MBS314, a GPRC5DxBCMAxCD3 trispecific antibody, in relapsed/refractory multiple myeloma (RRMM): Updated results from a Phase 1 dose escalation study

Abstract

Abstract Background: Multiple myeloma (MM) is a highly heterogeneous, incurable hematologic malignancy. BCMA and GPRC5D are highly expressed on MM cells, and targeted therapies such as T-cell engagers (TCEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T-cell (CAR-T) therapies have demonstrated promising efficacy and safety. However, rapid relapse due to antigen escape remains a major challenge. To address this, MBS314—a humanized trispecific antibody targeting GPRC5D, BCMA, and CD3—was developed to overcome resistance in RRMM and potentially improve survival outcomes. Here, we report updated results with additional patients (pts) and longer follow-up from an ongoing Phase I, multicenter, single-arm, open-label trial (NCT06232096) evaluating the safety and efficacy of MBS314. Methods: Eligible pts had RRMM with ≥3 prior lines of therapy, including an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI). In the dose-escalation phase, 9 target doses range from 0.3 mg to 120.0 mg. MBS314 was administered intravenously with step-up dosing (SUD) , followed by full-dose Q2W in subsequent administrations. Adverse events (AEs) were graded per CTCAE v5.0, while cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were assessed using ASTCT criteria. Efficacy was evaluated per IMWG guidelines. Results: As of July 25, 2025, 11 dose limiting toxicity (DLT)-evaluable pts received MBS314 and have at least 1 confirmed efficacy assessment (target dose range: 0.3–30.0 mg). Median age was 61 years (range: 48–68), 81.8% (n=9) had medium/high-risk cytogenetics, and median prior lines of therapy (LOT) were 5 (range: 3–9). Overall, 54.5% (n=6) were triple-class exposed/refractory, and 45.5% (n=5) had prior anti-BCMA therapy (3 CAR-T, 1 TCE, 1 ADC). After a median follow-up of 5 (2.5-15.6) months, pts received a median of 6 cycles (range: 1–13). All pts experienced ≥1 AE, with the most common being lymphocyte count decrease (100%, related to T-cell migration after being activated), CRS (81.8%, gr [1] 72.7%, no gr [2], gr [3] 9.1%); white blood cell count decrease (81.8%, gr [3] 54.5%); neutrophil count decreased (72.7%, gr [3/4] 36.4%) ; upper respiratory tract infection (72.7%, gr [3] 27.3%). No gr 5 AE, treatment discontinuations, ICANS events, or DLT events occurred, and the maximum tolerated dose was not reached. The overall response rate (ORR) was 63.6% (7/11), with all responders achieving ≥ very good partial response (VGPR). Notably, among pts with prior anti-BCMA exposure (n=5), 2 achieved sCR and 1 attained VGPR. In the 21.0–30.0 mg cohorts (n=6): We observed an 83.3% ORR including 50% stringent complete response (sCR); Among BCMA-naïve patients (n=4), the ORR was 100% with all responses ≥ VGPR; All responding patients achieved MRD negativity, with an 83.3% MRD- rate (5/6). Conclusion: MBS314 demonstrates encouraging clinical activity in heavily pretreated RRMM, particularly at doses of 21.0-30.0 mg where ORR exceeded 80%. The safety profile appears manageable, with deep and durable responses observed even in anti-BCMA-exposed patients. These promising preliminary results warrant further investigation of MBS314 as a potential therapeutic option for RRMM.