Bortezomib Approved for Subcutaneous Injection

The FDA has deemed subcutaneous injection as a safe and valid method of delivering the drug bortezomib (Velcade) in patients with multiple myeloma, expanding the potential pool of patients who can receive the drug while also significantly reducing the risk of developing the severe side effects associated with the drug.

Millenium: The Takeda Oncology Company, announced that the label for Velcade would be changed to reflect the FDA’s decision. The drug was approved in 2003 to treat multiple myeloma and mantle cell myeloma after receiving at least 1 prior therapy. The new indication covers all previous indications for Velcade.

“For the approval we received, there’s no reason anyone who is receiving the [intravenous] Velcade should not instead be able to receive the [subcutaneous] form,” said Dixie Esseltine, MD, vice president of clinical research at Millenium.

Esseltine explained that there was some evidence that bortezomib could be delivered subcutaneously because there was very little skin irritation associated with its delivery. After rabbit models and some unintentional subcutaneous deliveries seemed to confirm that bortezomib could safely be delivered subcutaneously, Millenium pursued more rigorous studies.

The new indications for bortezomib are the result of a study published in Lancet Oncology in May 2011. In the phase III, randomized, open-label, international trial, 222 patients with relapsed multiple myeloma who had not previously received bortezomib were divided into 2 arms, with 1 arm receiving bortezomib subcutaneously while the other arm received the drug intravenously.

After 4 cycles, patients in the subcutaneous arm of the study achieved an overall response rate (ORR) of 43% and a complete response (CR) rate of 7%, compared to 42% ORR and 8% CR in the intravenous arm, indicating similar efficacy regardless of how the drug was delivered. However, a key difference observed was the rate of peripheral neuropathy (PN) experienced between the 2 arms. In the subcutaneous arm, 6% of patients experienced grade 3 or higher PN, compared to 16% in the intravenous arm.

Likewise, 38% of patients in the subcutaneous arm experienced PN of any grade, compared with 53% in the intravenous arm. PN is the most common and most hazardous side effect experienced by patients taking bortezomib. Additional grade 3 events reported included thrombocytopenia (13% in subcutaneous, 19% in intravenous) and neuralgia (3% in subcutaneous, 9% in intravenous).

Positive results continued in follow-up, with the ORR at 53% for the subcutaneous arm and 51% for the intravenous arm after 8 cycles of bortezomib. After an 11.8-month median follow-up period, progression-free survival was 10.2 months in the subcutaneous group compared to 8.0 months in the intravenous group, and overall survival at 1 year was 72.6% in the subcutaneous group compared to 76.7% in the intravenous group.

Esseltine said that in addition to switching patients who are currently on the intravenous regimen of bortezomib, the new indication has the potential to reach patients who might have had difficulty with venous delivery.

“In obese patients and elderly patients, it can be very difficult to reach a vein,” Esseltine said. “This new indication gives those patients an easier way to receive bortezomib.”