Haematologica. 2023 Feb 2. doi: 10.3324/haematol.2022.282225. Online ahead of print.


The optimal carfilzomib dosing is a matter of debate. We analyzed the inhibition profiles of proteolytic proteasome subunits β5, β2 and β1 after low-dose (20/27 mg/m2) versus high-dose (≥36 mg/m2) carfilzomib in 103 pairs of peripheral blood mononuclear cells from patients with relapsed/refractory (RR) multiple myeloma (MM). β5 activity was inhibited (median inhibition >50%) in vivo by 20 mg/m2, whereas β2 and β1 were co-inhibited only by 36 and 56 mg/m2, respectively. Co-inhibition of β2 (P=0.0001) and β1 activity (P=0.0005) differed significantly between high-dose and low-dose carfilzomib. Subsequently, high-dose carfilzomib showed significantly more effective proteasome inhibition than low-dose drug in vivo (P=0.0003). We investigated the clinical data of 114 patients treated with carfilzomib combinations. High-dose carfilzomib demonstrated a higher overall response rate (P=0.03) and longer progression-free survival (PFS) (P=0.007) than low-dose carfilzomib. Therefore, we escalated the carfilzomib dose to ≥ 36 mg/m2 in 16 patients who progressed during low-dose carfilzomib-containing therapies. High-dose carfilzomib recaptured response (≥ partial remission) in 9 (56%) patients with a median PFS of 4.4 months. Altogether, we provide the first in vivo evidence in RRMM patients 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 RRMM being resistant to low-dose carfilzomib. The optimal carfilzomib dose should be ≥ 36 mg/m2 to reach a sufficient anti-tumor activity, while the balance between efficacy and tolerability should be considered in each patient.

PMID:36727403 | DOI:10.3324/haematol.2022.282225