatment with an IDH inhibitor, and 237 patients received a hypomethylating agent (HMA) plus venetoclax. For patients treated with LIT, the hazard ratios (HRs) of death over time were 0.58 [95% CI 0.47-0.72; P<0.002], 0.81 [95% CI 0.59-1.13; P=0.214] and 0.56 [95% CI 0.44-0.72; P<0.001] for IDHMUT, IDH1MUT, IDH2MUT respectively. Among patients receiving IC, the HRs were 1.05 [95% CI 0.68-1.69; P=0.777], 0.70 [95% CI 0.31-1.61; P=0.406] and 1.27 [95% CI 0.77-2.1; P=0.352] for IDHMUT, IDH1MUT, and IDH2MUT respectively. The HR of death for IDH1MUT patients treated with LIT with the addition of an IDH1 inhibitor (N=24) was significantly lower (HR 0.47 [95% CI 0.24-0.92; P=0.027] vs IDH1MUT patients treated without an IDH1 inhibitor, while an IDH2 inhibitor did not change survivial outcomes in patients with IDH2MUT (N=71). Discussion: To our knowledge this is the largest retrospective study characterizing the prevalence of IDH mutations in patients ≥ 60 years with AML. We demonstrated that IDH mutations were detected in ~27% of older patients with AML. Although there could have been selection bias as the Beat AML study had separate IDHMUT study arms, these findings are concordant with other studies showing an increase in frequency of IDH mutations with age. IDH2MUT was associated with a lower HR of death among patients treated with LIT, which was not seen in patients receiving IC. The high prevalence of IDH mutations suggests that IDH inhibitors used as single agents or in combination with lower-intensity therapies are an important class of drugs for this older patient population as they are generally well tolerated, that need further investigation.

Background: Systemic mastocytosis (SM) is a rare disease characterized by neoplastic mast cell (MC) infiltration of extracutaneous tissues. Nonadvanced SM (NonAdvSM) is associated with debilitating symptoms which may significantly reduce health-related quality of life (HRQoL). In up to 95% of patients (pts), SM is driven by the somatic KIT c.2447 A>T (p.D816V) missense mutation. Bezuclastinib (bezu; CGT9486) is an oral, potent, small molecule, selective type 1 tyrosine kinase inhibitor (TKI) with activity against KIT D816V. Results from Part 1 of the 3-part Summit trial demonstrated that bezu is well-tolerated and is associated with encouraging clinical activity, including both reduced MC burden and improvement in symptoms over a 12-week (wk) period vs placebo (PBO). Based on safety, PK, biomarker, and efficacy results, a dose of 100mg QD bezu (optimized formulation) was selected for Summit Part 2. Trial Design and Methods: Summit (NCT05186753) is a multi-center, Phase 2, double-blind, PBO-controlled RCT of bezu in pts with NonAdvSM who have inadequate control of symptoms despite treatment with best supportive care (BSC). A novel pt-reported outcome measure, the Mastocytosis Symptom Severity Daily Diary (MS2D2), was designed to assess disease-specific symptom severity in NonAdvSM pts. Eleven symptoms are included in the MS2D2 Total Symptom Score (TSS). Summit Part 1a randomized pts 1:1:1 to PBO, 100mg, or 200mg, original formulation while Part 1b randomized 1:1:1 to PBO, 100mg, or 150mg, optimized formulation. Pts completing Part 1 of the Summit trial were allowed to receive bezu in the open-label extension (OLE) Part 3 of the trial. Results: As Part 2 will evaluate safety and efficacy of 100 mg bezu at 24 wks, this abstract reports on pts treated with both bezu formulations at 100mg in Parts 1a or 1b, which had similar PK exposures. The presentation will focus on 24-wk outcomes in pts receiving the selected 100 mg bezu dose and participating in the OLE. In Summit Part 1, 19 pts received PBO and 18 received 100 mg bezu for 12 wks. At baseline (BL), the symptoms identified as most severe were within the skin and fatigue domains. At BL, pts were managing their symptoms of NonAdvSM with 2 (43%), 3 (24%), or ≥4 (32%) BSC medications. At the 12-wk assessment in Part 1 (datacut 18Dec2023), the safety and tolerability profile was encouraging, with the majority of TEAEs low grade and reversible without dose modification. The most common TEAEs (>10% in 100 mg bezu) included hair color changes, nausea, diarrhea, peripheral edema, GERD, taste disorder, and neutropenia. There were no reported bleeding or cognitive impairment events. Of 37 pts randomized to PBO or 100 mg QD bezu, 36 (97%) received bezu in the OLE; one pt randomized to the 100 mg original formulation dose reduced and subsequently discontinued due to TEAE of ALT increase. All 19 PBO pts (100%) crossed over to receive bezu in the OLE; of these, 9 were randomized to the 100mg QD bezu dose. Reduction in MC burden was robust among those treated with 100mg bezu - 94.4%, 100%, and 92.3% of pts had at least a 50% reduction in basal serum tryptase, KIT p.D816V variant allele frequency, and bone marrow MCs, respectively. Pts treated with 100 mg bezu had reduction in MS2D2 TSS by 49.1% vs 21.1% with PBO. On a 0-10 scale, the most severe MS2D2 symptom mean change from BL was -3.03 from a BL mean of 7.6 with bezu vs -1.04 from a BL mean of 7.7 with PBO. Individual symptoms of the MS2D2 TSS, as well as others not in the TSS including diarrhea and brain fog, improved more with bezu than with PBO; mean change from BL ranged from -1.66 to -2.69 with bezu vs. a range of -0.52 to -1.58 with PBO. LS mean change from BL in quality of life (Mastocytosis (MC)-QoL, a disease-specific measure) was -22.05 in pts treated with 100mg bezu versus -10.71 in pts treated with PBO. Objective measurements of skin lesions, including centrally adjudicated longitudinal assessments of skin photography, also significantly reduced on bezu. Conclusions: In Part 1 (12 wk assessment), treatment with 100mg bezu resulted in favorable safety and tolerability, significant and deep reductions across all markers of MC burden, and clinically meaningful reduction in all individual MS2D2 TSS symptoms and across domains. The presentation will report on durability and safety/tolerability data beyond 12 wks for those pts randomized to 100 mg in Part 1 and pts who crossed over from PBO in Part 1 to 100mg in Part 3. Summit Part 2 is actively enrolling.

Background: Isatuximab is an IgG1κ monoclonal antibody that binds with high affinity to CD38 expressed on plasma cells in light chain (AL) amyloidosis. Anti-CD38 antibodies have shown efficacy alone and in combination in a variety of settings for patients with multiple myeloma and light chain (AL) amyloidosis. Here we report the final analysis of a multi-center, cooperative group prospective phase II study of isatuximab in previously treated patients with AL amyloidosis (NCT03499808). Methods: Eligibility included: age ≥18 years, relapsed or refractory systemic AL amyloidosis, ≥1 prior line of therapy, measurable disease, ≥1 organ involved, not refractory to daratumumab, Eastern Cooperative Oncology Group performance status ≤2, creatinine clearance ≥25 mL/min, and NT-proBNP ≤8500 pg/mL. Patients received isatuximab intravenously 20 mg/kg weekly during the first 28-day cycle and every other week during cycles 2 through 24 for a maximum of 24 cycles. The primary objective was hematologic response with secondary objectives of organ response, safety, progression free survival, and overall survival. Results: Forty-three patients were registered, with 35 patients being eligible for response. The median age of the evaluable patients was 70 years (range, 40.1-79.5) with the majority (66%, n=23) having a lambda clonal plasma cell dyscrasia. The most common cytogenetic abnormality using fluorescence in situ hybridization was translocation t(11;14) observed in ten patients (29%). The most common prior treatment was a proteasome inhibitor (94%, n=33) while 46% (n=16) had undergone autologous stem cell transplant. Eighteen patients (51%) had single organ involvement while 17 (49%) had multiple organs involved. The distribution of organ involvement was typical for AL amyloidosis with cardiac involvement in 25 patients (71%) and renal involvement in 14 (40%). As of December 30, 2022, no new safety concerns were identified. The most common treatment related grade ≥3 adverse events included lymphopenia (n=3, 8.5%) and infection (n=2, 6%). The overall hematologic response rate was 77.1% with a rapid median time to partial response or better of 1.1 months. Two patients (6%) achieved a hematological complete response (CR), 18 (51%) had a very good partial response (VGPR), and 7 (20%) had a partial response (PR). At 24 months from hematologic response, the rate of patients still in response was estimated at 81% (95% confidence interval (CI): 67, 96). The 24-month estimated overall survival was 85% (95% CI: 73%, 97%). Renal response occurred in 50% (7/14) of patients with renal involvement with a median time to response of 18.5 months. Cardiac response occurred in 56% (14/25) of patients with cardiac involvement with a median time to response of 16.6 months. Conclusions: Isatuximab monotherapy resulted in high rates of hematologic response in relapsed AL amyloidosis which translated into organ responses. Treatment appears safe and was well tolerated. Support: NIH/NCI/NCTN grant awards U10CA180888, U10CA180819, CA180820, and CA180821; and in part by Sanofi-Aventis (Sanofi US)

Introduction: Brexu-cel is an autologous anti-CD19 CAR T-cell therapy approved in the US and EU for treatment of adults with R/R MCL (after ≥2 prior therapies in EU) based on a high objective response rate (ORR; 93%; 67% complete response [CR] rate) in pts who received the pivotal dose (2×106 anti-CD19 CAR T cells/kg; Cohort 1; N=60) in ZUMA-2 (NCT02601313; Wang et al, N Engl J Med 2020). After ~4 years (y) of median follow-up, Brexu-cel demonstrated a median overall survival (OS) of 46.4 months (mo) in 68 pts with R/R MCL in Cohort 1 (Goy et al. ASH 2023). Cohort 2 was established to assess a lower dose (0.5 x 106 anti-CD19 CAR T cells/kg); however, the risk/benefit ratio of the Cohort 1 dose was deemed the optimal dose before Cohort 2 reached full enrollment. Here we report primary outcomes of Cohort 2 and 5-y outcomes of Cohorts 1 and 2. Methods: Pts with R/R MCL and ≤5 prior therapies including a BTKi received optional bridging therapy (protocol-defined), lymphodepleting chemotherapy, and 1 infusion of brexu-cel. The primary endpoint was ORR (CR + partial response [PR]) per Lugano classification (Cheson et al. J Clin Oncol. 2014) by independent radiology review committee (IRRC) assessment. Key secondary endpoints were duration of response (DOR), best objective response (BOR), progression-free survival (PFS), OS, and safety. After ≥24 mo of assessment, pts could transition to long-term follow-up (LTFU), NCT05041309, where they were monitored for late-onset targeted/serious adverse events (AEs) possibly related to brexu-cel, presence of replication-competent retrovirus (RCR), and/or insertional mutagenesis. Descriptive statistics are reported herein. Results: As of the primary analysis data cutoff date, July 24, 2019, 17 pts enrolled in Cohort 2, 14 (82%) of whom were treated with brexu-cel with median follow-up of 16.0 mo (range, 13.9-18.0). Pt characteristics for Cohort 2 (N=14) were similar to Cohort 1; median (range) age and number or prior therapies was 61.5 y (52-73) and 3 (2-5); 100% US-treated, 79% male, 71% extranodal disease, 50% intermediate or high s-MIPI scores, 50% refractory to last therapy, and 43% had prior autologous stem cell transplantation. ORR was 93% (95% CI, 66.1-99.8) per IRRC; 64% had a CR (95% CI, 35.1-87.2), 29% had a PR (95% CI, 8.4-58.1) and 1 pt was not assessed. All 14 pts had ≥1 AE of any grade (Gr), with Gr ≥3 AEs occurring in 93% of pts; the most common being hypotension (50%), white blood cell count decrease (50%), anemia (43%), and neutrophil count decrease (43%). Rates of Gr ≥3 cytokine release syndrome (CRS) and neurological events were 7% and 43%, respectively. As of April 1, 2024, median follow-up (range) for Cohort 1 and 2 was 67.8 mo (58.2-88.6; N=68) and 72.3 mo (70.1-74.3; N=14), respectively. In Cohort 1, 24 pts were still alive (35%; 2 withdrew consent and 1 lost to follow up) and 44 pts died (65%). In Cohort 2, 8 pts were still alive (57%; 2 withdrew consent and 1 lost to follow up) and 6 pts died (43%). A total of 27 pts (Cohort 1, n=23; Cohort 2, n=4) enrolled in the LTFU study by data cutoff with a median follow-up time of 70.2 mo (range, 58.2-88.6). Median (95% CI) investigator-assessed DOR and PFS were 36.5 mo (17.7-48.9; n=60; 17 patients in ongoing response, all CR) and 25.3 mo (12.7-46.6; N=68) in Cohort 1; and 57.5 mo (4.7-not estimable [NE]; n=12; 3 pts in ongoing response, all CR) and 29.5 mo (3.3-NE; N=14) in Cohort 2. Median OS (95% CI) and 60-mo OS rates (95% CI) were 46.5 mo (24.9- 60.2) and 38.5% (26.7-50.1) in Cohort 1; and not reached (9.4-NE) and 53.6% (23.8-76.2) in Cohort 2. One pt had 3 ongoing AEs on LTFU, hypogammaglobulinemia and 2 viral infections that arose prior to LTFU. Two pts died on LTFU, both due to progressive disease; no new secondary malignancies or RCR cases were reported. Conclusions: Consistent with Cohort 1, brexu-cel demonstrated a high ORR, durable responses, and an expected safety profile in pts with R/R MCL in Cohort 2 despite the lower dose. However, small sample size limits interpretation of these results. With >5 y of median follow-up, pts in Cohort 1 and 2 continued to experience durable responses with high 60-mo OS rates. No new safety signals were detected and no secondary malignancies or RCR cases were reported in LTFU. Additionally, ZUMA-2 results are consistent with real-world outcomes of brexu-cel in the post BTKi R/R MCL setting (89% ORR and 81% CR rate; Wang Y, et al. J Clin Oncol. 2023). These results support the continued use of brexu-cel in R/R MCL.

Background: Positron emission tomography (PET) scan is the imaging modality of choice for initial staging and response assessment of follicular lymphoma (FL). Quantitative parameters such as standardized uptake value (SUV) have been investigated as putative prognosticators in FL, with high baseline SUVmax predicting aggressive disease. To date, there is no data to guide treatment choices in patients (pts) with high SUVmax but with no documented evidence of histologic transformation (HT). Specifically, it remains unclear whether anthracycline-containing regimens, such as R-CHOP, are more beneficial than R-Bendamustine (BR) in these pts. Therefore, we aimed to compare the efficacy of frontline R-CHOP and BR in newly diagnosed FL pts based on the SUVmax at baseline PET (bPET). Patients and Methods: Pts with newly diagnosed, biopsy-proven FL1-2 and FL3A who had a bPET scan and who received either first-line R-CHOP or BR within 6 months of diagnosis between 2002 and 2022 were evaluated. Analysis was restricted to pts with age < 70 years to reduce confounding of age with treatment selection. Cohorts included were the FOLL12 (n=562, Luminari et al JCO 2022) and the R-chemotherapy arm of the RELEVANCE (n=216, Morschhauser et al NEJM 2018) clinical trials, the prospectively enrolled Molecular Epidemiology Resource (MER) and the Lymphoma Epidemiology of Outcomes (LEO) cohorts (n=288) and a retrospective cohort from 13 Australian centers (n=219). Choice of chemotherapy regimen was per treating physician. Maintenance was per protocol (FOLL12/RELEVANCE) or per treating physician (MER/LEO/Australia). Event-free survival (EFS) and overall survival (OS) were defined as time from treatment initiation to progression, relapse, retreatment or death; both were censored at 72 months due to varying follow-up across cohorts. SUVmax was grouped by tertile within each cohort to account for potential differences in SUVmax distributions and patient populations across cohorts. Kaplan Meier curves and multivariable Cox models cohort-stratified and adjusted for clinical factors (FLIPI, ECOG PS, age, grade 3A) were used to evaluate outcomes. Results: The median age at diagnosis was 57 years (IQR 49-64). 651 (51%) pts were treated with R-CHOP and 634 (49%) with BR. Within the study cohorts, there was a prevalence of cases receiving BR compared to R-CHOP in the Australian (90% vs 10%) and MER/LEO (68% vs 32%) cohorts, while the opposite was observed in the RELEVANCE (16% vs 84%) and FOLL12 (37% vs 63; p<0.001) trials. Pts receiving R-CHOP were slightly younger (median 56 vs 58 years, p=0.005), more frequently had grade 3A (17% vs 7%, p<0.001), elevated LDH (27% vs 22%, p=0.029), bulky disease > 7 cm (44% vs 37%, p=0.019), lower ECOG PS (PS >1 7% vs 13%, p<0.001), and higher rate of high risk FLIPI (37% vs 30%, p=0.005). Baseline SUVmax was slightly lower in R-CHOP (median 10.7, IQR 7.9-14.9) vs BR (median 11.0, IQR 8.2-14.2) treated pts (p=0.0045). At a median follow-up of 56 months (range, 1-72 months), 415 pts (32%) had an event and 103 (8%) died. Higher SUVmax was not associated with EFS (middle tertile HR=0.96, 95% CI 0.76-1.22; upper tertile HR=0.86, 95% CI 0.68-1.09; p=0.45) or OS (middle tertile HR=1.28, 95% CI 0.80-2.05; upper tertile HR=0.97, 95% CI 0.59-1.59; p=0.44) in multivariable models stratified on cohort and adjusted for treatment and clinical factors. We then compared outcomes by treatment within tertiles of SUVmax. In multivariable models, R-CHOP had modestly inferior EFS to BR in low (HR=1.27, 95% CI 0.84-1.93) and middle tertiles (HR=1.49, 95% CI 0.99-2.25), and modestly superior OS to BR in low (HR=0.59, 95% CI 0.23-1.47) and middle (HR=0.79, 95% CI 0.37-1.71) tertiles. Both EFS (HR=1.06, 95% CI 0.71-1.58) and OS (HR=1.02, 95% CI 0.45-2.30) for R-CHOP were similar to BR in the highest tertile. No comparisons identified a statistically significant benefit for either therapy in multivariable models when evaluating SUVmax tertile subsets. Conclusions: In this large multicenter study of newly diagnosed FL pts with bPET who received frontline immunochemotherapy, higher baseline SUVmax was not associated with inferior outcomes after adjusting for treatment and clinical factors. Within the caveats of retrospective studies and confounding of treatment selection, these data provide no clear insights for SUVmax-based therapy selection in first-line follicular lymphoma pts treated with immunochemotherapy.

Background While central nervous system (CNS) disease is found in minority of patients (pts) at diagnosis of Ph+ ALL, later relapses can occur in pts despite adequate CNS prophylaxis. CNS disease can be managed with varying combinations of systemic, radiation, and intrathecal (IT) therapy and can be associated with significant toxicity, especially in older pts. While there are more durable systemic responses with 2nd or 3rd generation tyrosine kinase inhibitors (TKIs) based combinations, CNS penetration can vary by TKI. In this large multi-center study, we analyze the incidence of CNS disease in Ph+ ALL in the context of induction therapies and survival post relapse. Methods We conducted a multicenter observational study in collaboration with 10 U.S. academic centers under the COMMAND consortium and reviewed the incidence of CNS relapse in 505 Ph+ ALL pts. We evaluated baseline characteristics, treatment given prior to CNS relapse, and outcome post relapse. Results Baseline characteristics, initial treatment and outcome prior to CNS relapse Eighteen (3.56%) pts were identified to have CNS disease at relapse. Median age of the pts in years (yrs) was 51 (range [R], 22-75), median white blood cell (WBC) was 33.3 x 10(9)/L (R, 2.1-200) and 6 (33%) pts had additional cytogenetic abnormalities at diagnosis. Sixty-one percent (n= 11) of pts received intensive chemotherapy (IC) during induction; 2 (11%), 14 (78%) and 2(11%) of pts received 1st, 2nd or 3rd generation TKI-based combination during induction, respectively. All of pts achieved complete remission (CR), 45.5% achieved complete molecular remission (CMR) at 3 months from the time of diagnosis. Five (28%) pts received allogeneic stem cell transplantation (allo-HCT) as a consolidation therapy. Treatment received at CNS relapse and response The median time to CNS relapse after induction was 10.8 months (mo) (R, 2-79). All pts except 1 had isolated CNS relapse after CR1, 4/18 (22%) pts had T315I mutation at relapse. Twelve (67%) and 6 (33%) pts received intrathecal chemotherapy (IT) with TKI and systemic chemotherapy + TKI in addition to IT, respectively. Eleven (61%) pts received dasatinib, 5 (28%) pts received ponatinib and one (6%) pts each received bosutinib and imatinib at relapse. Ninety-three percent of pts achieved CR (n=3, not evaluable). Six (33%) pts underwent allo-HCT after CNS relapse, one of these transplanted pts had second allo-HCT. Survival after CNS relapse The median relapse free survival (RFS) and overall survival (OS) after CNS relapse was 9.8 (95% CI: 3.80-15.76) and 13.87 (95% CI: 4.08-23.65) mo, respectively. In subset analysis, we compared survival outcome among pts who had relapse without CNS involvement (n= 160/505 [32%]). The median RFS (9.9 vs 9.8, p= 0.88) and OS (31.53 vs 28.80, p= 0.57) after relapse was not significantly different among pts who had relapse with or without CNS involvement, respectively. We also compared OS among pts without relapse to those with relapse. The median OS was not reached (NR; 73% alive at 5 years), 28.80 and 31.53 months (p= <0.001) among pts with no relapse, relapse with CNS and without CNS involvement, respectively. Conclusion Our retrospective analysis from a large database showed that CNS relapses were uncommon (3.56%) in adult pts with Ph+ ALL. A majority of pts (89%) received a 2nd or a 3rd generation TKI during induction. Approximately one quarter of pts with CNS relapse had emergence of T315I mutation. While almost all pts achieved CR, the RFS was relatively short. We did not see significant differences in survival among pts who had relapse with or without CNS involvement.

Introduction: Teclistamab (Tec) is the first approved BCMA x CD3 bispecific antibody for the treatment of triple-class-exposed patients with relapsed/refractory multiple myeloma (RRMM) based on the pivotal MajesTEC-1 study. Tec was associated with high overall response rate (ORR) of 63% in heavily pretreated patients. After a longer follow-up of 30.4 months, CR rate was 46.1%, median duration of response (DOR) was 24 months (95% CI, 17.0 - not estimable), and median progression-free survival (PFS) was 11.4 months (95% CI, 8.8 - 16.4). Herein, we present updated analysis of real-world outcomes and safety with tec in RRMM with extended follow-up of more than 12 months. Methods: This is an international multicenter retrospective study of patients with RRMM treated with tec on-label at 9 academic centers from 5 countries (United States, United Kingdom, Greece, Spain, and Canada) through the International Myeloma Working Group (IMWG) Immunotherapy Committee. Patients with RRMM treated with commercial tec at the respective institutions between May 24, 2022 to January 4, 2024 were included. Median follow-up was 14 months with data collected until July 15, 2024. High-risk cytogenetic abnormalities (HRCA) was defined as 1q+, t(4;14), t(14;16), t(14;20), and/or del(17p). Response was assessed using the IMWG consensus criteria. Patient characteristics were summarized by frequency (percentage) or median (interquartile range [IQR] or range). PFS, overall survival (OS), DOR were evaluated using the Kaplan-Meier method. Results: There were 223 patients included in this analysis with the following characteristics: median age of 67 (range 33-91) with 24% ≥75 years; 45% female; 74% White, 10% Black, 9% Asian, and 7% other/unknown; 86 of 176 (49%) with high risk cytogenetics, including del(17p), t(4;14), t(14;16), t(14;20), and gain/amp 1q; 29.4% (37/126) with known extramedullary disease; 14% with creatinine clearance ≤30 ml/min. Patients received a median of 6 (IQR, 4-8) prior lines of therapy with 52% (107/206) being penta-drug refractory. Among 212 patients with available data, 161 (75.9%) patients would have been ineligible for MajesTEC-1. There were 94 (42%) patients who received prior BCMA-directed therapy (29.8% antibody-drug conjugate [ADC] alone; 45.7% CART alone; 6.3% bispecific antibody alone; 17.0% ADC and CART). Median time from diagnosis to tec initiation was 6.1 (range 0.6-29.2) years. For the 206 response-evaluable patients, ORR was 66%, including 25.2% ≥CR, 33.5% VGPR, and 7.3% PR. ORR for the 90 response-evaluable patients with prior BCMA-directed therapy was 54.5% (21.1% ≥CR, 26.7% VGPR, 6.7% PR). After a median follow-up of 14 (95%CI, 13-14) months, median PFS and OS were 8.8 (95% CI, 5.5-14) and 20 (95% CI, 18-not reached [NR]) months, respectively. 12-month PFS estimate was 46% (95% CI, 40%-54%), and 12-month OS rate was 65% (95% CI, 59%-72%). Median DOR was 17 (95% CI, 17-NR) months with 12-month estimate of 68% (95% CI, 60%-77%). Tec step-up dosing occurred in the outpatient setting for 57 (25.6%) patients. CRS occurred in 119 out of 222 (53.6%) patients with almost all being grade 1-2, except for 1 grade 4 event. ICANS occurred in 18 out of 216 (8.3%) patients (grade 1-2: 5.1%; grade 3-4: 2.8%). Any grade infection occurred in 130 (58.3%) patients; 25.1% of patients had grade ≥3 infection, including 10 patients with grade 5 infection. While receiving teclistamab, 79 (35.4%) patients had ≥2 infections. IVIG was given in 114 out of 164 (69.5%) patients. Conclusion: In this multicenter international real-world analysis of outcomes and safety associated with tec, ORR was high at 66% with 25.2% of patients achieving ≥CR. CR rates may be underestimated due to infrequent bone marrow confirmation in the real-world datasets. Encouragingly, ORR was 54.5% in BCMA exposed RRMM patients, including 21.1% with ≥CR. After a median follow-up of 14 months, heavily pretreated patients including patients with prior BCMA therapy had durable responses with median PFS of 8.8 months and median DOR of 17 months. There were no new safety signals noted in this real-world study. This is the largest real-world study to date of teclistamab with long-term follow-up of more than 12 months. Additional data including more patients, longer follow-up and results from difficult to treat subgroups will be presented at the meeting.

Mutations in genes that code for RAS isozymes (N- and K-) are the most common (40-50%) somatic variations in multiple myeloma (MM). While ~46% of patients with newly diagnosed MM carry a RAS/Raf mutation, >64% of patients with refractory/relapsed MM carry these mutations. RAS activation can also occur from upstream signaling through receptor tyrosine kinases (RTK) or loss-of-function mutations in GTPase-activating proteins (GAPs), which are prevalent in MM. Although covalent inhibitors targeting KRAS alleles are in various stages of clinical development, multiple mechanisms of resistance have been reported. We discovered and developed a novel, highly potent, and selective pan-RAS inhibitor, ADT-007, capable of suppressing MAPK/AKT signaling by blocking GTP activation of RAS. Here, we show that ADT-007 is effective against MM, particularly those MM cell lines harboring KRAS and NRAS mutations that are representative of relapsed/refractory myeloma (RRMM). For these studies, we compiled a panel of over 50 human myeloma cell lines (HMCLs) with broad biological and genetic heterogeneity that represent innate drug-response/resistance (refractory disease), as well as 10 pairs of parental and clonally-derived proteasome inhibitor (PI)- and immunomodulatory drug (IMD)- resistant HMCLs as models of acquired resistance (relapse). Using CRISPR-cas-directed gene editing, we also have generated clonal NRAS and KRAS mutants of drug-sensitive myeloma lines that initially had two wild-type alleles. All cell lines have been authenticated using the GenePrint 24 System and tested for mycoplasma contamination. First, we performed predictive analysis using single-cell RNA sequencing (scRNAseq; 10X Genomics) on all MM cell lines and demonstrated the potential efficacy of ADT-007 based on the subclonal expression of the target genes/pathways. Using in vitro chemosensitivity assays, ADT-007 was highly potent and effective in killing chemo-resistant and RAS-mutant myeloma cells as a single agent with IC50 values ranging from 0.76 to 12 nM with synergistic benefits if combined with PIs and IMDs. Combination indices (CI) were found to be consistently below 0.9, indicating a synergistic drug interaction. (Drug synergy was determined by CalcuSyn software based on Chou-Talalay's CI method and the isobologram algorithm). Caspase 3/7 assay and flow cytometry (Annexin V-FITC + propidium iodide) confirmed apoptosis induction by ADT-007. Furthermore, the in vitro efficacy of ADT-007 was significantly better (nM vs. µM IC50) than cyclorasin B4-27, a bicyclic peptidyl that has been reported as a potent pan-RAS inhibitor against several other cancers, and RMC-6236, a multi-selective noncovalent RAS(on) inhibitor which is in clinical trial for patients with advanced solid tumors harboring G12X, G13X, and Q61X mutations. Pre-vs-post-treatment bulk-RNA sequencing followed by pathway analysis (using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis) showed that ADT-007 suppressed KRAS and NRAS in a dose-dependent manner. Immunoblotting analysis confirmed the dose-dependent reduction of protein markers implicated in cell survival and chemotherapeutic resistance in myeloma, including c-myc, Ki-67, NFkB, IRF4, IKZF1 (Ikaros) and IKZF3 (Aiolos). Finally, we performed pre-vs-post-treatment single-cell transcriptomics analysis, which revealed a distinct shift in clusters representing myeloma single-cell subpopulations following ADT-007 treatment. High-dimensional mass cytometry (cytometry by time of flight or CyTOF) analysis using heavy metal-conjugated proteins in RRMM patient bone marrow-derived primary myeloma cells is currently underway to confirm the cytotoxic effect of ADT-007 ex vivo. ADT-1004 is an orally bioavailable prodrug of ADT-007 designed to improve water solubility and metabolic stability. ADT-1004 has shown strong antitumor activity in highly aggressive and clinically relevant mouse models of pancreatic cancer at dosages, is well tolerated, and is being developed by the NCI Stepping Stones program. Next, we plan to evaluate the antitumor activity of ADT-1004 in mouse xenograft models of human myeloma using immunocompromised mice. Our research will lay the groundwork for future development efforts needed to advance ADT-1004 to clinical trials involving patients with RRMM.

Background: Rituximab, gemcitabine, and oxaliplatin (R-GemOx) is a commonly utilized chemoimmunotherapy regimen for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL), especially for patients ineligible for autologous stem cell transplant (ASCT) or chimeric antigen receptor T cell therapy (CAR T). R-GemOx is used as a comparator arm in several active phase III clinical trials for R/R DLBCL, including the POLARGO (polatuzumab vedotion and R-GemOx), STARGLO (glofitamab and GemOx), SUNMO (mosunetuzumab and polatuzumab vedotin), LOTIS-5 (loncastuximab tesirine and rituximab), and EPCORE DLBCL-1 (epcoritamab) studies. However, real-world data are limited to understand the patterns of use and outcomes of R-GemOx in the US. Methods: We developed a retrospective multicenter US cohort (known as LEO CReWE) of patients with R/R DLBCL and other aggressive B-cell lymphomas at the eight US academic centers participating in the LEO Cohort Study (NCT02736357). Patients first diagnosed with DLBCL (including transformed and high-grade B-cell lymphoma) from 2007 - 2022 who received second line (2L) or later therapy for R/R DLBCL with R-GemOx were included. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Index line of therapy was defined as the first receipt of R-GemOx therapy in the 2L or later setting. Intent for CAR T and/or ASCT was evaluated at each line of therapy based on medical records at the time of treatment initiation. Subgroup analyses were pre-planned in groups of special interest, including those treated with R-GemOx without intent for ASCT or CAR T, those treated as a bridge to CAR T, and those aged 70 and older. Results: 183 patients with R/R DLBCL treated with R-GemOx were included. At time of initiation of R-GemOx, median age was 68 years (range 21-88), with 71 patients (39%) aged 70+ and 18 (10%) aged 80+. Many patients had high risk features including 13% with high grade B-cell lymphoma and 56% with IPI 3 or greater. 21% had an ECOG performance status of 2 or greater. Patients received a median of 2 lines of therapy prior to the index line of R-GemOx (range 1-7). 52% of patients did not achieve a complete response (CR) to first-line therapy, and 20% relapsed <12 months from an initial CR. In all patients receiving R-GemOx, the overall response rate (ORR) was 45% (29% CR). At a median follow-up of 39 months, median EFS was 2.3 months (95% CI: 1.8-3.2), with 12-month EFS of 21% and a 24-month EFS of 15%. Median OS was 13.5 months (95% CI: 9.6-18.1), with a 12-month OS of 52% and a 24-month OS of 38%. In patients treated without intent for ASCT or CAR T, ORR was 33% (18% CR). Median EFS was 2.0 months (95% CI: 1.6-2.5) with 12- and 24-month EFS of 14% and 9%, respectively. Median OS was 9.5 months (95% CI: 6.6-16.1) with 12- and 24-month OS of 45% and 29%, respectively. In patients receiving R-GemOx as bridging to ASCT or CAR T, ORR was 57% (35% CR). 35% received CAR T and 14% received ASCT, while the remainder did not receive the intended therapy as part of this line. Median EFS was 3.6 months (95% CI: 1.8-5.2) with 12- and 24-month EFS of 28% and 25%, respectively. Median OS was 17.4 months (95% CI: 13.4-NR); 12- and 24-month OS were 61% and 50%, respectively. In patients aged 70+, ORR was 53% (33% CR). Median EFS was 2.3 months (95% CI: 1.6-5.2), with 12- and 24-month EFS of 20% and 18%, respectively. Median OS was 13.9 months (95% CI: 8.6-30.2); 12- and 24-month OS were 57% and 39%, respectively. Conclusion: This study represents the largest reported cohort of patients treated with R-GemOx in US academic centers to date. The ORR of 45% and CR rate of 29% CR, as well as median EFS and OS of 2.3 and 13.5 months, respectively, are consistent with findings from previous phase II studies; these results highlight that responses to R-GemOx are not durable and the vast majority of patients require additional therapy. This study demonstrates real-world evidence of the efficacy of R-GemOx in a large cohort of patients with R/R DLBCL from the US over a long period, including both transplant-eligible and -ineligible patients, and patients treated in the CAR T era. These data aid in providing a benchmark for active clinical trials in the rapidly evolving landscape of R/R DLBCL therapies and allow potential comparison to a real-world cohort of patients with a broad range of clinical characteristics.

Introduction: Patients with non-Hodgkin Lymphoma (NHL), especially adolescents and young adults, can face late effects from treatment, including decreased fertility. Due to time constraints prior to treatment initiation and sometimes financial limitations, implementing fertility counseling and referral-based guideline care remains challenging. We aim to understand the occurrence and predictors of fertility counseling and preservation in patients with NHL in the Lymphoma Epidemiology of Outcomes (LEO) cohort study. Methods: The LEO cohort prospectively enrolled newly diagnosed patients with NHL from 2015-2020 at 8 academic medical centers in the US. Clinical. Treatment data were abstracted from medical records, pathology was reviewed and classified by a LEO pathologist, and participants completed a self-administered questionnaire. Participants were then prospectively followed to identify outcomes and collect additional patient reported data, including a survivorship questionnaire at follow-up 3 years (FU3) after diagnosis that included items on fertility counseling and preservation. The questionnaire contained two fertility questions analyzed: whether healthcare providers discussed the impact of lymphoma treatment on fertility, and whether providers discussed the process of fertility preservation. This analysis was based on participants aged 18-50 years at enrollment and who completed the fertility questions at FU3. Women who had undergone natural or procedural menopause and men who had undergone vasectomy pre-treatment were excluded. We estimated the association of demographic and clinical factors with fertility preservation using odds ratios (ORs) and 95% confidence intervals (CI) from univariate and multivariable logistic regression models. Results: Seventy-seven patients were included in the analysis: 36 females (46%) and 41 males (53%). The median age of diagnosis was 40 years (IQR 30-45), and 36 (47%) participants were in the age 18-39-year category. Participant self-identified race/ethnicity was 69% non-Hispanic White, 22% Hispanic, 4% Black and 3% Asian. Sixty (78%) patients were treated with alkylators, 12 (15.6%) with non-alkylators, and 5 (6.5%) with radiation. Fifty-five (71%) of the patients were classified as having aggressive lymphoma, with follicular, extranodal marginal zone, primary cutaneous follicle center, and nodal marginal zone B-cell lymphoma defined as indolent and remaining subtypes aggressive. Around 6% of female patients underwent fertility preservation after lymphoma diagnosis, compared to 12.2% of male patients. All the patients who had undergone fertility preservation after lymphoma diagnosis were in the 18-39-year age group. On univariate analysis, females were more likely to have undergone fertility toxicity and preservation discussions compared to males, with 72% of females and 59% of males recalling a discussion regarding fertility (OR 1.8, 95% CI 0.7-4.9, p=0.21). Those age 18-39 were significantly more likely to have undergone fertility discussion compared to those aged 40-50 (OR 10.2, 95% CI 3.3-39.2, p<0.001). Patients treated with alkylating therapy were significantly more likely to undergo fertility discussion when compared to those on non-alkylating therapy (OR 9.0, 95% CI 2.3-45.5, p<0.01). In addition, 75% of those with aggressive lymphoma compared to 41% of patients with indolent lymphoma had fertility discussion (OR 4.2, 95% CI 1.5-12.4, p=0.01). White patients were significantly less likely than Hispanic, Black and Asian patients to have fertility discussion (OR 0.2, 95% CI 0.04-0.6, p<0.01). In the multivariable analysis, alkylating therapy (OR 8.9, 95% CI 1.6-66.7) and age 18-39 years (OR 10.9, 95% CI 2.9-55.3) remained significant predictors of fertility discussion; White race was also trending towards significance (OR 0.2, 95% CI 0.04-1.0, p=0.08). Aggressive lymphoma subtype was not a significant predictor of fertility discussion. Conclusions: In this cohort of lymphoma survivors 3 years post-diagnosis, we found that Hispanic patients, those diagnosed at a younger age and exposed to alkylating chemotherapy agents were significantly more likely to undergo discussions regarding the effects of lymphoma treatment on fertility. Our study highlights the importance of all cancer patients of childbearing age having the opportunity to address fertility concerns during clinic visits.