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Marizomib ( MRZ) is an irreversible, pan-subunit proteasome inhibitor ( PI) in clinical development for relapsed/refractory multiple myeloma ( RRMM) and glioma. This study analysed MRZ, pomalidomide ( POM) and low-dose dexamethasone (Lo- DEX) [ PMD] in RRMM to evaluate safety and determine the maximum tolerated dose ( MTD) and/or recommended Phase 2 dose ( RP2D). Intravenous MRZ (0·3-0·5 mg/m2) was administered over 2 h on days 1, 4, 8, 11; POM (3-4 mg) on days 1-21; and Lo- DEX (5 or 10 mg) on days 1, 2, 4, 5, 8, 9, 11, 12, 15, 16, 22 and 23 of every 28-day cycle. Thirty-eight patients were enrolled that had received a median of 4 (range 1-10) prior lines of therapy; all patients received prior lenalidomide and bortezomib. No dose-limiting toxicities ( DLTs) were observed and 0·5 mg/m2 MRZ was determined to be the RP2D. The most common treatment-related ≥Grade 3 adverse events were: neutropenia (11/38 patients: 29%), pneumonia (4/38 patients 11%), anaemia (4/38 patients; 11%) and thrombocytopenia (4/38 patients; 11%). The overall response rate and clinical benefit rate was 53% (19/36) and 64% (23/36), respectively. In conclusion, PMD was well tolerated and demonstrated promising activity in heavily pre-treated, high-risk RRMM patients. [ABSTRACT FROM AUTHOR]

Proteasome inhibitors ( PIs) are highly active in multiple myeloma ( MM) but resistance is commonly observed. All clinical stage PIs effectively inhibit chymotrypsin-like ( CT-L) activity; one possible mechanism of resistance is compensatory hyperactivation of caspase-like (C-L) and trypsin-like (T-L) subunits, in response to CT-L blockade. Marizomib ( MRZ), an irreversible PI that potently inhibits all three 20S proteasome subunits with a specificity distinct from other PIs, is currently in development for treatment of MM and malignant glioma. The pan-proteasome pharmacodynamic activity in packed whole blood and peripheral blood mononuclear cells was measured in two studies in patients with advanced solid tumours and haematological malignancies. Functional inhibition of all proteasome subunits was achieved with once- or twice-weekly MRZ dosing; 100% inhibition of CT-L was frequently achieved within one cycle at therapeutic doses. Concomitantly, C-L and T-L activities were either unaffected or increased, suggesting compensatory hyperactivation of these subunits. Importantly, this response was overcome by continued administration of MRZ, with robust inhibition of T-L and C-L (up to 80% and 50%, respectively) by the end of Cycle 2 and maintained thereafter. This enhanced proteasome inhibition was independent of tumour type and may underlie the clinical activity of MRZ in patients resistant to other PIs. [ABSTRACT FROM AUTHOR]

The proteasome inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that the novel proteasome inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action and effects on proteasomal activities, and that it can overcome bortezomib resistance. Pomalidomide, like lenalidomide, has potent immunomodulatory activity and has been approved by the US Food and Drug Administration for the treatment of RRMM. Here, we demonstrate that combining low concentrations of marizomib with pomalidomide induces synergistic anti-MM activity. Marizomib plus pomalidomide-induced apoptosis is associated with: (i) activation of caspase-8, caspase-9, caspase-3 and PARP cleavage, (ii) downregulation of cereblon (CRBN), IRF4, MYC and MCL1, and (iii) suppression of chymotrypsin-like, caspaselike, and trypsin-like proteasome activities. CRBN-siRNA attenuates marizomib plus pomalidomide-induced MM cells death. Furthermore, marizomib plus pomalidomide inhibits the migration of MM cells and tumour-associated angiogenesis, as well as overcomes cytoprotective effects of bone marrow microenvironment. In human MM xenograft model studies, the combination of marizomib and pomalidomide is well tolerated, inhibits tumour growth and prolongs survival. These preclinical studies provide the rationale for on-going clinical trials of combined marizomib and pomalidomide to improve outcome in patients with RRMM. [ABSTRACT FROM AUTHOR]