Carfilzomib: A novel treatment in relapsed and refractory multiple myeloma

OncoTargets and Therapy

Volumn 5, Issue , 2012, Pages 237-244

  Fostier, Karel ^a   De Becker, Ann ^a   Schots, Rik ^a  

^a UNIVERSITY HOSPITAL BRUSSELS   (Belgium)

Author keywords

Carfilzomib; Myeloma; Proteasome inhibitor; Refractory; Relapsed

Indexed keywords

BORTEZOMIB; CARFILZOMIB; DELANZOMIB; DEXAMETHASONE; IXAZOMIB CITRATE; LENALIDOMIDE; OPROZOMIB; PROTEASOME; SALINOSPORAMIDE A;

ADVANCED CANCER; ADVERSE OUTCOME; ANEMIA; ARTHRALGIA; BACTEREMIA; CANCER RECURRENCE; CANCER RESISTANCE; CONGESTIVE HEART FAILURE; CYTOGENETICS; CYTOPENIA; DIARRHEA; DOSAGE SCHEDULE COMPARISON; DOSE RESPONSE; DRUG APPROVAL; DRUG BLOOD LEVEL; DRUG DOSE COMPARISON; DRUG DOSE ESCALATION; DRUG DOSE REDUCTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG MECHANISM; DRUG PROTEIN BINDING; DRUG SAFETY; DRUG SELECTIVITY; DRUG STRUCTURE; DRUG TARGETING; DRUG TOLERABILITY; DRUG USE; DRUG WITHDRAWAL; ENZYME SPECIFICITY; FATIGUE; FEVER; HUMAN; HYPERTENSION; KIDNEY FAILURE; KIDNEY FUNCTION; LONG TERM CARE; LOW DRUG DOSE; LYMPHOCYTOPENIA; MAXIMUM TOLERATED DOSE; MULTIPLE CYCLE TREATMENT; MULTIPLE MYELOMA; MYELOMA; NAUSEA; NEUROPATHY; NEUTROPENIA; OPTIMAL DRUG DOSE; PERIPHERAL NEUROPATHY; PNEUMONIA; RECURRENT CANCER; REVIEW; SEPSIS; STRUCTURE ACTIVITY RELATION; THROMBOCYTOPENIA; TREATMENT DURATION; TREATMENT RESPONSE; UNSPECIFIED SIDE EFFECT; VEIN OCCLUSION;

EID: 84873893188     PISSN: 11786930     EISSN: None     Source Type: Journal    
DOI: 10.2147/OTT.S28911     Document Type: Review

References (39)

1. Kumar SK, Rajkumar S V, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-2520.
2. Rock KL, Gramm C, Rothstein L, et al. Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell. 1994;78(5):761-771.
3. Adams J. The proteasome: a suitable antineoplastic target. Nat Rev Cancer. 2004;4(5):349-360.
4. Koepp DM, Harper J W, Elledge SJ. How the cyclin became a cyclin: regulated proteolysis in the cell cycle. Cell. 1999;97(4):431-434.
5. Pandit B, Gartel AL. Proteasome inhibitors induce p53-independent apoptosis in human cancer cells. Am J Pathol. 2011;178(1): 355-360.
6. Obeng EA, Carlson LM, Gutman DM, et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood. 2006;107(12):4907-4916.
7. Piva R, Ruggeri B, Williams M, et al. CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood. 2008;111(5):2765-2775.
8. Zhou HJ, Aujay MA, Bennett MK, et al. Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem. 2009;52(9):3028-3038.
9. Potts BC, Albitar MX, Anderson KC, et al. Marizomib, a proteasome inhibitor for all seasons: preclinical profile and a framework for clinical trials. Curr Cancer Drug Targets. 2011;11(3):254-284.
10. Kuhn DJ, Chen Q, Voorhees PM, et al. Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007;110(9):3281-3290.
11. Bianchi G, Oliva L, Cascio P, et al. The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood. 2009;113(13):3040-3049.
12. Oerlemans R, Franke NE, Assaraf YG, et al. Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood. 2008;112(6): 2489-2499.
13. Ruckrich T, Kraus M, Gogel J, et al. Characterization of the ubiquitin-proteasome system in bortezomib-adapted cells. Leukemia. 2009;23(6):1098-1105.
14. Suzuki E, Demo S, Arastu-Kapur S, et al. Bortezomib-resistant cell lines have increased proteasome levels but remain sensitive to Carfilzomib. ASH Annual Meeting Abstracts. 2009;114(22): Abstr: 2852.
15. O'Connor OA, Stewart AK, Vallone M, et al. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor Carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009;15(22):7085-7091.
16. Alsina M, Trudel S, Vallone M, et al. Phase 1 single agent antitumor activity of twice weekly consecutive day dosing of the proteasome inhibitor Carfilzomib (PR-171) in hematologic malignancies. ASH Annual Meeting Abstracts. 2007;110(11): Abstr: 411.
17. Jagannath S, Vij R, Stewart K, et al. Final results of PX-171-003-A0, part 1 of an open-label, single-arm, phase II study of Carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). J Clin Oncol. 2009;27(Suppl 15s):Abstr 8504.
18. diCapua Siegel DS, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 (Ph 2) study of Carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). ASH Annual Meeting Abstracts. 2010;116(21): Abstr: 985.
19. Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX-171-004) study of single-agent Carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood. 2012.
20. Vij R, Siegel DS, Kaufman JL, et al. Results of an ongoing open-label, phase II study of Carfilzomib in patients with relapsed and/or refractory multiple myeloma (R/R MM). J Clin Oncol. 2010; 28(Suppl 15s): Abstr 8000.
21. Richardson PG, Sonneveld P, Schuster M W, et al. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005;352(24):2487-2498.
22. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J Clin Oncol. 2007;25(25):3892-3901.
23. Wang L, Siegel DS, Jakubowiak AJ, et al. The speed of response to single-agent Carfilzomib in patients with relapsed and/or refractory multiple myeloma: an exploratory analysis of results from 2 multicenter phase 2 clinical trials. ASH Annual Meeting Abstracts. 2011;118(21): Abstr: 3969.
24. Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007; 67(13):6383-6391.
25. Squiffet P, Michiels S, Siegel DS, et al. Multivariate modelling reveals evidence of a dose-response relationship in phase 2 studies of single-agent Carfilzomib. ASH Annual Meeting Abstracts. 2011; 118(21): Abstr: 1877.
26. Papadopoulos K P, Lee P, Singhal S, et al. A Phase 1b/2 study of prolonged infusion carfilzomib in patients with relapsed and/or refractory (R/R) multiple myeloma: updated efficacy and tolerability from the completed 20/56 mg/m2 expansion cohort of PX-171-007. ASH Annual Meeting Abstracts. 2011;118(21): Abstr: 2930.
27. Jakubowiak AJ, Siegel DS, Singhal S, et al. Unfavorable cytogenetic characteristics do not adversely impact response rates in patients with relapsed and/or refractory multiple myeloma treated with single-agent Carfilzomib on the 003 (A1) study. ASH Annual Meeting Abstracts. 2011;118(21): Abstr: 1875.
28. Badros AZ, Vij R, Martin T, et al. Phase II study of Carfilzomib in patients with relapsed/refractory multiple myeloma and renal insufficiency. J Clin Oncol. 2010;28(Suppl 15s): Abstr: 8128.
29. Singhal S, Siegel DS, Martin T, et al. Integrated safety from phase 2 studies of monotherapy Carfilzomib in patients with relapsed and refractory multiple myeloma (MM): an updated analysis. ASH Annual Meeting Abstracts. 2011;118(21): Abstr: 1876.
30. Jagannath S, Vij R, Kaufman JL, et al. Long-term treatment and tolerability of the novel proteasome inhibitor Carfilzomib (CFZ) in patients with relapsed and/or refractory multiple myeloma (R/R MM). ASH Annual Meeting Abstracts. 2010;116(21): Abstr: 1953.
31. Arastu-Kapur S, Anderl JL, Kraus M, et al. Nonproteasomal targets of the proteasome inhibitors bortezomib and Carfilzomib: a link to clinical adverse events. Clin Cancer Res. 2011;17(9):2734-2743.
32. Jagannath SJ, Vij RV, Martin TM, Badros AB, Patel P P, McCulloch LM. Carfilzomib is associated with a low rate of typically mild to moderate, non-dose limiting treatment-emergent peripheral neuropathy. European Hematological Association Annual Meeting 2012; Amsterdam. Abstr: 0857.
33. Bensinger W, Wang M, Orlowski RZ, et al. Dose-escalation study of carfilzomib (CFZ) plus lenalidomide (LEN) plus low-dose dexamethasone (Dex) (CRd) in relapsed/refractory multiple myeloma (R/R MM). J Clin Oncol. 2010;28(15):8029.
34. Moreau P, Palumbo A, Stewart AK, et al. A randomized, multicenter, phase (Ph) III study comparing carfilzomib (CFZ), lenalidomide (LEN), and dexamethasone (Dex) to LEN and Dex in patients (Pts) with relapsed multiple myeloma (MM). J Clin Oncol. 2011; 29(15):TPS225.
35. Kisselev AF, van der Linden WA, Overkleeft HS. Proteasome inhibitors: an expanding army attacking a unique target. Chem Biol. 2012;19(1): 99-115.
36. Suzuki E, Demo S, Deu E, et al. Molecular mechanisms of bortezomib-resistant adenocarcinoma cells. PLoS One. 2011;6(12):e27996.
37. Lu S, Yang J, Song X, et al. Point mutation of the proteasome beta5 subunit gene is an important mechanism of bortezomib resistance in bortezomib-selected variants of Jurkat T cell lymphoblastic lymphoma/ leukemia line. J Pharmacol Exp Ther. 2008;326(2):423-431.
38. Lu S, Yang J, Chen Z, et al. Different mutants of PSMB5 confer varying bortezomib resistance in T lymphoblastic lymphoma/leukemia cells derived from the Jurkat cell line. Exp Hematol. 2009;37(7):831-837.
39. Ri M, Iida S, Nakashima T, et al. Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress. Leukemia. 2010;24(8):1506-1512.