BORTEZOMIB

 

Bortezomib (Velcade ®) is a proteasome inhibitor. It has been approved by the FDA in May 2003.

Dose: IV push in 4 doses for each cycle, on days 1, 4, 8, and 11 every 21 days. In January 2012, the FDA approved the SC route of administration. This decreases the rate of neuropathy. 

Most relevant side effects are:
 - Renal dysfunction
 - Decreased blood counts
 - Neuropathy
   Peripheral neuropathy (PN) is common and dose-limiting.
   It usually occurs within the first 5 cycles. Rare thereafter.
   It usually improves or resolves after discontinuation of bortezomib, after a median of 3 months.
   It manifests with:
       Hyperesthesia = neuropathic pain (most common), mainly in fingertips and toes
       Hypoesthesia = sensory loss (numbness)
       Paresthesias = changes in proprioception (tingling, pinprick sensation)
   Occasionally neuropathy involves the autonomic system, with postural dizziness, diarrhea, urinary
   disturbances, impotence, and other symptoms.
 - Injection site reactions (with SC injections)

 

Dose modifications of IV bortezomib with PN:

   GRADE   DEFINITION                      DOSE MODIFICATION
   
 1     Only paresthesias or pain       None if paresthesias only
                                           Reduce dose to 1.0 mg/m2 if pain
     2     Impaired function but not ADL   Reduce dose to 1.0 mg/m2
     3     Impaired ADL                    Hold until resolution of symptoms, then
                                           start again at 0.7 mg/m2 once a week
     4     Sensorimotor neuropathy that
           significantly impairs ADL       Discontinue bortezomib

 

 

 

Proteasome inhibition in cancer: development of PS-341.
Semin Oncol. 2001 Dec;28(6):613-9.
Adams J.

[Review]

Vitamin C inactivates the proteasome inhibitor PS-341 in human cancer cells.
Clin Cancer Res. 2006 Jan 1;12(1):273-80.
Zou W, Yue P, Lin N, He M, Zhou Z, Lonial S, Khuri FR, Wang B, Sun SY.
These authors studied the interaction between vitamin C and bortezomib in human cancer cell lines. They found that vitamin C abrogated the ability of bortezomib to inhibit the proteasome activity and induce apoptosis. There was a direct chemical interaction between vitamin C and bortezomib. Vitamin C directly binds to bortezomib and it may suppress the anticancer activity of bortezomib. These findings are relevant because many cancer patients routinely take multivitamins.

Efficacy of single-agent bortezomib vs. single-agent thalidomide in patients with relapsed or refractory multiple myeloma: a systematic comparison.
Eur J Haematol. 2007 Aug;79(2):93-9.
Prince HM, Adena M, Smith DK, Hertel J.

[Review]
This systematic review evaluates the efficacy of single-agent bortezomib vs single-agent thalidomide in patients with relapsed/refractory multiple myeloma. Authors included 1 bortezomib study with 333 patients and 15 thalidomide studies with 1007 patients). Authors conclude that bortezomib, when compared with thalidomide, induces a significantly higher response rate (41-53% vs 22-32%) and complete remission rate.

Green tea polyphenols block the anticancer effects of bortezomib and other boronic acid-based proteasome inhibitors.
Golden EB, Lam PY, Kardosh A, Gaffney KJ, Cadenas E, Louie SG, Petasis NA, Chen TC, Schönthal AH.
Blood. 2009 Jun 4;113(23):5927-37.
This study explores the interactions between bortezomib and some components of green tea in myeloma cell lines. Surprisingly, the authors found that several constituents of green tea, such as epigallocatechin gallate (EGCG) and other polyphenols prevented tumor cell death induced by bortezomib. These findings are important, because some cancer patients self-medicate with herbs, hoping to increase the anticancer effect of chemotherapy. Since green tea polyphenols may negate the therapeutic efficacy of bortezomib, the authors suggest that patients receiving bortezomib should avoid a large consumption of green tea products.

Prospective comparison of subcutaneous versus intravenous administration of bortezomib in patients with multiple myeloma.
Haematologica. 2008 Dec;93(12):1908-11.
Moreau P, Coiteux V, Hulin C, Leleu X, van de Velde H, Acharya M, Harousseau JL.
This is a phase I study of 24 patients with multiple myeloma randomized to receive bortezomib by standard IV bolus (12 patients) or SC injection (12 patients). Injection concentration was 1 mg/mL. SC administration resulted in similar systemic availability, pharmacodynamic activity, response rate, and toxicity profile to those seen with IV administration.

Efficacy and safety of once-weekly bortezomib in multiple myeloma patients.
Blood. 2010 Dec 2;116(23):4745-53.
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.
372 patients received bortezomib once a week and 139 twice a week. Results:
  - Outcomes at 3 years were similar, including CR rate, progression-free survival, and overall survival
  - Grade 3/4 peripheral neuropathy was seen in 8% of patients with the once a week dosing and in 28% with twice a week dosing
  - Discontinuation of treatment was necessary in 5% of patients with the once a week dosing and in 15% with twice a week dosing
  - Grade 2 peripheral neuropathy improved or resolved in two-thirds of patients, after a median of 2-3 months

Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study.
Lancet Oncol. 2011 May;12(5):431-40.
Moreau P, Pylypenko H, Grosicki S, Karamanesht I, Leleu X, Grishunina M, Rekhtman G, Masliak Z, Robak T, Shubina A, Arnulf B, Kropff M, Cavet J, Esseltine DL, Feng H, Girgis S, van de Velde H, Deraedt W, Harousseau JL.
This is a randomised, phase III study comparing efficacy and toxicity of bortezomib given IV (74 patients) vs SC (148 patients). Bortezomib was given to patients with relapsed myeloma, at a dose of 1.3 mg/m2 on days 1, 4, 8, 11 every 21 days, for a median of 8 cycles (range: 1-10).
SC injection were done reconstituting 3.5 mg with 1.4 mL NS (= 2.5 mg/mL). The drug was injected SC in the abdomen or the thighs, rotating the sites.
Results:
  - Response rate: 42% in both groups
  - Median time to progression: 9.4 months in the IV group and 10.4 months in the SC group (p= 0.39)
  - Overall survival at 1 year: 77% in the IV group and 73% in the SC group (p= 0·5)
  - Grade 3-4 adverse events: 70% in the SC group and 57% in the IV group (most commonly cytopenias)
  - Local reactions consisted of transient erythema
  - Peripheral neuropathy of any grade: 53% in the IV group and 38% in the SC group
  - Peripheral neuropathy of grade 3 or worse: 16% in the IV group and 6% in the SC group
The conclusion was that SC bortezomib had similar efficacy and decreased toxicity.

 

 

MECHANISM OF ACTION

Bortezomib is a dipeptide boronate that inhibits the chymotrypsin-like activity of the 26S proteasome. It inhibits the ubiquitin-mediated proteasome degradative pathway. Proteasome inhibitors induce the accumulation of misfolded proteins within the endoplasmic reticulum.

Proteins tagged with ubiquitin are degraded in the proteasome enzyme complex.
The 26S proteasome consists of 2 19S regulatory complexes and a 20S proteolytic core.
The 19S regulatory complexes bind the ubiquinated proteins, and direct them to the 20S core.
The 20S proteolytic core is made of two alpha-subunit rings and two beta-subunit rings. The proteolysis is mediated by 3 beta-subunits:
  - beta1 subunit = caspase-like activity
  - beta2 subunit = trypsin-like subunit
  - beta5 subunit = chymotrypsin-like activity

 

Molecular sequelae of proteasome inhibition in human multiple myeloma cells.
Proc Natl Acad Sci U S A. 2002 Oct 29;99(22):14374-9.
Mitsiades N, Mitsiades CS, Poulaki V, Chauhan D, Fanourakis G, Gu X, Bailey C, Joseph M, Libermann TA, Treon SP, Munshi NC, Richardson PG, Hideshima T, Anderson KC.

Molecular mechanisms mediating antimyeloma activity of proteasome inhibitor PS-341.
Blood. 2003 Feb 15;101(4):1530-4.
Hideshima T, Mitsiades C, Akiyama M, Hayashi T, Chauhan D, Richardson P, Schlossman R, Podar K, Munshi NC, Mitsiades N, Anderson KC.

Response to bortezomib is associated to osteoblastic activation in patients with multiple myeloma.
Br J Haematol. 2005 Oct;131(1):71-3.
Zangari M, Esseltine D, Lee CK, Barlogie B, Elice F, Burns MJ, Kang SH, Yaccoby S, Najarian K, Richardson P, Sonneveld P, Tricot G.
Response to bortezomib is associated with a significant increase in alkaline phosphatase.

Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells.
Blood. 2006 Jun 15;107(12):4907-16.
Obeng EA, Carlson LM, Gutman DM, Harrington WJ Jr, Lee KP, Boise LH.

Bortezomib down-regulates the cell-surface expression of HLA class I and enhances natural killer cell-mediated lysis of myeloma.
Blood. 2008 Feb 1;111(3):1309-17.
Shi J, Tricot GJ, Garg TK, Malaviarachchi PA, Szmania SM, Kellum RE, Storrie B, Mulder A, Shaughnessy JD Jr, Barlogie B, van Rhee F
.

Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein.
Blood. 2008 Sep 15;112(6):2489-99.
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.
These authors found that resistance of cells to bortezomib involved an Ala49Thr mutation located in the PSMB5 protein (the bortezomib-binding pocket of the proteasome beta5-subunit), and overexpression of PSMB5.

Histone deacetylases are critical targets of bortezomib-induced cytotoxicity in multiple myeloma.
Blood. 2010 Jul 22;116(3):406-17.
Kikuchi J, Wada T, Shimizu R, Izumi T, Akutsu M, Mitsunaga K, Noborio-Hatano K, Nobuyoshi M, Ozawa K, Kano Y, Furukawa Y.

 

 

REVERSIBILITY OF RENAL INSUFFICIENCY

Reversibility of renal impairment in patients with multiple myeloma treated with bortezomib-based regimens: identification of predictive factors.
Clin Lymphoma Myeloma. 2009 Aug;9(4):302-6.
Dimopoulos MA, Roussou M, Gavriatopoulou M, Zagouri F, Migkou M, Matsouka C, Barbarousi D, Christoulas D, Primenou E, Grapsa I, Terpos E, Kastritis E.
This study describes the outcomes of renal response in 46 myeloma patients with renal insufficiency treated with bortezomib + dexamethasone. Improvement of the renal function was observed in 59% of patients within a short period (median: 11 days, range: 8-41 days). Normalization of the renal function was seen in 30% of cases. 2 of 9 patients who required hemodialysis became dialysis independent.

Light chain-induced acute renal failure can be reversed by bortezomib-doxorubicin-dexamethasone in multiple myeloma: results of a phase II study.
J Clin Oncol. 2010 Oct 20;28(30):4635-41.
Ludwig H, Adam Z, Hajek R, Greil R, Tóthová E, Keil F, Autzinger EM, Thaler J, Gisslinger H, Lang A, Egyed M, Womastek I, Zojer N.
68 patients with light-chain myeloma and renal insufficiency (GFR <50 mL/min) received BDD therapy:
  - Bortezomib 1.0-1.3 mg/m2 IV on days 1, 4, 8, 11
  - Doxorubicin 9 mg/m2 IV on days 1, 4 or 1, 4, 8, 11
  - Dexamethasone 40 mg PO on days 1, 4, 8, 11
Renal response: 62%.
  - Renal CR: 31% (defined as GFR = or > 60)
  - Renal PR: 7% (defined as GFR increase >100%, from <15 to 30-60)
  - Renal MR: 24% (defined as GFR increase >50%, from <15 to <30, or from 15-30 to 30-60)

 

INDUCTION THERAPY

Bortezomib therapy alone and in combination with dexamethasone for previously untreated symptomatic multiple myeloma.
Br J Haematol. 2005 Jun;129(6):776-83.
Jagannath S, Durie BG, Wolf J, Camacho E, Irwin D, Lutzky J, McKinley M, Gabayan E, Mazumder A, Schenkein D, Crowley J.
32  patients with newly diagnosed myeloma were treated with bortezomib for a maximum of 6 cycles. Dexamethasone was added if less than PR was achieved after 2 cycles or less than CR was achieved after 4 cycles. Response rate was 88%, CR 6%, and near-CR (IFE positive) 19%. The most common significant (grade 2 or higher) adverse events were:
  - Peripheral neuropathy (31%), reversible in 50% of cases within a median of 3 months
  - Myalgia (28%)
  - Constipation (28%)
  - Fatigue (25%)

Bortezomib plus dexamethasone as induction treatment prior to autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: results of an IFM phase II study.
Haematologica. 2006 Nov;91(11):1498-505.
Harousseau JL, Attal M, Leleu X, Troncy J, Pegourie B, Stoppa AM, Hulin C, Benboubker L, Fuzibet JG, Renaud M, Moreau P, Avet-Loiseau H.
This study used bortezomib (+ dexamethasone) as induction therapy of patients with newly diagnosed myeloma, in the attempt of increase the CR rate before autologous SCT. Among 48 patients, response rate was 66%, CR 21%, and very good partial remission 10%.

Phase II PETHEMA trial of alternating bortezomib and dexamethasone as induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: efficacy and clinical implications of tumor response kinetics.
J Clin Oncol. 2007 Oct 1;25(28):4452-8.
Rosiñol L, Oriol A, Mateos MV, Sureda A, García-Sánchez P, Gutiérrez N, Alegre A, Lahuerta JJ, de la Rubia J, Herrero C, Liu X, Van de Velde H, San Miguel J, Bladé J.
40 patients with newly diagnosed myeloma received bortezomib and dexamethasone on an alternating basis as induction therapy before autologous SCT. Bortezomib was given at 1.3 mg/m2 IV on days 1, 4, 8, and 11 on cycles 1, 3, and 5, and dexamethasone was given at 40 mg PO on days 1-4, 9-12, and 17-20 on cycles 2, 4, and 6. Response rate was 65% (including 12.5% CR), and minor response 17.5%. Disease remission was achieved rapidly, usually within the first 2 cycles. Response rate after ASCT was 88%, with 33% CR and 22% VGPR.

Primary therapy with single agent bortezomib as induction, maintenance and re-induction in patients with high-risk myeloma: results of the ECOG E2A02 trial.
Leukemia. 2010 Aug;24(8):1406-11.
Dispenzieri A, Jacobus S, Vesole DH, Callandar N, Fonseca R, Greipp PR.
At the time of this publications, many myeloma experts believed that bortezomib overcame the negative impact of adverse cytogenetics in multiple myeloma. This study utilized bortezomib as primary therapy (i.e., induction x8 cycles, maintenance with 1 dose every other week, indefinitely, and salvage therapy - without stem cell transplantation) in patients with high-risk myeloma. Results:
  - Response rate: 48%
  - Median progression-free survival: 8 months (95% CI 6-12 months)
  - Overall survival at 1 year: 88%
  - Overall survival at 2 years: 76%

Bortezomib plus dexamethasone is superior to vincristine plus doxorubicin plus dexamethasone as induction treatment prior to autologous stem-cell transplantation in newly diagnosed multiple myeloma: results of the IFM 2005-01 phase III trial.
J Clin Oncol. 2010 Oct 20;28(30):4621-9.
Harousseau JL, Attal M, Avet-Loiseau H, Marit G, Caillot D, Mohty M, Lenain P, Hulin C, Facon T, Casassus P, Michallet M, Maisonneuve H, Benboubker L, Maloisel F, Petillon MO, Webb I, Mathiot C, Moreau P.

Bortezomib-based versus nonbortezomib-based induction treatment before autologous stem-cell transplantation in patients with previously untreated multiple myeloma: a meta-analysis of phase III randomized, controlled trials.
J Clin Oncol. 2013 Sep 10;31(26):3279-87.
Sonneveld P, Goldschmidt H, Rosiñol L, Bladé J, Lahuerta JJ, Cavo M, Tacchetti P, Zamagni E, Attal M, Lokhorst HM, Desai A, Cakana A, Liu K, van de Velde H, Esseltine DL, Moreau P.
This meta-analysis includes 1,572 myeloma patients who underwent autologous stem cell transplantation. 787 were treated with bortezomib-based induction therapy, and 785 treated with a non-bortezomib based induction chemotherapy. Results favored the first group:
  - Rate of nCR + CR: 38% in the bortezomib group and 24% in the non-bortezomib group
  - Median progression-free survival: 36 months in the bortezomib group and 29 months in the non-bortezomib group
  - 3-year overall survival: 80% in the bortezomib group and 75% in the non-bortezomib group

 

POST-TRANSPLANT MAINTENANCE/CONSOLIDATION

Bortezomib after dose-reduced allogeneic stem cell transplantation for multiple myeloma to enhance or maintain remission status.
Exp Hematol. 2006 Jun;34(6):770-5.
Kröger N, Zabelina T, Ayuk F, Atanackovic D, Schieder H, Renges H, Zander A.
18 patients with myeloma treated with mini-allogeneic stem cell transplantation received at least 2 cycles of bortezomib as consolidation therapy. In patients with measurable disease, CR was 30%, PR 50%, and minor response 20%.

 

SALVAGE THERAPY AFTER TRANSPLANT

Bortezomib with or without dexamethasone in relapsed multiple myeloma following allogeneic hematopoietic cell transplantation.
Haematologica. 2006 Jun;91(6):837-9.
Bruno B, Patriarca F, Sorasio R, Mattei D, Montefusco V, Peccatori J, Bonifazi F, Petrucci MT, Milone G, Guidi S, Giaccone L, Rotta M, Fanin R, Boccadoro M, Corradini P; Gruppo Italiano Trapianti di Midollo.
23 patients with myeloma in relapse after allogeneic stem cell transplant received bortezomib. Response rate was 61%, CR 22%, and progression free survival 6 months.

 

 


Giampaolo Talamo, M.D.