A new study suggests there is an “optimal” dose of carfilzomib for patients with relapsed or refractory multiple myeloma (MM).
Xiang Zhou, MD, of the University Hospital of Würzburg in Germany; Andrej Besse, PhD, of Cantonal Hospital St. Gallen in Switzerland; and colleagues conducted the research because “optimal carfilzomib dosing is a matter of debate.”
They used 103 pairs of peripheral blood mononuclear cells from patients with relapsed or refractory MM to analyze the inhibition profiles of proteolytic proteasome subunits β5, β2, and β1 in response to carfilzomib. They compared low-dose carfilzomib (20 mg/m2 or 27 mg/m2) with high-dose carfilzomib (≥36 mg/m2) in the samples.
Carfilzomib 20 mg/m2 inhibited β5 activity in vivo (median inhibition, >50%). However, β2 and β1 were co-inhibited only by doses of 36 mg/m2 and 56 mg/m2, respectively. Co-inhibition of β2 (P=.0001) and β1 activity (P=.0005) differed significantly between high and low doses. Furthermore, high-dose carfilzomib showed “significantly more effective proteasome inhibition” in vivo than low-dose carfilzomib (P=.0003).
The researchers also evaluated the clinical data from 114 patients who received carfilzomib combinations. Patients who received high-dose carfilzomib had a significantly higher overall response rate (P=.03) and longer progression-free survival (PFS) (P=.007) than those who received low-dose carfilzomib. Due to this, the study’s investigators escalated the carfilzomib dose to ≥36 mg/m2 in 16 patients who progressed while receiving low-dose carfilzomib-containing therapies. High-dose carfilzomib “recaptured response” in some patients who progressed, the study’s authors wrote, noting that nine (56%) patients achieved at least a partial remission. The median PFS was 4.4 months.
“Altogether, we provide the first in vivo evidence in [patients with relapsed or refractory MM] that the molecular activity of high-dose carfilzomib differs from that of low-dose carfilzomib by co-inhibition of β2 and β1 proteasome subunits and, consequently, high-dose carfilzomib achieves a superior anti-MM effect than low-dose and recaptures response in [relapsed or refractory] MM being resistant to low-dose carfilzomib,” the study’s authors wrote.
Based on the study’s results, the researchers concluded the “optimal” carfilzomib dose should be ≥36 mg/m2 to “reach a sufficient antitumor activity. They emphasized that the “balance between efficacy and tolerability should be considered in each patient.”
Zhou X, Besse A, Peter J, et al. High-dose carfilzomib achieves superior anti-tumor activity over low dose and recaptures response in relapsed/refractory multiple myeloma resistant to low-dose carfilzomib by co-inhibiting the β2 and β1 subunits of the proteasome complex. Haematologica. 2023. doi:10.3324/haematol.2022.282225