Continued Overall Survival Advantage Reported From Pivotal Trial of Velcade (Bortezomib) for Injection Based Therapy in Patients With Previously Untreated Multiple Myeloma

SAN FRANCISCO, December 08, 2008 /PRNewswire/ -- Millennium: The Takeda Oncology Company today reported updated results based on extended follow up of patients from the large, international Phase III VISTA(1) trial showing continued survival improvement for patients with previously untreated multiple myeloma given VELCADE, melphalan and prednisone (VcMP). The VELCADE combination demonstrated consistent efficacy in all patient sub-groups, including those with poor prognostic characteristics, such as advanced age, poor risk cytogenetics and renal impairment. These data were presented at the 50th Annual Meeting of the American Society of Hematology (ASH), held December 5-9, 2008 in San Francisco, California.

"The ultimate goal in treating multiple myeloma is to prolong the patient's life," said Professor Jesus San-Miguel, M.D., Ph.D., Hospital Universitario de Salamanca and Principal Investigator of the trial. "The follow-up data from the VISTA study showed that the addition of VELCADE to melphalan and prednisone continued to demonstrate a long-term survival advantage for patients with previously untreated multiple myeloma."

The VISTA trial enrolled 682 patients with previously untreated multiple myeloma ineligible for stem cell transplantation. The first interim analysis was presented at ASH 2007. Data with a median follow up of 25.9 months were presented at this year's ASH meeting. In addition, a detailed analysis evaluated the impact of subsequent therapy on the overall survival (OS) results. The updated results, which were presented by Professor San-Miguel, included:

"This update demonstrates that the use of VELCADE upfront delivers an improvement in overall survival, which is maintained over time. Importantly, this benefit was observed regardless of subsequent therapy," said Nancy Simonian, M.D., Chief Medical Officer, Millennium.

Patients in the VcMP arm of the study received nine 6-week cycles of VELCADE at 1.3 mg/m(2) (days 1, 4, 8, 11, 22, 25, 29 and 32 in cycles 1 through 4 and days 1, 8, 22 and 29 in cycles 5 through 9) with melphalan 9 mg/m(2) and prednisone 60 mg/m(2) (days 1 through 4 in cycles 1 through 9), or melphalan plus prednisone, in the same dose and schedule administered to the patients in the VcMP arm. Patients remained on VcMP therapy for a median of 46 weeks (eight cycles) out of the planned nine cycles versus 39 weeks (seven cycles) with melphalan and prednisone.

Multiple myeloma is the second most common hematologic malignancy and although the disease is predominantly a cancer of the elderly (the median age of onset is 70 years), 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.

VELCADE is 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. VELCADE is approved in more than 87 countries worldwide.

In the U.S., VELCADE is indicated for the treatment of patients with multiple myeloma. VELCADE also 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.

Risks associated with VELCADE therapy include new or worsening peripheral neuropathy, hypotension throughout therapy, cardiac and pulmonary disorders, reversible posterior leukoencephalopathy syndrome, gastrointestinal adverse events, thrombocytopenia, neutropenia, tumor lysis syndrome and hepatic events. Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Nursing mothers are advised not to breastfeed while receiving 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 new onset of decreased left ventricular ejection fraction has been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. There have been 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. There have been reports of Reversible Posterior Leukoencephalopathy Syndrome (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. Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. Patients on oral antidiabetic medication while receiving VELCADE should check blood sugar levels frequently.

Adverse Reaction Data

Safety data from Phase II and III studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the Phase III, VELCADE plus DOXIL(R) [doxorubicin HCl liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma.

In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise and weakness) (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated) (39%), thrombocytopenia and appetite decreased (including anorexia) (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia and headache (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo) (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of >/=Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%).

In the Phase III VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events for VELCADE in combination with MP vs MP, respectively, were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%).

Millennium: The Takeda Oncology Company, 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 Pharmaceuticals, Inc. was acquired by Takeda Pharmaceutical Company Ltd. in May, 2008. The Company's research, development and commercialization activities are focused in oncology.

Posted: December 2008

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