Home > News > Carfilzomib—A Selective Proteasome Inhibitor for the Treatment of Relapsed and/or Refractory Multiple Myeloma
Haematological Malignancies, Multiple Myeloma
Read Time: < 1 min

Carfilzomib—A Selective Proteasome Inhibitor for the Treatment of Relapsed and/or Refractory Multiple Myeloma

Published Online: June 25th 2012 Oncology & Hematology Review (US), 2012;8(2):106-110 DOI: https://doi.org/10.17925/OHR.2012.08.2.106
Authors: David S Siegel, Ravi Vij, Ruben Niesvizky
Quick Links:
Abstract
Article
Article Information
Abstract:
Overview

Multiple myeloma (MM) is a plasma cell malignancy characterized by overproduction of monoclonal immunoglobulins, hypercalcemia, renal injury, anemia, and osteolytic lesions. Despite markedly improved clinical outcomes since the introduction of first-generation immunomodulatory drugs and proteasome inhibitors, survival is very short in patients who relapse and are refractory to these therapies. Carfilzomib is a selective proteasome inhibitor currently being developed for the treatment of MM. In clinical studies, carfilzomib has achieved durable responses in relapsed and/or refractory MM and demonstrated acceptable tolerability with minimal peripheral neuropathy and no evidence of cumulative toxicity. Herein we summarize the key clinical data for single-agent carfilzomib in the relapsed and/or refractory disease setting and provide an overview of the current clinical development of the drug, both as monotherapy and in combinations.

Keywords

Multiple myeloma, proteasome inhibitor, relapsed/refractory, selective, safety, tolerability

Article:

Multiple myeloma (MM) is a plasma cell malignancy characterized by the overproduction of monoclonal immunoglobulins and the presence of hypercalcemia, renal injury, anemia, osteolytic lesions, and frequent infections.1,2 Other complications include hyperviscosity and amyloidosis.1,2 It is the second most common hematologic malignancy after non-Hodgkin’s lymphoma and will represent nearly 15 % of new hematologic malignancies diagnosed in 2012 in the US.3

MM is generally a disease of older individuals;4 the median age at diagnosis is approximately 69 years.5 With the approvals of the newer agents bortezomib, thalidomide, and lenalidomide, the median overall survival (OS) has improved from approximately two years in the late 1970s to 4.4–7.1 years in the decade since 2000.6 However, in patients with relapsed disease that is refractory to the aforementioned agents, the median event-free survival and OS times are five and nine months, respectively.7

A number of factors may influence the course of disease in an individual patient with MM. Advanced age, poor performance status, the presence of specific cytogenetic markers (e.g., deletion 17p, t(4;14)), the presence of immunoglobulin (Ig)A isotype, serum creatinine ≥2 mg/dl, extramedullary disease, and renal insufficiency each independently predict worse outcomes.1,8 Additional items of concern relate to the patient’s treatment history and include prior therapy-associated toxicity and prior stem cell transplant. The newer agents (i.e., bortezomib, thalidomide, and lenalidomide) have distinct toxicity profiles (including myelosuppression, peripheral neuropathy, and venous thromboembolic events [VTEs]),9 and the effective management of adverse events (AEs) associated with these agents is crucial to ensure that patients are able to receive the most effective treatment with minimal need for interruption.

To view the full article in PDF or eBook formats, please click on the icons above.

Article Information:
Disclosure

David S Siegel, MD, PhD, has been consultant for, received honoraria from, and served as a Board of Directors or Advisory Committee member for Millennium and Celgene. Ravi Vij, MD, has been on the speakers bureau for Celgene and Millennium, served on advisory boards for Celgene and Onyx, and received research support from Onyx and Celgene. Ruben Niesvizky, MD, has had research supported by Celgene, Millennium, and Onyx, been on the speakers bureau for Celgene and Millennium, and served as consultant for Celgene, Millennium, and Onyx.

Support

The studies described in this article were supported by Onyx Pharmaceuticals, Inc.

Received

2012-06-29T00:00:00

References

  1. Raab MS, Podar K, Breitkreutz I, et al., Multiple myeloma, Lancet, 2009;374(9686):324–39.
  2. Kyle RA, Rajkumar SV, Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma, Leukemia, 2009;23(1):3–9.
  3. American Cancer Society, Cancer Facts & Figures 2012, Atlanta, Georgia, US: American Cancer Society, 2012.
  4. Bergsagel PL. Epidemiology, etiology, and molecular pathogenesis. In: Anderson KC (ed.), Multiple Myeloma, London, UK: Remedica, 2003:17–37.
  5. Howlader N, Noone AM, Krapcho M, et al. (eds), SEER Cancer Statistics Review, 1975–2009 (Vintage 2009 Populations), Bethesda, Maryland, US: National Cancer Institute, 2012.
  6. Sirohi B, Powles R, Multiple myeloma, Lancet, 2004; 363(9412):875–87.
  7. Kumar SK, Lee JH, Lahuerta JJ, et al., Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter International Myeloma Working Group study, Leukemia, 2012;26(1):149–57.
  8. Ludwig H, Durie BG, Bolejack V, et al., Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: an analysis of 10 549 patients from the International Myeloma Working Group, Blood, 2008;111(8):4039–47.
  9. Lee CK, Barlogie B, Munshi N, et al., DTPACE: an effective, novel combination chemotherapy with thalidomide for previously treated patients with myeloma, J Clin Oncol, 2003;21(14):2732–9.
  10. Hanada M, Sugawara K, Kaneta K, et al., Epoxomicin, a new antitumor agent of microbial origin, J Antibiot (Tokyo), 1992;45(11):1746–52.
  11. Kim KB, Myung J, Sin N, Crews CM, Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: insights into specificity and potency, Bioorg Med Chem Lett, 1999;9(23):3335–40.
  12. Meng L, Kwok BH, Sin N, Crews CM., Eponemycin exerts its antitumor effect through the inhibition of proteasome function, Cancer Res, 1999;59(12):2798–801.
  13. Meng L, Mohan R, Kwok BH, et al., Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity, Proc Natl Acad Sci U S A, 1999;96(18):10403–8.
  14. Groll M, Kim KB, Kairies N, et al., Crystal structure of epoxomicin:20S proteasome reveals a molecular basis for selectivity of α’, β’-epoxyketone proteasome inhibitors, J Am Chem Soc, 2000;122(6):1237–8.
  15. 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):6383–91.
  16. Yang J, Wang Z, Fang Y, et al., Pharmacokinetics, pharmacodynamics, metabolism, distribution, and excretion of carfilzomib in rats, Drug Metab Dispos, 2011;39(10):1873–82.
  17. Kuhn DJ, Chen Q, Voorhees PM, et al., Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitinproteasome pathway, against preclinical models of multiple myeloma, Blood, 2007;110(9):3281–90.
  18. 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):2734–43.
  19. 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):7085–91.
  20. Alsina M, Trudel S, Furman RR, et al., A phase 1 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 Jul 3 [Epub ahead of print].
  21. 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(15Suppl.):Abstract 8504.
  22. Siegel DS, Martin T, Wang M, et al., A phase 2 study of singleagent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma, Blood, 2012 July 25 [Epub ahead of print].
  23. 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;119(24):5661–70.
  24. Niesvizky R, Vij R, Martin T, et al., Carfilzomib pharmacokinetics, safety, and activity in patients with relapsed or refractory multiple myeloma and renal dysfunction: final results, Haematologica, 2011;96(Suppl. 2):370–1.
  25. Vij R, Siegel DS, Jagannath S, et al., An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib, Br J Haematol, 2012; [Epub ahead of print].
  26. Richardson PG, Barlogie B, Berenson J, et al., A phase 2 study of bortezomib in relapsed, refractory myeloma, N Engl J Med, 2003;348(26):2609–17.
  27. Jagannath S, Barlogie B, Berenson J, et al., A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma, Br J Haematol, 2004;127(2):165–72.
  28. Richardson PG, Sonneveld P, Schuster MW, et al., Bortezomib or high-dose dexamethasone for relapsed multiple myeloma, N Engl J Med, 2005;352(24):2487–98.
  29. Papadopoulos KP, 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 20/56mg/m2 expansion cohort of PX-171-007, Blood, 2011;118(21):Abstract 2930.
  30. Jakubowiak AJ, Dytfeld D, Griffith KA, et al., A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma, Blood, 2012; [Epub ahead of print].
  31. Kolb B, Hulin C, Caillot D, et al., Phase I/II study of carfilzomib plus melphalan-prednisone (CMP) in elderly patients with de novo multiple myeloma, J Clin Oncol, 2012;30(Suppl.):Abstract 8009.
  32. Sonneveld P, Hacker E, Zweegman S, et al., Carfilzomib combined with thalidomide and dexamethasone (CARTHADEX) as induction treatment prior to high-dose melphalan (HDM) in newly diagnosed patients with multiple myeloma (MM). A trial of the European Myeloma Network EMN, Blood, 2011;118(21):Abstract 633.
  33. Mikhael JR, A phase I/II trial of cyclophosphamide, carfilzomib, thalidomide, and dexamethasone (CYCLONE) in patients with newly diagnosed multiple myeloma, J Clin Oncol, 2012;30(15):Abstract 8010.
  34. Hajek R, Single-agent carfilzomib versus a best supportive care regimen in patients with relapsed and refractory multiple myeloma: FOCUS (PX-171-011), a randomized, open-label, phase 3 study, Haematologica, 2012;97(S2):Abstract 1553.
  35. Papadopoulos KP, Lee P, Gordon MS, et al., Updated results of a phase 1b/2 study using a 30-min infusion of carfilzomib (CFZ) in patients (pts) with relapsed malignancies, Ann Oncol, 2010;21(Suppl. 8):viii170.
  36. Sadaka B, Alloway RR, Woodle ES, Clinical and investigational use of proteasome inhibitors for transplant rejection, Expert Opin Investig Drugs, 2011;20(11):1535–42.
  37. 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, Blood, 2011;118(21):Abstract 1876.

Further Resources

Share this Article
Related Content In Multiple Myeloma
  • Copied to clipboard!
    accredited arrow-downarrow_leftarrow-right-bluearrow-right-dark-bluearrow-right-greyarrow-right-orangearrow-right-whitearrow-right-bluearrow-up-orangeavatarcalendarchevron-down consultant-pathologist-nurseconsultant-pathologistcrosscrossdownloademailexclaimationfeedbackfiltergraph-arrowinterviewslinkmdt_iconmenumore_dots nurse-consultantpadlock patient-advocate-pathologistpatient-consultantpatientperson pharmacist-nurseplay_buttonplay-colour-tmcplay-colourAsset 1podcastprinter scenerysearch share single-doctor social_facebooksocial_googleplussocial_instagramsocial_linkedin_altsocial_linkedin_altsocial_pinterestlogo-twitter-glyph-32social_youtubeshape-star (1)tick-bluetick-orangetick-whiteticktimetranscriptup-arrowwebinar Department Location NEW TMM Corporate Services Icons-07NEW TMM Corporate Services Icons-08NEW TMM Corporate Services Icons-09NEW TMM Corporate Services Icons-10NEW TMM Corporate Services Icons-11NEW TMM Corporate Services Icons-12Salary £ TMM-Corp-Site-Icons-01TMM-Corp-Site-Icons-02TMM-Corp-Site-Icons-03TMM-Corp-Site-Icons-04TMM-Corp-Site-Icons-05TMM-Corp-Site-Icons-06TMM-Corp-Site-Icons-07TMM-Corp-Site-Icons-08TMM-Corp-Site-Icons-09TMM-Corp-Site-Icons-10TMM-Corp-Site-Icons-11TMM-Corp-Site-Icons-12TMM-Corp-Site-Icons-13TMM-Corp-Site-Icons-14TMM-Corp-Site-Icons-15TMM-Corp-Site-Icons-16TMM-Corp-Site-Icons-17TMM-Corp-Site-Icons-18TMM-Corp-Site-Icons-19TMM-Corp-Site-Icons-20TMM-Corp-Site-Icons-21TMM-Corp-Site-Icons-22TMM-Corp-Site-Icons-23TMM-Corp-Site-Icons-24TMM-Corp-Site-Icons-25TMM-Corp-Site-Icons-26TMM-Corp-Site-Icons-27TMM-Corp-Site-Icons-28TMM-Corp-Site-Icons-29TMM-Corp-Site-Icons-30TMM-Corp-Site-Icons-31TMM-Corp-Site-Icons-32TMM-Corp-Site-Icons-33TMM-Corp-Site-Icons-34TMM-Corp-Site-Icons-35TMM-Corp-Site-Icons-36TMM-Corp-Site-Icons-37TMM-Corp-Site-Icons-38TMM-Corp-Site-Icons-39TMM-Corp-Site-Icons-40TMM-Corp-Site-Icons-41TMM-Corp-Site-Icons-42TMM-Corp-Site-Icons-43TMM-Corp-Site-Icons-44TMM-Corp-Site-Icons-45TMM-Corp-Site-Icons-46TMM-Corp-Site-Icons-47TMM-Corp-Site-Icons-48TMM-Corp-Site-Icons-49TMM-Corp-Site-Icons-50TMM-Corp-Site-Icons-51TMM-Corp-Site-Icons-52TMM-Corp-Site-Icons-53TMM-Corp-Site-Icons-54TMM-Corp-Site-Icons-55TMM-Corp-Site-Icons-56TMM-Corp-Site-Icons-57TMM-Corp-Site-Icons-58TMM-Corp-Site-Icons-59TMM-Corp-Site-Icons-60TMM-Corp-Site-Icons-61TMM-Corp-Site-Icons-62TMM-Corp-Site-Icons-63TMM-Corp-Site-Icons-64TMM-Corp-Site-Icons-65TMM-Corp-Site-Icons-66TMM-Corp-Site-Icons-67TMM-Corp-Site-Icons-68TMM-Corp-Site-Icons-69TMM-Corp-Site-Icons-70TMM-Corp-Site-Icons-71TMM-Corp-Site-Icons-72