Skip to main content
SpringerLink
Log in

Novel Proteasome Inhibitors

  • Chapter
  • First Online:
Advances in Biology and Therapy of Multiple Myeloma

  • 602 Accesses

Abstract

Proteasome inhibition is a rational approach to the therapy of multiple myeloma both alone and in combination with other agents, where proteasome inhibitors help induce chemosensitization and overcome drug resistance. These concepts were initially validated with laboratory-grade proteasome inhibitors and then with the clinically relevant peptide boronic acid bortezomib. A second generation of proteasome inhibitors is now being evaluated both preclinically and clinically, including carfilzomib, CEP-18770, marizomib, and MLN9708, among others. Though all of these agents target predominantly the chymotrypsin-like activity of the proteasome expressed by the β5 subunit, they also have novel and unique properties, including different chemistries, pharmacokinetics, proteasome binding characteristics, and other proteasome subunit specificities. Characterization of these agents has provided a strong rationale for their translation into the clinic, and initial studies suggest that at least several of them could become part of our future chemotherapeutic armamentarium against myeloma. In this chapter, these various properties of the so-called second-generation proteasome inhibitors will be examined, and the biological and clinical basis of their potential will be reviewed.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

Bax:

Bcl-2-associated X protein

Bcl-2:

B cell CLL/lymphoma-2

BH3:

Bcl-2 homology 3

Bid:

BH3-interacting domain death agonist

BIM:

Bcl-2-interacting mediator of cell death

Bor:

Bortezomib

CDK:

Cyclin-dependent kinase

ChT-L:

Chymotrypsin-like

C-L:

Caspase-like

CR:

Complete remission

DLT:

Dose-limiting toxicity

DOR:

Duration of response

IκB:

Inhibitor of nuclear factor kappa B

IPSI:

Immunoproteasome-specific inhibitor

ISS:

International Staging System

JNK:

c-Jun-N-terminal kinase

Len:

Lenalidomide

LMP:

Low molecular mass polypeptide

Mcl-1:

Myeloid cell leukemia sequence 1

MECL:

Multicatalytic endopeptidase complex-like

MR:

Minor response

MTD:

Maximum tolerated dose

NF-κB:

Nuclear factor kappa B

ORR:

Overall response rate

PBMCs:

Peripheral blood mononuclear cells

PGPH:

Post-glutamyl peptide hydrolyzing also referred to as the caspase-like (C-L) activity

PR:

Partial remission

RANKL:

Tumor necrosis factor-mediated receptor activator of NF-κB ligand

sCR:

Stringent CR

Smac:

Second mitochondria-derived activator of caspases

T-L:

Trypsin-like

Thal:

Thalidomide

TTP:

Time to progression

UPR:

Unfolded protein response

VGPR:

Very good PR

References

  1. Orlowski RZ, Stinchcombe TE, Mitchell BS et al (2002) Phase I trial of the proteasome inhibitor PS-341 in patients with refractory hematologic malignancies. J Clin Oncol 20(22):4420–7

    Article  PubMed  CAS  Google Scholar 

  2. Richardson PG, Barlogie B, Berenson J et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348(26):2609–17

    Article  PubMed  CAS  Google Scholar 

  3. Richardson PG, Sonneveld P, Schuster MW et al (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med 352(24):2487–98

    Article  PubMed  CAS  Google Scholar 

  4. Orlowski RZ, Nagler A, Sonneveld P et al (2007) 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 25(25):3892–901

    Article  PubMed  CAS  Google Scholar 

  5. San Miguel JF, Schlag R, Khuageva NK et al (2008) Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359(9):906–17

    Article  PubMed  CAS  Google Scholar 

  6. Rock KL, Gramm C, Rothstein L et al (1994) Inhibitors of the proteasome block the degradation of most cell proteins and the generation of peptides presented on MHC class I molecules. Cell 78:761–71

    Article  PubMed  CAS  Google Scholar 

  7. Orlowski RZ, Kuhn DJ (2008) Proteasome inhibitors in cancer therapy: lessons from the first decade. Clin Cancer Res 14(6):1649–57

    Article  PubMed  CAS  Google Scholar 

  8. Shah JJ, Orlowski RZ (2009) Proteasome inhibitors in the treatment of multiple myeloma. Leukemia 23(11):1964–79

    Article  PubMed  CAS  Google Scholar 

  9. Dick LR, Fleming PE (2010) Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today 15(5–6):243–9

    Article  PubMed  CAS  Google Scholar 

  10. Adams J, Behnke M, Chen S et al (1998) Potent and selective inhibitors of the proteasome: dipeptidyl boronic acids. Bioorg Med Chem Lett 8(4):333–8

    Article  PubMed  CAS  Google Scholar 

  11. Adams J, Palombella VJ, Sausville EA et al (1999) Proteasome inhibitors: a novel class of potent and effective antitumor agents. Cancer Res 59(11):2615–22

    PubMed  CAS  Google Scholar 

  12. Hanada M, Sugawara K, Kaneta K et al (1992) Epoxomicin, a new antitumor agent of microbial origin. J Antibiot 45(11):1746–52

    Article  PubMed  CAS  Google Scholar 

  13. Sin N, Kim KB, Elofsson M et al (1999) Total synthesis of the potent proteasome inhibitor epoxomicin: a useful tool for understanding proteasome biology. Bioorg Med Chem Lett 9:2283–8

    Article  PubMed  CAS  Google Scholar 

  14. Meng L, Mohan R, Kwok BH, Elofsson M, Sin N, Crews CM (1999) Epoxomicin, a potent and selective proteasome inhibitor, exhibits in vivo antiinflammatory activity. Proc Natl Acad Sci USA 96(18):10403–8

    Article  PubMed  CAS  Google Scholar 

  15. Kim KB, Myung J, Sin N, Crews CM (1999) Proteasome inhibition by the natural products epoxomicin and dihydroeponemycin: insights into specificity and potency. Bioorg Med Chem Lett 9(23):3335–40

    Article  PubMed  CAS  Google Scholar 

  16. Kuhn DJ, Chen Q, Voorhees PM et al (2007) Potent activity of carfilzomib, a novel, irreversible inhibitor of the ubiquitin-proteasome pathway, against preclinical models of multiple myeloma. Blood 110(9):3281–90

    Article  PubMed  CAS  Google Scholar 

  17. Demo SD, Kirk CJ, Aujay MA et al (2007) Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 67(13):6383–91

    Article  PubMed  CAS  Google Scholar 

  18. Parlati F, Lee SJ, Aujay M et al (2009) Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome. Blood 114(16):3439–47

    Article  PubMed  CAS  Google Scholar 

  19. Paoluzzi L, Gonen M, Bhagat G et al (2008) The BH3-only mimetic ABT-737 synergizes the antineoplastic activity of proteasome inhibitors in lymphoid malignancies. Blood 112(7): 2906–16

    Article  PubMed  CAS  Google Scholar 

  20. Paoluzzi L, Gonen M, Gardner JR et al (2008) Targeting Bcl-2 family members with the BH3 mimetic AT-101 markedly enhances the therapeutic effects of chemotherapeutic agents in in vitro and in vivo models of B-cell lymphoma. Blood 111(11):5350–8

    Article  PubMed  CAS  Google Scholar 

  21. Dasmahapatra G, Lembersky D, Kramer L et al (2010) The pan-HDAC inhibitor vorinostat potentiates the activity of the proteasome inhibitor carfilzomib in human DLBCL cells in vitro and in vivo. Blood 115(22):4478–87

    Article  PubMed  CAS  Google Scholar 

  22. DiLiberto M, Huang X, Zewdu R et al (2009) Selective inhibition of CDK4/CDK6 sensitizes bone marrow myeloma cells for killing by proteasome inhibitors carfilzomib and PR-047 through cell cycle-dependent expression of pro-apoptotic Noxa and Bim. Blood (ASH Annual Meeting Abstract) 114:2854

    Google Scholar 

  23. Huang X, Di Liberto M, Ely S et al (2009) Induction of sequential G1 arrest and synchronous S phase entry by reversible CDK4/CDK6 inhibition sensitizes myeloma cells for cytotoxic killing through loss of IRF-4. Blood (ASH Annual Meeting Abstract) 114:299

    Google Scholar 

  24. O’Connor OA, Stewart AK, Vallone M et al (2009) 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 15(22):7085–91

    Article  PubMed  Google Scholar 

  25. Arastu-Kapur S, Shenk K, Parlati F, Bennett MK (2008) Non-proteasomal targets of proteasome inhibitors bortezomib and carfilzomib. Blood (ASH Annual Meeting Abstract) 112:2657

    Google Scholar 

  26. Alsina M, Trudel S, Vallone M, Molineaux C, Kunkel L, Goy A (2007) Phase 1 single agent antitumor activity of twice weekly consecutive day dosing of the proteasome inhibitor carfilzomib (PR-171) in hematologic malignancies. Blood (ASH Annual Meeting Abstract ) 110:411

    Google Scholar 

  27. Jagannath S, Vij R, Stewart K et al (2009) 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 27(15s), ASCO Annual Meeting Abstract 8504

    Google Scholar 

  28. http://www.onyx-pharm.com/view.cfm/690/Onyx-Pharmaceuticals-Announces-Positive-Top-Line-Carfilzomib-Data-from-Phase-2b-Study; 2010.

  29. Siegel D, Wang L, Orlowski RZ et al (2009) PX-171-004, an ongoing open-label, phase II study of single-agent carfilzomib (CFZ) in patients with relapsed or refractory myeloma (MM); updated results from the bortezomib-treated cohort. Blood (ASH Annual Meeting Abstract) 114:303

    Google Scholar 

  30. Wang L, Siegel D, Kaufman JL et al (2009) Updated results of bortezomib-naïve patients in PX-171-004, an ongoing open-label, phase II study of single-agent carfilzomib (CFZ) in patients with relapsed or refractory myeloma (MM). Blood (ASH Annual Meeting Abstract) 114:302

    Google Scholar 

  31. Richardson PG, Weller E, Jagannath S et al (2009) Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol 27(34):5713–9

    Article  PubMed  CAS  Google Scholar 

  32. Richardson PG, Weller E, Lonial S et al (2010) Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood 116(5):679–86

    Article  PubMed  CAS  Google Scholar 

  33. Bensinger W, Wang M, Orlowski RZ et al (2010) 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 28(15s), ASCO Annual Meeting Abstract 8029

    Google Scholar 

  34. Muchamuel T, Aujay M, Bennett MK et al (2008) Preclinical pharmacology and in vitro characterization of PR-047, an oral inhibitor of the 20S proteasome. Blood (ASH Annual Meeting Abstract) 112:3671

    Google Scholar 

  35. Zhou HJ, Aujay MA, Bennett MK et al (2009) Design and synthesis of an orally bioavailable and selective peptide epoxyketone proteasome inhibitor (PR-047). J Med Chem 52(9):3028–38

    Article  PubMed  CAS  Google Scholar 

  36. Muchamuel T, Kapur S, Kirk CJ et al (2009) Dose intensive administration of PR-047, a novel orally bioavailable inhibitor of the 20S proteasome, is well tolerated in experimental animals. Blood (ASH Annual Meeting Abstract) 114:4910

    Google Scholar 

  37. Roccaro AM, Sacco A, Aujay M et al (2010) Selective inhibition of chymotrypsin-like activity of the immunoproteasome and constitutive proteasome in Waldenstrom macroglobulinemia. Blood 115(20):4051–60

    Article  PubMed  CAS  Google Scholar 

  38. Huang X, Bailey K, Di Liberto M et al (2008) Induction of sustained early G1 arrest by selective inhibition of CDK4 and CDK6 primes myeloma cells for synergistic killing by proteasome inhibitors carfilzomib and PR-047. Blood (ASH Annual Meeting Abstract) 112:3670

    Google Scholar 

  39. Feling RH, Buchanan GO, Mincer TJ, Kauffman CA, Jensen PR, Fenical W (2003) Salinosporamide A: a highly cytotoxic proteasome inhibitor from a novel microbial source, a marine bacterium of the new genus salinospora. Angew Chem Int Ed Engl 42(3):355–7

    Article  PubMed  CAS  Google Scholar 

  40. Fenteany G, Schreiber SL (1998) Lactacystin, proteasome function, and cell fate. J Biol Chem 273(15):8545–8

    Article  PubMed  CAS  Google Scholar 

  41. Ling T, Potts BC, Macherla VR (2010) Concise formal synthesis of (−)-salinosporamide A (marizomib) using a regio- and stereoselective epoxidation and reductive oxirane ring-opening strategy. J Org Chem 75(11):3882–5

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  43. Singh AV, Palladino MA, Lloyd GK, Potts BC, Chauhan D, Anderson KC (2010) Pharmacodynamic and efficacy studies of the novel proteasome inhibitor NPI-0052 (marizomib) in a human plasmacytoma xenograft murine model. Br J Haematol 149(4):550–9

    Article  PubMed  CAS  Google Scholar 

  44. Ahn KS, Sethi G, Chao TH et al (2007) Salinosporamide A (NPI-0052) potentiates apoptosis, suppresses osteoclastogenesis, and inhibits invasion through down-modulation of NF-kappaB regulated gene products. Blood 110(7):2286–95

    Article  PubMed  CAS  Google Scholar 

  45. Chauhan D, Singh A, Brahmandam M et al (2008) Combination of proteasome inhibitors bortezomib and NPI-0052 trigger in vivo synergistic cytotoxicity in multiple myeloma. Blood 111(3):1654–64

    Article  PubMed  CAS  Google Scholar 

  46. Roccaro AM, Leleu X, Sacco A et al (2008) Dual targeting of the proteasome regulates survival and homing in Waldenstrom macroglobulinemia. Blood 111(9):4752–63

    Article  PubMed  CAS  Google Scholar 

  47. Chauhan D, Singh AV, Ciccarelli B, Richardson PG, Palladino MA, Anderson KC (2010) Combination of novel proteasome inhibitor NPI-0052 and lenalidomide trigger in vitro and in vivo synergistic cytotoxicity in multiple myeloma. Blood 115(4):834–45

    Article  PubMed  CAS  Google Scholar 

  48. Huang X, Louie T, Di Liberto M et al (2007) Targeting cdk4/6 in combination therapy overcomes proteasome inhibitor resistance in multiple myeloma through synergistic mitochondria depolarization. Blood (ASH Annual Meeting Abstracts) 110:667

    Google Scholar 

  49. Kurzrock R, Hamlin P, Younes A et al (2007) Phase 1 clinical trial of a novel proteasome inhibitor (NPI-0052) in patients with lymphomas and solid tumors. Blood (ASH Annual Meeting Abstract) 110:4504

    Google Scholar 

  50. Hamlin PA, Aghajanian C, Hong D et al (2008) First-in-human phase 1 dose escalation study of NPI-0052, a novel proteasome inhibitor, in patients with lymphoma and solid tumor. Blood (ASH Annual Meeting Abstracts) 112:4939

    Google Scholar 

  51. Hamlin PA, Aghajanian C, Younes A et al (2009) First-in-human phase I study of the novel structure proteasome inhibitor NPI-0052. J Clin Oncol 27(15s):3516, ASCO Annual Meeting Abstract

    Google Scholar 

  52. Price T, Padrik P, Townsend A et al (2008) Clinical trial of NPI-0052 (2nd generation proteasome inhibitor) in patients having advanced malignancies with expanded RP2D cohorts in lymphoma and CLL. Blood 112:4934, ASH Annual Meeting Abstract

    Google Scholar 

  53. Townsend AR, Millward M, Price T et al (2009) Clinical trial of NPI-0052 in advanced malignancies including lymphoma and leukemia (advanced malignancies arm). J Clin Oncol 27(15s):3582, ASCO Annual Meeting Abstract

    Google Scholar 

  54. Spencer A, Millward M, Mainwaring P et al (2009) Phase 1 clinical trial of the novel structure proteasome inhibitor NPI-0052. Blood 114:2693, ASH Annual Meeting Abstract

    Google Scholar 

  55. Richardson P, Hofmeister C, Jakubowiak A et al (2009) Phase 1 clinical trial of the novel structure proteasome inhibitor NPI-0052 in patients with relapsed and relapsed/refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstract) 114:431

    Google Scholar 

  56. Dorsey BD, Iqbal M, Chatterjee S et al (2008) Discovery of a potent, selective, and orally active proteasome inhibitor for the treatment of cancer. J Med Chem 51(4):1068–72

    Article  PubMed  CAS  Google Scholar 

  57. Piva R, Ruggeri B, Williams M et al (2008) CEP-18770: A novel, orally active proteasome inhibitor with a tumor-selective pharmacologic profile competitive with bortezomib. Blood 111(5):2765–75

    Article  PubMed  CAS  Google Scholar 

  58. Trippier PC, McGuigan C, Balzarini J (2010) Phenylboronic-acid-based carbohydrate binders as antiviral therapeutics: monophenylboronic acids. Antivir Chem Chemother 20(6):249–57

    PubMed  CAS  Google Scholar 

  59. Sanchez E, Li M, Steinberg JA et al (2010) The proteasome inhibitor CEP-18770 enhances the anti-myeloma activity of bortezomib and melphalan. Br J Haematol 148(4):569–81

    Article  PubMed  CAS  Google Scholar 

  60. Marangon E, Sala F, Sessa C, et al. Pharmacokinetics and pharmacodynamics of the new proteasome inhibitor CEP-18770 Preliminary results from a phase I study. J Am Soc Mass Spectrom 2009;20(5, Supplement 1):Annual ASMS Meeting Abstract 452

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  62. Donelan J, Bannerman B, Bano K et al (2009) Antitumor activity of MLN9708, a second-generation proteasome inhibitor, in preclinical models of lymphoma. Blood 114:3724, ASH Annual Meeting Abstract

    Article  Google Scholar 

  63. Lee E, Bannerman B, Fitzgerald M et al (2009) MLN9708 elicits pharmacodynamic response in the bone marrow compartment and has strong antitumor activity in a preclinical intraosseous model of plasma cell malignancy. Blood 114:1834, ASH Annual Meeting Abstract

    Google Scholar 

  64. Fitzgerald M, Cao Y, Bannerman B et al (2009) Evaluating the antitumor activity of MLN9708 in a disseminated mouse model of double transgenic iMyc Ca/Bcl-XL plasma cell malignancy. Blood 114:3835, ASH Annual Meeting Abstract

    Google Scholar 

  65. Janz S, Van Ness BG, Neppalli V et al (2009) The novel proteasome inhibitor MLN9708 demonstrates efficacy in a genetically-engineered mouse model of denovo plasma cell malignancy. Blood 114:3849, ASH Annual Meeting Abstract

    Google Scholar 

  66. Rodler ET, Infante JR, Siu LL et al (2010) First-in-human, phase I dose-escalation study of investigational drug MLN9708, a second-generation proteasome inhibitor, in advanced nonhematologic malignancies. J Clin Oncol 28:3071, ASCO Annual Meeting Abstract

    Google Scholar 

  67. Kloetzel PM, Ossendorp F (2004) Proteasome and peptidase function in MHC-class-I-mediated antigen presentation. Curr Opin Immunol 16(1):76–81

    Article  PubMed  CAS  Google Scholar 

  68. Kuhn DJ, Hunsucker SA, Chen Q, Voorhees PM, Orlowski M, Orlowski RZ (2009) Targeted inhibition of the immunoproteasome is a potent strategy against models of multiple myeloma that overcomes resistance to conventional drugs and nonspecific proteasome inhibitors. Blood 113(19):4667–76

    Article  PubMed  CAS  Google Scholar 

  69. Muchamuel T, Basler M, Aujay MA et al (2009) A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat Med 15(7):781–7

    Article  PubMed  CAS  Google Scholar 

  70. Trikha M, Corringham R, Klein B, Rossi JF (2003) Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 9(13):4653–65

    PubMed  CAS  Google Scholar 

  71. Yasui H, Hideshima T, Richardson PG, Anderson KC (2006) Novel therapeutic strategies ­targeting growth factor signalling cascades in multiple myeloma. Br J Haematol 132(4): 385–97

    PubMed  CAS  Google Scholar 

  72. Hong DS, Angelo LS, Kurzrock R (2007) Interleukin-6 and its receptor in cancer: implications for Translational Therapeutics. Cancer 110(9):1911–28

    Article  PubMed  CAS  Google Scholar 

  73. Voorhees PM, Chen Q, Kuhn DJ et al (2007) Inhibition of interleukin-6 signaling with CNTO 328 enhances the activity of bortezomib in preclinical models of multiple myeloma. Clin Cancer Res 13(21):6469–78

    Article  PubMed  CAS  Google Scholar 

  74. Voorhees PM, Chen Q, Small GW et al (2009) Targeted inhibition of interleukin-6 with CNTO 328 sensitizes pre-clinical models of multiple myeloma to dexamethasone-mediated cell death. Br J Haematol 145(4):481–90

    Article  PubMed  CAS  Google Scholar 

  75. Singh AV, Bandi M, Aujay M et al (2009) PR-924, a selective inhibitor of the immunoproteasome subunit LMP-7 blocks multiple myeloma cell growth both in vitro and In vivo. Blood 114:612, ASH Annual Meeting Abstract

    Article  Google Scholar 

  76. Jagannath S, Barlogie B, Berenson JR et al (2005) Bortezomib in recurrent and/or refractory multiple myeloma. Initial clinical experience in patients with impaired renal function. Cancer 103(6):1195–200

    Article  PubMed  CAS  Google Scholar 

  77. Chanan-Khan AA, Kaufman JL, Mehta J et al (2007) Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood 109(6):2604–6

    Article  PubMed  CAS  Google Scholar 

  78. Blade J, Sonneveld P, SanMiguel F et al (2008) Pegylated liposomal doxorubicin plus bortezomib in relapsed or refractory multiple myeloma: efficacy and safety in patients with renal function impairment. Clin Lymphoma Myeloma 8(6):352–5

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The author would like to acknowledge research support from the National Cancer Institute (P50-CA-142509, P01-CA-124787, R01-CA-102278, R01-CA-134786), as well as the Multiple Myeloma Research Foundation and The Leukemia & Lymphoma Society.

Author information

Authors and Affiliations

  1. The Department of Lymphoma & Myeloma, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 429, Houston, TX, 77030, USA

    Robert Z. Orlowski

  2. Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 429, Houston, TX, 77030, USA

    Robert Z. Orlowski

Authors
  1. Robert Z. Orlowski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Robert Z. Orlowski .

Editor information

Editors and Affiliations

  1. Dana-Farber Cancer Institute, Harvard Medical School, Binney St. 44 44, Boston, 02115, Massachusetts, USA

    Nikhil C. Munshi

  2. Dana-Farber Cancer Institute, Dept. Medical Oncology, Harvard Medical School, Binney St. 44, Boston, 02115, Massachusetts, USA

    Kenneth C. Anderson

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Orlowski, R.Z. (2013). Novel Proteasome Inhibitors. In: Munshi, N., Anderson, K. (eds) Advances in Biology and Therapy of Multiple Myeloma. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5260-7_7

Download citation

Publish with us

Policies and ethics

Search

Navigation