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The aim of this prospective, multicenter Phase IIa study was to investigate whether daily intravenous busulfan (IV Bu) with bortezomib is a safe and effective conditioning regimen prior to second, salvage autologous hematopoietic stem cell transplantation (ASCT) for relapsed multiple myeloma (MM) patients.
Thirty patients with relapsed MM were enrolled at 11 centers in the US and Canada. Median age at second ASCT was 59 years (range: 48-73). Median time from first ASCT to second ASCT was 28.0 months (range: 12-119). At the time of second ASCT, 7 (23.3%) patients were in very good partial response (VGPR), 12 (40.0%) in partial response (PR), 2 (6.7%) in stable disease (SD), and 9 (30.0%) in progressive disease (PD).
Patients received a test IV Bu dose (0.8 mg/kg) over 2 hours between Days -12 and -9. The test PK dosing was based on adjusted ideal body weight (AIBW= ideal BW + 0.25 [actual BW – ideal BW]) for all patients except for those whose actual BW is less than or equal to the ideal BW. For those subjects, actual BW was used. Pharmacokinetic (PK) analysis determined Bu exposure as area under the concentration-time curve (AUC), and provided optimized doses so that a total target AUC would achieve 20,000 mM*min. These optimized doses were administered over 3 hours, once daily from Day -5 to Day -2. Confirmatory PK was conducted on Day -5; Bu doses were further adjusted on Days -3 and -2, if needed. Bortezomib (1.3 mg/m2) was intravenously administered on Day -1.
The most common grade 3 or 4 adverse events (CTCAE v3.0) were febrile neutropenia (50.0%), stomatitis (43.3%), and nausea (13.3%). One transplant-related death occurred due to pulmonary complications in a patient with Parkinson's disease on Day 20. There were no reported instances of seizure, worsening neuropathy, or hepatic veno-occlusive disease meeting the Baltimore criteria.
Post-transplant disease response using the 2006 IMWG criteria was available for 28 patients. At 3 months, there were 2 (6.7%) CR, 5 (16.7%) VGPR, 4 (13.3%) PR, 8 (26.7%) SD, and 9 (30.0%) PD. At 6 months, there was 1 (3.3%) stringent CR, 1 (3.3%) CR, 4 (13.3%) VGPR, 7 (23.3%) SD, and 14 (46.7%) PD. Median progression-free survival was 191 days, while median overall survival was not reached.
Test PK showed that 40.0% (n=12/30) of patients had AUC <1,000 (n=11) and AUC >1,500 μM*min (n=1). If body weight-based doses had been used without test PK, these patients (40%) would have been dosed outside the target total AUC range (>24,000 or < 16, 000 μM*min) for conditioning. The confirmatory PK on Day -5 revealed that a total AUC fell within the target range in 28 patients (93.3%), while two (6.7%) needed dose reduction on Days -3 and -2.
In conclusion, a combination of IV Bu and bortezomib prior to second ASCT had acceptable safety profile and induced 20% VGPR or better responses at 6 months. No cases of VOD were observed in this group of patients in whom dose optimization using pre-transplant test PK was utilized.