Bortezomib Does Not Impair Cytokine Induced Mobilization of Stem Cells Prior to Autologous Transplantation in Multiple Myeloma.

Abstract

Bortezomib (VELCADE®) is a selective inhibitor of the proteasome approved for the treatment of relapsed or refractory multiple myeloma (MM). Emerging evidence indicates that bortezomib is also effective alone or in combination with cytotoxic agents in the front-line treatment of myeloma. Given the superiority of high dose therapy with autologous transplant compared to conventional therapy in myeloma, the application of bortezomib to novel front-line therapies depends in part on its effects on subsequent stem cell mobilization and engraftment. Previous reports have demonstrated successful chemotherapy induced mobilization of stem cells following bortezomib. To determine the effects of bortezomib on cytokine mobilization and engraftment of stem cells, we conducted a study of bortezomib administered prior to high-dose melphalan with autologous stem cell transplant. Following induction therapy, two cycles of bortezomib 1.3 mg/m2 were administered on days 1, 4, 8, and 11 of a 21-day treatment cycle. One week after the last dose of bortezomib, stem cells were mobilized with G-CSF 10 mcg/kg/day for 5 days and harvested by large volume apheresis (20 L/day) until a minimum of 2.5 x 106 CD34+ cells/kg were collected. Melphalan 100 mg/m2/day x 2 days was administered followed by reinfusion of peripheral blood stem cells 48 hours later. GM-CSF 250 mcg/m2/day was given post-transplant until the ANC ≥ 1,500/mm3 for 2 consecutive days. Forty patients were enrolled in this study with 37 continuing on to autologous transplant. Study population consists of 24 male and 16 female patients with the median age at enrollment of 56 years (range 38–69). Myeloma characteristics at diagnosis were as follows (number of patients): IgG (29), IgA (10), light chain only (1), with stage I (1), II (12), or stage III (27) disease. Prior to receiving bortezomib, 20 patients had been previously treated with an anthracycline containing regimen and 22 with thalidomide for induction therapy. Two patients did not receive any prior chemotherapy. Two patients did not proceed to stem cell harvest, one secondary to disease progression on bortezomib and the other because of a stroke suffered during G-CSF mobilization. Stem cell collection was successful in 37 of 38 patients with the first collection containing a median of 4.24 x 106 CD34+ cells/kg. The majority of patients (29) required a single pheresis session, 7 required two sessions, and 1 patient required 5 sessions. The only patient failing stem cell collection had received extensive radiation to the pelvis in addition to a prior history of breast cancer for which she received adjuvant chemotherapy. All transplanted patients successfully engrafted with a median time to neutrophil engraftment (ANC ≥ 500/mm3) of 11 days (range 9–14 days). Platelet engraftment (platelet count ≥ 20,000/mm3 sustained for 7 days without transfusion) occurred at a median of 11 days (range 9–31 days). In an intention-to-treat analysis at 100 days post-transplant, we observed a compete response (CR) in 6 patients (15%), a near CR in 10 patients (25%) with an additional 19 partial responses (48%) for an overall response rate of 88%. We conclude that pre-transplant treatment with 2 cycles of bortezomib following anthracycline or thalidomide containing chemotherapy does not adversely affect stem cell yield or time to engraftment and results in high CR / near CR rates.