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VELCADE Induction Followed by VELCADE Maintenance Improves Clinical Outcomes in Previously Untreated Multiple Myeloma Patients

CAMBRIDGE, Mass. - (BUSINESS WIRE) - Millennium: The Takeda Oncology Company today reported results from two large, multi-center, randomized Phase III clinical trials of VELCADE (bortezomib) based combinations for induction therapy, and single-agent maintenance therapy in patients with previously untreated multiple myeloma (MM). These data were presented at the 52^nd annual meeting of the American Society of Hematology (ASH), held December 4-7 in Orlando, Florida.

The first study was conducted among 750 previously untreated MM patients and compared VELCADE, doxorubicin and dexamethasone (PAD) induction followed by autologous stem cell transplant (ASCT) and single-agent VELCADE maintenance (every other week for two years) against vincristine, doxorubicin and dexamethasone (VAD) induction followed by ASCT and thalidomide maintenance. These cooperative group data were generated by the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and the German Multiple Myeloma Group (GMMG) and were presented by Pieter Sonneveld, M.D., University Hospital, Rotterdam, The Netherlands on Sunday, December 5.

The second study was conducted in 502 previously untreated MM patients ineligible for high-dose therapy and stem cell transplantation. Patients were randomized to one of three induction combinations: VELCADE and dexamethasone (VcD); VELCADE, thalidomide, dexamethasone (VcTD); or VELCADE, melphalan and prednisone (VcMP), all followed by weekly VELCADE maintenance (four weeks on, one week off) for 25 weeks. These data were presented by Ruben Niesvizky, M.D., Weill Cornell Medical College, New York, NY on Monday, December 6.

"The HOVON/GMMG study in younger, transplant-eligible patients demonstrated the potential impact of VELCADE based induction and maintenance therapy in prolonging progression-free and overall survival," said Nancy Simonian, M.D. Chief Medical Officer, Millennium. "In the UPFRONT study, all three VELCADE based combinations demonstrated high response rates, which were all further increased after maintenance treatment with weekly VELCADE."

HOVON-65/GMMG-HD4 Randomized Phase III Trial Comparing Bortezomib, Doxorubicin, Dexamethasone (PAD) Vs VAD Followed by High-Dose Melphalan (HDM) and Maintenance with Bortezomib or Thalidomide In Patients with Newly Diagnosed Multiple Myeloma (MM) (Abstract #40)

This Phase III trial in 750 previously untreated MM patients with a median age of 57 was conducted by Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON). The updated results, which were presented by Professor Sonneveld showed:

• The overall PFS was longer in the VELCADE arm compared to the VAD- thalidomide arm (median 36 months v 27 months; HR=0.75; p<0.01)
• The overall survival was improved in the VELCADE arm compared to the VAD-thalidomide arm (HR=0.73; p=0.02); the median was not reached
• The complete response/near complete response (CR/nCR) rate was 49 percent in the VELCADE arm and 34 percent in the VAD-thalidomide arm (p<0.01)
• At 24 months, the rate of patients who started maintenance therapy and remained on maintenance therapy was 48 percent in the VELCADE arm and 28 percent in the VAD-thalidomide arm
• In the VELCADE arm, 26 percent of patients experienced peripheral neuropathy of Grade 3 or higher, compared with 12 percent of patients in the VAD-thalidomide arm

Patients were randomized to receive three cycles of VAD or PAD induction therapy. The PAD regimen was comprised of VELCADE 1.3 mg/m², days 1, 4, 8, 11, doxorubicin 9 mg/m² on days 1-4, and dexamethasone at 40 mg on days 1-4, 9-12, 17-20. VAD was comprised of vincristine at 0.4 mg/m² on days 1-4, doxorubicin at 9 mg/m² on days 1-4 and dexamethasone at 40 mg on days 1-4. Patients could receive either one or two ASCT including high-dose melphalan (HDM) at 200 mg/m². Maintenance therapy consisted of thalidomide (T) 50 mg daily (arm A) or VELCADE 1.3 mg/m², every two weeks (arm B) for 2 years. Primary endpoint was PFS, other endpoints were complete response (CR) (EBMT), immunofixation positive CR (nCR), VGPR pre-and post HDM and survival. The protocol specified analysis was intention-to-treat and censored for patients who received Allo-SCT after high-dose melphalan.

Phase 3b UPFRONT Study: Safety and Efficacy of Weekly Bortezomib Maintenance Therapy After Bortezomib-Based Induction Regimens in Elderly, Newly Diagnosed Multiple Myeloma Patients (Abstract #619)

This Phase IIIb trial in 502 previously untreated MM patients is a U.S. community-based, randomized, open-label study comparing the safety and efficacy of three VELCADE based induction regimens: VELCADE and dexamethasone (VcD); VELCADE, thalidomide and dexamethasone (VcTD); and VELCADE, melphalan and prednisone (VcMP); all followed by single-agent VELCADE maintenance. The updated results, which were presented by Dr. Niesvizky, showed:

• The Overall Response Rate (ORR) was 71 percent, 79 percent and 73 percent in the VcD, VcTD and VcMP arms respectively after maintenance
• The CR/nCR rates were 31 percent, 38 percent and 34 percent in the VcD, VcTD and VcMP arms respectively after maintenance
• Median PFS was 13.8 months, 18.4 months, and 17.3 months in the VcD, VcTD and VcMP arms respectively after a median follow-up of 13.4 months
• The rate of grade 3 or higher adverse events after induction was 70 percent in the VcD arm, 84 percent in the VcTD arm and 79 percent in the VcMP arm
• After maintenance, the rate of grade 3 or higher adverse events increased by 7 percent in the VcD arm, 6 percent in the VcTD arm and 2 percent in the VcMP arm
• The most common grade 3 or higher adverse events were peripheral neuropathy, fatigue, neutropenia and diarrhea

Patients with previously untreated, symptomatic, measurable MM were randomized (1:1:1) to receive 49 weeks of therapy: 24 weeks of induction with VcD, VcTD, or VcMP (VcD: Vc 1.3 mg/m², days 1, 4, 8, 11; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcTD: Vc 1.3 mg/m², days 1, 4, 8, 11; T 100 mg/d, d1–21; D 20 mg, days 1, 2, 4, 5, 8, 9, 11, 12 [cycles 1–4]), days 1, 2, 4, 5 [cycles 5–8]); VcMP: Vc 1.3 mg/m², days 1, 4, 8, 11; M 9 mg/m² and P 60 mg/m², day 1–4, every other cycle), followed by 25 weeks of maintenance with weekly Vc (1.6 mg/m², days 1, 8, 15, 22; rest period days 23-35).

About Millennium

Millennium: The Takeda Oncology Company, a leading biopharmaceutical company based in Cambridge, Mass., markets VELCADE, a first-in-class proteasome inhibitor, 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. Additional information about Millennium is available through its website, www.millennium.com.

About VELCADE

VELCADE is co-developed by Millennium and Ortho Biotech Oncology Research & Development, a unit of 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. Takeda Pharmaceutical Company Limited and Janssen Pharmaceutical K.K. entered into a co-promote agreement in May 2010 for VELCADE in Japan. VELCADE is approved in more than 90 countries and has been used to treat more than 160,000 patients worldwide.

Indications and Important Safety Information

What is VELCADE (bortezomib) Used For?

VELCADE is approved for the treatment of patients with multiple myeloma (a cancer of the plasma cells). VELCADE is also approved for the treatment of patients with mantle cell lymphoma (a cancer of lymph nodes) who have already received other treatments.

How is VELCADE administered?

VELCADE is prescribed by a physician experienced in the use of medications to treat cancer. It is administered as an injection into your vein (IV) by a health care professional.

Who Should Not Receive VELCADE?

Before you receive treatment with VELCADE, tell your doctor about all of your medical conditions. You should not receive VELCADE if you are:

• allergic to bortezomib, boron or mannitol
• pregnant or plan to become pregnant
• breastfeeding. Discuss with your doctor when it is safe to restart breastfeeding after finishing your treatment.

The effects of VELCADE in children have not been evaluated.

What are the Possible Side Effects of VELCADE?

VELCADE can cause serious side effects including:

• Neutropenia (low levels of neutrophils, a type of white blood cell) and Thrombocytopenia (low levels of platelets). VELCADE can cause low levels of white blood cells (infection fighting cells) and/or platelets (clot-forming cells). You will have regular blood tests to check your cell counts during your treatment with VELCADE. If the number of these cells is very low, your doctor may change the dose and/or schedule of VELCADE. If your white blood cells become low, you can be at higher risk for infections. Tell your doctor if you develop a fever or believe you have an infection. If platelets become very low, there is an increased risk of bleeding. Your doctor may recommend a platelet transfusion. There have been cases of bleeding in the stomach, bowels and brain during treatment with VELCADE.
• Gastrointestinal Problems. VELCADE treatment can cause nausea, vomiting, diarrhea, and constipation. If your symptoms are severe, your doctor may recommend IV fluids and/or medications.
• Peripheral neuropathy. VELCADE can cause damage to the nerves, a condition called peripheral neuropathy. You may feel muscle weakness, tingling, burning, pain, and loss of feeling in your hands and feet, any of which can be severe. Tell your doctor if you notice any of these symptoms. Your doctor may change the dose and/or schedule of VELCADE or stop it altogether.
• Low blood pressure. VELCADE can cause a drop in blood pressure. Tell your doctor if you have low blood pressure, feel dizzy or feel as though you might faint. If you are taking drugs that lower blood pressure, your medications might need to be adjusted. If you are not drinking enough liquids, your doctor may need to administer IV fluids.

• Heart problems. VELCADE treatment can cause or worsen heart rhythm problems and heart failure. Your doctor may closely monitor you if you have, or are at risk for, heart disease. Tell your doctor if you experience chest pressure or pain, palpitations, swelling of your ankles or feet, or shortness of breath.
• Lung Disorders. There have been reports of lung disorders in patients receiving VELCADE. Some of these events have been fatal. Tell your doctor if you experience any cough, shortness of breath, wheezing or difficulty breathing.
• Liver disease. If you have liver problems, it can be harder for your body to get rid of VELCADE. VELCADE has caused sudden liver failure in patients who were taking many medications or had other serious medical conditions. Symptoms of liver problems include a yellow discoloration of the eyes and skin (jaundice) and changes in liver enzymes measured in blood tests. Your doctor will closely monitor you if you have liver disease. In patients with moderate or severe liver disease, VELCADE should be started at a lower dose. Additional dose adjustments may be made based on your tolerance of the drug.
• Tumor Lysis Syndrome (TLS). TLS can occur with cancer treatments and your doctor will be monitoring blood and urine for any signs of this syndrome. If you develop TLS, your doctor will take appropriate steps to treat it.
• Reversible Posterior Leukoencephalopathy Syndrome (RPLS). There have been reports of a rare, reversible condition involving the brain called RPLS in patients treated with VELCADE. Patients with RPLS can have seizures, high blood pressure, headaches, tiredness, confusion, blindness or other vision problems. VELCADE treatment should be stopped in cases of RPLS.

The most common side effects seen in patients receiving VELCADE include: thrombocytopenia, neutropenia, nausea, peripheral neuropathy, neuralgia (nerve pain), pyrexia (high temperature), diarrhea, anemia, leukopenia (low levels of white blood cells), decreased appetite, fatigue, constipation, vomiting, dehydration, dyspnea (difficulty breathing), cough, asthenia (low energy), insomnia (trouble sleeping), peripheral edema (swelling of the limbs), and headache.

What other information should you discuss with your doctor?

You should also tell your doctor if you:

• have kidney disease. If you are on dialysis, your doctor will administer VELCADE after the dialysis procedure.
• are taking medication for diabetes. VELCADE can affect your blood glucose levels. Your doctor may require close monitoring of your blood glucose levels and change the dose of your diabetes medicine while you are being treated with VELCADE.
• have liver disease.
• are using medicines like ketoconazole (an anti-fungal) and ritonavir (an anti-viral), which will require close monitoring during treatment with VELCADE.
• are using any other medications (including over the counter drugs), herbal or dietary supplements, or holistic treatments.
• develop a rash of any type while receiving VELCADE.

The side effects of VELCADE may impair your ability to drive or operate machinery.

These are not all of the possible side effects with VELCADE. It is important to always contact your doctor if you experience any side effects while on VELCADE. If you have any questions about VELCADE, contact your doctor. Additional information and full prescribing information is available at www.VELCADE.com.

Please see the full prescribing information for VELCADE including warnings and precautions.

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).

Editors' Note: This press release is also available under the Media section of the Company's website at: www.millennium.com/media

Millennium: The Takeda Oncology Company
Manisha Pai, 617-551-7877
Manisha.Pai@mpi.com
or
Lauren Musto, 617-551-7848
Lauren.Musto@mpi.com