The U.S. FDA ( Food and Drug Administration ) approved a supplemental New Drug Application ( sNDA ) for Velcade ( Bortezomib ).
This approval expands the label to include the treatment of patients with multiple myeloma who have received at least one prior therapy.

Bortezomib is the first in a new class of anticancer agents known as proteasome inhibitors.
It appears to act on myeloma cells in several ways, directly to cause myeloma cell death as well as indirectly inhibiting their growth and survival by acting on the bone microenvironment.
The anti-myeloma effects of Bortezomib are thought to be due to its ability to block a key survival protein, known as nuclear factor – kappaB ( NF-kB).
NF-κB acts as a transcription factor, turning on genes that cause production of proteins that stimulate cell growth.

The approval was based on data from the randomized phase III APEX study that compared single-agent Bortezomib to a traditional multiple myeloma therapy, high-dose Dexamethasone.

The APEX trial enrolled 669 patients with relapsed multiple myeloma ( patients had received one to three prior therapies ) at 93 Centers in North America, Europe and Israel.

The APEX trial was halted one year early after an independent Data Monitoring Committee concluded the findings of a pre-specified interim analysis showed a statistically significant improvement in time-to-disease progression in favor of Bortezomib.

In the overall study population, Bortezomib was superior to high-dose Dexamethasone based on time to progression, overall survival, and response rate.

In addition:

- Overall, 40 percent fewer patients died in the Bortezomib arm relative to the Dexamethasone arm;

- Overall response rate of 38 percent with Bortezomib, with a median duration of response of 8.0 months compared with a response rate of 18 percent, with a median duration of response of 5.6 months for Dexamethasone;

- Six percent of patients treated with Bortezomib had a complete response and 7 percent had a near complete response as compared to less than one percent each with Dexamethasone;

After a median of 8.3 months of follow-up, improvement in median time to progression was 78 percent with Bortezomib relative to Dexamethasone.

Among the 251 second-line multiple myeloma patients ( those who had only one prior therapy ), Bortezomib was superior based on time to progression, response rate, and overall survival.

In addition:

- Overall, 55 percent fewer patients died in the Bortezomib arm relative to the Dexamethasone arm;

- Overall response rate with Bortezomib was 45 percent ( median duration of response was 8.1 months ) compared with 26 percent for Dexamethasone ( median duration of response 6.2 months );

- Six percent of patients treated with Bortezomib had a complete response and 6 percent had a near complete response as compared to two percent each with Dexamethasone.

Bortezomib is contraindicated in patients with hypersensitivity to Bortezomib, boron, or mannitol.

Risks associated with Bortezomib therapy include: new or worsening peripheral neuropathy, hypotension, cardiac disorders, gastrointestinal adverse events, thrombocytopenia and tumor lysis syndrome.

Women of childbearing potential should avoid becoming pregnant while being treated with Bortezomib.

In 331 patients who were treated with Bortezomib 1.3 mg/m2 dose in the Phase III APEX study, the most commonly reported adverse events were: asthenic conditions ( 61% ), diarrhea ( 57% ), nausea ( 57% ), constipation ( 42% ), peripheral neuropathy ( 36% ), vomiting ( 35% ), pyrexia ( 35% ), thrombocytopenia ( 35% ), psychiatric disorders ( 35% ) and anorexia and appetite decreased ( 34% ).

Fourteen percent of patients reported at least one episode of grade 4 toxicity; the most common grade 4 toxicities were: thrombocytopenia ( 4% ), neutropenia ( 2% ) and hypercalcemia ( 2% ).

A total of 144 patients on Bortezomib ( 44% ) reported serious adverse events during the study.
The most commonly reported severe drug reactions were: pyrexia ( 6% ), diarrhea ( 5% ), dyspnea and pneumonia ( 4% ) and vomiting ( 3% ).


Source: Millennium Pharmaceuticals, 2005


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