PROTEASOME INHIBITORS–A RATIONAL FOR CLINICAL USE IN THE TREATMENT OF MULTIPLE MYELOMA

  • Ivan Z Petković Klinika za onkologiju, Univerzitetski Klinički Centar Niš, Srbija
  • Ivica Pejčić Klinika za onkologiju, Univerzitetski Klinički Centar Niš, Srbija
  • Svetislav Vrbić Klinika za onkologiju, Univerzitetski Klinički Centar Niš, Srbija
Keywords: proteasome, proteasome inhibitors, multiple myeloma, rational therapy,

Abstract


Proteasome inhibitors (PI) represent the class of medicaments which lead to inhibition of catalytic chymotrypsin–like proteolytic protea­some subunits. Blockade ofthis specific structure drives to complete ubiquitin–proteasome machinery withdrawal.  Total intracellular pro­tein flow is regulated by the proteasome activity which acts through basal and signal activated proteolysis as the result of cell stimuli.Blockade of proteasome activity contribute to cell protein hyper concentration which resultswith activation of cell death mechanisms. This is primary end­point of PI activity against the cancer cell. Mul­tiple myeloma (ММ) represents the second most frequent blood cancer. The backbone of therapy constitute of triple–combination of long–acting corticosteroid (dexamethason), imunomodulatory drugs (IMiDs), such as thalidomide, lenalidomi­deorpomalidomide, and PI. Treatment strategy involves the use of induction therapy, after which, if disease is sensitive, high dose therapy should be followed by autologous hematopoietic stem cell transplantation.The above-mentioned treatment modality is reserved for younger pati­ents (≤65 years), while elderly have medical treatmentwithout transplantation.Whether main­tenance therapy shouldbe applied after remission is achieved,remains a matter of great controversy, although many centers apply it as "off label" use. Reversible PIs include: borte­zomib and ixazomib, and irreversible PI include: carfilzomib, oprozomib and marizomib. These drugs are found to have tolerable safety profile with the accent on peripheral neuropathy, ga­strointestinal and moderate hematological toxicityas the most usual adverse events. This article will consider clinical pharmacology of PIs.

Author Biographies

Ivan Z Petković, Klinika za onkologiju, Univerzitetski Klinički Centar Niš, Srbija

Odsek za maligne hemopatije, melanom, sarkome mekih tkiva i tumore nepoznatog primarnog ishodišta Klinika za onkologiju Knez selo, Niš

MD, PhD, specijalista interne medicine

Ivica Pejčić, Klinika za onkologiju, Univerzitetski Klinički Centar Niš, Srbija

Odsek za maligne hemopatije, melanom, sarkome mekih tkiva i tumore nepoznatog primarnog ishodišta Klinika za onkologiju Knez selo, Niš

MD, PhD, specijalista interne medicine

Svetislav Vrbić, Klinika za onkologiju, Univerzitetski Klinički Centar Niš, Srbija

Odsek za maligne hemopatije, melanom, sarkome mekih tkiva i tumore nepoznatog primarnog ishodišta Klinika za onkologiju Knez selo, Niš

MD, PhD, specijalista interne medicine

References

Nobel Prize Committee 2004. "Nobel Prize Awardees in Chemistry, 2004. Retrieved 2016: 2–29.

Adams J. The proteasome: structure, function, and role in the cell. Cancer Treat Rev 2003; 29: 3–9.

Montagut C, Rovira A, Albanell J. The proteasome: a novel target for anticancer therapy. ClinTranslOncol 2006; 8 (5): 313–7.

Moreau P, San Miguel J, Ludwig H, Schouten H, Mohty M, Dimopoulos, Dreyling M. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow–up. Ann Oncol 2013; 24 (6): 133–7.

SEER Stat Fact Sheets: Мultiple myeoloma [database on the internet]. National Cancer Institute (US). c2012 [updated 2015; cited on 2015 march 02]; Available from: seer.cancer.gov/statfacts/html/prost.html

Glickman MH, Adir N. The proteasome and the delicate balance between destruction and rescue. PloSBiol 2004; 2 (1): e13

Groll M, Ditzel L, Löwe J, Stock D, Bochtler M, Bartunik HD, Huber R. Structure of the 20S proteasome from yeast at 2.4 A resolution. Nature 1997; 386 (6624): 463–71.

Groll M, Heinemeyer W, Jäger S, Ullrich T, Bochtler M, Wolf DH, Huber R. The catalytic sites of 20S proteasomes and their role in subunit maturation: A mutational and crystallographic study. Proc Nat Acad Sci 1999; 96 (20): 10976–83.

Heinemeyer W, Fischer M, Krimmer T, Stachon U, Wolf DH. The active sites of the eukaryotic 20S proteasome and their involvement in subunit precursor processing. J BiolChem 1997; 272 (40): 25200–9.

Risseeuw EP, Daskalchuk TE, Banks TW, Liu E, Cotelesage J, Hellmann H, et al. Protein interaction analysis of SCF ubiquitin E3 ligase subunits from Arabidopsis. Plant J 2003; 34 (6): 753–67.

Groll M, Bajorek M, Köhler A, Moroder L, Rubin DM, Huber R, et al. A gated channel into the proteasome core particle. Nat StructBiol 2000; 7 (11): 1062–7.

Navon A, Goldberg AL. Proteins are unfolded on the surface of the ATPase ring before transport into the proteasome. Mol Cell 2001; 8 (6): 1339–49.

DeMartino GN, Slaughter CA. The proteasome, a novel protease regulated by multiple mechanisms. J BiolChem 1999; 274 (32): 22123–6.

Myung J, Kim KB, Crews CM. The ubiquitin–proteasome pathway and proteasome inhibitors.Med Res Rev 2001; 21 (4): 245–73.

Kisselev AF, Akopian TN, Castillo V, Goldberg AL. Proteasome active sites allosterically regulate each other, suggesting a cyclical bite–chew mechanism for protein breakdown. Mol Cell 1999; 4 (3): 395–402.

Mani A, Gelmann EP. The ubiquitin–proteasome pathway and its role in cancer. J ClinOncol 2005; 23 (21): 4776–89.

Zavrski I, Jakob C, Schmid P, Krebbel H, Kaiser M, Fleissner C, et al. Proteasome: an emerging target for cancer therapy. Anticancer Drugs 2005; 16 (5): 475–81.

Popat R, Oakervee HE, Hallam S, Curry N, Odeh L, Foot N, et al. Bortezomib, doxorubicin and dexamethasone (PAD) front–line treatment of multiple myeloma: updates results after long–term follow–up. Br J Haematol 2008; 141 (4): 512–6.

Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Gastineau DA, et al. Impact of lenalidomide therapy on stem cell mobilization and engraftment post-peripheral blood stem cell transplantation in patients with newly diagnosed myeloma.Leukemia 2007; 21 (9): 2035–42.

Palumbo A, Falco P, Corradini P, Falcone A, Di Raimondo F, Giuliani N, et al. Melphalan, Prednisone, and Lenalidomide treatment for newly diagnosed myeloma: a report from the GIMEMA–Italian Multiple Myeloma Network. J ClinOncol 2007; 25 (28): 4459–65.

Millenium Pharmaceuticals Inc. VELCADE (bortezomib) Prescribing Information (R–evision 17) www.velcade.com[database on the internet][cited on 25 March 2016]

Bonvini P, Zorzi E, Basso G, Rosolen A. Bortezomib–mediated 26S proteasome inhibition causes cell–cycle arrest and induces apoptosis in CD30+ anaplastic large cell lymphoma. Leukemia 2007; 21 (4): 838–42.

San Miguel JF, Schlag R, Khuageva NK, Dimopoulos M, Shpilberg O, Kropff M, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008; 359: 906–17.

Mateos MV, Richardson PG, Schlag R, Khuageva NK, Dimopoulos M, Shpilberg O, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow–up and impact of subsequent therapy in the phase III VISTA trial. J ClinOncol 2010; 28 (13): 2259–66.

Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, et al. Bortezomib or high–dose dexamethasone for relapsed multiple myeloma. N ENgl J Med 2005; 352 (24): 2487–98.

Jagannath S, Barlogie B, Berenson JR, Siegel DS, Irwin D, Siegel DS, et al. Updated survival analysis after prolonged follow–up of the phase 2, multicenter CREST study of bortezomib in relapsed or refractory multiple myeloma. Br J Haematol 2008; 143 (4): 537–40.

Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu Z, Grishunina M, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011;12(5): 431–40.

Arnulf B, Pylypenko H, GrosickiS,Karamanesht I, Leleu X, van de Velde H, et al. Updated survival analysis of a randomized phase III study of subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma. Haematologica 2012;97(12): 1925–8.

Carfilzomib. NCI Drug Dictionary.[database on the internet][cited on 25 March 2016]

Vij R, Wang M, Kaufman JL, Lonial S, Jakubowiak AJ, Stewart AK, et al. An open–label, single–arm, Phase 2 (PX–171–004) study of single–arm carfilzomib in bortezomib–naive patients with relapsed and/or refractory multiple myeloma. Blood 2012; 119 (24): 5661–70.

Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A Phase II study of single–agent carfilzomib (PX–171–003–A1) in patients with relapsed and refractory multiple myeloma. Blood 2012; 120 (14): 2817–25.

Onyx Pharmaceuticals Inc.KYPROLIS (carfilzomib), prescribing information. www.kyprolis.com/ prescribing –information.[database on the internet][cited on 25 March 2016]

Herndon TM, Deisseroth A, Kaminskas E, Kane RC, Koti RC, Rothmann MD, et al. U.S. Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clin Cancer Res 2013;19 (17): 4559–63.

Stewart AK, Rajkumar SV, Dimopoulos MA, Masszi T, Špička I, Oriol A, et al. Carfilzomib, lenalidomid, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015; 372 (2): 142–52.

Bringhen S, Petrucci MT, Larocca A, Conticello C, Rossi D, Magarotto V, et al. Carfilzomib, cyclo-phosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood 2014; 124 (1): 63–9.

Korde N, Roschewski M, Zingone A, Kwok M, Manasanch EE, Bhutani M, et al. Treatment with carfilzomib–lenalidomid-dexamethasone with lenalidomid extension in patients with smoldering or newly diagnosed multiple myeloma. JAMA Oncol 2015; 1 (6): 746–54.

Siegel D, Martin T, Nooka A, Harvey RD, Vij R, Niesvizky R, et al. Integrated safety profile of single–agent carfilzomib: Experience from 526 patients enrolled in 4 phase 2 clinical studies. Haematologica 2013; 98 (11): 1753–61.

Kupperman E, Lee EC, Cao Y, Bannerman B, Fitzgerald M, Berger A, et al. Evaluation of the proteasome inhibitor MLN9708 in preclinical models of human cancer. Cancer Res 2010; 70 (5): 1970–80.

Richardson PG, Baz R, Wang M, Jakubowiak AJ, Laubach JP, Harvey RD, et al. Phase 1 study of twice–weekly ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeoloma patinents. Blood 2014; 124 (7): 1038–46.

Kumar SK, Bensinger WI, Zimmerman TM, Reeder CB, Berenson JR, Berg D, et al. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma. Blood 2014; 124 (7): 1047–55.

Richardson PG, Hofmeister CC, Rosenbaum CA, et al. Twice-Weekly Oral MLN9708 (Ixazomib Citrate), An Investigational Proteasome Inhibitor, In Combination With Lenalidomide (Len) and Dexamethasone (Dex) In Patients (Pts) With Newly Diagnosed Multiple Myeloma (MM): Final Phase 1 Results and Phase 2 Data. Blood (ASH Annual Meeting Abstracts) 2013; 122(21):Abstract 535.

Gupta N, Goh YT, Min CK,et al. Phase 1 pharmacokinetic (PK) study of ixazomib citrate (MLN9708) plus lenalidomide and dexamethasone in Asian patients (pts) with relapsed/refractory multiple myeloma (RRMM). Haematologica 2014; 99 (Suppl 1): 372 (Abstract P981).

San Miguel J, Hajek R, Spicka I, et al. Oral MLN9708, an investigational proteasome inhibitor, in combination with melphalan and prednisone in patients with previously untreated multiple myeloma: a Phase I study. Haematologica2012; 97(Suppl1): 118–9 (Abstract 0293).

Gupta N, Zhao Y, Hui A-M, Esseltine DL, Venkatakrishnan K. Switching from body surface area-based to fixed dosing for the investigational proteasome inhibitor ixazomib: a population pharmacokinetic analysis. Br J ClinPharmacol2015; 79 (5): 789–800.

Richardson PG, Moreau P, Laubach JP, Gupta N, Hui AM, Anderson KC, et al. The investigational proteasome inhibitor ixazomib for the treatment of multiple myeloma.Future Oncol 2015; 11 (8): 1153–68.

Moreau P, Masszi T, Grzasko N, et al. Ixazomib, an investigational oral proteasome inhibitor, in combination with lenalidomide and dexamethasone, significantly extends progression–free survival for patients with relapsed and/or refractory multiple myeloma: the phase 3 Tourmaline–MM1 study(ASH 2015 meeting abstract).

Feling RH, Buchanan GO, Mincer TJ, et al. Salinosporamid A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a murine bacterium of the new genus salinospora. AngewChemInt Ed Engl 2003; 42 (3): 355–7.

Chauhan D, Catley L, Li G, Podar K, Hideshima T, Velankar M, et al. A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib. Cancer Cell 2005; 8 (5): 407–19.

Richardson PG, Spencer A, Canell P, Harrison SJ, Catley L, Underhill C, et al. Phase 1 clinical evaluation of twice–weekly marizomib (NPI–0052), a novel proteasome inhibitor, in patients with relapsed/refractory multiple myeloma (MM). Blood 2011; 118 (21): 140–141 (Abstract 302).

Ghobrial IM, Kaufman JL, Siegel DS, et al. Clinical profile of single–agent modified–release oprozomib tablets in patients with hematologic malignancies: updated results from a multicenter, open–label, dose escalation Phase 1b/2 study. Blood 2013; 122 (21): 3184 (Abstract 3184).

Published
2016/11/28
Section
Review Paper