Targeted Treatments for Multiple Myeloma: Specific Role of Carfilzomib

Overview

Journal Pharmgenomics Pers Med

Publisher Dove Medical Press

Date 2015 Feb 19

PMID 25691814

Citations 11

Authors

Dhivya Sugumar

Jesse Keller

Ravi Vij

Affiliations

Soon will be listed here.

Abstract

Carfilzomib is a selective, irreversible proteasome inhibitor, initially approved in the US in 2012 as single-agent therapy for relapsed and refractory multiple myeloma. Numerous Phase II studies have evaluated carfilzomib in the relapsed and refractory as well as the newly diagnosed setting, and Phase III studies are entering their final analysis. Data continue to grow to support its use as both single-agent therapy and in combination with immunomodulatory and other novel agents. This review discusses the role of carfilzomib in the treatment of multiple myeloma. Its mechanism of action, pharmacokinetics, and role in clinical management will be reviewed.

Citing Articles

Carfilzomib-Induced Tumor Lysis Syndrome and Biventricular Heart Failure in a Patient With Multiple Myeloma.

Azad F, Moyer R, Miranda C, Gravina M Cureus. 2023; 15(1):e33538.

PMID: 36779143 PMC: 9907735. DOI: 10.7759/cureus.33538.

Syrbactin proteasome inhibitor TIR-199 overcomes bortezomib chemoresistance and inhibits multiple myeloma tumor growth in vivo.

Pierce M, Robinson R, Ibarra-Rivera T, Pirrung M, Dolloff N, Bachmann A Leuk Res. 2019; 88:106271.

PMID: 31778912 PMC: 6937391. DOI: 10.1016/j.leukres.2019.106271.

A Practical Review of Proteasome Pharmacology.

Thibaudeau T, Smith D Pharmacol Rev. 2019; 71(2):170-197.

PMID: 30867233 PMC: 6423620. DOI: 10.1124/pr.117.015370.

Targeting the Proteasome in Refractory Pediatric Leukemia Cells: Characterization of Effective Cytotoxicity of Carfilzomib.

Swift L, Jayanthan A, Ruan Y, Anderson R, Boklan J, Trippett T Target Oncol. 2018; 13(6):779-793.

PMID: 30446871 DOI: 10.1007/s11523-018-0603-0.

Cardiovascular adverse events in modern myeloma therapy - Incidence and risks. A review from the European Myeloma Network (EMN) and Italian Society of Arterial Hypertension (SIIA).

Bringhen S, Milan A, Ferri C, Wasch R, Gay F, Larocca A Haematologica. 2018; 103(9):1422-1432.

PMID: 30049825 PMC: 6119131. DOI: 10.3324/haematol.2018.191288.

References

Badros A, Vij R, Martin T, Zonder J, Kunkel L, Wang Z . Carfilzomib in multiple myeloma patients with renal impairment: pharmacokinetics and safety. Leukemia. 2013; 27(8):1707-14. PMC: 3740399. DOI: 10.1038/leu.2013.29. View

Anderson K, Alsina M, Bensinger W, Biermann J, Cohen A, Devine S . Multiple myeloma, version 1.2013. J Natl Compr Canc Netw. 2013; 11(1):11-7. DOI: 10.6004/jnccn.2013.0004. View

Siegel D, Martin T, Wang M, Vij R, Jakubowiak A, Lonial S . A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012; 120(14):2817-25. PMC: 4123387. DOI: 10.1182/blood-2012-05-425934. View

Sawyer J . The prognostic significance of cytogenetics and molecular profiling in multiple myeloma. Cancer Genet. 2011; 204(1):3-12. DOI: 10.1016/j.cancergencyto.2010.11.002. View

Blade J, Fernandez-Llama P, Bosch F, Montoliu J, Lens X, Montoto S . Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution. Arch Intern Med. 1998; 158(17):1889-93. DOI: 10.1001/archinte.158.17.1889. View

Munshi N, Anderson K, Bergsagel P, Shaughnessy J, Palumbo A, Durie B . Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011; 117(18):4696-700. PMC: 3293763. DOI: 10.1182/blood-2010-10-300970. View

Siegel D, Martin T, Nooka A, Harvey R, Vij R, Niesvizky R . Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase II clinical studies. Haematologica. 2013; 98(11):1753-61. PMC: 3815177. DOI: 10.3324/haematol.2013.089334. View

Kuhn D, Chen Q, Voorhees P, Strader J, Shenk K, Sun C . Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood. 2007; 110(9):3281-90. PMC: 2200918. DOI: 10.1182/blood-2007-01-065888. View

Morgan G, Walker B, Davies F . The genetic architecture of multiple myeloma. Nat Rev Cancer. 2012; 12(5):335-48. DOI: 10.1038/nrc3257. View

10.

OConnor O, Stewart A, Vallone M, Molineaux C, Kunkel L, Gerecitano J . 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):7085-91. PMC: 4019989. DOI: 10.1158/1078-0432.CCR-09-0822. View

11.

van de Donk N, Lokhorst H, Dimopoulos M, Cavo M, Morgan G, Einsele H . Treatment of relapsed and refractory multiple myeloma in the era of novel agents. Cancer Treat Rev. 2010; 37(4):266-83. DOI: 10.1016/j.ctrv.2010.08.008. View

12.

Orlowski M, Wilk S . Catalytic activities of the 20 S proteasome, a multicatalytic proteinase complex. Arch Biochem Biophys. 2000; 383(1):1-16. DOI: 10.1006/abbi.2000.2036. View

13.

Demo S, Kirk C, Aujay M, Buchholz T, Dajee M, Ho M . Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res. 2007; 67(13):6383-91. DOI: 10.1158/0008-5472.CAN-06-4086. View

14.

Jagannath S, Richardson P, Sonneveld P, Schuster M, Irwin D, Stadtmauer E . Bortezomib appears to overcome the poor prognosis conferred by chromosome 13 deletion in phase 2 and 3 trials. Leukemia. 2006; 21(1):151-7. DOI: 10.1038/sj.leu.2404442. View

15.

Neben K, Lokhorst H, Jauch A, Bertsch U, Hielscher T, van der Holt B . Administration of bortezomib before and after autologous stem cell transplantation improves outcome in multiple myeloma patients with deletion 17p. Blood. 2011; 119(4):940-8. DOI: 10.1182/blood-2011-09-379164. View

16.

Kyle R, Rajkumar S . Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2008; 23(1):3-9. PMC: 2627786. DOI: 10.1038/leu.2008.291. View

17.

Avet-Loiseau H, Leleu X, Roussel M, Moreau P, Guerin-Charbonnel C, Caillot D . Bortezomib plus dexamethasone induction improves outcome of patients with t(4;14) myeloma but not outcome of patients with del(17p). J Clin Oncol. 2010; 28(30):4630-4. DOI: 10.1200/JCO.2010.28.3945. View

18.

Jakubowiak A, Siegel D, Martin T, Wang M, Vij R, Lonial S . Treatment outcomes in patients with relapsed and refractory multiple myeloma and high-risk cytogenetics receiving single-agent carfilzomib in the PX-171-003-A1 study. Leukemia. 2013; 27(12):2351-6. PMC: 3865533. DOI: 10.1038/leu.2013.152. View

19.

Alsina M, Trudel S, Furman R, Rosen P, OConnor O, Comenzo R . A phase I single-agent study of twice-weekly consecutive-day dosing of the proteasome inhibitor carfilzomib in patients with relapsed or refractory multiple myeloma or lymphoma. Clin Cancer Res. 2012; 18(17):4830-40. DOI: 10.1158/1078-0432.CCR-11-3007. View

20.

Wang M, Martin T, Bensinger W, Alsina M, Siegel D, Kavalerchik E . Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood. 2013; 122(18):3122-8. PMC: 3814729. DOI: 10.1182/blood-2013-07-511170. View