marizomib and pomalidomide

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Drug Approval; Drug Discovery; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lactones; Molecular Targeted Therapy; Multiple Myeloma; Oligopeptides; Pyrroles; Thalidomide; Vorinostat

The activity observed with proteasome inhibitors and immunomodulatory drugs (IMIDs) in multiple myeloma (MM) has prompted the development of second- and third-generation agents with similar, but not exactly the same, mechanisms of action as their predecessors. This review summarizes the mechanism of action and the available data on the clinical activity of novel proteasome inhibitors (carfilzomib, oprozomib, ixazomib, and marizomib) and novel IMIDs (pomalidomide), stressing the similarities and differences with bortezomib, and with thalidomide and lenalidomide, respectively. In summary, these novel agents have shown clinical activity as single agents and in combination with dexamethasone, with similar or even higher efficacy than their parental drugs; moreover, they may even overcome resistance, indicating that there are some differences in their mechanisms of action and resistance. These data indicate that both the inhibition of the proteasome and the modulation of the immune system are good strategies to target MM tumor cells and this, along with the absence of complete cross-resistance observed among these drugs, open new avenues to optimize their use through the most appropriate sequencing and combinations.

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Immunologic Factors; Lactones; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Pyrroles; Recurrence; Thalidomide; Treatment Outcome

Marizomib (MRZ) is a novel, irreversible proteasome inhibitor in clinical development for the treatment of relapsed or relapsed and refractory multiple myeloma (RRMM). MRZ inhibits the 3 proteolytic activities of the 20S proteasome with specificity distinct from bortezomib and carfilzomib. Study NPI-0052-101 Part 1 enrolled relapsed or RRMM patients into an open-label, dose-escalation design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of MRZ administered intravenously on 2 different schedules: schedule A (0.025-0.7 mg/m(2) once weekly on days 1, 8, and 15 of 4-week cycles) and schedule B (0.15-0.6 mg/m(2) twice weekly on days 1, 4, 8, and 11 of 3-week cycles; concomitant dexamethasone was allowed with schedule B). Patients had received an average of 4.9 and 7.3 prior treatment regimens (schedules A and B, respectively). MRZ schedule A was administered to 32 patients, and the RP2D was established as 0.7 mg/m(2) infused over 10 minutes. Schedule B was administered to 36 patients, and the RP2D was determined to be 0.5 mg/m(2) infused over 2 hours. The most common (>20% of patients) related adverse events were fatigue, headache, nausea, diarrhea, dizziness, and vomiting. Six patients achieved clinical benefit responses (defined as minimal response or better), including 5 partial responses (1 patient on schedule A and 4 on schedule B; 3 of these 4 patients received concomitant dexamethasone). MRZ was generally well tolerated, and results suggest activity in previously treated RRMM patients. Combination studies using pomalidomide and dexamethasone are now underway. The trial was registered at www.clinicaltrials.gov as #NCT00461045.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Female; Humans; Lactones; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Pyrroles; Recurrence; Thalidomide

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, caspase-like, 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.

Topics: Adaptor Proteins, Signal Transducing; Angiogenesis Inhibitors; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Caspases; Cell Line, Tumor; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Humans; Lactones; Mice, SCID; Multiple Myeloma; Peptide Hydrolases; Poly(ADP-ribose) Polymerases; Proteasome Inhibitors; Pyrroles; RNA, Small Interfering; Thalidomide; Transplantation, Heterologous; Ubiquitin-Protein Ligases