High-dose carfilzomib achieves superior anti-tumor activity over low-dose and recaptures response in relapsed/refractory multiple myeloma resistant to lowdose carfilzomib by co-inhibiting the β2 and β1 subunits of the proteasome complex.

Publication

High-dose carfilzomib achieves superior anti-tumor activity over low-dose and recaptures response in relapsed/refractory multiple myeloma resistant to lowdose carfilzomib by co-inhibiting the β2 and β1 subunits of the proteasome complex.

Journal Paper/Review - Jun 1, 2023

Zhou Xiang, Besse Andrej, Peter Jessica, Steinhardt Maximilian Johannes, Vogt Cornelia, Nerreter Silvia, Teufel Eva, Stanojkovska Emilia, Xiao Xianghui, Hornburger Hannah, Haertle Larissa, Mendez Lopez Max, Munawar Umair, Riedel Angela, Han Seungbin, Maurits Elmer, Overkleeft Hermann S, Florea Bogdan I, Einsele Hermann, Kortüm K Martin, Driessen Christoph, Besse Lenka, Rasche Leo

Citation

Zhou X, Besse A, Peter J, Steinhardt M, Vogt C, Nerreter S, Teufel E, Stanojkovska E, Xiao X, Hornburger H, Haertle L, Mendez Lopez M, Munawar U, Riedel A, Han S, Maurits E, Overkleeft H, Florea B, Einsele H, Kortüm K, Driessen C, Besse L, Rasche L. High-dose carfilzomib achieves superior anti-tumor activity over low-dose and recaptures response in relapsed/refractory multiple myeloma resistant to lowdose carfilzomib by co-inhibiting the β2 and β1 subunits of the proteasome complex. Haematologica 2023; 108:1628-1639.

Type

Journal Paper/Review (English)

Journal

Haematologica 2023; 108

Publication Date

Jun 1, 2023

Issn Electronic

1592-8721

Pages

1628-1639

Brief description/objective

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. Coinhibition 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 carfilzomib 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 nine (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 coinhibition of β2 and β1 proteasome subunits and, consequently, high-dose carfilzomib achieves a superior anti-MM effect than low-dose carfilzomib and recaptures the response in RRMM 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.