Population-based meta-analysis of bortezomib exposure–response relationships in multiple myeloma patients


Bortezomib (Velcade®) is a reversible proteasome inhibitor that shows potent antineoplastic activity, by inhibiting the constitutively increased proteasome activity in myeloma cells, and is approved as a first-line therapy for multiple myeloma (MM). Although clinically successful, bortezomib exhibits a relatively narrow therapeutic index and can induce dose-limiting toxicities such as thrombocytopenia. This study aims to develop a quantitative and predictive pharmacodynamic model to investigate bortezomib dosing-regimens in a rational and efficient manner. Mean temporal profiles of bortezomib pharmacokinetics, proteasome activity, M-protein concentrations, and platelet counts following bortezomib monotherapy were extracted from published clinical studies. A population–based meta-analysis of bortezomib anti-myeloma activity and thrombocytopenia was conducted sequentially with a Stochastic Approximation Expectation Maximization algorithm in Monolix. The final pharmacodynamic model integrates drug-target interactions and cell signaling dynamics with temporal biomarkers of clinical efficacy and toxicity. Bortezomib pharmacokinetics, disease progression, and platelet dynamic profiles were well characterized in MM patients, and a local sensitivity analysis of the final model suggests that increased proteasome concentration could ultimately attenuate bortezomib antineoplastic activity in MM patients. In addition, model simulations confirm that a once-weekly dosing schedule represents an optimal therapeutic regimen with comparable antineoplastic activity but significantly reduced risk of thrombocytopenia. In conclusion, a pharmacodynamic model was successfully developed, which provides a quantitative, mechanism-based platform for probing bortezomib dosing-regimens. Further research is needed to determine whether this model could be used to individualize bortezomib regimens to maximize antineoplastic efficacy and minimize thrombocytopenia during MM treatment.

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

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 99

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5


  1. 1.

    Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC (2009) Multiple myeloma. Lancet 374:324–339

  2. 2.

    Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Blade J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC, Assessment of Proteasome Inhibition for Extending Remissions I (2005) Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 352:2487–2498

  3. 3.

    Bross PF, Kane R, Farrell AT, Abraham S, Benson K, Brower ME, Bradley S, Gobburu JV, Goheer A, Lee SL, Leighton J, Liang CY, Lostritto RT, McGuinn WD, Morse DE, Rahman A, Rosario LA, Verbois SL, Williams G, Wang YC, Pazdur R (2004) Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res 10:3954–3964

  4. 4.

    Leveque D, Carvalho MC, Maloisel F (2007) Review. Clinical pharmacokinetics of bortezomib. Vivo. 21:273–278

  5. 5.

    Uttamsingh V, Lu C, Miwa G, Gan LS (2005) Relative contributions of the five major human cytochromes P450, 1A2, 2C9, 2C19, 2D6, and 3A4, to the hepatic metabolism of the proteasome inhibitor bortezomib. Drug Metab Dispos. 33:1723–1728

  6. 6.

    Zhang L, Mager DE (2015) Physiologically-based pharmacokinetic modeling of target-mediated drug disposition of bortezomib in mice. J Pharmacokinet Pharmacodyn 42:541–552

  7. 7.

    Chen D, Frezza M, Schmitt S, Kanwar J, Dou QP (2011) Bortezomib as the first proteasome inhibitor anticancer drug: current status and future perspectives. Curr Cancer Drug Targets 11:239–253

  8. 8.

    Jakob C, Egerer K, Liebisch P, Turkmen S, Zavrski I, Kuckelkorn U, Heider U, Kaiser M, Fleissner C, Sterz J, Kleeberg L, Feist E, Burmester GR, Kloetzel PM, Sezer O (2007) Circulating proteasome levels are an independent prognostic factor for survival in multiple myeloma. Blood 109:2100–2105

  9. 9.

    Chudasama VL, Ovacik MA, Abernethy DR, Mager DE (2015) Logic-based and cellular pharmacodynamic modeling of bortezomib responses in U266 human myeloma cells. J Pharmacol Exp Ther 354:448–458

  10. 10.

    Bringhen S, Larocca A, Rossi D, Cavalli M, Genuardi M, Ria R, Gentili S, Patriarca F, Nozzoli C, Levi A, Guglielmelli T, Benevolo G, Callea V, Rizzo V, Cangialosi C, Musto P, De Rosa L, Liberati AM, Grasso M, Falcone AP, Evangelista A, Cavo M, Gaidano G, Boccadoro M, Palumbo A (2010) Efficacy and safety of once-weekly bortezomib in multiple myeloma patients. Blood 116:4745–4753

  11. 11.

    Mould DR (2012) Model-based meta-analysis: an important tool for making quantitative decisions during drug development. Clin Pharmacol Ther 92:283–286

  12. 12.

    Moreau P, Karamanesht II, Domnikova N, Kyselyova MY, Vilchevska KV, Doronin VA, Schmidt A, Hulin C, Leleu X, Esseltine DL, Venkatakrishnan K, Skee D, Feng H, Girgis S, Cakana A, van de Velde H, Deraedt W, Facon T (2012) Pharmacokinetic, pharmacodynamic and covariate analysis of subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma. Clin Pharmacokinet 51:823–829

  13. 13.

    Ogawa Y, Tobinai K, Ogura M, Ando K, Tsuchiya T, Kobayashi Y, Watanabe T, Maruyama D, Morishima Y, Kagami Y, Taji H, Minami H, Itoh K, Nakata M, Hotta T (2008) Phase I and II pharmacokinetic and pharmacodynamic study of the proteasome inhibitor bortezomib in Japanese patients with relapsed or refractory multiple myeloma. Cancer Sci 99:140–144

  14. 14.

    Papandreou CN, Daliani DD, Nix D, Yang H, Madden T, Wang X, Pien CS, Millikan RE, Tu SM, Pagliaro L, Kim J, Adams J, Elliott P, Esseltine D, Petrusich A, Dieringer P, Perez C, Logothetis CJ (2004) Phase I trial of the proteasome inhibitor bortezomib in patients with advanced solid tumors with observations in androgen-independent prostate cancer. J Clin Oncol 22:2108–2121

  15. 15.

    Reece DE, Sullivan D, Lonial S, Mohrbacher AF, Chatta G, Shustik C, Burris H 3rd, Venkatakrishnan K, Neuwirth R, Riordan WJ, Karol M, von Moltke LL, Acharya M, Zannikos P, Keith Stewart A (2011) Pharmacokinetic and pharmacodynamic study of two doses of bortezomib in patients with relapsed multiple myeloma. Cancer Chemother Pharmacol. 67:57–67

  16. 16.

    Berenson JR, Jagannath S, Barlogie B, Siegel DT, Alexanian R, Richardson PG, Irwin D, Alsina M, Rajkumar SV, Srkalovic G, Singhal S, Limentani S, Niesvizky R, Esseltine DL, Trehu E, Schenkein DP, Anderson K (2005) Safety of prolonged therapy with bortezomib in relapsed or refractory multiple myeloma. Cancer 104:2141–2148

  17. 17.

    Jagannath S, Barlogie B, Berenson J, Siegel D, Irwin D, Richardson PG, Niesvizky R, Alexanian R, Limentani SA, Alsina M, Adams J, Kauffman M, Esseltine DL, Schenkein DP, Anderson KC (2004) A phase 2 study of two doses of bortezomib in relapsed or refractory myeloma. Br J Haematol. 127:165–172

  18. 18.

    Kropff M, Bisping G, Schuck E, Liebisch P, Lang N, Hentrich M, Dechow T, Kroger N, Salwender H, Metzner B, Sezer O, Engelhardt M, Wolf HH, Einsele H, Volpert S, Heinecke A, Berdel WE, Kienast J, Deutsche Studiengruppe Multiples M (2007) Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 138:330–337

  19. 19.

    Lonial S, Waller EK, Richardson PG, Jagannath S, Orlowski RZ, Giver CR, Jaye DL, Francis D, Giusti S, Torre C, Barlogie B, Berenson JR, Singhal S, Schenkein DP, Esseltine DL, Anderson J, Xiao H, Heffner LT, Anderson KC, Investigators SC (2005) Risk factors and kinetics of thrombocytopenia associated with bortezomib for relapsed, refractory multiple myeloma. Blood 106:3777–3784

  20. 20.

    Tokuhira M, Watanabe R, Nemoto T, Hanzawa K, Sagawa M, Tomikawa T, Mori S, Kizaki M (2011) Successful treatment with a modified bortezomib schedule of weekly and longer intervals for patients with refractory/resistance multiple myeloma. Leuk Res. 35:591–597

  21. 21.

    Van Wart SA, Shoaf SE, Mallikaarjun S, Mager DE (2014) Population-based meta-analysis of furosemide pharmacokinetics. Biopharm Drug Dispos. 35:119–133

  22. 22.

    Levy G (1994) Pharmacologic target-mediated drug disposition. Clin Pharmacol Ther. 56:248–252

  23. 23.

    Mager DE, Krzyzanski W (2005) Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition. Pharm Res. 22:1589–1596

  24. 24.

    Friberg LE, Henningsson A, Maas H, Nguyen L, Karlsson MO (2002) Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol. 20:4713–4721

  25. 25.

    Nayak MK, Kulkarni PP, Dash D (2013) Regulatory role of proteasome in determination of platelet life span. J Biol Chem. 288:6826–6834

  26. 26.

    Zhang L, Mager DE (2019) Systems modeling of bortezomib and dexamethasone combinatorial effects on bone homeostasis in multiple myeloma patients. J Pharm Sci. 108:732–740

  27. 27.

    Dispenzieri A, Lacy MQ, Greipp PR (2004) Multiple myeloma. In: Gertzand MA, Greipp PR (eds) Hematologic malignancies: multiple myeloma and related plasma cell disorders. Springer, Berlin, pp 53–110

  28. 28.

    Harrold JM, Straubinger RM, Mager DE (2012) Combinatorial chemotherapeutic efficacy in non-Hodgkin lymphoma can be predicted by a signaling model of CD20 pharmacodynamics. Cancer Res. 72:1632–1641

  29. 29.

    Kirouac DC, Du JY, Lahdenranta J, Overland R, Yarar D, Paragas V, Pace E, McDonagh CF, Nielsen UB, Onsum MD (2013) Computational modeling of ERBB2-amplified breast cancer identifies combined ErbB2/3 blockade as superior to the combination of MEK and AKT inhibitors. Sci Signal. 6:ra68.

  30. 30.

    Lavielle M (2013) Monolix—a software for the analysis of nonlinear mexed effects models. The Monolix Group,

  31. 31.

    Bergstrand M, Hooker AC, Wallin JE, Karlsson MO (2011) Prediction-corrected visual predictive checks for diagnosing nonlinear mixed-effects models. AAPS J. 13:143–151

  32. 32.

    Ihaka R, Gentleman R (1996) R: A language for data analysis and graphics. J Comput Graph Stat. 5:299–314

  33. 33.

    Dick LR, Fleming PE (2010) Building on bortezomib: second-generation proteasome inhibitors as anti-cancer therapy. Drug Discov Today. 15:243–249

  34. 34.

    Jonsson F, Ou Y, Claret L, Siegel D, Jagannath S, Vij R, Badros A, Aggarwal S, Bruno R (2015) A tumor growth inhibition model based on m-protein levels in subjects with relapsed/refractory multiple myeloma following single-agent carfilzomib use. CPT Pharmacometrics Syst Pharmacol. 4:711–719

  35. 35.

    Akhlaghi F, Monbaliu J, Kadambi V, Li Y (2009) Blood and plasma pharmacokinetics of bortezomib in relation to blood 20S proteasome activity after single and multiple dosing in cynomongolus monkeys. American Conference on Pharmacometrics

  36. 36.

    Giles C (1981) The platelet count and mean platelet volume. Br J Haematol. 48:31–37

  37. 37.

    Sasaki T, Takane H, Ogawa K, Isagawa S, Hirota T, Higuchi S, Horii T, Otsubo K, Ieiri I (2011) Population pharmacokinetic and pharmacodynamic analysis of linezolid and a hematologic side effect, thrombocytopenia, in Japanese patients. Antimicrob Agents Chemother. 55:1867–1873

  38. 38.

    Durie BG, Harousseau JL, Miguel JS, Blade J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV, International Myeloma Working G (2006) International uniform response criteria for multiple myeloma. Leukemia 20:1467–1473

  39. 39.

    Kumar S, Rajkumar SV (2008) Many facets of bortezomib resistance/susceptibility. Blood 112:2177–2178

  40. 40.

    Oerlemans R, Franke NE, Assaraf YG, Cloos J, van Zantwijk I, Berkers CR, Scheffer GL, Debipersad K, Vojtekova K, Lemos C, van der Heijden JW, Ylstra B, Peters GJ, Kaspers GL, Dijkmans BA, Scheper RJ, Jansen G (2008) Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood 112:2489–2499

  41. 41.

    Shaughnessy JD Jr, Qu P, Usmani S, Heuck CJ, Zhang Q, Zhou Y, Tian E, Hanamura I, van Rhee F, Anaissie E, Epstein J, Nair B, Stephens O, Williams R, Waheed S, Alsayed Y, Crowley J, Barlogie B (2011) Pharmacogenomics of bortezomib test-dosing identifies hyperexpression of proteasome genes, especially PSMD4, as novel high-risk feature in myeloma treated with Total Therapy 3. Blood 118:3512–3524

  42. 42.

    Mager DE, Mascelli MA, Kleiman NS, Fitzgerald DJ, Abernethy DR (2003) Simultaneous modeling of abciximab plasma concentrations and ex vivo pharmacodynamics in patients undergoing coronary angioplasty. J Pharmacol Exp Ther. 307:969–976

  43. 43.

    Hamilton AL, Eder JP, Pavlick AC, Clark JW, Liebes L, Garcia-Carbonero R, Chachoua A, Ryan DP, Soma V, Farrell K, Kinchla N, Boyden J, Yee H, Zeleniuch-Jacquotte A, Wright J, Elliott P, Adams J, Muggia FM (2005) Proteasome inhibition with bortezomib (PS-341): a phase I study with pharmacodynamic end points using a day 1 and day 4 schedule in a 14-day cycle. J Clin Oncol. 23:6107–6116

  44. 44.

    Yao R, Hu X, Zhou S, Zhang Q, Huang H, Sun N, Guo W, Yu K, Lin Y (2019) Once-weekly bortezomib had similar effectiveness and lower thrombocytopenia occurrence compared with twice-weekly bortezomib regimen in treating patients with newly diagnosed multiple myeloma in China. Medicine (Baltimore). 98:e17147

  45. 45.

    Pei XY, Dai Y, Felthousen J, Chen S, Takabatake Y, Zhou L, Youssefian LE, Sanderson MW, Bodie WW, Kramer LB, Orlowski RZ, Grant S (2014) Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells. PLoS ONE 9:e89064

  46. 46.

    Ahn JE, French JL (2010) Longitudinal aggregate data model-based meta-analysis with NONMEM: approaches to handling within treatment arm correlation. J Pharmacokinet Pharmacodyn. 37:179–201

  47. 47.

    Argyriou AA, Iconomou G, Kalofonos HP (2008) Bortezomib-induced peripheral neuropathy in multiple myeloma: a comprehensive review of the literature. Blood 112:1593–1599

  48. 48.

    Kapoor P, Ramakrishnan V, Rajkumar SV (2012) Bortezomib combination therapy in multiple myeloma. Semin Hematol. 49:228–242

  49. 49.

    Orlowski RZ, Nagler A, Sonneveld P, Blade J, Hajek R, Spencer A, San Miguel J, Robak T, Dmoszynska A, Horvath N, Spicka I, Sutherland HJ, Suvorov AN, Zhuang SH, Parekh T, Xiu L, Yuan Z, Rackoff W, Harousseau JL (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. 25:3892–3901

  50. 50.

    Petrucci MT, Giraldo P, Corradini P, Teixeira A, Dimopoulos MA, Blau IW, Drach J, Angermund R, Allietta N, Broer E, Mitchell V, Blade J (2013) A prospective, international phase 2 study of bortezomib retreatment in patients with relapsed multiple myeloma. Br J Haematol. 160:649–659

  51. 51.

    Quach H, Horvath N, Cannell P, Mikhael JR, Butcher BE, Prince HM (2009) Safety and efficacy results from an international expanded access programme to bortezomib for patients with relapsed and/or refractory multiple myeloma: a subset analysis of the Australian and New Zealand data of 111 patients. Intern Med J. 39:290–295

Download references


This study was supported, in part, by the National Institutes of Health [Grant GM57980]. The authors would like to thank Dr. Vaishali Chudasama, Dr. Sihem Ait-Oudhia, and Dr. Scott Van Wart for their helpful suggestions during model development. The authors wish to express their gratitude to the authors of the referenced studies from which the data was obtained, as their contribution made this analysis possible.

Author information

Correspondence to Donald E. Mager.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 84 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Mager, D.E. Population-based meta-analysis of bortezomib exposure–response relationships in multiple myeloma patients. J Pharmacokinet Pharmacodyn (2020).

Download citation


  • Multiple myeloma
  • Bortezomib
  • Tumor burden
  • Thrombocytopenia
  • Pharmacokinetics
  • Pharmacodynamics