Thursday, July 26, 2007

Thalidomide: evaluation of clinical parameters, cytokines, angiogenic markers, mast cells and marrow CD57+ cytotoxic T cells as outcome predictors

Mileshkin L, Honemann D, Gambell P, Trivett M, Hayakawa Y, Smyth M, Beshay V, Ritchie D, Simmons P, Milner AD, Zeldis JB, Prince HM.

Medical Oncologist Department of Haematology and Medical Oncology, Peter MacCallum Cancer Center, St Andrew’s Place, East Melbourne, VIC 3002, Australia. Linda.Mileshkin@petermac.org.

BACKGROUND AND OBJECTIVES In vitro studies suggest that thalidomide has an immunoregulatory role and alters the marrow microenvironment. We assessed laboratory and clinical parameters in patients with myeloma treated with thalidomide as potential prognostic markers and looked for changes with therapy.

DESIGN AND METHODS Seventy-five patients with relapsed/refractory myeloma received thalidomide in a phase II trial. Serial samples of platelet-poor plasma and bone marrow were tested for angiogenic cytokines including vascular endothelial growth factor (VEGF), marrow microvessel-density (MVD), mast cells and CD57+ cell expression. The effects of these parameters on response rate (RR), progression-free survival (PFS) and overall survival (OS) were analyzed.

RESULTS Elevated baseline VEGF predicted for a superior RR (p=0.018) and PFS. Elevated CD57+ cells also predicted superior PFS (p=0.012). MVD did not predict for RR, PFS or OS, but MVD and VEGF fell significantly in responders. Multivariate analysis identified that inferior OS was associated with age >65 years (p=0.017), raised lactate dehydrogenase (p=0.001), raised hepatocyte growth factor levels (p=0.012) and low pre-treatment CD57+ cells (p<0.001).>

INTERPRETATION AND CONCLUSIONS Our findings support the suggestion that thalidomide has anti-angiogenic and immunomodulatory effects in myeloma. The preferred method for assessing angiogenesis is plasma VEGF levels and the assessment of CD57+ cells for patients with myeloma receiving novel immunomodulatory drugs should be further investigated.

PMID: 17640854 [PubMed - as supplied by publisher]

Monday, July 23, 2007

New drug: FDA approves IND-P276

Nicholas Piramal India Ltd announced that the Company has received USFDA approval for its Investigational New Drug application of its lead cancer compound 'P-276-00' to treat Multiple Myeloma.

Clinical trials will start at
Harvard University's Dana Farber Cancer Institute.

P 276-00 is a new chemical entity that blocks pathways necessary for cancer cell growth and survival.

The Clinical Studies will be coordinated by Dr Kenneth Anderson. The Principal Investigator of the trial will be Dr. Noopur Raje, M.D., at the Dana Farber -
Massachusetts General Hospital. Dr. Noopur Raje is part of the Jerome Lipper Cancer center at the Dana-Farber Cancer Institute. St. Vincent's Hospital in New York and Emory University Medical Center in Atlanta will also participate in the study.

Thursday, July 19, 2007

Obesity Found to be a Risk Factor for Multiple Myeloma

An obese person is more likely than a lean person to develop multiple myeloma, according to researchers from Brigham and Women's Hospital, Harvard Medical School, and Harvard School of Public Health. Their findings indicate that Body Mass Index (BMI) - a statistical measure that scales weight to height - provides an indicator for one's risk of developing multiple myeloma, a cancer of the blood cells that produce antibodies. Multiple myeloma currently affects more than 50,000 people in the U.S., and the five-year survival rates of the cancer are below 40 percent.

The study, published in the July issue of Cancer Epidemiology, Biomarkers & Prevention, a journal of the American Association for Cancer Research, takes its data from over 100,000 participants in the on-going Nurses' Health Study and Health Professionals Follow-up Study, two similar large-scale studies. The study findings were similar to those from previously published studies that included smaller numbers of multiple myeloma patients, and/or were based on a one-time recording of height and weight.

"I find the results of these studies encouraging, since they show consistent results about the first risk factor for multiple myeloma that people can actually modify," said the study's lead author Brenda M. Birmann, Sc.D., a researcher in the Department of Medicine at Brigham and Women's Hospital and Harvard Medical School. "Treatment options for this disease are improving, but it is also important to identify risk factors that could be modified. We would like to learn how to prevent its occurrence."

The Brigham and Women's Hospital-based Nurses' Health Study has followed the health of female registered nurses since 1976, and the Health Professionals Follow-up Study, based at Harvard School of Public Health, has followed males from several health professions since 1986. These studies recorded height, weight and physical activity for each person enrolled, as well as diet, medications, smoking habits and other health behaviors, and has updated that information every two to four years. Of the 136,623 participants who qualified for their study protocol, Birmann and her colleagues confirmed 215 cases of multiple myeloma.

Body Mass Index (BMI) is computed by dividing a person's weight by the square of their height. A BMI between 18.5 and 25 is considered optimal, a BMI of 25-29 is considered overweight, and a BMI of 30 or higher is considered obese.

The association between BMI and multiple myeloma was strongest among men with a BMI of 30 or more. When compared with leaner men (those with a BMI below 22), obese men, the researchers said, were over twice as likely to develop multiple myeloma. The effect was less pronounced among overweight or obese women, yet those women also had an increased risk.

The study also looked at whether regular exercise is related to risk of multiple myeloma. There was not a clear effect of exercise on risk, although the results among women suggested that those who exercise more might have a lower risk. "We cannot say with certainty that exercise reduces the risk of multiple myeloma, but there is ample evidence that regular exercise offers many other health benefits," Birmann said.

The study findings do show, however, that the effect of BMI on risk of multiple myeloma is separate from any possible effect of physical activity.

According to Birmann, previous research has identified possible biological links between obesity and multiple myeloma. For example, adipocytes, cells found in fat tissue, produce a cell signal, called interleukin-6 (IL-6), which promotes the immune system's inflammation response. In obese people, this can cause an overproduction of IL-6, which in turn creates a cellular environment that sustains multiple myeloma. "The IL-6 chemical pathway is one possible way obesity could influence the risk of developing diseases like cancer or cardiovascular disease, but the answer might also lie in other relationships between obesity and cancer," Birmann said.

Further research, she said, will uncover more about the relationships between obesity and cancers such as multiple myeloma. The researchers believe their findings may lead to examination in greater detail of the BMI/multiple myeloma link, including the role of IL-6 and other chemical signals, energy metabolism, and other risk factors such as weight change or weight cycling.

This research was funded through grants from the Dana-Farber/Harvard Cancer Center Specialized Program in Research Excellence in Multiple Myeloma, the National Cancer Institute and the National Institutes of Health.

Source: http://www.aacr.org

Wednesday, July 18, 2007

Low-Molecular-Weight Heparin Improves Survival Rate

Use of low-molecular-weight heparin (LMWH) to treat patients with cancer appears to reduce their rate of mortality compared with best supportive care, according to a meta-analysis of clinical trials. Researchers reported the findings at the 21st Congress of the International Society of Thrombosis and Haemostasis (ISTH). "The pooled data from the trials showed a significant overall improvement in survival for low-molecular-weight-heparin users," says lead investigator and presenter Sylvie Laporte, PharmD, Department of Clinical Pharmacology, University Hospital of St-Etienne, Saint-Etienne, France.

The investigators conducted an electronic search of major research databases as well as a manual search of medical conference proceedings. They looked for randomised clinical trials (RCTs) comparing LMWH with placebo or no treatment in cancer patients, and trials comparing LMWH with other vitamin K antagonist (VKA) cancer treatments in patients with venous thromboembolism (VTE). The researchers used standard statistical models and practices to analyse the pooled data and used overall survival at the end of follow-up as their endpoint. They selected 10 RCTs comparing LMWH with best supportive care, six trials with LMWH versus placebo/no treatment (912 patients, 2 RCTs pending), and four trials with LMWH versus VKA in cancer patients with VTE (1,120 patients). Overall survival rate with LMWH was significantly higher than with best supportive care ([P =.02), with an overall hazard ratio of 0.87, which translates to a 13% reduction in mortality in the LMWR-treated patients.

"These results support the potentially beneficial effect of LMWH on cancer survival, although lack of power precludes an unequivocal conclusion concerning patients with and without VTE separately. Additional trials are required to define the tumour types and disease stages most likely to show a real survival benefit," the authors conclude.

Tuesday, July 17, 2007

Emerging data on the use of anthracyclines in combination with bortezomib in multiple myeloma

Voorhees PM, Orlowski RZ.

Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hill, NC 27599, USA. peter_voorhees@med.unc.edu

Since the inception of infusional vincristine/doxorubicin/pulsed dexamethasone (VAD) for the treatment of multiple myeloma, anthracyclines have remained an important class of antimyeloma agents. More recently, the introduction of pegylated liposomal doxorubicin with improved pharmacokinetic characteristics has led to the development of newer anthracycline-containing regimens with improved toxicity profiles. Bortezomib, a first in class reversible inhibitor of the proteasome, has also emerged as an important novel agent for the treatment of multiple myeloma and is currently approved for patients with relapsed/refractory disease progressing after 1 previous therapy. Although both classes of agents have potent proapoptotic activity, they also induce activation of an antiapoptotic prosurvival program that limits their own efficacy, a process known as inducible chemotherapy resistance. Importantly, in preclinical studies, each of these drugs has been shown to attenuate chemotherapy resistance induced by the other, and combinations of the 2 have demonstrated striking synergistic activity. Furthermore, early phase I/II clinical trials have shown impressive activity of pegylated liposomal doxorubicin and conventional doxorubicin in combination with bortezomib in patients with newly diagnosed and relapsed/refractory myeloma. Phase II/III clinical trials evaluating these regimens in patients with newly diagnosed and relapsed/refractory disease have recently completed accrual and will better define the role of these combinations in myeloma therapy. Herein, we review the preclinical data supporting the use of bortezomib with anthracyclines and the promising clinical data with these combinations.

PMID: 17562254 [PubMed - in process]

Monday, July 16, 2007

VELCADE(R) Produced Complete Remission Rates in 54% of Patients with Previously Treated Multiple Myeloma

June 28 -- Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM) today reported on the presentation of results from clinical trials of VELCADE based therapies that showed high complete remission / complete response(1) (CR) rates in previously treated multiple myeloma (MM) patients. These findings were presented at the prestigious 11th International Myeloma Workshop (IMW) in Kos, Greece. Highlights included:

· VELCADE, cyclophosphamide and prednisone (VCP) demonstrated an overall response rate (ORR) of 93 percent including a CR(1) rate of 54 percent. At one year, 100 percent of patients were alive.

· VELCADE, lenalidomide and dexamethasone (VRD) showed an ORR of 68 percent with a 5 percent CR(1) rate in a pilot study of heavily pretreated patients, including those who had been previously treated with VELCADE or lenalidomide.

"By combining the power of VELCADE with other active agents, we are seeing some of the strongest reported efficacy in previously treated multiple myeloma patients," said Nancy Simonian, M.D., Chief Medical Officer, Millennium. "The wealth of combination data that are being generated promises to strengthen the U.S. market-leading role of VELCADE."

Weekly VELCADE, Cyclophosphamide and Prednisone in Myeloma (Abstract #PO- 639)

"VELCADE has shown synergistic activity with alkylating agents by generating substantially high and durable complete remission rates," said Donna Reece, M.D., Princess Margaret Hospital. "This is an important finding for the field of multiple myeloma and leads us to believe that the combination of VELCADE and cyclophosphamide warrants further investigation in the front-line setting with the goal of prolonging patients' survival."

The Phase II study was designed to evaluate the efficacy and safety of VCP in relapsed / refractory MM patients. The study included 13 evaluable patients, who received VELCADE at 1.5 mg/m2 on days 1, 8 and 15 of a 28-day schedule. Patients also received 300 mg/m2 of cyclophosphamide on days 1, 8, 15 and 22 and prednisone at 100 mg every two days. Patients were treated for up to eight cycles. Response was assessed by the European Group for Blood and Marrow Transplant (EBMT) criteria. Results were presented by Dr. Reece and showed an ORR (CR + partial response + minor response) of 93 percent, including a high CR rate of 54 percent. At one year, all patients were alive (one-year survival rate). Therapy demonstrated excellent patient tolerance with side effects similar to those seen with each agent alone.

Phase II Study of VELCADE, Lenalidomide and Dexamethasone in Relapsed / Refractory Multiple Myeloma (Abstract #PO-660)

The Phase II multi-center study evaluated the efficacy and safety of this novel combination therapy. The trial included 19 evaluable relapsed / refractory MM patients, including those who had received prior VELCADE, lenalidomide, thalidomide or stem cell transplantation. The patients received VELCADE at 1.0 mg/m2 on days 1, 4, 8 and 11 of a 21-day schedule; lenalidomide at 15 mg on days 1 through 14; and dexamethasone at 40 mg for cycles one through four and 20 mg for cycles five through eight. Patients received a median of five cycles. Responses were assessed using the EBMT criteria. Results were presented by Paul Richardson, M.D., Dana-Farber Cancer Institute, and showed a 68 percent ORR, including a CR rate of 5 percent. Therapy was well tolerated with no grade 3 or higher toxicities.

About Multiple Myeloma

Multiple myeloma 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 U.S., more than 50,000 individuals have MM and 20,000 new cases are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths annually.

About VELCADE

VELCADE is being co-developed by Millennium Pharmaceuticals, Inc. and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of VELCADE in the U.S., Janssen-Cilag is responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for commercialization in Japan. For a limited period of time, Millennium and Ortho Biotech Inc. will co-promote VELCADE in the U.S. VELCADE is approved in more than 80 countries worldwide.

In the U.S., VELCADE is indicated for the treatment of patients with multiple myeloma who have received at least one prior therapy. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. In the European Union and many other countries worldwide, VELCADE is approved for patients with multiple myeloma after first relapse.

Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, hypotension observed throughout therapy, cardiac and pulmonary disorders, gastrointestinal adverse events, thrombocytopenia, neutropenia and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Cases of severe sensory and motor peripheral neuropathy have been reported. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with few or no risk factors for decreased left ventricular ejection fraction. There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome in patients receiving VELCADE. Some of these events have been fatal. A higher proportion of these events have been reported in Japan. There have been rare reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. VELCADE is associated with thrombocytopenia and neutropenia. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. Complete blood counts (CBC) should be frequently monitored during treatment with VELCADE. Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions.

Safety Data: In 1163 patients in multiple myeloma and mantle cell lymphoma studies, the most commonly reported adverse events were asthenic conditions (64%), nausea (55%) in single-agent VELCADE, diarrhea (52%), constipation (41%), peripheral neuropathy (39%), thrombocytopenia (36%), appetite decrease, including reports of anorexia (36%), pyrexia (34%), vomiting (33%) and anemia (29%). Twenty percent of patients reported at least one episode of grade 4 toxicity; the most common grade 4 toxicities were thrombocytopenia (5%) and neutropenia (3%). Fifty percent of patients reported serious adverse events. The most commonly reported serious adverse events were pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-866-VELCADE (1-866-835-2233).

About Millennium

Millennium Pharmaceuticals, Inc., a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a novel cancer product, and has a robust clinical development pipeline of product candidates. Millennium's research, development and commercialization activities are focused in two therapeutic areas: oncology and inflammation. By applying its knowledge of the human genome, understanding of disease mechanisms and industrialized drug discovery platform, Millennium is developing an exciting pipeline of innovative product candidates. Millennium's website is www.millennium.com.

This press release contains "forward-looking statements," including statements about the Company's growth and development of products. Various important risks may cause the Company's actual results to differ materially from the results indicated by these forward-looking statements, including: adverse results in its drug discovery and clinical development programs; failure to obtain patent protection for its discoveries; commercial limitations imposed by patents owned or controlled by third parties; the Company's dependence upon strategic alliance partners to develop and commercialize products and services based on its work; difficulties or delays in obtaining regulatory approvals to market products and services resulting from its development efforts; product withdrawals; competitive factors; difficulties or delays in manufacturing the Company's products; government and third-party reimbursement rates; the commercial success of VELCADE and INTEGRILIN(R) (eptifibatide) Injection; achieving revenue consistent with internal forecasts; and the requirement for substantial funding to conduct research and development and to expand commercialization activities. For a further list and description of the risks and uncertainties the Company faces, see the reports it has filed with the Securities and Exchange Commission. The Company disclaims any intention or obligation to update or revise any forward- looking statements, whether as a result of new information, future events or otherwise.

(1) Complete remission / complete response includes both immunofixation positive and negative readouts

CONTACT: Media, Jennifer Snyder, +1-617-444-1439, or Investors, Kyle
Kuvalanka, +1-857-498-0818, both for Millennium Pharmaceuticals, Inc.

SOURCE Millennium Pharmaceuticals, Inc. http://
www.millennium.com

100 percent response rate achieved with VELCADE, lenalidomide and dexamethasone in newly diagnosed patients

June 28-- Millennium Pharmaceuticals, Inc. (Nasdaq: MLNM) today reported on the presentation of results from four clinical trials of VELCADE based therapies that showed consistently high survival and complete remission / complete response(1) (CR) rates in newly diagnosed multiple myeloma (MM) patients. These data were presented at the prestigious 11th International Myeloma Workshop (IMW) in Kos, Greece. Highlights included:

- VELCADE, melphalan and prednisone (VMP) demonstrated a CR(1) rate of 43 percent, the strongest rate ever reported for a melphalan prednisone combination therapy. At 38 months, 85 percent of patients were alive. This is the highest reported three-year survival rate in the front-line treatment setting.

- VELCADE, adriamycin and dexamethasone (referred to as VcAD or PAD) showed a CR(1) rate of 29 percent prior to stem cell transplantation (SCT), which further improved to 57 percent following SCT. At one year, 100 percent of patients were alive, and at two years, 95 percent of patients were alive. This is the highest reported two-year survival rate in the front-line treatment setting. Median overall survival (OS) has not yet been reached after four years.

- VELCADE, DOXIL(R) (pegylated liposomal doxorubicin) and dexamethasone (VDD) showed a CR(1) rate of 43 percent prior to SCT, which increased to 65 percent following SCT. At 16 months, 100 percent of patients were alive.

- VELCADE, lenalidomide and dexamethasone (VRD) showed an overall response rate (ORR) of 100 percent, including a CR(1) rate of 20 percent.

"These spectacular results underscore the crucial role of VELCADE in front-line multiple myeloma," said Sagar Lonial, M.D., Emory University. "VELCADE has consistently delivered survival rates that are among the highest seen to date in this disease setting. These high survival rates were driven by the substantial complete remission rates seen when VELCADE has been added to multiple therapies. Oncologists generally use the most efficacious agents as front-line treatment to maximize outcomes for patients, and as such, VELCADE will be a leading therapy in this disease setting."

Frontline VMP in Elderly Multiple Myeloma Patients: Extended Follow-Up (Abstract #PO-718)

"The addition of VELCADE has produced the best complete remisssion and three-year survival rates ever reported with a melphalan prednisone therapy, providing results that are as powerful as stem cell transplantation without the associated side effects, recovery time and expense," said Maria-Victoria Mateos, M.D., Ph.D., Grupo Espanol de Multiple Myeloma. "With VELCADE added to this combination, we now are able to offer all patients, including those who historically could not have a transplant, an alternative that provides complete remission and prolongs lives."

The Phase I / II study evaluated efficacy and safety of VMP combination therapy in untreated MM patients aged 65 years or older with a median age of 75 years. The study included 54 evaluable patients ineligible for SCT. Patients received VELCADE at 1.0 mg/m(2) or 1.3 mg/m(2) on days 1, 4, 8, 11, 22, 25, 29 and 32 for four six-week cycles, then on days 1, 8, 15 and 22 for five five-week cycles. Patients also received melphalan at 9 mg/m(2) and prednisone at 60 mg/m(2) on days 1 through 4 of each cycle. Response was assessed using the European Group for Blood and Marrow Transplant (EBMT) criteria. Results were presented by Dr. Mateos and showed a CR rate of 43 percent. At 38 months, 85 percent of patients were alive. Side effects were predictable and manageable, similar to those seen in previous VELCADE clinical trials.

Long Term Follow-Up of VcAD (or PAD) for Untreated Multiple Myeloma (Abstract #PO-725)

The open-label Phase I / II study investigated the efficacy of VcAD combination therapy in untreated MM patients. The trial included 40 evaluable patients, who were treated for four cycles prior to SCT. Patients received either VELCADE at 1.3 mg/m(2) (VcAD-1) or 1.0 mg/m(2) (VcAD-2) on days 1, 4, 8 and 11 of a 21-day schedule. Patients also received doxorubicin at 9 mg/m(2) on days 1 through 4 and dexamethasone at 40 mg on days 1 through 4, 8 through 11, and 15 through 18 during cycle one and on days 1 through 4 during cycles two through four. Responses were classified using the EBMT criteria. Results were presented by Rakesh Popat, M.D., St. Bartholomew's Hospital, and showed in the VcAD-1 arm a CR rate of 29 percent prior to SCT, which improved to 57 percent following SCT. At one year, 100 percent of patients were alive with 95 percent of patients alive at two years. Median OS has not yet been reached after four years. Side effects, including peripheral neuropathy, were predictable and manageable, similar to those seen in previous VELCADE clinical trials.

Combination Therapy with VELCADE, DOXIL and Dexamethasone in Newly Diagnosed Myeloma: Updated Results of a Phase II Clinical Trial (Abstract #PO- 721)

The Phase II trial evaluated the efficacy of VDD combination therapy in untreated MM patients. The trial enrolled 40 patients, who received VELCADE at 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21-day schedule. Patients also received DOXIL at 30 mg/m(2) on day 4 and dexamethasone at 40 mg on days 1 through 4 or 20 mg corresponding with the VELCADE schedule. After four cycles of VDD, patients proceeded to SCT or continued VDD maintenance therapy. Responses were determined based on the EBMT criteria. Results were presented by Andrzej Jakubowiak, M.D., Ph.D., University of Michigan Comprehensive Cancer Center, and demonstrated a CR rate of 43 percent prior to SCT, which improved to 65 percent following SCT. At 16 months, 100 percent of patients were alive. Side effects were predictable and manageable, similar to those seen in previous VELCADE clinical trials.

Phase I / II Study of Upfront VELCADE, Lenalidomide and Dexamethasone in Multiple Myeloma: Early Results (Abstract #PO-715)

This Phase I / II study of VRD combination therapy was designed to determine the maximum tolerated dose (MTD) and efficacy in untreated MM patients. The preliminary analysis included 15 evaluable patients, who received VELCADE at 1.0 mg/m(2) or 1.3 mg/m(2) on days 1, 4, 8 and 11 of a 21- day schedule. Patients also received lenalidomide at 15, 20 or 25 mg on days 1 through 14 and dexamethasone at 40 mg corresponding with the VELCADE schedule. Patients were treated for up to eight cycles at four planned dose levels. MTD has not yet been reached. Response was assessed by modified EBMT criteria. Results were presented by Paul Richardson, M.D., Dana-Farber Cancer Institute, and showed an ORR (CR + partial response + minor response) of 100 percent, including a CR rate of 20 percent. Side effects were manageable and included hypophosphatemia, infections and thrombocytopenia. No grade 3 or higher peripheral neuropathy was observed.

About Multiple Myeloma

Multiple myeloma 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 U.S., more than 50,000 individuals have MM and 20,000 new cases are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths annually.

About VELCADE

VELCADE is being co-developed by Millennium Pharmaceuticals, Inc. and Johnson & Johnson Pharmaceutical Research & Development, L.L.C. Millennium is responsible for commercialization of VELCADE in the U.S., Janssen-Cilag is responsible for commercialization in Europe and the rest of the world. Janssen Pharmaceutical K.K. is responsible for commercialization in Japan. For a limited period of time, Millennium and Ortho Biotech Inc. will co-promote VELCADE in the U.S. VELCADE is approved in more than 80 countries worldwide.

In the U.S., VELCADE is indicated for the treatment of patients with multiple myeloma who have received at least one prior therapy. VELCADE is indicated for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy. VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. In the European Union and many other countries worldwide, VELCADE is approved for patients with multiple myeloma after first relapse.

Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, hypotension observed throughout therapy, cardiac and pulmonary disorders, gastrointestinal adverse events, thrombocytopenia, neutropenia and tumor lysis syndrome. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Cases of severe sensory and motor peripheral neuropathy have been reported. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Acute development or exacerbation of congestive heart failure, and/or new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with few or no risk factors for decreased left ventricular ejection fraction. There have been rare reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome in patients receiving VELCADE. Some of these events have been fatal. A higher proportion of these events have been reported in Japan. There have been rare reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. VELCADE is associated with thrombocytopenia and neutropenia. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. Complete blood counts (CBC) should be frequently monitored during treatment with VELCADE. Rare cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions.

Safety Data: In 1163 patients in multiple myeloma and mantle cell lymphoma studies, the most commonly reported adverse events were asthenic conditions (64%), nausea (55%) in single-agent VELCADE, diarrhea (52%), constipation (41%), peripheral neuropathy (39%), thrombocytopenia (36%), appetite decrease, including reports of anorexia (36%), pyrexia (34%), vomiting (33%) and anemia (29%). Twenty percent of patients reported at least one episode of grade 4 toxicity; the most common grade 4 toxicities were thrombocytopenia (5%) and neutropenia (3%). Fifty percent of patients reported serious adverse events. The most commonly reported serious adverse events were pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

For more information about VELCADE clinical trials, patients and physicians can contact the Millennium Medical Product Information Department at 1-866-VELCADE (1-866-835-2233).

About Millennium

Millennium Pharmaceuticals, Inc., a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a novel cancer product, and has a robust clinical development pipeline of product candidates. Millennium's research, development and commercialization activities are focused in two therapeutic areas: oncology and inflammation. By applying its knowledge of the human genome, understanding of disease mechanisms and industrialized drug discovery platform, Millennium is developing an exciting pipeline of innovative product candidates. Millennium's website is www.millennium.com.

This press release contains "forward-looking statements," including statements about the Company's growth and development of products. Various important risks may cause the Company's actual results to differ materially from the results indicated by these forward-looking statements, including: adverse results in its drug discovery and clinical development programs; failure to obtain patent protection for its discoveries; commercial limitations imposed by patents owned or controlled by third parties; the Company's dependence upon strategic alliance partners to develop and commercialize products and services based on its work; difficulties or delays in obtaining regulatory approvals to market products and services resulting from its development efforts; product withdrawals; competitive factors; difficulties or delays in manufacturing the Company's products; government and third-party reimbursement rates; the commercial success of VELCADE and INTEGRILIN(R) (eptifibatide) Injection; achieving revenue consistent with internal forecasts; and the requirement for substantial funding to conduct research and development and to expand commercialization activities. For a further list and description of the risks and uncertainties the Company faces, see the reports it has filed with the Securities and Exchange Commission. The Company disclaims any intention or obligation to update or revise any forward- looking statements, whether as a result of new information, future events or otherwise.

(1) Complete remission / complete response includes both immunofixation positive and negative readouts

CONTACT: Media, Jennifer Snyder, +1-617-444-1439, Investors, Kyle
Kuvalanka, +1-857-498-0818, both of Millennium Pharmaceuticals, Inc.

SOURCE Millennium Pharmaceuticals, Inc. http://www.millennium.com

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