Table 3.
Selected inhibitors of the 20S proteasome
| Name and manufacturer | Description | Administration | Regulatory status | Response in representative trials (IMWG criteria)35 | Common adverse effects |
|---|---|---|---|---|---|
| Bortezomib (Millennium) | Boronate Reversible action Targets β5 > β1 >β2 |
Intravenous or subcutaneous | FDA-approved for frontline therapy for RRMM, and MCL after one prior line of therapy | Single-agent bortezomib versus high-dose dexamethasone in RRMM: ORR 38% versus 18% 1-year OS 80% versus 66%16 Bortezomib, lenalidomide and dexamethasone in NDMM: ORR 100% 21-month OS 97%143 |
Peripheral neuropathy Nausea Vomiting Diarrhoea Constipation Cytopenias Infection |
| Carfilzomib (ONYX) | Epoxyketone Irreversible action Targets β5 >β2/β1 |
Intravenous | FDA-approved for RRMM | RRMM previously treated with an immunomodulatory drug proteasome inhibitor: ORR 23%36 |
Shortness of breath Heart failure Reduced rates of peripheral neuropathy compared with bortezomib |
| Ixazomib (Millennium) | Boronate Reversible action Targets β5 > β1 |
Oral | FDA-approved for RRMM Early-phase clinical trials in AML, follicular lymphoma and peripheral T-cell lymphoma |
IRD versus RD in RRMM: PFS 20.6 versus 14.7 months; CR 11.7% versus 6% IRD in NDMM: 93% ≥PR; 67% ≥VGPR; 24% ≥CR; 14% ≥sCR Ixazomib plus lenalidomide as maintenance post ASCT: safety profile established, other responses not yet reported Ixazomib alone in RRMM with no or little exposure to bortezomib: 34% ≥PR; 6% sCR149 |
Skin rash Peripheral oedema Peripheral neuropathy Fatigue Cytopenia Infection |
| ONX 0912 (oprozomib; ONYX) | Epoxyketone Irreversible action Targets β5 |
Oral | Early-phase clinical trials in haematological malignancies and solid tumours | Single-agent oprozomib in RRMM and WM: 25% CBR and80% CBR (in one dose), respectively150 | Nausea Vomiting Diarrhoea |
| NPI 0052 (marizomib; Nereus) | β-lactone Irreversible action Targets β5 >β2 >β1 |
Intravenous | Early-phase clinical trials in RRMM, NSCLC, pancreatic cancer, melanoma, lymphoma and advanced-stage solid tumours | Single-agent marizomib in RRMM: ORR 20% (by EBMT criteria)151 |
Not reported |
|
CEP-18770 (delanzomib;) |
Boronate Reversible action Targets β5 >β1 |
Intravenous Oral |
Early-phase clinical trials in RRMM (terminated), solid tumours and lymphoma | Not reported | Not reported |
AML, acute myeloid leukaemia; ASCT, autologous stem-cell transplantation; CBR, clinical benefit rate; CR, complete response; EBMT, European Group for Blood and Marrow Transplant; IMWG, International Myeloma Working Group; IRD, ixazomib, lenalidomide, dexamethasone; NDMM, newly diagnosed multiple myeloma; NSCLC, non-small cell lung cancer; ORR, overall response rate; OS, overall survival; PR, partial response; RD, lenalidomide, dexamethasone; RRMM, relapsed and/or refractory multiple myeloma; sCR, stringent complete response; VGPR, very good partial response; WM, Waldenström’s macroglobulinaemia.