Report from the FDA Approval Summary for Bortezomib for Injection in the Treatment of Multiple Myeloma (2004)

Purpose: Multiple myeloma is a malignant plasma cell disorder accounting for about 10% of hematological malignancies. Despite treatment advances, including hematopoietic stem-cell transplantation to facilitate administration of high-dose cytotoxic chemotherapy, the median survival remains approximately 3 years and long-term remissions are rare. Bortezomib (Velcade, formerly known as PS-341; Millennium Pharmaceuticals, Cambridge MA) is a dipeptide boronic acid that inhibits the 20S proteasome involved in the degradation of intracellular proteins, including those affecting cell cycle regulation in mammalian cells. Described herein are the analyses by the United States Food and Drug Administration (FDA) of clinical and nonclinical data submitted in the New Drug Application. Chemistry manufacturing and controls, animal toxicology, and biopharmaceutical data are described. The results of Phase I and Phase II clinical studies in patients with multiple myeloma are summarized. The marketing approval and postmarketing commitments are discussed. Results: Toxicology studies in the rat and monkey identified hematological, lymphoid, cardiac, renal, gastrointestinal, and neurological toxicities of bortezomib. A steep dosetoxicity effect was noted at doses >0.9 mg/m 2 . Administration of doses >3.0 mg/m 2 to monkeys resulted in cardiovascular collapse and death 12–14 h postdose. Histopathological evidence of axonal and myelin degeneration of dorsal root ganglia, peripheral nerves, and spinal cord were observed in monkeys and rodents; concurrent clinical observations included tremors and decreased activity. Pharmacokinetic studies in patients with advanced malignancies demonstrated that the mean elimination half-life after the first bortezomib dose varied from 9 to 15 h at doses ranging from 1.45 to 2.00 mg/m 2 . The drug is metabolized by cytochrome P450 –3A4, -2D6, -2C19, -2C9, and -1A2. Three Phase I studies were performed in a total of 123 patients with advanced malignancies. Dose-limiting toxicity included diarrhea and sensory neurotoxicity. No dose-limiting hematological toxicity was reported. Safety and efficacy were evaluated in an open-label, Phase II study of 202 patients with multiple myeloma who had received at least two prior therapies and had demonstrated disease progression on their most recent therapy. A smaller dose finding study of 54 patients provided additional supportive information. Bortezomib was administered by i.v. bolus on days 1, 4, 8, and 11 in a 21-day cycle for up to eight cycles. The initial dose was 1.3 mg/m 2 except for 28 patients in the dose-finding study who received a 1.0 mg/m 2 dose. The primary study end point in this single-arm trial was response rate, easily measured and thought to correlate with clinical benefit in patients with myeloma. One hundred eighty-eight patients who met the inclusion criteria were included in the FDA efficacy analysis population. Complete responses (CRs) were observed in 5 patients and partial responses (PRs) in 47 patients for an overall response (OR) rate (OR CR PR) of 28%. The dose finding study of 54 patients showed a higher response rate for patients given 1.3 mg/m 2 compared with 1.0 mg/m 2 twice weekly for two of the 3-week schedule, but the study was too small for statistical dose-response comparisons. The most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness) in 65%, nausea (64%), diarrhea (51%), appetite decreased (including anorexia; 43%), constipation (43%), thrombocytopenia (43%), peripheral neuropathy (37%, including peripheral sensory neuropathy and peripheral neuropathy aggravated), pyrexia (36%), vomiting (36%), and anemia (32%).