High-dose carfilzomib achieves superior anti-tumor activity over lowdose 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

Zhou, X.; Besse, A.; Peter, J.; Steinhardt, M.J.; Vogt, C.; Nerreter, S.; ... ; Rasche, L. (2023)

Article / Letter to editor

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.

• All authors: Zhou, X.; Besse, A.; Peter, J.; Steinhardt, M.J.; Vogt, C.; Nerreter, S.; Teufel, E.; Stanojkovska, E.; Xiao, X.; Hornburger, H.; Haertle, L.; Lopez, M.M.; Munawar, U.; Riedel, A.; Han, S.; Maurits, E.; Overkleeft, H.S.; Florea, B.I.; Einsele, H.; Kortüm, K.M.; Driessen, C.; Besse, L.; Rasche, L.
• Date: 2023-02-02
• Journal: Haematologica
• Volume: 108
• Issue: 6
• DOI: doi:10.3324/haematol.2022.282225
• Link: https://haematologica.org/article/view/haematol.2022.282225