Work

150: A randomized phase I trial of melphalan + bortezomib as conditioning for autologous transplant for myeloma

Year: 2007

Type: article

Abstract: Background: High dose therapy and autologous transplant (HDT) clearly benefits most patients with myeloma, but the addition of other chemotherapeutics or TBI to high dose melphalan (M) does not improve outcomes. Bortezomib (B) is a proteasome inhibitor which synergizes with chemotherapy due to its effects on DNA repair enzymes. Recent data has shown that B upregulates the anti-apoptotic protein MCL-1, which would suggest that the sequence of administration may be critical to the combination of B and M. We hypothesize that B followed by M is inferior to M followed by B. To test this hypothesis, we designed a randomized phase I trial combining B and Melphalan 200 mg/m2 (Mel200) in order to determine the toxicity, optimal dose and sequence of administration. Methods: Patients were randomized to receive either B 24 hours before Mel 200 or B 24 hours after Mel 200. Doses for B range from 1.0mg/m2 up to 1.6mg/m2 as defined using a Basyian phase I design. Standard transplant criteria were used for enrolling patients with the addition of requiring measurable numbers of plasma cells within the marrow at the time of transplant (>5% plasma cells by biopsy or M-protein >1.0). Enrolled patients underwent BM aspirate on day -4 (before B) and day 0 (before PBSC infusion). Bone marrows were tested for annexin V staining, and myeloma cells were sorted for protein analysis. Routine demographics, toxicity, and engraftment data was also collected. Results: Eleven patients have been enrolled to date, with 10 evaluable. B doses range from 1.0-1.3mg/m2 per current dose escalation. Age range was 48-74 years. No patient had resistant disease at the time of transplant, and only one patient had previously undergone HDT. Time to WBC and Plt engraftment were not different from historical cohorts receiving MEL 200 alone. Six patients have been randomized to the B’before’ arm, and 5 in the B ‘after’ arm. There was no significant difference in myeloma cell annexin V staining on day -4 between the 2 groups, however there was an increase in the percent of Annexin V (+) MM cells for the group randomized to the ‘after’ arm compared to the ‘before’ arm (33.3% [after] vs 4.1% [before]). To date there is no difference in bone marrow IL6 levels between the 2 randomized groups. Accrual continues.Tabled 1Annexin V staining of Myeloma cells in the MarrowDay -4Day 0‘Before’ Arm0.894.08‘After’ Arm1.1233.3‘Before’ B before M. ‘After’ B after M Open table in a new tab ‘Before’ B before M. ‘After’ B after M

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2006.12.154