PK/PD relationship of the monoclonal anti-BAFF antibody tabalumab in combination with bortezomib in patients with previously treated multiple myeloma: comparison of serum M-protein and serum Free Light Chains as predictor of Progression Free Survival
Pascal Chanu (1), Laurent Claret (1), Rene Bruno (1), David B. Radtke (3), Susan P. Carpenter (2), James E. Wooldridge (3), Damien M. Cronier (4)
(1) Pharsight Consulting Services, Lyon and Marseille, France, (2) Applied Molecular Evolution, San Diego, USA, (3) Eli Lilly and Company, Indianapolis, USA, (4) Eli Lilly and Company, Windlesham, UK
Objectives: The serum levels of M-protein were recently used in a PK/PD modeling study as a surrogate for tumor burden in multiple myeloma (MM) patients. The decrease in serum M-protein after 8 weeks of treatment proved successful as a predictor of progression-free survival (PFS) and overall survival (OS) [1-3]. However, patients with oligo- or non-secretory disease cannot be included in such analyses. Alternatively, serum Free Light chains (FLCs) can be measured in a greater number of MM patients [4,5], and could represent a useful tool to predict survival in a broader patient population. Here we present a PK/PD study aimed at comparing the use of M-protein and FLCs as surrogates for MM tumor burden and as a predictor of PFS.
Methods: Tabalumab is a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF). A combination of tabalumab and bortezomib (BTZ) was evaluated in a Phase 1 study in multiple myeloma patients [6,7]. The serum levels of tabalumab, M-protein and FLCs were connected in PK/PD models by Non Linear Mixed Effect Modeling [8]. The predicted decrease in serum levels of M-protein and FLCs were used to predict PFS using a previously published model [2].
Results: The PK of tabalumab was described by a 2-compartment model with mixed clearance. The PD model previously developed for M-protein [1] proved adequate to describe both M-protein and FLCs serum levels, with parameter estimates for FLCs reflective of their faster turn over. The models predicted a different dose-response relationship of tabalumab for the decrease in serum M-protein or FLCs at week 8 of treatment. However, the decrease in the serum levels of both M-prot and FLCs were predictive of preliminary PFS results in the patient population.
Conclusions: The time course of serum levels of M-protein and FLCs were successfully described by the PK/PD models developed in this study. The models characterized a different dose-response relationship for the activity of tabalumab on the 2 biomarkers. Both M-protein and FLCs responses were, however, predictive of PFS in the patient population.
References:
[1] Jonsson et al. PAGE 19 (2010) Abstr 1705 [www.page-meeting.org/?abstract=1705]
[2] Bruno et al. Blood (ASH Annual Meeting Abstracts), 118 (21): 1881, 2011
[3] Dispenzieri et al., 2008, Blood, 111(10):4908-4915
[4] Dispenzieri et al., 2009, Leukemia, 23: 215-224
[5] Raje et al., 2011, ASCO Meeting
[6] Raje et al., 2012, ASH Mee
[7] Chanu et al., 2012, AAPS NBC Meeting
