FDA Expands Bortezomib Label for Multiple Myeloma
Published Online:2:29 PM, Mon August 11, 2014
Michael Vasconcelles, MD
The expanded approval was based on findings from the phase II RETRIEVE study that explored intravenous bortezomib retreatment in 130 patients with multiple myeloma. In this study, readministration of bortezomib in patients who received a median of two prior therapies resulted in an overall response rate (ORR) of 38.5% for a median duration of 6.5 months. The expansion to the indication was also accompanied by dosing guidelines, efficacy, and safety updates.
“For the past 11 years, Velcade has played an important role as the only therapy proven to extend overall survival for patients with newly diagnosed and relapsed multiple myeloma,” Michael Vasconcelles, MD, global head of Oncology Therapeutic Area Unit, Takeda, the manufacturer of the drug, said in a press release. “With these newly approved dosing guidelines, physicians will be able to provide their patients, who have previously received Velcade, with an effective treatment extending Velcade use across the continuum of care of multiple myeloma.”
In the open-label, single-arm phase II RETRIEVE study the retreatment dose was determine by mirroring the last tolerated dose received in a previous bortezomib-based regimen. This was allowed to range between 1.0 and 1.3 mg/m2 twice weekly for two weeks followed by a 10-day rest period. The coadministration of dexamethasone was allowed in the trial.
The most common all-grade adverse event was thrombocytopenia, which occurred in 52% of patients in the study. The most common grade 3/4 adverse events were thrombocytopenia (24%) and peripheral neuropathy (6%). The most commonly reported serious adverse reactions were thrombocytopenia (3.8%), diarrhea (2.3%), herpes zoster, and pneumonia (1.5% each). Adverse reactions that led to the discontinuation of bortezomib occurred in 13% of patients.
In a large meta-analysis that examined the safety and efficacy of bortezomib retreatment in patients with multiple myeloma, similar results were found for 1051 patients across 23 studies. Results from this literature review were published in the June 2014 edition of Clinical Lymphoma Myeloma and Leukemia.
Across all studies, the weighted average ORR was 39.1% with a median time to progression of 7.5 months. The median overall survival (OS) was 16.6 months. Better ORR was seen in patients who received fewer therapies (≤4) and were relapsed but not refractory prior to retreatment. For these patients, the ORR was 43.4% and 57.2%, respectively. The higher ORR for relapsed only patients was mirrored in time to progression (8.5 months) and OS (19.7 months).
In this analysis, the most common grade 3/4 adverse events included thrombocytopenia (35%), neutropenia (15%), anemia (14%), pneumonia (10%), and peripheral neuropathy (3%).
In 2012, a subcutaneous administration route for bortezomib was approved by the FDA, based on results from a phase III study showing equivalent efficacy to intravenous administration. In this study, the ORR with subcutaneous bortezomib was 43% compared with 42% in the intravenous arm in 222 bortezomib-naïve patients with multiple myeloma.
The rate of grade 3/4 peripheral neuropathy in the subcutaneous arm was 6% compared with 16% in the intravenous arm. Other grade 3/4 side effects also demonstrated marked declines with the subcutaneous route versus intravenous, including thrombocytopenia (13% vs 19%) and neuralgia (3% vs 9%).
At the time of this approval, it was noted that the subcutaneous formulation could be utilized across all approved bortezomib indications.