Showing papers by "Thomas Martin published in 2022"

Teclistamab in Relapsed or Refractory Multiple Myeloma.

Abstract: BACKGROUND Teclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma. METHODS In this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better). RESULTS Among 165 patients who received teclistamab, 77.8% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2). CONCLUSIONS Teclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).

Ciltacabtagene Autoleucel, an Anti–B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up

Abstract: PURPOSE CARTITUDE-1, a phase Ib/II study evaluating the safety and efficacy of ciltacabtagene autoleucel (cilta-cel) in heavily pretreated patients with relapsed/refractory multiple myeloma, yielded early, deep, and durable responses at 12 months. Here, we present updated results 2 years after last patient in (median follow-up [MFU] approximately 28 months), including analyses of high-risk patient subgroups. METHODS Eligible patients had relapsed/refractory multiple myeloma, had received ≥ 3 prior lines of therapy or were double refractory to a proteasome inhibitor and immunomodulatory drug and had received prior proteasome inhibitor, immunomodulatory drug, and anti-CD38 therapy. Patients received a single cilta-cel infusion 5-7 days after lymphodepletion. Responses were assessed by an independent review committee. RESULTS At a MFU of 27.7 months (N = 97), the overall response rate was 97.9% (95% CI, 92.7 to 99.7); 82.5% (95% CI, 73.4 to 89.4) of patients achieved a stringent complete response. Median duration of response was not estimable. Median progression-free survival (PFS) and overall survival (OS) were not reached; 27-month PFS and OS rates were 54.9% (95% CI, 44.0 to 64.6) and 70.4% (95% CI, 60.1 to 78.6), respectively. Overall response rates were high across all subgroups (95.1%-100%). Duration of response, PFS, and/or OS were shorter in patients with high-risk cytogenetics, International Staging System stage III, high tumor burden, or plasmacytomas. The safety profile was manageable with no new cilta-cel–related cytokine release syndrome and one new case of parkinsonism (day 914 after cilta-cel) since the last report. CONCLUSION At approximately 28 months MFU, patients treated with cilta-cel maintained deep and durable responses, observed in both standard and high-risk subgroups. The risk/benefit profile of cilta-cel remained favorable with longer follow-up.

NCCN Guidelines® Insights: Multiple Myeloma, Version 3.2022.

Abstract: The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, initial workup, treatment, follow-up, and supportive care for patients with various plasma cell neoplasms, including multiple myeloma. These NCCN Guidelines Insights highlight some of the important updates/changes specific to the treatment of patients with multiple myeloma in the 2022 version of the guidelines.

Anti-CD38 antibody therapy for patients with relapsed/refractory multiple myeloma: differential mechanisms of action and recent clinical trial outcomes

Abstract: CD38 is a transmembrane glycoprotein that functions both as a receptor and an ectoenzyme, playing key roles in the regulation of calcium signaling and migration of immune cells to tumor microenvironments. High expression on multiple myeloma (MM) cells and limited expression on normal cells makes CD38 an ideal target for the treatment of MM patients. Two monoclonal antibodies directed at CD38, isatuximab and daratumumab, are available for use in patients with relapsed and/or refractory MM (RRMM); daratumumab is also approved in newly diagnosed MM and light-chain amyloidosis. Clinical experience has shown that anti-CD38 antibody therapy is transforming treatment of MM owing to its anti-myeloma efficacy and manageable safety profile. Isatuximab and daratumumab possess similarities and differences in their mechanisms of action, likely imparted by their binding to distinct, non-overlapping epitopes on the CD38 molecule. In this review, we present the mechanistic properties of these two antibodies and outline available evidence on their abilities to induce adaptive immune responses and modulate the bone marrow niche in MM. Further, we discuss differences in regulatory labeling between these two agents and analyze recent key clinical trial results, including evidence in patients with underlying renal impairment and other poor prognostic factors. Finally, we describe the limited existing evidence for the use of isatuximab or daratumumab after disease progression on prior anti-CD38 mono- or combination therapy, highlighting the need for additional clinical evaluations to define optimal anti-CD38 antibody therapy selection and sequencing in RRMM.

Optimizing Thromboembolism Prophylaxis for the Contemporary Age of Multiple Myeloma.

Abstract: Venous thromboembolism (VTE) is a major complication in all patients with cancer. Compared with the general population, patients with multiple myeloma (MM) have a 9-fold increase in VTE risk, likely because of their malignancy, its treatments, and other additional patient-related factors. In MM, thromboembolism events tend to occur within 6 months of treatment initiation, regardless of treatment regimen; however, the use of immunomodulatory agents such as thalidomide or lenalidomide, especially in combination with dexamethasone or multiagent chemotherapy, is known to create a significant risk for VTE. Currently, official recommendations for VTE prophylaxis in MM outlined in various national guidelines or multidisciplinary society panels are based on expert opinion, because data from randomized controlled trials are scarce. Large studies which have mainly focused on the efficacy of thromboprophylaxis in patients with cancer at higher risk for VTE either had a very low representation of patients with MM, or excluded them all together, limiting our ability to draw evidence-based conclusions on how to effectively protect MM population from VTE. In this brief perspective, we highlight some of the greatest challenges that have hampered the field concerning the availability of high-quality clinical trial data for the formulation of best VTE prophylaxis strategies in patients with newly diagnosed MM, as well as the rationale for the latest updates in the NCCN Guidelines on this topic.

Primary outcomes by 1q21+ status for isatuximab-treated patients with relapsed/refractory multiple myeloma: subgroup analyses from ICARIA-MM and IKEMA

Abstract: Not available.

Meta-analysis of ciltacabtagene autoleucel versus physician’s choice therapy for the treatment of patients with relapsed or refractory multiple myeloma

Abstract: Abstract Objective: In the absence of head-to-head trials, indirect treatment comparisons (ITCs) between ciltacabtagene autoleucel (cilta-cel; in CARTITUDE-1) and treatments used in real-world clinical practice (physician’s choice of treatment [PCT]), were previously conducted. We conducted multiple meta-analyses using available ITC data to consolidate the effectiveness of cilta-cel versus PCT for patients with triple-class exposed relapsed or refractory multiple myeloma (RRMM). Methods: Five ITCs were assessed for similarity to ensure robust comparisons using meta-analysis. Effectiveness outcomes were overall survival (OS), progression-free survival (PFS), time to next treatment (TTNT), and overall response rate (ORR). A robust variance estimator was used to account for the use of CARTITUDE-1 in each pairwise ITC. Analyses were conducted in both treated and enrolled populations of CARTITUDE-1. Results: Four ITCs were combined for evaluation of OS. Results were statistically significantly in favor of cilta-cel versus PCT in treated patients (hazard ratio [HR]: 0.24, 95% confidence interval [CI]: 0.22–0.26). Three ITCs were combined for evaluation of PFS and TTNT. Cilta-cel reduced the risk of progression and receiving a subsequent treatment by 80% (HR: 0.20 [95% CI: 0.06, 0.70]) and 83% (HR: 0.17 [95% CI: 0.12, 0.26]), respectively. Three ITCs were combined for evaluation of ORR. Cilta-cel increased the odds of achieving an overall response by 86-times versus PCT in treated patients. Findings were consistent in the enrolled populations and across sensitivity analyses. Conclusions: Evaluating multiple indirect comparisons, cilta-cel demonstrated a significantly superior advantage over PCT, highlighting its effectiveness as a therapy in patients with triple-class exposed RRMM.

S188: teclistamab in combination with daratumumab, a novel, immunotherapy-based approach for the treatment of relapsed/refractory multiple myeloma: updated phase 1b results

Abstract: Background: Teclistamab (JNJ-64007957) is a B-cell maturation antigen (BCMA) × CD3 T-cell redirecting bispecific antibody currently under investigation in patients with relapsed/refractory multiple myeloma (RRMM). Daratumumab is a CD38-targeting monoclonal antibody with direct on-tumor and immunomodulatory mechanisms of action. The preliminary results from the phase 1b multicohort TRIMM-2 study showed tolerable safety with no overlapping toxicities, and encouraging efficacy, supporting the combination of teclistamab with daratumumab for the treatment of RRMM. Aims: We report updated results from the TRIMM-2 study with additional patients and longer follow-up. Methods: Eligible patients were ≥18 years of age with a MM diagnosis and previously treated with ≥3 prior lines of therapy (including a proteosome inhibitor [PI] and immunomodulatory drug [IMiD]) or were double-refractory to a PI and IMiD. Patients who had received anti-CD38 therapy ≤90 days prior were excluded. Written informed consent was obtained from all eligible patients. Patients received subcutaneous (SC) daratumumab 1800 mg per approved schedule and teclistamab SC 1.5–3 mg/kg once weekly or every 2 weeks. Primary objectives of the study were to identify the recommended phase 2 dose for the teclistamab and daratumumab combination and to assess safety of the combination. Responses were assessed by IMWG criteria. Adverse events (AEs) were graded per CTCAE v5.0, except for cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS), which were graded per ASTCT guidelines. Results: At the Jan 13, 2022 data cutoff, the median follow-up was 7.2 months (range 0.1–16.6). Among the safety population (N=46), 52% were females, and the median age was 67 years (range 50–79). Patients received a median of 6 prior lines of therapy (range 2–17); 74% of patients were triple-class exposed; 63% were penta-drug exposed, and 15% were anti-BCMA exposed. Overall, 91% of patients had ≥1 AE of any grade; 78% had grade 3/4 AEs. The most common AE was CRS (61%; all grade 1/2); median time to onset was 2 days and median duration was 2 days. Other AEs included neutropenia (54%; grade 3/4 50%), anemia (46%; grade 3/4 28%), thrombocytopenia (33%; grade 3/4 28%), and diarrhea (33%; grade 3/4 2%). Infections occurred in 29 patients (63%; grade 3/4 28%). One patient had grade 1 ICANS that was fully resolved. Among 37 response-evaluable patients, the overall response rate was 78% (29/37); 27 patients (73%) had very good partial response (VGPR) or better (Table). While the median duration of response was not reached, median time to first response across dosing cohorts was 1.0 month (range 0.9–2.8). Upregulation of CD38+/CD8+ T cells and proinflammatory cytokines was observed after teclistamab dosing in combination with daratumumab, supporting potential synergy of the combination in patients with prior anti-CD38 exposure. Updated results will be presented. Image:Summary/Conclusion: Teclistamab in combination with daratumumab is a novel immunotherapy approach that may yield improved clinical efficacy in heavily pretreated patients with RRMM.

Adjusted comparison of outcomes between patients from CARTITUDE-1 versus multiple myeloma patients with prior exposure to PI, IMiD and anti-CD38 antibody from the prospective, multinational LocoMMotion study of real-world clinical practice.

Abstract: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy studied in patients with triple-class exposed multiple myeloma (TCE-MM) in the single arm CARTITUDE-1 study. To assess cilta-cel's effectiveness compared to real-world clinical practice (RWCP), we performed adjusted comparisons using individual patient data from CARTITUDE-1 and LocoMMotion, a prospective, multinational study of patients with TCE-MM. Comparisons were performed using inverse probability weighting (IPW). In CARTITUDE-1, 113 patients were enrolled, and 97 patients were infused with cilta-cel. In LocoMMotion, 248 patients were enrolled, and 170 patients were included in comparisons vs. infused patients. 92 unique regimens were used in LocoMMotion, most frequently carfilzomib-dexamethasone (13.7%), pomalidomide-cyclophosphamide-dexamethasone (13.3%) and pomalidomide-dexamethasone (11.3%). Adjusted comparisons showed that patients treated with cilta-cel were 3.12-fold more likely to respond to treatment vs. RWCP (RR 3.12, 95% CI: 2.24, 4.00), had a reduced risk of progression or death by 85% (PFS HR 0.15, 95% CI: 0.08, 0.29), and a lower risk of death of 80% (OS HR 0.20, 95% CI: 0.09, 0.41). Incremental improvement vs. baseline in HRQOL for cilta-cel vs. RWCP at week 52 as measured by EORTC QLQ-C30 Global Health Status was 13.4 (95% CI: 3.5, 23.6) and increased to 30.8 (95% CI: 21.8, 39.8) when including death as additional information regarding patients' health status. Patients treated with cilta-cel experienced more adverse events vs. RWCP (any grade:100% vs. 83.5%). Results from this study demonstrate improved efficacy outcomes of cilta-cel vs. RWCP and highlight its potential as a novel and effective treatment option for patients with TCE-MM.

S184: evaluating teclistamab in patients with relapsed/ refractory multiple myeloma following exposure to other b-cell maturation antigen (bcma)-targeted agents

Abstract: Background: Teclistamab (JNJ-64007957) is a T cell redirecting bispecific antibody that targets both B-cell maturation antigen (BCMA) and CD3 receptors to induce T cell mediated cytotoxicity of BCMA-expressing myeloma cells. MajesTEC-1 is an open-label, multicohort, phase 1/2 study evaluating teclistamab in patients (pts) with relapsed/ refractory multiple myeloma (RRMM) previously treated with ≥3 prior lines of therapy (LOT). An overall response rate (ORR) of 62.0% in pts with no prior anti-BCMA treatment (tx) was previously reported in a pooled analysis from phase 1 and phase 2 cohort A at a median follow-up of 7.8 mo. Aims: We report efficacy and safety results of teclistamab from cohort C, which enrolled patients who had prior exposure to anti-BCMA treatment. Methods: Eligible pts (age ≥18 y) had multiple myeloma (MM) per IMWG criteria and were previously treated with ≥3 prior LOT, including a PI, IMiD, anti-CD38 antibody, and anti-BCMA treatment (chimeric antigen receptor T cell therapy [CAR-T] or Ab drug conjugate [ADC]). Pts were enrolled using a Simon’s stage design to receive weekly subcutaneous teclistamab 1.5 mg/kg (step-up doses of 0.06 and 0.3 mg/kg). ORR per IMWG 2016 criteria was the primary endpoint. All AEs were graded per CTCAE v4.03; immune effector cell–associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) were graded per ASTCT guidelines. Results: In cohort C, 38 pts (median age 63.5 y [range 32–82]; 63% male) received teclistamab (median prior LOT 6 [range 3–14]) at the data cutoff date of Sep 7, 2021. Of the 38 patients, 25 (66%) were refractory to an anti-BCMA treatment, and 32 (84%) were refractory to last LOT. Among 25 efficacy-evaluable patients, 16 (64%) received prior ADC, 11 (44%) received prior CAR-T, and 2 pts received both. The ORR was 40% (95% CI, 21–61) at a median follow-up of 6.9 mo (range 0.7–8.7). Complete response or better were observed in 5 pts (20%). In ADC-exposed and CAR-T-exposed pts, the ORR was 38% (95% CI, 15–65) and 45% (95% CI, 17–77), respectively. Responses were rapid in most, with deepening of responses over time in 7 of 25 pts. While the median duration of response was not reached, median time to first response was 1.2 mo (range, 0.2–4.9) and to best response was 2.1 mo (range, 1.1–5.7). No new safety concerns were observed, and the safety profile was comparable with that of BMCA tx-naive pts. Infections were reported in 16 pts (42%; grade 3/4, 26%). Most common AEs (n=38) were CRS (63%; all grade 1/2; median time to CRS onset: 3 d [range, 2–6], duration of CRS: 2 d [range, 1–4]), thrombocytopenia (42%; grade 3/4, 29%), neutropenia (55%; grade 3/4, 50%), lymphopenia (40%; grade 3/4, 37%), and anemia (39%; grade 3/4 29%), Grade 3 ICANS was reported in 1 pt which resolved with supportive care and the pt remained on tx. Anti-teclistamab Abs were not detected in any pts. Baseline BCMA expression levels were comparable with those reported in BCMA tx-naive pts. Updated efficacy and safety results will be presented for 40 pts. Summary/Conclusion: These preliminary results observed with serial targeting of BCMA with teclistamab following ADC or CAR-T tx suggest a promising ORR with early responses that deepen over time. Additionally, a well-tolerated safety profile was observed in patients treated with anti-BCMA tx.

P961: ciltacabtagene autoleucel, a bcma-directed car-t cell therapy, in patients with relapsed/refractory multiple myeloma: 2-year post lpi results from the phase 1b/2 cartitude-1 study

Abstract: Background: The phase 1b/2 CARTITUDE-1 study (NCT03548207) reported early, deep, and durable responses with ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T (CAR-T) cell therapy with 2 B-cell maturation antigen (BCMA)–targeting single-domain antibodies, in heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM). At a median follow-up of ~1 year, the overall response rate (ORR) was 97%, with 67% of patients achieving stringent complete response (sCR). Progression-free survival (PFS) and overall survival (OS) rates at 1 year were 77% and 89%, respectively. Aims: To report updated 2-year post last patient in (LPI) results (total median follow-up of ~30 months). CARTITUDE-1 results at a median follow-up of 21.7 months are reported here. Methods: All patients provided informed consent. Patients with RRMM had received ≥3 prior lines of therapy (LOT) or were refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD). Patients had received a PI, IMiD, and anti-CD38 antibody. After apheresis, bridging therapy was allowed. A single cilta-cel infusion was administered at a target dose of 0.75×106 CAR+ viable T cells/kg 5-7 days after lymphodepletion. The primary objectives were to evaluate the safety and efficacy of cilta-cel. Response assessments were based on International Myeloma Working Group criteria by independent review committee. Minimal residual disease (MRD) negativity at 10-5 was assessed by next-generation sequencing. Results: 97 patients (male: 59%; median age: 61 years) received cilta-cel as of July 22, 2021. The median number of prior LOT was 6 (range: 3-18). 84% of patients were penta-drug exposed, 88% were triple-class refractory, 42% were penta-drug refractory, and 99% were refractory to their last LOT. The ORR was 97.9% (95% CI: 92.7-99.7), with 94.9% of patients achieving very good partial response and 82.5% achieving sCR. Median time to first response was 1.0 month, median time to best response was 2.6 months, and median time to ≥CR was 2.9 months. Median duration of response was not reached. Among 61 MRD-evaluable patients, 92% were MRD negative at 10-5, which was sustained in 44% of patients (27/61) for ≥6 months and in 18% of patients (11/61) for ≥12 months. Median PFS and OS were not reached. The 2-year PFS rate was 60.5% (95% CI: 48.5-70.4) overall. The 2-year PFS rate was 91% for patients with sustained MRD negativity ≥6 months and 100% for those with sustained MRD negativity ≥12 months. No new safety signals or new cases of CAR-T cell neurotoxicity, movement/neurocognitive treatment-emergent adverse events, or treatment-related deaths were reported since 1-year median follow-up. Over a median follow-up of ~2-years, 15 second primary malignancies occurred in 11 patients. Summary/Conclusion: A single cilta-cel infusion resulted in deepening and durable responses in heavily pretreated patients with RRMM at a median follow-up of ~2 years. The safety profile was manageable. Follow-up in CARTITUDE-1 is ongoing. We will present landmark 2-year post LPI data, with ~8 months of additional follow-up (~30 months total median follow-up). Cilta-cel is also being evaluated in earlier LOT and outpatient settings across the CARTITUDE program, including NCT04133636, NCT04181827, NCT04923893.

P06: updated results from the phase 1/2 majestec-1 study of teclistamab, a b-cell maturation antigen x cd3 bispecific antibody, in patients with relapsed/refractory multiple myeloma

Abstract: Teclistamab (JNJ-64007957) is a bispecific antibody that binds to both B-cell maturation antigen (BCMA) and CD3 receptors to induce T cell-mediated cytotoxicity of BCMA-expressing myeloma cells. Results from phase 1 of the MajesTEC-1 study, an ongoing phase 1/2 study in heavily-pretreated relapsed/refractory multiple myeloma (RRMM; NCT03145181), showed a tolerable safety profile at the recommended phase 2 dose (RP2D) and encouraging efficacy. Here we report initial data from the phase 2 portion of MajesTEC-1 (NCT04557098) as well as updated results from phase 1. Patients (pts; ≥18 y) had MM per International Myeloma Working Group (IMWG) criteria, measurable disease, and were exposed to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. In phase 1, pts were relapsed, refractory, or intolerant to established therapies. In phase 2, pts received ≥3 prior lines of therapy (LOT). The primary objectives were to identify the RP2D and to characterize safety and tolerability of teclistamab at the RP2D in phase 1, and to evaluate the efficacy at the RP2D (primary endpoint: ORR) in phase 2. The RP2D was weekly subcutaneous teclistamab 1500 μg/kg following step-up doses of 60 and 300 μg/kg. Responses were assessed by the investigator per IMWG criteria. Adverse events (AEs) were graded per CTCAE v4.03. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT criteria. As of June 14, 2021, 159 pts (median age 64.0 y [range 33–84]; 15% ≥75 y; 59% male) were treated at the RP2D (phase 1: 40 pts; phase 2: 119 pts). Pts received a median of 5 prior LOT (range 2–15); 100% were triple-class exposed, 69% were penta-drug exposed, 77% were triple-class refractory, and 29% were penta-drug refractory. In 159 pts, the most common nonhematologic AEs at the RP2D were CRS (any grade: 67%; grade 3 occurred in 1 pt, no grade 4 or 5), injection site erythema (23%; all grade 1/2), and fatigue (22%; grade 3/4: 2%). Of the hematologic AEs, most common were neutropenia (53%; grade 3/4: 45%), anemia (41%; grade 3/4: 27%), and thrombocytopenia (33%; grade 3/4: 18%). Four pts (2.5%) developed ICANS (all grade 1/2; all resolved). No new safety signals were identified in phase 2. Phase 2 pharmacokinetic and pharmacodynamic data supported those reported in phase 1. At the RP2D, teclistamab exposure was sustained across the dosing interval and exceeded target exposure levels. Across both phases, induction of proinflammatory cytokines and T cell activation were observed at the RP2D. Phase 2 efficacy data are immature. At 8.2-mo median follow-up (range 1.2–15.2), responses in the phase 1 pts at the RP2D (n=40) were consistent with previous reports (ORR: 65% [95% CI 48–79]; ≥VGPR: 60% [95% CI 43–75]; ≥complete response: 40% [95% CI 25–57]). Responses deepened over time, and with longer follow-up of responders compared with previously presented data (median follow-up of 9.5 mo vs 7.1 mo), remained durable (Figure). 85% (22/26) of responders are continuing on treatment, including 1 pt with 15.2 mo of follow-up. Median duration of response (DOR) was not reached, with 6-month DOR rate of 90% [95% CI 63–97]. The safety of teclistamab is supported by data from 159 pts treated at the RP2D. Teclistamab continues to show deep and durable responses with a manageable safety profile in heavily-pretreated pts with RRMM.

Updated results from a matching-adjusted indirect comparison of efficacy outcomes for ciltacabtagene autoleucel in CARTITUDE-1 versus idecabtagene vicleucel in KarMMa for the treatment of patients with relapsed or refractory multiple myeloma

Abstract: Abstract Objective This study used the latest available data cuts from the CARTITUDE-1 and KarMMa clinical trials to update previously published matching-adjusted indirect treatment comparisons (MAICs) assessing the comparative efficacy of ciltacabtagene autoleucel (cilta-cel) versus the FDA-approved idecabtagene vicleucel (ide-cel) dose range of 300 to 450 × 106 CAR-positive T-cells in the treatment of patients with relapsed or refractory multiple myeloma (RRMM) who were previously treated with a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (i.e. triple-class exposed). Methods MAICs were performed with the latest available individual patient data for cilta-cel (CARTITUDE-1) and published summary-level data for ide-cel (KarMMa). The analyses included treated patients from CARTITUDE-1 who satisfied the eligibility criteria for KarMMa. The MAIC adjusted for unbalanced baseline covariates of prognostic significance identified in the literature and by clinical expertise. Comparative efficacy was assessed for overall response rate (ORR), complete response or better (≥CR) rate, duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Results Cilta-cel was associated with statistically significantly improved ORR (odds ratio [OR]: 94.93 [95% confidence interval [CI]: 21.86, 412.25; p < .0001]; relative risk [RR]: 1.34), ≥CR rate (OR: 5.65 [95% CI: 2.51, 12.69; p < .0001]; RR: 2.23), DoR (hazard ratio [HR]: 0.52 [95% CI: 0.30, 0.88; p = .0152]), PFS, (HR: 0.38 [95% CI: 0.24, 0.62; p < .0001]), and OS (HR: 0.43 [95% CI: 0.22, 0.88; p = .0200]) compared with ide-cel. Conclusions These analyses demonstrate improved efficacy with cilta-cel versus ide-cel for all outcomes over longer follow-up and highlight its therapeutic potential in triple-class exposed RRMM patients.

HDAC Inhibition Regulates Cardiac Function by Increasing Myofilament Calcium Sensitivity and Decreasing Diastolic Tension

Abstract: We recently established a large animal model that recapitulates key clinical features of heart failure with preserved ejection fraction (HFpEF) and tested the effects of the pan-HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). SAHA reversed and prevented the development of cardiopulmonary impairment. This study evaluated the effects of SAHA at the level of cardiomyocyte and contractile protein function to understand how it modulates cardiac function. Both isolated adult feline ventricular cardiomyocytes (AFVM) and left ventricle (LV) trabeculae isolated from non-failing donors were treated with SAHA or vehicle before recording functional data. Skinned myocytes were isolated from AFVM and human trabeculae to assess myofilament function. SAHA-treated AFVM had increased contractility and improved relaxation kinetics but no difference in peak calcium transients, with increased calcium sensitivity and decreased passive stiffness of myofilaments. Mass spectrometry analysis revealed increased acetylation of the myosin regulatory light chain with SAHA treatment. SAHA-treated human trabeculae had decreased diastolic tension and increased developed force. Myofilaments isolated from human trabeculae had increased calcium sensitivity and decreased passive stiffness. These findings suggest that SAHA has an important role in the direct control of cardiac function at the level of the cardiomyocyte and myofilament by increasing myofilament calcium sensitivity and reducing diastolic tension.

P922: health-related quality of life with teclistamab, a b-cell maturation antigen x cd3 bispecific antibody, in patients with relapsed/refractory multiple myeloma from majestec-1

Abstract: Background: Because patients with multiple myeloma (MM) have impaired health-related quality of life (HRQoL), it is important that patient-reported outcomes (PROs) are assessed in addition to clinical outcomes. Teclistamab (JNJ-64007957) is a B-cell maturation antigen (BCMA) x CD3 bispecific antibody designed to mediate T cell-induced lysis of BCMA-expressing MM cells. In the phase 1/2 MajesTEC-1 trial, initial results from the pivotal cohort (patients who received ≥3 prior lines of therapy [LOT], including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody) showed that teclistamab was well tolerated with encouraging efficacy. Aims: We report PROs of the pivotal cohort from MajesTEC-1. Methods: MajesTEC-1 included patients aged ≥18 years with documented relapsed/refractory multiple myeloma (RRMM) as per the International Myeloma Working Group diagnostic criteria, progressive/measurable disease, and previous exposure to ≥3 prior LOT. Patients who had received prior anti-BCMA treatment were ineligible. Patients were given weekly subcutaneous teclistamab at the recommended phase 2 dose (1.5 mg/kg with step-up doses of 0.06 and 0.3 mg/kg). PRO assessments were performed at screening and at every even treatment cycle; results for cycles 2-8 are reported here. HRQoL was assessed by EORTC QLQ-C30 (range: 0–100; with higher scores indicating better global health status [GHS] but greater symptom severity [symptom scales]) and EuroQol 5-dimensional descriptive system (using the visual analog scale [VAS] with “0” indicating worst imaginable health state and “100” indicating best imaginable health state). Mixed-effects model with repeated measures was used to determine treatment effect. Meaningful improvement was defined as the proportion of patients with a change of ≥10 points. Kaplan-Meier estimate was used to determine time to worsening. Results: The analysis included 110 patients, with median follow-up duration of 7.8 months. The PRO compliance rates were high at baseline (85–90%) and through treatment cycles 2–8 (80–94%). Overall HRQoL was improved with teclistamab, as shown by improved GHS scores (cycle 2–8) and reduced pain (-4.2 [cycle 2] to -15.1 [cycle 8]; Table), with no overall changes in physical functioning and fatigue. Meaningful improvements from baseline to cycle 8 were observed in GHS (50% of patients), physical function (35%), pain (65%), and fatigue (73%). Meaningful improvement in overall health (VAS) was also observed in 50% of patients. Median time to improvement from baseline was ~1.5 months with longer time to improvement seen for nausea/vomiting and fatigue. Across all symptoms, median time to worsening ranged from 2 months to not estimable. Image:Summary/Conclusion: Teclistamab provided rapid, clinically meaningful improvements in HRQoL in patients with RRMM, which are consistent with clinical outcomes in MajesTEC-1.