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Studies Suggest Bortezomib Effective in Treating All Stages of Multiple Myeloma

SAN DIEGO, Dec. 6 /PRNewswire-FirstCall/ -- Millennium Pharmaceuticals, Inc. (NASDAQ:MLNM) today announced encouraging results from several studies exploring the use of VELCADE in treating all stages of multiple myeloma (MM). These data were presented at the 46th Annual Meeting of the American Society of Hematology (ASH) taking place this week in San Diego, CA.

Overall response rates from ongoing investigator-initiated studies evaluating VELCADE in combination with other commonly used agents in untreated multiple myeloma ranged from 95 percent to 73 percent; complete and near-complete responses were observed. Also presented were the final data analysis of the APEX trial, a phase III randomized study of patients who had relapsed after one or more lines of prior therapy. VELCADE was significantly superior to high-dose dexamethasone based on time to progression, survival, overall response rates and complete response rates.

"The unprecedented survival advantage reported with VELCADE in the relapsed setting, coupled with the preliminary response rates with VELCADE in these ongoing, front-line, investigator-initiated studies are very encouraging," said David Schenkein, M.D., vice president, clinical oncology development, Millennium. "We believe these data may signal a significant step forward for patients with multiple myeloma. As a result, we and our development and commercialization collaborator, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., are looking forward to the initiation of three phase III trials in the next six months to further evaluate the safety and efficacy of VELCADE in previously untreated multiple myeloma patients."

VELCADE(R) (bortezomib) for Injection as a front-line treatment
In an ongoing multi-center phase II trial conducted by Sundar Jagannath, M.D., St. Vincent's Comprehensive Cancer Center, New York, and investigators in the Salick Health Care Research Network, VELCADE was studied alone and in combination with dexamethasone in patients with previously untreated, symptomatic MM. The trial enrolled 42 patients with 32 evaluable for response.

* The overall response rate was 88 percent with a complete and near complete response rate of 25 percent;
* Six of eight patients achieved complete or near complete responses on VELCADE alone;
* In addition, stem cell harvesting and engraftment was successful in 100 percent of patients (eight out of eight) with all transplant patients making complete hematologic recoveries; and,
* Adverse events were similar to those observed in other clinical trials with VELCADE and included gastrointestinal events, neuropathy, fatigue, and hematologic toxicities.

"Our findings indicate VELCADE could be a promising drug for front-line use in previously untreated patients with myeloma," said Dr. Jagannath. "Additionally, it was encouraging to find that stem cell harvest and engraftment were not adversely affected by treatment with VELCADE. We look forward to the results of the future randomized phase III studies."

Three additional studies evaluated the safety and activity of VELCADE in combination with other therapies in previously untreated patients. An ongoing phase II study, led by James Cavenagh, M.D., St. Bartholomew's Hospital in London, explored the combination of VELCADE (formerly PS-341), dexamethasone and doxorubicin (PAD) in patients with previously untreated MM. Data from 21 patients showed:

* The overall response rate was 95 percent with a complete and near complete response rate of 29 percent prior to stem cell transplantation;
* Twenty of 21 evaluable patients underwent successful stem cell mobilization for transplantation; and,
* The major adverse event reported was neuropathy which was found to be generally mild and improving in all patients upon completion of therapy.

A second ongoing phase II study, led by Jean-Luc Harousseau, M.D., University Hospital of Nantes in Nantes, France, explored the combination of VELCADE and dexamethasone in patients with previously untreated MM. Data from 30 evaluable patients showed:

* An overall response rate of 73 percent with a complete response and near complete response rate of 17 percent; and,
* Adverse events were similar to those observed in other clinical trials with VELCADE and included gastrointestinal events, fatigue, neuropathy, pyrexia and thrombocytopenia.

A third ongoing phase II study, led by M. Victoria Mateos, M.D., Hematology Grupo Espanol de Multiple Myeloma, Spain, explored the combination of VELCADE and melphalan and prednisone in elderly untreated MM patients. Data from 11 evaluable patients showed:

* An overall response rate of 91 percent with a complete and near complete response rate of 18 percent; and,
* Adverse events were similar to those observed in other clinical trials with VELCADE(R) (bortezomib) for Injection and included anemia, neutropenia, gastrointestinal events and thrombocytopenia.

In a single institutional experience reported by Raymond Alexanian, M.D., of The University of Texas M.D. Anderson Cancer Center the combination of VELCADE with thalidomide and dexamethasone was evaluated in untreated MM patients. Data from 30 evaluable patients showed:

* The overall response rate was 80 percent; and,
* Most common adverse events included infection, hypotension, deep vein thrombosis, neutropenia and thrombocytopenia.

A separate ongoing phase II trial evaluated the safety and activity of VELCADE as a single agent in previously untreated MM patients. Led by Paul Richardson, M.D., of the Dana Farber Comprehensive Cancer Center in Boston, the preliminary study data from 27 evaluable patients showed:

* The overall single agent response rate was 45 percent with a complete response rate of four percent; and,
* Adverse events were similar to those observed in other clinical trials with VELCADE and included neuropathy, gastrointestinal events and fatigue.

APEX final results in relapsed patients
APEX, a phase III, multi-center trial with 669 patients, was the first and largest randomized study to achieve a survival advantage in relapsed MM. VELCADE was superior to high-dose dexamethasone based on time to progression (p<.0001 survival="" and="" response="" rate="" additional="" findings="" include:=""> * Overall response rate of 38 percent with VELCADE, with a duration of response of eight months; compared with a response rate of 18 percent, with a duration of response of 5.6 months for dexamethasone;
* The VELCADE arm had a complete response or near complete response rate of 13 percent, versus dexamethasone of two percent;
* Improvement in median time to progression was 78 percent in the VELCADE arm; and,
* During the first year, there was an estimated 41 percent reduction in risk of death in patients receiving VELCADE compared to those receiving dexamethasone.

A subset analysis from this same study in 251 patients who had only one prior therapy also showed the VELCADE arm was superior based on time to progression (p<.0021 response="" rate="" and="" one-year="" survival=""> * Overall response rate with VELCADE was 45 percent (duration of response was 8.1 months) compared with 26 percent for dexamethasone (duration of response 6.2 months);
* The VELCADE arm had a complete response and near complete response rate of 13 percent, versus dexamethasone of four percent;
* Statistically significant time-to-progression benefit of seven months versus 5.6 months for dexamethasone; and,
* One-year survival was improved significantly from 89 percent in the VELCADE arm compared with 72 percent for dexamethasone.

The safety profiles of VELCADE and dexamethasone were predictable and toxicities were manageable with VELCADE having a favorable risk-to-benefit ratio. The most common side effects reported with VELCADE were diarrhea, nausea, fatigue, peripheral neuropathy, thrombocytopenia and anemia.

"Our sNDA submission for second-line treatment with VELCADE was based on data from the APEX study, which achieved a statistically significant survival benefit in patients receiving VELCADE versus standard therapy, and we are pleased the agency has granted priority review for the submission," said Schenkein.

About Multiple Myeloma (MM)
Multiple myeloma is a cancer of the bone marrow in which white blood cells called plasma cells, normally responsible for the production of antibodies (proteins that fight infection and disease), are overproduced. The proliferation of these abnormal plasma cells, known as myeloma cells, causes decreased production of normal red and white blood cells, and of normal disease-fighting antibodies, as well as the growth of tumors that spread to multiple sites - hence the term multiple myeloma. The decreased white blood cell production damages the immune system while the myeloma tumors cause bone destruction that manifests as pain and fractures.

MM is the second most common hematologic malignancy and although the disease is predominantly a cancer of the elderly (the average age of onset is 65 to 70 years of age), recent statistics indicate both increasing incidence and younger age of onset. In the United States, more than 40,000 individuals have MM and over 14,000 new cases of the disease are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths due to multiple myeloma each year.

About VELCADE(R) (bortezomib) for Injection
VELCADE is approved for the treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy. The effectiveness of VELCADE is based on response rates. There are no controlled trials demonstrating a clinical benefit, such as improvement in survival. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol.

Risks associated with VELCADE(R) (bortezomib) for Injection therapy include new or worsening peripheral neuropathy, orthostatic hypotension, congestive heart failure, gastrointestinal adverse events, thrombocytopenia, and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE.

In 228 patients who were treated with VELCADE(R) (bortezomib) for Injection 1.3 mg/m(2)/dose in phase II studies, the most commonly reported adverse events were asthenic conditions (65%), nausea (64%), diarrhea (51%), decreased appetite including anorexia (43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%), pyrexia (36%), vomiting (36%), and anemia (32%). Fourteen percent of patients experienced at least one episode of Grade 4 toxicity, with the most common toxicities being thrombocytopenia (3%) and neutropenia (3%). A total of 113 (50%) of the 228 patients experienced Serious Adverse Events (SAEs) during studies. The most commonly reported SAEs included pyrexia (7%), pneumonia (7%), diarrhea (6%), vomiting (5%), dehydration (5%), and nausea (4%).

For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-(866)-VELCADE.

Source: Millenium Pharmaceuticals, Inc.

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