MBS314, a G Protein-Coupled Receptor Family C Group 5 Member D (GPRC5D) x B-Cell Maturation Antigen (BCMA) x CD3 Trispecific Antibody, in Relapsed and/or Refractory Multiple Myeloma (RRMM): Preliminary Results from a Phase Ⅰ, First-in-Human, Open-Label, Dose Escalation Study

Background:

T-cell-engaging (TCE) therapeutical antibodies, such as Teclistamab and Talquetamab have shown promising efficacy in RRMM. However, MM usually had heterogeneous cell populations with independent expressions of BCMA and GPRC5D, so MM inevitably relapses and becomes refractory to treatment, representing a patient (pt) population with unmet needs. MBS314 is a humanized tri-specific antibody against GPRC5D, BCMA, and CD3 for RRMM. Previously presented preclinical results had shown MBS314 was a promising TCE for MM and also had excellent safety with low CD3 binding affinity. Here we present preliminary clinical results of the phase Ⅰ trial evaluating the safety and efficacy of MBS314 (NCT06232096).

Methods:

Pts havd RRMM that is RR to established therapies, including an immunomodulatory drug (IMiD), a proteasome inhibitor. The dose-escalation part (7 cohorts ranging from 0.03 to 60 mg) of this phase I, multicenter, single-arm, open-label clinical trial has enrolled at 3 study sites in China. The study objectives include safety, dose finding (Recommended Phase II Dose), and antitumor activity. Eligible pts received intravenous (IV) step-up dosing (SUD) of MBS314 in a 28-day dose limiting toxicity (DLT) period, and then a target dose from C1D22 every 2 weeks until disease progression or unacceptable toxicity. Response was investigator-assessed using IMWG criteria.

Results:

As of June 29^th 2024, MBS314 were received by 4 pts, which have escalated to the third dose level. Overall, median age was 56 years (range: 48–67), 3 pts (75%) had high-risk cytogenetics, median number of prior lines of therapies (LOT) was 3 (3-7), 75%/75% triple-class exposed/refractory, 50% previously received treatment with BCMA targets (1 with BCMA CAR-T; 1 with BCMA bispecific antibody). The median number of MBS314 cycles administered was 2.0 (range: 1.5-3.0).

Maximum tolerated dose was not reached. All four patients (100.0%) experienced grade (G) 1 cytokine release syndrome (CRS) that was cured without treatment with tocilizumab, and no G2 or higher occurred. Median time to onset was 23.08 hours (range: 2.2-67.1), and median duration was 4.0 hours (range: 1.2-29.3). Grade 3 treatment-related adverse events include: decreased lymphocyte count, decreased white blood cell count, increased blood glucose, and hypertension. No pts experienced serious adverse events (SAEs), G4-5 AEs, skin toxicity, or immune effector cell-associated neurotoxicity syndrome (ICANS).

The two pts in the 1st and 2nd dose levels achieved stable disease and partial response, respectively.

Conclusion:

This study demonstrated that in pts with heavily pretreated RRMM, MBS314 showed favorable safety and remarkable antitumor activity in the preliminary data, even at low doses.