Population Pharmacokinetics for Belantamab Mafodotin Monotherapy and Combination Therapies in Patients with Relapsed/Refractory Multiple Myeloma.

Background and objective: Belantamab mafodotin is an antibody-drug conjugate (ADC) comprising a monoclonal antibody targeting B-cell maturation antigen (BCMA) conjugated to the microtubule inhibitor monomethyl auristatin F via a protease-resistant maleimidocaproyl linker (cysteine maleimidocaproyl monomethyl auristatin F [cys-mcMMAF]). Belantamab mafodotin monotherapy population pharmacokinetics (PopPK) were previously described in relapsed/refractory multiple myeloma (RRMM). This analysis aimed to further characterize the PopPK of belantamab mafodotin ADC and cys-mcMMAF when administered intravenously in patients with RRMM using data from monotherapy and combination therapy studies.

Methods: Data from belantamab mafodotin monotherapy trials (DREAMM-2 [NCT03525678], DREAMM-3 [NCT04162210], DREAMM-12 [NCT04398745], DREAMM-14 [NCT05064358]) and combination trials with lenalidomide/dexamethasone (DREAMM-6 [NCT03544281]) or bortezomib/dexamethasone (DREAMM-6, DREAMM-7 [NCT04246047]) were used to develop PopPK models using non-linear mixed-effect modeling. The models described ADC pharmacokinetics using a linear, two-compartment model with decreasing clearance (CL) over time described by a sigmoidal time function, and cys-mcMMAF pharmacokinetics using a linear two-compartment model with cys-mcMMAF input rate governed by proteolytic ADC degradation that was modulated by a drug-to-antibody ratio that declined exponentially after each dose. Models were externally validated using DREAMM-8 (NCT04484623) study data (belantamab mafodotin plus pomalidomide/dexamethasone).

Results: The analyses included 977 patients, with 8880 measurable ADC and 6354 measurable cys-mcMMAF concentrations. Final ADC model covariates included soluble BCMA (sBCMA), albumin, serum immunoglobulin G, body weight, and body mass index (BMI) all at baseline as well as race and combination therapy. The final cys-mcMMAF model included covariates of baseline sBCMA, serum immunoglobulin G, albumin, body weight, BMI, and race. Typical ADC parameter estimates were 0.926 L/day for initial CL, 10.8 L for steady-state volume of distribution, and 13.0 days for initial elimination half-life. Following monotherapy, CL was reduced by 33.2% to 0.619 L/day over time, resulting in an elimination half-life of 16.8 days. Following combination treatment, CL was reduced by 44.0% to 0.518 L/day, resulting in an elimination half-life of 19.1 days. Cys-mcMMAF had typical values of 642 L/day for CL and 12.3 L for the central volume of distribution. The models adequately described ADC/cys-mcMMAF pharmacokinetics as confirmed during external validation. Alternate models with β2 microglobulin in place of baseline sBCMA also described the pharmacokinetics well. Simulated cycle 1 ADC exposures were most affected by disease-related characteristics: greater disease burden resulted in lower exposure. Predicted cycle 1 ADC and cys-mcMMAF exposures were not meaningfully different between combinations and monotherapy. Mild-to-severe renal impairment, mild-to-moderate hepatic impairment according to National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification, age, ethnicity, region, prior treatments, and prior anti-CD38 therapy did not affect ADC or cys-mcMMAF pharmacokinetics or exposures.

Conclusions: The updated PopPK models adequately described ADC and cys-mcMMAF pharmacokinetics. Mild-to-severe renal impairment, mild-to-moderate hepatic impairment (NCI-ODWG), age, ethnicity, region, prior treatments, and prior anti-CD38 therapy did not significantly impact ADC or cys-mcMMAF pharmacokinetics, and combinations showed no meaningful difference in cycle 1 exposure compared with monotherapy.