Exposure-Response Analyses of Various Efficacy and Safety Endpoints in Support of Registrational Dose Selection of Linvoseltamab in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Milberg Oleg , Chiu Joannellyn , Hazra Anasuya , Upadhyay Sameer , Kroog Glenn S. , Rodriguez Lorenc Karen , Davis John D. , DiCioccio A. Thomas , Harnisch Lutz O. , Chittenden Jason 
Published: December 2024

Introduction:

B-cell maturation antigen (BCMA) is highly expressed on the surface of plasma cells from patients with multiple myeloma (MM). Linvoseltamab, a human bispecific antibody that is being developed for the treatment of relapsed/refractory MM (RRMM), functions via the simultaneous engagement of CD3 on T cells and BCMA on plasma cells to direct T cell-mediated killing of BCMA-expressing cells. In support of registrational dose selection for linvoseltamab, exposure-response (E-R) analyses were performed for various efficacy and safety endpoints in the Phase 1/2 LINKER-MM1 study of linvoseltamab in RRMM (NCT03761108) via time-to-event (TTE) and categorical data analyses. The results supported the proposed therapeutic dose for linvoseltamab and identified covariates that would explain the variability in responses among patients for the E-R endpoints.

Methods:

Efficacy endpoints included progression-free survival (PFS), overall survival (OS), and objective response rate (ORR), and safety endpoints included neutropenia, all infections, and opportunistic infections. For categorical data analysis, constant and logistic regression models were evaluated for each endpoint-exposure relationship. A multivariate model was identified for the best exposure metric by stepwise covariate analysis with pruning iterations. For TTE analysis, initial univariate analyses were followed by multivariate analyses, and alongside rigorous model validation, led to the derivation of 75%:25% interquartile range hazard ratios (HRs) of the most significant covariates.

Results:

The developed methods efficiently distilled up to 110 clinically relevant covariates (including up to 30 exposure metrics predicted by a population pharmacokinetics model, as well as markers of disease burden, patient demographics, etc.). The odds ratio for ORR was predicted to be 3.67× higher for patients in Phase 1/2 who received a 200 vs 50 mg linvoseltamab dose. TTE multivariate analysis in Phase 2, which compared the 200 vs 50 mg cohorts, resulted in a 49.5% (HR: 0.505 [0.349-0.73]) decrease in risk of progression or death and a 33.8% (HR: 0.662 [0.441-0.993]) decrease in risk of death in the 200 mg cohort. Covariates that suggested greater overall health and less severe disease at the start of treatment (indicated by higher levels of red blood cells, lower levels of soluble BCMA, serum M protein and lactate dehydrogenase, and no plasmacytomas, all at baseline) were associated with a greater probability of response to therapy and longer durations of PFS and OS. OS and ORR showed a strong overlap in significant covariates. Based on the safety E-R analyses for first infection and neutropenia (grade ≥3), increasing linvoseltamab exposure is hypothesized to decrease the probability of occurrence of these safety endpoints, which is consistent with an improvement in the general health and immune system of treated patients.

Conclusions:

This E-R analysis identified a set of covariates that not only confirmed dose-related improvements in efficacy and safety, but also illuminated the influence of disease burden markers on these outcomes. This approach offers a data-driven, mechanistic insight into RRMM therapy and dose optimization. Overall, the E-R analyses support the target full dose of 200 mg over the 50 mg dose following the step-up regimen.