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Relapsed or refractory multiple myeloma (MM) remains a challenging disease to treat despite the introduction of immunomodulatory drugs (IMiDs), proteasome inhibitors (PIs), and anti-CD38 monoclonal antibodies (mAbs) which have substantially improved patient survival [1]. BCMA (B cell maturation antigen)—with high expression in plasmablasts (PBs) and mature plasma cells (PCs)—has emerged as a key therapeutic target in MM. In heavily pretreated patients with RRMM, BCMA-targeted CAR-T and bispecific TCEs therapies [2, 3] have demonstrated objective response rates (ORR) ranging from 61% to 97%. However, these treatments are associated with a high overall incidence of cytokine release syndrome (CRS) at 66.7%–94.8%, and immune effector cell-associated neurotoxicity syndrome (ICANS) at rates of 3%–18%. EMB-06 is a novel Fabs-in-tandem immunoglobulin (Ig) (FIT-Ig) molecule [4], consisting of 2 + 2 Fab arms capable of binding simultaneously to BCMA and CD3 with differential binding affinities. EMB-06 demonstrated potent redirected T-cell cytotoxicity against BCMA-expressing myeloma cells with low cytokine release in preclinical studies [5], by optimizing the affinity, valency, and geometry of the binding arm. We conducted the first in-human (FIH) Phase 1 dose escalation study of EMB-06 in 40 patients with RRMM (NCT04735575). All patients were both PI- and IMiD-experienced, without previous BCMA-targeted therapy (Full eligibility criteria in the Table S1). EMB-06 was administered once weekly by intravenous (IV) infusion. Fixed dose levels of 0.2, 0.6, 2, 6, 15, 30, 60, 120, 200, and 300 mg were planned (Figure S1). To reduce CRS or infusion reactions, premedication (including glucocorticoids, antihistamines, antipyretics) is required. Clinical assessments and samplings were conducted per the Tables S2 and S3. CRS and ICANS were graded according to American Society for Transplantation and Cellular Therapy (ASTCT) grading criteria [6]. All other AEs were graded according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0. Response was assessed by investigators using 2016 IMWG response criteria [7]. Minimal residual disease (MRD) was evaluated by Next Generation Flow (at a threshold of 10−5). The Clopper–Pearson method was used to calculate 95% confidence intervals (CI) for the percentages of patients with a response. Time-to-event endpoints were evaluated by Kaplan–Meier analysis. No formal hypothesis testing was planned. A total of 40 patients received EMB-06 across 11 sites in China and Australia. By study end, 35 discontinued (20 PD, 6 study termination, 3 AE, 2 withdrawal, 2 investigator decision, 2 other), while 5 continued treatment off-study under compassionate use (Figure S2). The median treatment duration was 11.7 weeks (range, 0.1–107.1). In the overall population, the median age was 65 years (range, 45–82). Extramedullary disease was present in two patients (5%). Nine (22.5%) had at least one high-risk cytogenetic abnormality. International Staging System (ISS) stage III disease was present in 4 patients (10%). Patients had received a median of three previous lines of therapy (range, 2–6), 18 (45%) patients were triple-class exposed, and 12 (30%) had triple-class refractory disease. Other baseline characteristics are summarized in Table S4. Across all tested dose levels, only one patient at the 60 mg dose level experienced a DLT (Table S5), which included Grade 3 viral, bacterial, and fungal pneumonias, along with abnormal hepatic function and cardiac failure. The most common TEAEs were cytopenias (70%), including anemia (57.5%), neutropeniaa (42.5%), and thrombocytopeniab (32.5%) (Table 1). Of the 17 patients reported with neutropenia, 12 received granulocyte colony-stimulating factor therapy. Infections occurred in 28 patients (70%), and 15 patients (37.5%) had G3 or above. Opportunistic infections occurred in three (7.5%) patients, with one Grade 3 fungal pneumonia (Table S6). Hypogammaglobulinemia occurred in 19 patients (47.5%) as determined by AE reporting and/or laboratory analyses (IgG level, < 400 mg/dL); 12 patients (30%) received IVIg. Infusion-related reactions were also reported in three patients (7.5%), all of which were Grade 1 or 2. CRS occurred in 10 patients (25.0%); all of them were Grade 1–2 and fully resolved (Table S7, Figure S3). At the targeted dose range of 120–300 mg, the CRS rate was 61.5%, with no CRS event at the 120 mg dose. Notably, there were no dose modifications of EMB-06 due to CRS. The median time to CRS onset was one day (range, 1–2) after the most recent dose, and the median duration was three days (range, 1–6). Supportive measures were provided to three patients (30.0%), including the administration of tocilizumab (two patients) and low-flow oxygen by nasal cannula (one patient) (Table S7). No cases of ICANS were reported (Table S8). No deaths were considered treatment-related (Table S9). Out of 38 response evaluable patients, the ORR was 39.5% (95% CI, 24.0–56.6) with the earliest efficacy signal observed in 2 mg (one sCR). The median time to response was 1.2 months (range, 1.1–2.1). At targeted doses of 120–300 mg, 11 (91.7%; 95% CI, 61.5–99.8) of 12 patients responded, including one MRD-negative sCR and three MRD-negative CRs (Figure 1B). Among the eight patients who had a CR or better, seven were MRD negative (Figure 1B). Responses were durable and deepened over time, even with treatment delays of 3 months or above (Figure 1C). At a median follow-up of 10.2 months (95% CI, 3.7–11.3), the median DoR was not reached (95% CI, 22.1 to not estimable), with only one patient experiencing progressive disease at a DoR of 22.1 months. The PK and anti-drug antibodies (ADA) assessments both included data from 39 patients. The PK of EMB-06 was dose-proportional across 0.2–300 mg (Figure S4). Steady-state was reached after 9 weeks of weekly dosing. The mean terminal elimination half-life (t1/2) was approximately 8.3 days. Four patients (10.3%) developed ADA after EMB-06 administration, and three of them were transient, and no patient developed ADA at 120-300 mg. The presence of ADAs had no significant impact on the PK of EMB-06. At C2D1, peripheral B cell (CD19+) numbers showed a statistically significant (p < 0.0001; Figure S5A) reduction in responders compared with non-responders, with a median change of −95.0% (IQR: −97.7% to −85.0%) from baseline. Serum IgG levels demonstrated a sustained reduction in responders, with a median change of −53.9% (IQR: −67.3% to −39.3%) by C2D1, versus 5.9% (IQR: −10.6% to 29.9%) increment for non-responders (Figure S5B). The difference between the two groups was highly significant (p < 0.0001; Figure S6). This divergence persisted through subsequent cycles. These results indicate that peripheral B-cell depletion and sustained reductions in serum IgG levels are strongly associated with clinical response, highlighting their potential utility as PD biomarkers. While cross-trial comparisons should be approached with caution, a differentiated safety profile was observed with EMB-06. EMB-06 treatment induced no ICANS and a lower incidence of CRS compared to other BCMA TCE, of which CRS rates vary from 60% to 70%. Considering the limited number of patients treated, further optimization of the step-up dosing regimen should be considered to further reduce CRS rates. Besides CRS, cytopenia and infection are also AEs of special interest, underscoring the critical need for patient education, preventive measures, especially Ig supplementation, and regular monitoring, as well as timely treatment of infections. Our findings that durable responses persisted despite treatment interruptions of ≥ 3 months support the feasibility of response-guided dosing intervals as a potentially more cost-effective and patient-centered approach. In contrast, continuous TCE exposure has been associated with the emergence of BCMA-negative subclones [8] and T-cell exhaustion [9], which may compromise long-term benefit. Accordingly, flexible, response-adapted dosing strategies warrant further investigation as a means to sustain efficacy while reducing treatment-related risks. Responders to EMB-06 and other BCMA TCEs showed marked B-cell depletion and sustained serum IgG reduction, indicating effective targeting of both B cells and long-lived plasma cells, and suggesting the potential applicability of EMB-06 to B-cell- or plasma cell–mediated autoimmune disorders. Supporting this, other studies have investigated BCMA-targeted approaches in autoimmune contexts [10]. Future larger studies with more diverse patient populations are needed to further validate these results and assess the broader applicability of the treatment. Based on the PK/PD data, as well as safety and efficacy assessments, doses ranging from 120 to 300 mg may represent the efficacious doses for further optimization. Conception and design: Peter Tan, Jian-Qing Mi, Qiaoyang Lu, and Yonghong Zhu. Patient recruitment and clinical data collection: Peter Tan, Li Bao, Qingsong Yin, Chunrui Li, Sorab Jehangir Shavaksha, Henry Miles Prince, Zhen Cai, Shan Gao, Qiang Wang, Di Wang, Yi Tao, Yuanfang Liu, Yi Li, Yi Tao, Yuanfang Liu, and Jian-Qing Mi. Data analysis and interpretation: Peter Tan, Jian-Qing Mi, Qiaoyang Lu, Qiumei Deng, and Yonghong Zhu. Manuscript writing: All authors. Final approval of manuscript: All authors. Accountable for all aspects of the work: All authors. The study was designed by employees of EpimAb Biotherapeutics in collaboration with the investigators. The authors would like to thank all the patients who participated in the study and their families and caregivers, the physicians and nurses who cared for patients and supported this clinical trial, staff members at the study sites, and staff members involved in data collection and analyses. This research has been presented in oral presentation format at the 2024 American Society of Hematology—66th Annual Meeting. This study was funded by EpimAb Biotherapeutics. This study was conducted in accordance with the Declaration of Helsinki and its later amendments and was approved by human research ethics committees of each investigational site. Mingfei Zhang, Qiumei Deng, Qiaoyang Lu, Chengjun Jiang, Fang Ren, Danqing Wu, Shuqi Zeng, and Yonghong Zhu are employees of EpimAb Biotherapeutics. The datasets generated and analyzed during the current study are not publicly available but may be made available from the corresponding author upon reasonable request. Data S1: Supporting Information. 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