3. Introduction
In 2010, The United States Cancer Statistics Working Group Web report cited about 119,000
cases of multiple myeloma (MM) with nearly 55,000 deaths, from 1999-2007.1
MM is the
second most common hematologic (blood) cancer in the US, characterized by proliferation of
plasma cells in the bone marrow. The clonal MM cells increasingly secrete abnormal
immunoglobulins (M-protein), with concomitant decrease in normal immunoglobulin secretion>
MM also causes reductions in red blood cell, white blood cell and platelet production, resulting
in anemia, compromised immunity, and bleeding, respectively. Risk factors include age (>65
yrs), males>females, and greater incidence in African Americans>Caucasians.2
MM is incurable,
however, earlier detection and availability of new drugs has reduced the number of deaths in
myeloma patients.3
Treatment options are dependent on factors such as age, poor physical
condition and coexisting conditions. For patients resistant to conventional treatments, a new class
of antitumor agent, bortezomib, a proteasome inhibitor, has shown promise.
Bortezomib
Bortezomib (PS-341, Velcade®) is a dipeptide boronic acid proteasome inhibitor with high
affinity and selectivity for the catalytic site of the 26S proteosome, a large proteolytic enzyme
complex found in all cells, that regulates intracellular degradation of ubiquinated proteins
involved in cell cycle, apoptosis, transcription, cell adhesion, angiogenesis and chemotaxis.4
PS-
341 showed significant efficacy in inhibiting MM cell growth, apoptosis, angiogenesis in murine
model and in-vitro assays using MM cell lines.5
Bortezomib in-vitro, induced apoptosis,
inhibited cell growth and reversed drug resistance of human MM cells6
, showed synergies with
dexamethasone, melphalan or doxorubicin in sensitive or resistant MM cells.7
Mechanism of Action
The cellular basis for the therapeutic efficacy of bortezomib is attributed to inhibition of specific
cytokines in MM cells8
and the surrounding microenvironment. Bortezomib targets the
oncogenic effects of NF-kB9
, reversed resistance to apoptosis (programmed cell death) in MM
cell microenvironment induced by TNF-α (tumor necrosis factor-α).10
in-vivo anti-myeloma activity in murine model; inhibited tumor growth, decreased angiogenesis,
and prolonged survival of severe combined immunodeficvient mice bearing human mm cells.10
Clinical trials
The antitumor efficacy of PS-341 in preclinical studies led to development of bortezomib trials
using relapsed, refractory MM patient.
Table 1: Phase 1 PS-431 clinical trial
Clinical Trial Patient #, dose regimen Overall Outcome
Phase 1 (PS-341)11
2002
n=27; four PS-341 doses,
twice/week for 4 wks+2 weeks
rest (6 weeks total)
All 9 refractory patients achieved some
response; 1 patient was a complete responder
Tolerated dose=1.04 mg/mm2
Phase 1 PS-341 clinical trial was a 6-week dose escalation, international, open armed study using
27 MM patients, including nine refractory cases (Table 1).11
The compelling response rate in all
the refractory MM patients led to two landmark Phase 2 trials using bortezomib.
3
4. Table 2: Phase 2 (SUMMIT and CREST) Bortezomib clinical trials
Clinical Trial Patient #, dose regimen Overall Outcome
Phase II SUMMIT trial
(Bertezomib)12
2003
n=202; Bertezomib (1.3 mg/mm2
), iv,
twice weekly for 2 weeks 1 week without
treatment, for upto 8 cycles (24 weeks in
total); patients with suboptimal response,
dexamethasone (20 mg daily was added
on day of and day after bortezomib dose
Overall response rate =35%; 4%
complete response; time to
progression increased 2-4 fold;
median duration of response=12
months; median survival=16
months
Phase II CREST trial
(Bertezomib)13
2004
N=54; 2 doses of bortezomib (1.3 vs.1.0
mg/m2
)
Increased response rate in one third
lower dose group (with reduced
toxicity); 33% improvement when
dexamethasone added to
suboptimal responders
Phase 2 SUMMIT trial was a multi-center, open labeled, nonrandomized study using 202
heavily-treated patients with relapsed and refractory MM.12
Patients received bortezomib during
each cycle, on Days 1, 4, 8, and 11 of the 2-week dosing period. Evaluations were performed
between Days 15 and 18 of cycles 2, 4, 6, and 8. Overall response rate was 35% (67 patients,
with 19 showing complete or near-complete response using the Criteria of the European Group
for Blood and Multiple Myeloma). A significant 2-4 fold increase (seven months) in the time to
progression, compared to chemotherapy course received prior to enrolment, was reported in all
202 patients. Dexamethasone addition (97 patients) showed improvement in patients who were
partial responders to bortezomib alone. Most common adverse effect was cumulative, dose-
related peripheral neuropathy (12%), with thrombocytopenia as the most common Grade 3 AE
(28%) and dose-related peripheral neuropathy.12
Phase 2 CREST randomized trial compared two doses of bortezomib (1.3 vs 1.0 mg/ mm2
) in 54
relapsed, refractory MM patients. The lower dose produced good response rates, with reduced
toxicities in one third of patients.13
One year survival rate was 80% vs 66%.
Table 3: Phase 3 (APEX) Bortezomib clinical trial
Clinical Trial Patient #, dose regimen Overall Outcome
Phase 3 APEX trial
(Bortezomib vs high dose
Dexamethasone) 14
APEX 2005
N=669; relapsed MM; randomized
trial who had arel after 1-3 other
therapies
Response rate= 38% (bortezomib) vs
18% (dexamethasone), complete
response (20 vs 2 patients); Median
time to progression 6.22 months
(189 days) vs 3.49 months (106
days); median duration of
response=8 vs 5.6 months
Phase 3 APEX trial14
: n=669; randomized; compared bortezomib with high dose dexamethasone
in relapsed MM patients (had 1-3 other therapies); significant improvement in response rate to
bortezomib alone than with dexamathasone alone (43% vs 18%); time to progression (6.2 vs 3.4
months); one year survival rate (80% vs 67%); response rate (both complete and partial) (38%
vs18%), with complete response observed in 20 patients in bortezomib group vs 2 in the
dexamethasone group; p<001.
Combination studies involving bortezomib plus other antutmor agents (melphalan or
doxorubicin), or thalidomide (n=56) in refractory MM patients produced response rates of 50-
76% and 97% (22% complete or partial response), respectively
Conclusions
Targeted therapy of patients with relapse, refractory MM with the proteasome inhibitor,
bortezomib, has shown promising results in several clinical trials. Age and plasma cells in bone
marrow appear to be significant predictors of a response; lower response rates were evident in
4
5. patients >65 years and when plasma cells are <50%. Overall, toxicities were moderate and were
managed with dose and/or schedule modification. A lower dose of bortezomib with fewer
adverse effects can be an option for patients who did not tolerate high doses of bortezomib. Not
all patients responded to bortezomib, although most responders had good response rates wither
with bortezomib alone or in combination with dexamethasone. Combination doses of a
proteasome inhibitor (bortezomib) with conventional chemotherapeutic agent (thalidomide,
dexamethasone, merphalan) have been shown to significantly increase the response rate
(including the complete response rates). An invaluable trila would study the effects of
bortezomib on newly diagnosed MM patients.
Clinical implications of basic research.
Preclin studies suggest B has synergistic activity with rituximab. Can generate T-cell populations
to be used to treat MM. Has been approved in 90 countries, used to treat >160,000 patients
wordwide.
References
1. (US Cancer Statistics Working Group. US Cancer Statistics: 1999-2007. Incidence and
Mortality Web-based Report. Atlanta (Ga) Dept Health H. Services, Center for Disease Control
and Protection and the National Cancer Institute, 2010 (http://www.cdc.gov/uscs).
2. (EdwardA, Stadtmauer. N Engl J Med 2003; 349: 2550-2555).
5. Jesus-San Miguel, Perspective on the current use of bortezomib in multiple myoloma
6. Adams, palombella, sausville et al. Proteasome inhibitors: a novel class of potent and effective
antitumor agents. Cancer Res.1999; 59: 2615- 2622). Hematology 2006; 91 97): 871-872).
7. (Panwalker et al. Nuclear factor-kappaB modulation as a therapeutic approach in hematologic
8. (Mitsaides N, Mitsaides CS, Poulaki V et al.,Molecualr sequelae of proteosome inhibotrs in
human MM cells. Proc. Natl. Acd. Sci USA 2002; 99: 14374-14379
Mitsiades et al. The proteasome inhibitor PS-341 potentiates sensitivity of MM cells to
conventional chemotherapeutic agents.: therapeutic applications. Blood; 2003; 101: 2377-10.
(leBlanc et al. Proteasome inhibitor PS-341inhibits human myelom cell growth and prolongs
survival in a murine model. Cancer Re. 2002; 62: 4996-5000.2380Acad. Sci USA 2002; 99:
14374-14379 malignancies. Cancer 2004; 100:1578-1589).
11. (Orlowski et al. Phase 1 trial of the proteasome inhibitor PS-341 in patients with refractory
hematologic malignancies. J clin Oncol. 2002; 20:4420-4427)
12. SUMMIT trial- Richardson et. Al; N Engl J Med, 2003; 348: 2609-2017 A phase 2 study of
bortezomib in relapsed. Refractory myeloma, N=202
13. CREST trial – Jaganath et al. A phase 2 study of 2 doses of bortezomib in relapsed or
refractory myeloma; Br. J Hematol 2004; 127: 165-172, N=54
(Shaughnessy J et al. Prognostic impact of cytogenetic and interphase fluorescence in-situ
hybridization defined chromosome 13 deletion in MM.
Phase 3 – Richardson PG, Sonnerveld P, Schuster, MW et al. Bortezomib or high doose
dexamethasone for Multiple Myeloma. New Engl J Med. 2005; 352: 2487-2498.
14. (Bruno, Rotta, Gaccione Lancet Oncol;2004; 5:430-442.
Orlawski RZ, Kuhn DJ, Proteosome inhib.B induces apoptosis, reversed drug-resistance of MM
in cells by blocking cytokine circuits, cell adhesion, and angiogenesis in-vitro
Hideshima T, Richardson P, Chauhan D et al. The proteasome inhibitor PS-341 inhibits growth,
induces apoptosis and overcomes drug resistance in human multiple myeloma cells. Cancer Res.
2001; 61: 3071-3076);
5
6. patients >65 years and when plasma cells are <50%. Overall, toxicities were moderate and were
managed with dose and/or schedule modification. A lower dose of bortezomib with fewer
adverse effects can be an option for patients who did not tolerate high doses of bortezomib. Not
all patients responded to bortezomib, although most responders had good response rates wither
with bortezomib alone or in combination with dexamethasone. Combination doses of a
proteasome inhibitor (bortezomib) with conventional chemotherapeutic agent (thalidomide,
dexamethasone, merphalan) have been shown to significantly increase the response rate
(including the complete response rates). An invaluable trila would study the effects of
bortezomib on newly diagnosed MM patients.
Clinical implications of basic research.
Preclin studies suggest B has synergistic activity with rituximab. Can generate T-cell populations
to be used to treat MM. Has been approved in 90 countries, used to treat >160,000 patients
wordwide.
References
1. (US Cancer Statistics Working Group. US Cancer Statistics: 1999-2007. Incidence and
Mortality Web-based Report. Atlanta (Ga) Dept Health H. Services, Center for Disease Control
and Protection and the National Cancer Institute, 2010 (http://www.cdc.gov/uscs).
2. (EdwardA, Stadtmauer. N Engl J Med 2003; 349: 2550-2555).
5. Jesus-San Miguel, Perspective on the current use of bortezomib in multiple myoloma
6. Adams, palombella, sausville et al. Proteasome inhibitors: a novel class of potent and effective
antitumor agents. Cancer Res.1999; 59: 2615- 2622). Hematology 2006; 91 97): 871-872).
7. (Panwalker et al. Nuclear factor-kappaB modulation as a therapeutic approach in hematologic
8. (Mitsaides N, Mitsaides CS, Poulaki V et al.,Molecualr sequelae of proteosome inhibotrs in
human MM cells. Proc. Natl. Acd. Sci USA 2002; 99: 14374-14379
Mitsiades et al. The proteasome inhibitor PS-341 potentiates sensitivity of MM cells to
conventional chemotherapeutic agents.: therapeutic applications. Blood; 2003; 101: 2377-10.
(leBlanc et al. Proteasome inhibitor PS-341inhibits human myelom cell growth and prolongs
survival in a murine model. Cancer Re. 2002; 62: 4996-5000.2380Acad. Sci USA 2002; 99:
14374-14379 malignancies. Cancer 2004; 100:1578-1589).
11. (Orlowski et al. Phase 1 trial of the proteasome inhibitor PS-341 in patients with refractory
hematologic malignancies. J clin Oncol. 2002; 20:4420-4427)
12. SUMMIT trial- Richardson et. Al; N Engl J Med, 2003; 348: 2609-2017 A phase 2 study of
bortezomib in relapsed. Refractory myeloma, N=202
13. CREST trial – Jaganath et al. A phase 2 study of 2 doses of bortezomib in relapsed or
refractory myeloma; Br. J Hematol 2004; 127: 165-172, N=54
(Shaughnessy J et al. Prognostic impact of cytogenetic and interphase fluorescence in-situ
hybridization defined chromosome 13 deletion in MM.
Phase 3 – Richardson PG, Sonnerveld P, Schuster, MW et al. Bortezomib or high doose
dexamethasone for Multiple Myeloma. New Engl J Med. 2005; 352: 2487-2498.
14. (Bruno, Rotta, Gaccione Lancet Oncol;2004; 5:430-442.
Orlawski RZ, Kuhn DJ, Proteosome inhib.B induces apoptosis, reversed drug-resistance of MM
in cells by blocking cytokine circuits, cell adhesion, and angiogenesis in-vitro
Hideshima T, Richardson P, Chauhan D et al. The proteasome inhibitor PS-341 inhibits growth,
induces apoptosis and overcomes drug resistance in human multiple myeloma cells. Cancer Res.
2001; 61: 3071-3076);
5
