The Proteasome Inhibitor VELCADE (bortezomib) for Injection
What is VELCADE?
The proteasome inhibitor VELCADETM (bortezomib), formerly known as PS-341, LDP-
341 and MLN-341, is an investigational drug that is being evaluated for its potential role
in the treatment of multiple myeloma as well as other cancers. A phase III study was
recently initiated in which VELCADE will be compared to high-dose dexamethasone in
patients with relapsed myeloma.
What is the proteasome?
The proteasome is an enzyme complex found in all cells of the body and plays a key role
in the function of both normal and malignant cells.
How does VELCADE work?
VELCADE inhibits proteasomes from functioning normally. In laboratory studies,
proteasome inhibition prevents growth and division of cancer cells, decreases the
production of certain growth stimulants for tumor cells, suppresses the interaction of
multiple myeloma cells with the bone marrow environment and causes tumor cells to
undergo programmed cell death. In laboratory studies, cancer cells appear to be more
sensitive to proteasome inhibition than healthy cells.
What are the results to date in studies of myeloma?
VELCADE was evaluated in a phase II study (SUMMIT) that enrolled 202 patients with
relapsed and refractory myeloma who had received at least two prior therapies. Results
were presented at the American Society of Hematology meeting in December, 2002, but
only results for the first 78 patients treated have been published. These patients received
an average of five prior lines of therapy, including 74 percent who previously received
thalidomide, and 54 percent who received high dose chemotherapy with stem cell
transplantation.
VELCADE was given intravenously as a 3-5 second infusion twice a week for 2 weeks
followed by 10 days of rest and then the course was repeated. To date 78 patients have
been assessed for their response. 68% of these patients experienced a reduction or
stabilization in their paraprotein level. Specifically, 27 percent had a greater than 90
percent reduction. The median time to progressive disease had not been reached after
10.2 months of follow-up.
Another Phase II trial (CREST) evaluating two different doses of VELCADE in patients
with multiple myeloma who relapsed after one line of therapy was also presented at the
American Society of Hematology meeting in Dec., 2002, with similar results. Preliminary
results were also presented on Phase I combinations of VELCADE with both thalidomide
and liposomal doxorubicin in patients with refractory myeloma.
Are there any side effects?
In preliminary data from the Phase II studies, the most commonly reported side effects
included nausea, fatigue, diarrhea, headache, decreased platelets, and peripheral

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neuropathy (numbness, tingling and pain in the extremities), but generally the drug was
well tolerated. Adverse events resulted in some patients discontinuing the study early.
Are there clinical trials?
This drug is now being tested in a Phase III clinical trial in the U.S., Canada and Europe
in over 600 patients to compare the safety and effectiveness of VELCADE to high dose
dexamethasone in patients whose disease has relapsed.
The future?
The Phase III study will answer important questions on the potential role of VELCADE
in the treatment of relapsed and refractory patients. In addition, some laboratory and
clinical evidence suggests that it may work well in combination with other drugs.
Additional clinical trials are being developed and conducted to further evaluate the use of
VELCADE in multiple myeloma and other malignancies.

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