Phase I Trial of Bortezomib (V) in Combination with “DT-PACE”: Toxicity, Stem Cell Collection and Engraftment in Newly Diagnosed Multiple Myeloma (MM) Patients (Pts).

Several studies have established the safety and efficacy of V in various regimens before stem cell mobilization and transplant (SCT). The primary objective of our study was to determine the MTD of V (3 dose levels: 0.7, 1.0, 1.3 mg/m² days 1, 4, and 8) in combination with DT-PACE (dexamethasone 40 mg/day and thalidomide 200–400 mg/day orally x 4 days, Cisplatinum 10 mg/m², Adriamycin 10 mg/m², cyclophosphamide 400 mg/m² and Etoposide 40 mg/m² all given by IVCI for 4 days) in newly diagnosed MM. Pts received 2 cycles (C) of VDT-PACE; stem cells were collected after C 1. G-CSF 10-ug/kg/day was given from day 5 until stem cell collection (GCSF was held on day 8 of V). The secondary endpoint was to evaluate the effects of V during mobilization on engraftment. Eleven Pts enrolled, six on dose level I; 3 on dose level II and 2 on dose level III. Median age was 58 yrs (42–70), 9 were males. Four had no prior therapy and 7 had one prior cycle including DT (n=4) and DT-PACE (n=3). Median B2M was 2.9 mg/L (range: 1.9–8.5) and BM plasma cells was 45% (range: 10–80). No DLT was observed. Pts, mostly with cycle 2, had G- 3/4 hematological toxicity requiring transfusiona and neutropenic fever requiring hospitalization. G-3 toxicity included diarrhea (n= 2), (DVT= 3) despite enoxaparin, hypotension (n=3) including syncope (n=2). G-2 included bradycardia (n= 3) and peripheral neuropathy (n= 3). Stem cells were collected at a median of 13 days (range: 12–15). Pts had a median of 20.57 (range: 7.85 – 33.3) x 10⁶ CD 34+/kg in 1 (n=4), 2 (n=6) and 3 days (n=1). Two pts collected additional cells after C 2, both received prior DT-PACE. All 11 Pts responded; CR (n=1), near CR (n=1) and PR (n=9); to date, all pts had received SCT; conditioning regimens were melphalan 200 mg/m² (n=9) and 140 (n=2), 2 pts had tandem SCTs. Median CFU-C of the infused CD-34 cells was 320.2 (range: 57–1000) x 10⁴/kg. Median time to ANC > 1000/mcl was 14 days (range: 13–25), plt > 20, 000/mcl was 16 days (range: 10–50) and > 50,000 was 25 days (range: 15–57). CMV antigenemia with fever and delayed engraftment was seen in one pt and autologous GVHD (skin and gut), biopsy proven, was seen in one pt. After SCT, pts achieved CR (n=3), nCR (n=4) and PR (n=4). At a median follow up of 252 days (range: 23–467), 1 pt had relapsed at 8 m with high-risk MM, hypodiploid clone. The results were compared to a control group (pts mobilized with DT-PACE; n=14). They had a median of 14.5 days to first day of phoresis (range: 11– 22) with a median 17.8 x 10⁶ CD 34+/kg (range: 9- 35) collected in 1 (n=6), 2 (n=5) and 3 days (n=3). Median CFU-C was 540 (range: 153–1388) x 10⁴/kg. For the control group; ANC > 1000 was reached at a median of 12 days (range: 11–20) and plt > 20000 at 18 days (range: 13–25) and > 50,000 at 19 (range: 15–38). There was no statistically significant correlation between total CD34 count and times to engraftment between both groups. There was a tendency for pts treated with V to have lower CFU-C (p=0.0565), the clinical significance is unclear. In conclusion: the VDT-PACE regimen was associated with expected and acceptable toxicities. There was a rapid response in all pts treated. Adequate numbers of stem cells were collected with prompt engraftment after SCT. VDT-PACE regimen has the advantage of short induction time prior to SCT and should be evaluated in a randomized fashion before SCT against other regimens like DT and VDT with regards to quality of life and long-term toxicities.