Seoul St. Mary''s Hospital

Abstract Introduction: In RRMM, increasing rates of pt attrition and decreasing durability of responses with each line of therapy (LOT) necessitate early treatment (tx) with the most effective therapies. Immunotherapies that are widely accessible across different MM tx settings have the potential to change the trajectory of RRMM. Teclistamab (Tec), the first approved BCMA×CD3 bispecific antibody (BsAb) for heavily pretreated RRMM, provided deep, durable responses in MajesTEC-1, with improved efficacy and safety in earlier LOTs. Daratumumab (Dara), a standard-of-care (SoC) foundational CD38 targeted therapy with direct on-tumor activity, has been shown to deplete immunosuppressive T-cells and expand cytotoxic T-cells, creating an immune-permissive microenvironment for synergistic Tec-mediated killing of MM cells. MajesTEC-3 (NCT05083169) evaluates Tec-Dara vs SoC DPd/DVd in RRMM. We report initial results for this first phase 3 study of BsAb therapy in MM. Methods: Eligible pts had 1-3 prior LOTs including a PI and lenalidomide (Len; pts with 1 prior LOT must have been Len-refractory) with progressive disease (PD) on or after the last LOT. Pts with prior BCMA-directed therapy or refractory to anti-CD38 were excluded; prior anti-CD38 exposure was permitted. Pts were randomized 1:1 to Tec-Dara or DPd/DVd. The Tec-Dara group received 28-day cycles (C) of Tec (1.5 mg/kg QW in C1-2 [C1 preceded by the approved step-up dose schedule]; 3 mg/kg Q2W in C3-6; and 3 mg/kg Q4W in C7+) with Dara; steroids were not required after C1 Day 8. Tec and Dara dosing were aligned with the approved Dara schedule. DPd/DVd were administered per approved schedules. Progression-free survival (PFS) by IRC was the primary endpoint; secondary endpoints included complete response or better (≥CR), overall response, minimal residual disease (MRD) negativity (10–5; next-generation sequencing), overall survival (OS), time to worsening of symptoms (MySIm-Q), and safety. Results: 587 pts were randomized (Tec-Dara, n=291; DPd/DVd, n=296). Median (range) age was 64 (25-88) yrs, median number of prior LOTs was 2 (1-3). With 34.5-mo median follow-up, Tec-Dara significantly improved PFS vs DPd/DVd (HR, 0.17; 95% CI, 0.12-0.23; P<0.0001); mPFS was NR and 18.1 mo, and 36-mo PFS rate was 83.4% and 29.7%, respectively. PFS benefit was consistent across all prespecified and clinically relevant pt subgroups, including age ≥75 yrs, Len-refractory, high-risk cytogenetics, ≥60% bone marrow plasma cells, soft-tissue plasmacytomas, and anti-CD38 exposed. Significantly higher rates of ≥CR (81.8% vs 32.1%; OR, 9.56; 95% CI, 6.47-14.14), overall response (89.0% vs 75.3%; OR, 2.65; 95% CI, 1.68-4.18), and MRD-negativity (58.4% vs 17.1%; OR, 6.78; 95% CI, 4.53-10.15) were observed with Tec-Dara (P<0.0001). There were 45 deaths with Tec-Dara and 96 with DPd/DVd, primarily due to PD (4.6%; 20.3%). OS significantly favored Tec-Dara (HR, 0.46; 95% CI, 0.32-0.65; P<0.0001), including across all prespecified subgroups. The 36-mo OS rates were 83.3% and 65.0%, respectively and >90% of Tec-Dara pts alive at 6 mo were also alive at 30 mo. Median time to worsening of MM symptoms was NR with Tec-Dara vs 39.9 mo with DPd/DVd (HR, 0.50; 95% CI, 0.34-0.72; P=0.0002). At data cutoff, 49.4% of pts remained on study tx (Tec-Dara, 71.0%; DPd/DVd, 28.3%). Median tx duration was twice as long with Tec-Dara vs DPd/DVd (32.4 vs 16.1 mo). Frequency of grade 3/4 (Tec-Dara, 95.1%; DPd/DVd, 96.6%) and grade 5 (7.8%; 6.2%) treatment-emergent adverse events (TEAEs), were comparable (safety set: Tec-Dara, n=283; DPd/DVd, n=290). Serious TEAEs occurred in 70.7% Tec-Dara and 62.4% DPd/DVd pts; tx discontinuations due to TEAEs were low (4.6% vs 5.5%). Any grade infections occurred in 96.5% and 84.1% of Tec-Dara and DPd/DVd pts, respectively; grade 3/4 infections occurred in 54.1% and 43.4%. New onset grade ≥3 infections decreased over time, coinciding with transition to Q4W dosing and supported by antimicrobial and Ig prophylaxis guidance. CRS rate was 60.1% (grade 1/2: 44.2%/15.9%) and ICANS was 1.1% with Tec-Dara. Conclusion: We demonstrate the clinically remarkable and statistically significant PFS and OS benefits of Tec-Dara vs SoC triplets in RRMM, with 83.4% of Tec-Dara pts alive and progression-free at 3 yrs. Infections with Tec-Dara were well managed with established protocols. This highly effective, off-the-shelf, immunotherapy combination represents a new SoC for RRMM as early as first relapse.

Background Sex-based differences exist in the characteristics and prognosis of patients with atrial fibrillation (AF) and coronary artery disease (CAD). It is still unknown whether optimal antithrombotic therapy differs by sex. Objectives This study aimed to evaluate the efficacy and safety of edoxaban therapy in AF with stable CAD, according to sex category. Methods This prespecified substudy of the EPIC-CAD (Edoxaban Versus Edoxaban With Antiplatelet Agent in Patients With Atrial Fibrillation and Chronic Stable Coronary Artery Disease [EPIC-CAD]) trial compared edoxaban monotherapy with dual antithrombotic therapy (edoxaban plus a single antiplatelet agent). The primary outcome was net adverse clinical events (a composite of death, myocardial infarction, stroke, unplanned revascularization, or clinically relevant bleeding) at 12 months. Median follow-up was 12.0 months (IQR: 11.6-12.9). Results Of 1,040 randomized patients, 238 (22.9%) were women; in the dual-therapy group (n = 516), 110 (21.3%) were women and in the monotherapy group (n = 524), 128 (24.4%) were women. Women were older, had lower body weight, lower creatinine clearance, and more frequently met the edoxaban dose-reduction criteria. The risk of primary outcome was similar between women and men (adjusted HR [aHR]: 1.15; 95% CI: 0.71-1.87; P = 0.559). Edoxaban monotherapy significantly reduced primary events in men compared with dual therapy (aHR: 0.36; 95% CI: 0.23-0.57; P < 0.001), but not in women (aHR: 0.74; 95% CI: 0.33-1.64; P = 0.455). No significant interaction between the randomized treatment and sex was observed (P for interaction = 0.09). Conclusions Edoxaban monotherapy reduced primary net adverse events at 12 months in men but not in women. No significant interaction with sex was observed. Further research is needed to identify sex-specific antithrombotic strategies for patients with AF and CAD. (Edoxaban Versus Edoxaban With Antiplatelet Agent in Patients With Atrial Fibrillation and Chronic Stable Coronary Artery Disease [EPIC-CAD]; NCT03718559)

Little is known about the relationship between post-procedural Doppler velocity index (DVI) and long-term clinical outcomes following transcatheter aortic valve replacement (TAVR). This study aimed to evaluate the association between post-procedural DVI and five-year outcomes for both self-expandable and balloon-expandable transcatheter aortic valves. In this study, we compared outcomes based on post-procedural Doppler velocity index (DVI) in patients who underwent either self-expandable (n=457) or balloon-expandable (n=455) TAVR between June 2015 and September 2023. Patients were divided into two discharge DVI groups (≤0.5 vs. >0.5). The relationship between discharge DVI and five-year all-cause mortality was analyzed using Kaplan-Meier analysis. Among 912 patients who underwent follow-up echocardiography within 30 days post-TAVR, 38.4% had a DVI ≤0.5, with 29.3% in the self-expandable group and 47.5% in the balloon-expandable group. Discharge DVI ≤0.5 was not associated with increased five-year all-cause mortality in either the self-expandable (67.7% vs. 59.6%, p=0.621) or balloon-expandable (69.9% vs. 70%, p=0.703) valve groups. Kaplan-Meier analysis showed no significant differences in five-year all-cause mortality between the DVI groups across both valve types: Evolut high DVI, Evolut low DVI, Sapien high DVI, and Sapien low DVI groups (59.4% vs. 68.1% vs. 70.2% vs. 69.8%, p=0.18, Figure 1). Overall, DVI ≤0.5 was not associated with adverse outcomes following TAVR (69% vs. 65.1%, p=0.708). DVI ≤0.5 was not predictive of adverse outcomes following TAVR with either the balloon-expandable or self-expandable valve.