The presentation discusses role of proteasome inhibitors in the treatment of multiple myeloma.

1. Alok Gupta

2.  The Ubiquitin-Proteasome Pathway
 80% of intracellular protein degradation.

6.  Imajoh-Ohmi,et al. Lactacystin, a specific inhibitor
of the proteasome, induces apoptosis in human
monoblast U937 cells. Biochem. Biophys.
Res.Commun., 217: 1070–1077, 1995.
 Fujita, E, et al. Enhancement of CPP32-like activity
in the TNF-treated U937 cells by the proteasome
inhibitors. Biochem. Biophys. Res. Commun., 224:
74–79, 1996.

7.  Orlowski, et al. Tumor growth inhibition induced in
a murine model of human Burkitt’s lymphoma by a
proteasome inhibitor. Cancer Res., 58: 4342–4348,
1998.
◦ peptidyl aldehyde

8.  Dipeptide boronic acid analogue that
possesses pharmacological characteristics
better suited for clinical testing in patients.
◦ Adams, J, et al.Proteasome inhibitors: a novel class of potent and effective
antitumor agents. Cancer Res., 59: 2615–2622, 1999.
PS-341= BORTEZOMIB

10.  Proteasome inhibition seem incompatible
with life.

11.  CLL cells were 10-times more sensitive to
lactacystin than normal lymphocytes
◦ Masdehors, P et al. Increased sensitivity of CLL-derived lymphocytes to apoptotic
death activation by the proteasome- specific inhibitor lactacystin. Br. J. Haematol.,
105: 752–757, 1999.
 Malignant plasma cells from multiple
myeloma patients were 20–40-times more
sensitive to bortezomib-mediated apoptosis
than blood mononuclear cells
◦ Hideshima, T., The proteasome inhibitor PS-341 inhibits growth, induces apoptosis,
and overcomes drug resistance in human multiple myeloma cells. Cancer Res., 61:
3071–3076, 2001.

15.  Dipeptide boronic acid derivative
 Highly, specifically and reversibly inhibit
proteasome activity.
 Inhibits the chymotryptic-like peptidase
activity of the proteasome.

17.  ER-mediated apoptosis- accumulation of
misfolded proteins(immunoglobulins).
 Modulation of the bone marrow
microenvironment Decreased IL-6 levels.
 Decreased transcription of pro-angiogenic
factors: growth-regulated oncogene α and
vascular endothelial growth factor (VEGF).
 Sensitize tumour cells to other
chemotherapeutic agents

18. 1. Pharmacokinetic and pharmacodynamic
evaluations of bortezomib
2. The dose and schedule of administration,
3. The safety profile,
4. The first evidence of efficacy in
haematological malignancies, specially in
patients with MM.

19.  Aghajanian C, et al. A Phase I trial of the novel
proteasome inhibitor PS341 in advanced solid tumour
malignancies. Clinical Cancer Research 2002; 8: 2505–
2511.
 Orlowski RZ, et al. Phase I trial of the proteasome
inhibitor PS-341 in patients with refractory hematologic
malignancies. Journal of Clinical Oncology 2002; 20:
4420–4427.

20.  Plasma concentration decline in a biphasic manner.
◦ distribution half-life : 0.22 and 0.46 hours
◦ elimination half-life : more than 10 hours
 Reversible inhibition of the proteasome’s chymotrypsin-like
activity- dose and time dependent .

21.  Inactivated through oxidative deboronation by both
cytochrome P450 mediated (mainly CYP3A4 and 2C19)
 Excreted in bile and urine.
 Bortezomib is a poor inhibitor and not an inducer of
cytochrome P450 isoenzymes.
 However, the opposite has not been assessed.
 1.3 mg/m2 on days 1, 4, 8 and 11, followed by a 10-
day rest period

22. Based on the results of phase II clinical trials, bortezomib received
accelerated US FDA approval on May 13, 2003.

24. Bortezomib does not appear to destroy stem cells or megakaryocytes.
However, due to NF-κB inhibition, platelet budding from megakaryocytes is
compromised in patients receiving bortezomib.
Deferred if platelet count is severely depressed (< 30,000/μL) , can be due to
disease if persistant.

25.  Mechanism- limited knowledge
1. Mitochondrial damage
2. Endoplasmic reticulum damage
3. Disregulation of neurotrophins

26.  Animal models- site of abnormality
◦ Spinal cord - morphologically normal.
◦ The sciatic nerve - pathologic changes involving
predominantly the Schwann cells and myelin,
although axonal degeneration was also noted.
◦ Dorsal root ganglia (DRG) neurons-
intracytoplasmatic vacuolization due to
mitochondrial and endoplasmic reticulum damage.
 Neurophysiologic study-all 3 major fiber
types, ie, Aβ, Aδ, and C.

27.  National Cancer Institute–Common Toxicity
Criteria [NCI-CTC],
 Eastern Cooperative Oncology Group criteria,
 World Health Organization criteria,
 Total Neuropathy Score (TNS)

28.  Identification of at risk population
 Close monitoring so as to identify Grade II
neuropathy at an early stage
 Weekly dosing
 Subcutaneous route

32. Lancet Oncol 2011; 12: 431–40

38.  Symptoms of BIPN improve or completely
resolve in most patients after a median
interval of 3 months

40.  Renal insufficiency- can be safely used,
including those undergoing dialysis.
 Hepatic insuficiency- slight hepatic
impairment should be closely monitored, and
patients with significant liver disease should
not receive bortezomib.
 Prophylactic acyclovir - recommended

41.  Why needed?
1. To improve on the ORR with proteasome
inhibitors.
2. Bortezomib resistance is emerging.
3. Limited activity in solid tumors.
4. Reversible peripheral neuropathy.
5. IV route of administration.