An integrated population pharmacokinetic/pharmacodynamic (popPK/PD) model to select the linvoseltamab (LINVO) dosing regimen in patients with high-risk smoldering multiple myeloma (HR-SMM).

7525 Background: LINVO is a BCMA×CD3 bispecific antibody approved for triple-class exposed relapsed/refractory (RR) multiple myeloma (MM) after ≥3 therapies (EU) or ≥4 prior lines of therapy (USA). LINVO 200 mg was approved based on the deep and durable responses and manageable safety profile observed in the LINKER-MM1 study (objective response rate ORR 71%; NCT03761108). LINVO 200 mg demonstrated promising efficacy and a generally manageable safety profile as an early intervention in HR-SMM (ORR 100%; Phase Ph 2 LINKER-SMM1 NCT05955508; IMS 2025 OA-68) and as frontline therapy in newly diagnosed (ND) MM (ORR 86%; Ph 1/2 LINKER-MM4 NCT05828511; ASH 2025 #697). We present results from a semi-mechanistic popPK/PD model of LINVO integrating data from pts with RRMM, NDMM, and HR-SMM, to support full dose selection for a Ph 3 HR-SMM study. Methods: A popPK/PD model was developed from LINKER-MM1 RRMM data to predict LINVO concentration (conc) and disease burden dynamics (soluble BCMA, total involved + uninvolved free light chain FLC conc). Free LINVO conc was a strong predictor of ORR and progression-free survival in the LINKER-MM1 model. The model was updated with data from LINVO administration in pts with NDMM and HR-SMM. Based on baseline disease characteristics in pts with HR-SMM, the model was used to predict free and total LINVO conc for regimens with full doses of 50, 100, and 200 mg in a clinical trial simulation setting. The model assumed that T-cell–mediated tumor killing was dependent on free LINVO forming the T-cell + drug + MM cell complex. The variability in observed response rates across studies was presumed to arise due to differences in disease burden, MM plasma cell proliferation, and T-cell fitness, with the killing rate expected to be more similar between HR-SMM and NDMM than between HR-SMM and RRMM. Results: The dose regimen chosen for evaluation in a Ph 3 HR-SMM study comprised a 200 mg dose given weekly in cycle (C) 1 with the frequency decreasing to every 2 weeks after C1, every 4 weeks after C6, and every 8 weeks after C13. Following initial weekly dosing in this regimen, the free LINVO conc predicted in HR-SMM matched the free LINVO conc predicted in the higher efficacy arm of LINKER-MM4 and the higher efficacy arm in Ph 2 of LINKER-MM1. The model predicted that the 200 mg dose regimen would achieve deep responses (measured by substantial reduction in FLC conc) as rapidly as Week 8, and continue through Week 30, despite the reduced dosing frequency. Conclusions: The totality of evidence, including efficacy and safety data in pts with SMM, dose-ranging data (PK/PD, safety, and efficacy) in pts with NDMM and RRMM, and exploratory analyses integrating exposure and response markers across studies, supports selection of the less intensive LINVO 200 mg dose regimen (compared with NDMM and RRMM) in the Ph 3 HR-SMM study. Clinical trial information: NCT03761108 ; NCT05828511 ; NCT05955508 .