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FDA Approves Bortezomib for Patients With Previously Untreated Multiple Myeloma

CAMBRIDGE, Mass. and OSAKA, Japan, June 20 /PRNewswire/ -- Millennium Pharmaceuticals, The Takeda Oncology Company, and Takeda Pharmaceutical Company Limited ("Takeda", TSE: 4502) today announced that the U.S. Food and Drug Administration (FDA) approved VELCADE for patients with previously untreated multiple myeloma (MM). The Company's co-development partner, Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (J&JPRD) also has filed a corresponding application with the European Medicines Evaluation Agency (EMEA).

"This comes as wonderful news for patients. The VISTA(1) trial showed 30% complete remission rate with bortezomib compared to 4% for the control arm. Importantly, patients treated with bortezomib also experienced a survival benefit," said Paul Richardson, M.D., a senior investigator for the study and Clinical Director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute.

"We are excited for patients with previously untreated multiple myeloma, who now can benefit from VELCADE, including its ability to deliver a significant increase in overall survival. VELCADE treatment also is available for multiple myeloma patients in the second- and third-line settings, where it already is approved," said Deborah Dunsire, M.D., President and CEO, Millennium Pharmaceuticals, The Takeda Oncology Company.

The current approval was based on an international, multicenter, open label, active-control trial in previously untreated patients with symptomatic multiple myeloma. Patients were randomized to receive either nine 6 week cycles of oral melphalan (M) plus prednisone (P) or MP plus VELCADE. Patients received M (9 mg/m2) plus P (60 mg/m2) daily for four days every 6 weeks or the same MP schedule with bortezomib (1.3 mg/m2) IV on days 1, 4, 8, 11, 22, 25, 29 and 32 of every 6 week cycle for 4 cycles then once weekly for 4 weeks on days 1, 8, 22 and 29 of every 6 week cycle for 5 additional cycles. Antiviral prophylaxis was recommended for patients on the VELCADE study arm. Time-to-progression (TTP) was the primary efficacy endpoint. Overall survival (OS), progression-free survival (PFS) and response rate (RR) were secondary endpoints. A total of 682 patients were randomized: 338 to receive MP and 344 to receive the combination of bortezomib plus MP. The median age of patients for both groups was 71 years. Demographics and baseline disease characteristics were similar between the two groups.

The safety profile of VELCADE in combination with MP is consistent with the known safety profiles of both VELCADE and MP.

In VISTA, 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%).

Important Safety Information
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 greater than or equal to 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%).

Source: Millennium Pharmaceuticals

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