Phase I/II Trial of Bortezomib Maintenance Following Autolgous Peripheral Blood Progenitor Cell Transplantation as Treatment for Intermediate- and Advanced-Stage Multiple Myeloma.

Patients (median age 55 yrs, range 37 – 73 yrs) with chemotherapy-responsive, intermediate- and advanced-stage multiple myeloma were assigned to maintenance therapy with bortezomib beginning a minimum of three and a maximum of four months after the day of autologous peripheral blood progenitor cell transplantation following a standard preparative regimen of high-dose melphalan (200 mg/sq.m.). Eligibility for the initiation of maintenance therapy required post-transplant neutrophil and platelet recovery (defined as minimum ANC > 1000 mm⁻³ and untransfused platelet count of >30,000 mm⁻³). Cohorts of three patients each were entered at one of three dose levels of bortezomib (1.0, 1.3, and 1.6 mg/m²) given IV once weekly for 3 weeks followed by a one-week rest period constituting one treatment cycle for a total of eight treatment cycles. To-date, 17 patients were considered eligible for study treatment and 13 patients received at least one dose of maintenance therapy. Reasons for not proceeding to maintenance included one patient with an ANC < 1000 mm⁻³, one patient with a serum creatinine > 2mg/dl, and four additional patients unable to travel to the treatment center. The median time from diagnosis of myeloma to transplant was 8 months (range, 4 to 19 mos), and the median time from autologous transplant to the initiation of bortezomib maintenance was 4 mos. Protocol adherence was excellent with only one patient missing the final dose of treatment. After completion of the Phase I portion of the study, the dose-limiting toxicity was determined to be 1.6 mg/m² based on grade 3 diarrhea in two patients after 2 and 3 cycles of treatment, respectively. All subsequent patients entered were treated at the maximum tolerated dose of 1.3 mg/m². Other, non-dose-limiting toxicities included, fatigue (11 pts), anorexia (1 pt), nausea (6 pts), dizziness (3 pts), headache (4 pts), peripheral neuropathy (6 pts), thrombocytopenia (3 pts), neutropenia (1 pt), dry cough (2 pts), upper respiratory infection (3 pts), and Herpes zoster reactivation (3 pts). Disease assessment consisted of serum and urine protein electrophereses monthly for all patients, and bone marrow aspiration quarterly for those patients with nonsecretory myeloma; repeat bone surveys were required for all patients 3, 9, 15, and 21 months post transplant. While one patient required termination of study drug at the end of treatment cycle 8 due to unacceptable side effects, no patients required termination of study drug for disease progression. Six patients currently continue to be followed every three months for evidence of disease recurrence in the post-treatment period; others continue on treatment. This phase I/II trial demonstrates that bortezomib can be safely administered as a maintenance treatment following conventional autologous peripheral blood progenitor cell transplantation with a maximum tolerated dose of 1.3 mg/m² given three times per month for eight months; treatment consolidated the remission achieved by autologous transplant as will be presented. Further study will determine the impact of bortezomib maintenance on recurrence.