Phase I/II Trial of Bortezomib Maintenance in Order To Prolong Remission-Duration Following Autologous Peripheral Blood Progenitor Cell Transplantation as Treatment for Intermediate- and Advanced-Stage Multiple Myeloma.

Pts (median age 60 yrs, range 37 – 73 yrs) with intermediate- and advanced-stage multiple myeloma were assigned to maintenance therapy with bortezomib beginning a minimum of three and a maximum of four mos after the day of autologous PBPC transplantation following a standard preparative regimen of high-dose melphalan (200 mg/m²). Eligibility for the initiation of maintenance required nl organ function, post-transplant neutrophil and plt recovery (defined as ANC ≥ 1000 mm⁻³ and untransfused plt ≥30,000 mm⁻³). Cohorts of 3 pts each were entered at 1 of 3 dose levels of bortezomib (1.0, 1.3, and 1.6 mg/m²) given IV q wk for 3 wks followed by a 1-wk rest period constituting 1 treatment cycle for a total of 8 cycles. To-date, 29 pts were eligible for study treatment and 23 pts received at least 1 dose of maintenance. Reasons for not proceeding to maintenance included 1 pt with an ANC < 1000 mm⁻³, 1 pt with a serum creatinine > 2 mg/dl, and 4 additional pts unable to travel to the center. The median t from diagnosis to transplant was 11.4 mos (range, 4.9 to 59.7 mos), and the median t from autologous transplant to the initiation of bortezomib maintenance was 3.7 mos. Protocol adherence was excellent with one pt missing the final dose of treatment and one other pt discontinuing therapy due to personal reasons. After completion of the Phase I portion of the study, the DLT was determined to be 1.6 mg/m² based on grade 3 diarrhea in 2 pts after 2 and 3 cycles of treatment, respectively. All subsequent pts entered were treated at the MTD of 1.3 mg/m². Other, non-dose-limiting toxicities included thrombocytopenia (14 pts), neuropathy (12 pts), anemia (12 pts), fatigue (11 pts), neutropenia (8 pts), musculoskeletal pain (7pts), nausea (5 pts), Herpes zoster reactivation (4 pts), diarrhea (3 pts), edema (3 pts), cough (2 pts), as well as upper respiratory infection, chills, fever, dyspepsia, and anorexia (1 pt each). Disease assessment consisted of serum and urine PEP monthly for all pts, and bone marrow aspiration quarterly for those pts with nonsecretory myeloma. Repeat bone surveys were required for pts 3, 9, 15, and 21 mos post-transplant. 2 pts required termination of the study drug, 1 at the end of treatment cycle 8 and the other during cycle 3, due to unacceptable side effects. 2 separate pts terminated the study due to disease progression, 1 during cycle 5 and the other during cycle 6, respectively. One additional pt discontinued further study treatments due to personal reasons during cycle 2. All 23 pts are eligible for response assessment. 13 pts continue to be followed every 3 mos for evidence of disease recurrence in the post-treatment period while 4 others continue on treatment. After a median follow-up from transplantation of 17.1 mos (range 4.1 to 30.3 mo), 6 pts have relapsed while none have died of recurrent myeloma. The current median relapse-free survival is 15.8 mos. This phase I/II trial demonstrates that bortezomib can be safely administered as a maintenance after conventional autologous PBPCl transplantation with an MTD of 1.3mg/m² given 3 times per month for 8 mos; treatment consolidated remission achieved by autologous transplant as will be presented. These preliminary results, when compared to published results of autologous transplantation for myeloma, suggest that with further follow-up, bortezomib maintenance may favorably impact t- to-recurrence.