Leleu, Xavier

Introduction Multiple myeloma (MM) is considered incurable. Despite improved outcomes with novel agents, including BCMA-targeted chimeric antigen receptor (CAR) T-cell therapies, antibody-drug conjugates (ADCs), and bispecific antibodies, patients with relapsed/refractory MM (RRMM) often have poor prognoses. LINKER-MM1 (NCT03761108) is a global, single-arm, Phase 1/2 study of linvoseltamab, a BCMA×CD3 bispecific antibody, in patients with RRMM who were either triple-class exposed (TCE; previously treated with a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody) during ≥3 prior lines of therapy (LOTs), or triple-class refractory to these therapies. Here, we present comparisons of clinical outcomes from LINKER-MM1 with those of a current, international, real-world (RW) external control arm (ECA; NCT05673967). Methods The ECA was derived from 16 academic sites of the International Myeloma Foundation International Myeloma Working Group (IMWG) (N=203; 309 eligible LOTs) and compared with linvoseltamab (N=105; Phase 2 200 mg cohort). Patients in the ECA initiated ≥1 anti-MM therapy after meeting key LINKER-MM1 eligibility criteria. Weighted random sampling and inverse probability of treatment weighting were used to select 1 LOT per patient and balance the ECA and trial populations on prespecified prognostic factors (Kumar S, et al. IMS 2023). The primary endpoint was objective response rate (ORR; IMWG criteria) determined by an independent central review committee (ICRC) based on myeloma laboratories. An independent data review committee reviewed comparability of cohorts and endpoint assessments prior to conducting comparative analyses. Results Median follow-up was 14.3 months for the linvoseltamab cohort (data cutoff: Jan 6, 2024) and 13.4 months for the ECA. After weighting, 15 prognostic factors were balanced between cohorts. Patients in the ECA received 68 distinct regimens, most commonly CAR T-cell therapies (11.3%) and ADCs (10.3%). After balancing the cohorts, patients in the ECA evaluable for response had ICRC-assessed ORR of 46.3% (40.8% by treating physician assessment), among whom 24.0% had very good partial response or better (≥VGPR). When including patients who died without evaluable response, ECA ICRC-assessed ORR was 44.2%. Linvoseltamab induced significantly higher ICRC-assessed ORR (69.5% vs 46.3%, odds ratio [OR] 2.65 [95% confidence interval (CI) 1.66-3.69]) and rate of ≥VGPR (62.9% vs 24.0%, OR 5.37 [95% CI 3.61-8.49]) compared with ECA regimens. Conclusion Despite current use of novel therapies, there is no well-established RW standard of care (SOC) for patients with TCE RRMM treated at IMWG sites. To our knowledge, this is the first RW ECA study in MM with a high percentage of anti-BCMA therapies and response ascertainment for all patients by ICRC. Linvoseltamab induced significantly higher response rates, including rate of ≥VGPR, compared with current RW SOC therapies, highlighting its potential as a highly effective treatment in patients with TCE RRMM.

Introduction Linvoseltamab is an investigational, BCMA×CD3 bispecific antibody designed for the treatment of RRMM. High objective response rates (ORR) to linvoseltamab 200 mg in the LINKER-MM1 trial (NCT03761108) were demonstrated across high-risk subgroups, including patients aged ≥75 years, patients with high-risk cytogenetics, and patients with penta-class refractory status. The aim of this study was to compare ORR, overall and in key subgroups, between patients in Phase 2 of the LINKER-MM1 trial and patients in an international RW SOC external control arm (ECA). Methods The ECA was derived from a chart review of 16 academic sites across 10 countries that are part of the International Myeloma Foundation (IMF)-International Myeloma Working Group (IMWG) and 2 US electronic health record databases (COTA and Guardian Research Network [GRN]). Included patients initiated ≥1 anti-MM treatment after meeting key eligibility criteria of LINKER-MM1. Weighted random sampling and inverse probability of treatment weighting (IPTW) were used to select 1 line of therapy (LOT) per patient and balance the overall ECA and trial populations on prespecified prognostic factors (Kumar S, et al. IMS 2023). For ORR assessment, LINKER-MM1 and IMF-IMWG used independent central review committees per IMWG criteria, COTA used algorithmic assessment based on IMWG criteria, and GRN used physician-assessed responses. Prior to conducting comparative analyses, an independent committee of epidemiology and oncology experts reviewed the comparability of the cohorts and endpoint assessments, and approved study continuation. ORR among patients in LINKER-MM1 and patients in the ECA was compared overall and across prespecified subgroups (≥10 patients per subgroup), including age, race, cytogenetic risk score, international Staging System (ISS), presence of extramedullary plasmacytoma (EMP), refractory class, bone marrow plasma cell (BMPC) proportion, and number of prior LOTs. Results Median duration of follow-up was 14.3 months (data cut-off: January 6, 2024) for patients receiving linvoseltamab (n=105) and 13.6 months for the ECA (n=307; n=194, n=72, and n=41 from IMF-IMWG, COTA, and GRN, respectively). Following IPTW, 13 prognostic factors with <30% missingness were balanced between cohorts, with an effective sample size in the ECA of 197. After adjustment, ORR was significantly higher in patients who received linvoseltamab compared with patients in the ECA (69.5% vs 45.7%, odds ratio [OR] 2.5 [95% confidence interval (CI) 1.6-4.1]) and in key subgroups with age 65-74 years (76.9% vs 48.3%, OR 3.6 [1.6-8.6]), age ≥75 years (72.4% vs 48.5%, OR 2.8 [1.1-7.4]), Black or African American race (82.4% vs 25.0%, OR 14.0 [3.0-85.4]), White race (68.9% vs 49.7%, OR 2.2 [1.3-4.0]), standard cytogenetic risk (72.3% vs 51.3%, OR 2.5 [1.3-4.8]), ISS stage III (58.8% vs 19.7%, OR 5.8 [1.5-25.2]), absence of EMP (71.6% vs 49.3%, OR 2.6 [1.5-4.6]), triple-class refractory status (68.2% vs 45.7%, OR 2.6 [1.5-4.4]), quadruple-class refractory status (66.7% vs 45.9%, OR 2.4 [1.3-4.3]), 4-5 prior LOTs (65.1% vs 40.4%, OR 2.8 [1.3-6.0]), and >5 prior LOTs (75.7% vs 36.1%, OR 5.5 [2.4-13.6]). Numerically higher (not statistically significant) or similar ORR was observed for patients receiving linvoseltamab compared with patients in the ECA with age <65 years (59.5% vs 46.8%, OR 1.7 [0.79-3.6]), high-risk cytogenetics (65.0% vs 63.1%, OR 1.1 [0.41-2.9]), ISS stage I (73.3% vs 64.6%, OR 1.5 [0.62-3.7]), ISS stage II (67.6% vs 53.5%, OR 1.8 [0.72-4.7]), presence of EMP (58.8% vs 56.9%, OR 1.1 [0.32-3.8]), penta-class refractory status (64.3% vs 48.5%, OR 1.9 [0.78-4.8]), BMPC <50% (77.0% vs 67.2%, OR 1.6 [0.61-4.3]), BMPC ≥50% (41.7% vs 36.0%, OR 1.3 [0.36-4.7]), and ≤3 prior LOTs (68.0% vs 66.4%, OR 1.1 [0.43-2.9]). Separate findings will be presented for IMF-IMWG and COTA/GRN data at the congress. Conclusions Linvoseltamab induced better ORR vs RW SOC treatments overall, and better or similar ORR in the key subgroups assessed, highlighting its therapeutic value across a range of patients with RRMM with heterogeneous risk profiles and levels of disease burden.

Introduction Patients (pts) with multiple myeloma (MM) have a higher risk of progression/death following an inadequate response to frontline ASCT (van de Velde Eur J Haematol 2017). Therapies (Tx) with novel mechanisms of action may further improve response outcomes. Ide-cel previously demonstrated frequent, deep, and durable responses in KarMMa (Munshi N Engl J Med 2021) and significantly improved median progression-free survival (PFS) and overall response rate (ORR) versus standard regimens in KarMMa-3 (Rodríguez-Otero N Engl J Med 2023) in pts with triple-class-exposed relapsed and refractory MM. KarMMa-2 (NCT03601078) is a multicohort, phase 2, multicenter trial evaluating the efficacy and safety of ide-cel in pts with MM; cohort 2c included pts with NDMM who had an inadequate response to frontline Tx with ASCT. In cohort 2c, with a median follow-up of 27.9 months, ide-cel demonstrated deep and durable responses; complete response (CR) rate was 74.2% (ORR, 87.1%), with a 24-month PFS rate of 83.1% (Dhodapkar Blood 2022). Here, we report results with an additional 11.5 months of median follow-up for updated efficacy and safety data, and health-related quality of life (HRQoL) outcomes in cohort 2c. Methods Eligible pts had NDMM, received ≥ 3 cycles of induction Tx (including a proteasome inhibitor, an immunomodulatory agent, and dexamethasone), had < very good partial response (VGPR) 70-110 days after ASCT (single/tandem), and had Eastern Cooperative Oncology Group performance status ≤ 1. Pts received a single infusion of ide-cel (dose range: 150-450 × 10 6 CAR+ T cells) after lymphodepletion and could receive maintenance Tx post-infusion at investigator's discretion. The primary endpoint CR rate and secondary endpoints ORR, duration of response (DOR), PFS, overall survival (OS), safety, and patient-reported outcomes on HRQoL, assessed via European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Core 30 Questionnaire (QLQ-C30) and EORTC Quality of Life Multiple Myeloma Module 20 Questionnaire (QLQ-MY20), are reported. The exploratory endpoint of minimal residual disease (MRD) negativity (sensitivity, 10 -5) is also reported. Results At data cutoff (May 3, 2023), with a median follow-up of 39.4 (range, 31.6-44.7) months, all 31 pts who were infused with ide-cel were alive; 28 (90.3%) remained in follow-up, with 3 (9.7%) having discontinued due to disease progression. The ORR and CR rates were 87.1% and 77.4%, respectively ( Table); best overall response in 1 pt improved from VGPR to stringent CR. The median DOR was not reached (NR; 95% CI, NR-NR), neither was median PFS (95% CI, 38.0-NR) or median OS (95% CI, NR-NR); the 36-month event-free rates were 80.9%, 76.8%, and 100.0%, respectively. In pts who did not receive lenalidomide (LEN) maintenance, 9 (29.0%) had disease progression; of the 8 pts who received LEN maintenance post ide-cel infusion, none experienced disease progression. At 36 months, MRD negativity was confirmed in 9/14 (64.3%) evaluable pts; all 9 achieved ≥ CR. In this extended follow-up, safety results were generally consistent with the previous data cutoff. All pts experienced ≥ 1 any-grade adverse event (AE), most commonly hematologic, including neutropenia (80.6%), anemia (38.7%), leukopenia (32.3%), and thrombocytopenia (29.0%); infection and infestation AEs occurred in 74.2% of pts. No grade 5 AEs were reported. Incidence of any-grade cytokine release syndrome (58.1%; no grade ≥ 3) was unchanged and there were no additional reports of parkinsonism since the previous report. Overall, HRQoL improved ( Figure) and MM disease symptoms were stable over time based on the EORTC QLQ-C30 and QLQ-MY20, respectively, following ide-cel treatment; by month 3, > 75% of pts had improved or stable global health status/QoL. Conclusions Ide-cel continued to demonstrate deep, durable responses in pts with an inadequate response to frontline ASCT, no new safety signals were observed with extended follow-up, and no deaths were reported. No pts who received LEN maintenance post ide-cel experienced disease progression. Ide-cel treatment resulted in stable or improved HRQoL. Overall, ide-cel continued to demonstrate a favorable clinical benefit-risk profile in NDMM after ASCT. Study support 2seventy bio and Celgene, a Bristol-Myers Squibb Company.

Background HPN217 is a B Cell Maturation Antigen (BCMA)-targeting tri-specific T cell engager (TCE). HPN217 contains three binding domains including anti-BCMA for MM cell binding, anti-albumin for half-life extension, and anti-CD3 for T cell engagement and activation. HPN217 is a small (~50 kDa) globular protein, designed to increase the therapeutic window by minimizing off-target toxicities and cytokine release syndrome (CRS). HPN217 is under investigation in patients (pts) with heavily pretreated relapsed/refractory MM (RRMM). Methods This study is designed to assess the safety, pharmacology and early clinical activity of HPN217 using fixed and step-dose (prime dose followed by target doses) regimens in dose escalation cohorts along with expansion of selected regimens for further evaluation. Pts with RRMM who have received at least 3 prior therapies including a proteasome inhibitor, an immunomodulatory drug, and CD38-targeted therapy are eligible. Prior exposure to a BCMA-targeting agent is permitted. Primary objectives include evaluation of safety, tolerability, pharmacokinetics (PK), and determination of the Recommended Phase 2 Dose(s) (RP2D). Secondary objectives include preliminary efficacy. HPN217 is administered IV once weekly or once every 2 weeks. Adverse events (AEs) are graded by CTCAE 5.0, and ASTCT for cytokine release syndrome (CRS) and ICANS. Clinical activity is assessed per IMWG Response Criteria. Results Dose escalation has been completed. 97 pts were enrolled across 15 dose escalation cohorts and expansion of 3 regimens with the highest target dose levels from dose escalation (12mg weekly; 24mg every 2 weeks; 24mg weekly for 1 cycle followed by 24mg every 2 weeks). As of 26 June 2023, across all cohorts, 94 pts were treated and had received a median (range) of 6 (2-19) prior lines of treatment (62% penta-exposed, 17% BCMA-targeted therapy, 68% prior transplantation). Median age was 70 (38-85) years. 36 pts (38%) remain on treatment. The most common (≥25%) treatment-emergent adverse events (TEAEs) across all cohorts and in the 12mg and 24mg cohorts are summarized in Table 1. Dose limiting toxicities (DLTs) of reversible transaminitis (Gr 3, n=1; Gr 4, n=1) in 2 pts at 2.86 mg fixed dose during dose escalation informed the choice of 2.15 mg as priming dose in the highest step dose cohorts; a maximum tolerated dose (MTD) has not been reached in step dose cohorts. All CRS events were grade 1-2 except one event of grade 3 CRS at 24 mg. Grade 1 ICANS was reported in 2 pts. Responses were observed at doses ≥ 2.15 mg. Among the 12mg and 24mg cohorts, 55% (22/40) of efficacy-evaluable pts currently have had a confirmed response (PR or better) including 2 pts with prior BCMA directed CAR-T cell therapy; disease assessments for recently enrolled patients are pending. Among pts with a response, 73% (16/22) have had a confirmed response of VGPR or better. Across all dose levels, the median time on treatment for pts with a confirmed response was 40 weeks (range 8.3-114 weeks), including 9 patients on treatment for over 12 months, with data maturing to include longer follow-up on patients recently enrolled. HPN217 exhibited linear and dose proportional PK across all dose groups with a median half-life of 68 hours (range 26-197 hours). Transient cytokine increases were higher with the initial/priming dose compared to subsequent/target doses. Conclusions Dose escalation of HPN217, a novel half-life extended BCMA-targeting T-cell engager, has been completed; the MTD was not reached in step dose cohorts. The 12mg and 24mg target doses are well tolerated with manageable adverse event profiles similar to those at lower dose levels and are associated with robust and durable clinical responses. Additional follow up of recently enrolled pts in 12 mg and 24 mg cohorts will inform the choice of the RP2D(s), and complete data on all pts enrolled will be presented. NCT04184050

Introduction: ISB 1342 is a humanized CD38xCD3 bispecific T-cell engager using Ichnos proprietary Bispecific Engagement by Antibodies based on the T cell receptor (BEAT ®) platform, designed to simultaneously bind CD38 on multiple myeloma (MM) cells and CD3ε on T cells, to induce tumor killing. This mechanism of action is different from existing monospecific CD38 targeting therapies and was designed to overcome resistance to daratumumab in MM. ISB 1342 exhibits potent killing of the primary MM cells and MM cell lines with low sensitivity to daratumumab ( Pouleau B. et al. Blood 2023; 142 (3): 260-273). We report here, the updated findings from the weekly dose-escalations of intravenous (IV) and subcutaneous (SC) injections of an ongoing, single-agent phase 1 study (NCT03309111) of ISB 1342 in patients with RRMM. Methods: Adult patients with RRMM that relapsed after or were refractory to prior therapies, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody; received ISB 1342 on a weekly (QW) schedule by IV or SC injection with a priming dose on the first day in 2 parallel dose-escalation schemas. Patients had measurable disease per the International Myeloma Working Group (IMWG) criteria (2016). Dose escalation in the QW schedule began at 0.2/0.3 mg/kg priming/treatment dose and followed a “3 + 3” design. The primary study objectives are to determine the maximum tolerated dose (MTD) and select a recommended phase 2 dose (RP2D) of ISB 1342. Secondary objectives includ evaluation of anti-myeloma activity, pharmacokinetics (PK), pharmacodynamics, and immunogenicity of ISB 1342. Results: As of July 18, 2023, based on ongoing clinical database, 39 subjects had received weekly IV infusions of ISB 1342 in 8 dose-escalation groups from 0.2/0.3 mg/kg to 4.0/16.0 mg/kg as priming/treatment dose; and 7 additional subjects had received weekly SC injections at 2.0/8.0 mg/kg. Two different formulations have been tested in SC group. Median number of cycles administered was 2. The majority were male (57%) and white (74%); 13% were Black or African American. The median age was 69 years (range, 54-76) and the median time since diagnosis was 6.6 years (range, 2.8-22.2). The median number of prior anti-myeloma lines of therapy was 6 (range 1-12). Twenty-one (67%) subjects were considered to be triple-class refractory and 18 (48%) penta-drug refractory. Forty-one (89%) subjects experienced treatment-related adverse events (TRAEs) of any grade. Most TRAEs were grade 1-2, including infusion related reactions (37%), cytokine release syndrome (CRS, 34%, all grade 1or 2), anemia (24%), neutropenia (24%), and thrombocytopenia (17%). Five subjects in SC group (71% of SC) had injection site reaction, all grade 1 or 2. Grade 3 or higher TRAEs occurring in more than 5% of subjects were infusion related reaction (no grade 4), anemia (no grade 4), neutropenia, leukopenia. No Grade 5 TRAE was observed. After QW IV infusion, ISB 1342 serum concentration peaked at the end of infusion and then showed bi-exponential decline. ISB 1342 serum exposures increased in a dose linear fashion across the tested IV infusion dose range. The limited PK data after SC injection suggest slow presentation of ISB 1342 into the systemic circulation leading to lower C max and delayed T max relative to IV. Transient increases in serum cytokines were observed within 24 hours after ISB 1342 dosing, including IFNg, TNFa, IL-2, IL-6 and IL-10. Transient increases in T-cell activation were observed by flow cytometry at 24-48 hours after ISB 1342 dosing at 1.0 / 4.0 μg/kg and above, based on increased expression of CD69 on peripheral blood CD4+ and CD8+ T-cell populations (Figure 1). Comparison of the available data from subjects treated at 2 / 8 μg/kg (Cohort 109) indicated reduced T-cell activation following SC compared to IV administration of ISB 1342. The efficacy signals observed in Cohorts 108 and 109 are consistent with the estimates of the lower boundary of the predicted efficacious dose range using a quantitative systems pharmacology (QSP) model based on preclinical data. Updated clinical data, including response rates and safety data, will be present at the meeting. Conclusions: Treatment with ISB 1342 was well tolerated at higher dose levels evaluated. Observed CRS events were moderate. No increased risk of infection has been observed . Updated safety, efficacy, biomarker and PK data will be presented.