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

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.Bio-organic Synthesi

Salvage therapy with "Dara-KDT-P(A)CE" in heavily pretreated, high-risk, proliferative, relapsed/refractory multiple myeloma

The multi-agent therapy “VDT-PACE” represents an established regimen in relapsed/refractory multiple myeloma (RRMM). Here, we report on our experience with a “modified VDT-PACE” incorporating new generation anti-MM agents daratumumab and carfilzomib (“Dara-KDT-P(A)CE”). We retrospectively analyzed 38 patients with RRMM treated with “Dara-KDT-P(A)CE”. The median age was 62 (range 45–82) years, and the patients were heavily pretreated with a median of 5 (range 2–12) prior lines of therapy. Twenty-one (55%) patients suffered from penta-refractory MM. High-risk cytogenetics was present in 31 (81%) patients. The patients received a median of 2 (range 1–10) cycles of this therapy, and the overall response rate (ORR) was 70%. Patients with penta-refractory MM and high-risk cytogenetics showed similar ORR of 65% and 79%, respectively. The median progression-free survival (PFS) and overall survival were 4.1 (95% CI 2.7–5.4) and 8.4 (95% CI 6.7–10.0) months, respectively. Patients with lactate dehydrogenase >250 IU/L showed significantly shorter PFS in comparison with others patients (p = 0.006). We used this regimen as bridging therapy prior to chimeric antigen receptor T-cell infusion in four patients. In conclusion, “Dara-KDT-P(A)CE” is an effective salvage therapy for patients with heavily pretreated, multi-refractory, high-risk RRMM lacking alternative options

12. Februar 1917

Stadtarchiv Solingen, Bergische Arbeiterstimme 12. Februar 1917 Die Geschäftsleitung der „Freien Presse“ in Elberfeld setzt ein neue Redaktion ein. Damit wird aus dem Organ der Minderheit eine Zeitung der Mehrheitssozialdemokratie              Aus der Partei.              Die „Freie Presse“.    An der Spitze der „Freien Presse“ in Elberfeld lesen wir folgendes:                       An unsere Leser!    Der Kriegszustand und seine Begleiterscheinungen bringen, wie für fast alle Staatsbür..