Effect of the Proteasome Inhibitor Bortezomib in Combination with “DT-PACE” on Stem Cell Collection and Engraftment in Newly Diagnosed Multiple Myeloma (MM) Patients (Pts).
Authors: Badros Ashrof Z. , Bolaños-Meade Javier , Rapoport Aaron , Ratterree Bashi , Natt Sabrina , Ruehle Kathy , McNamara Kathy , Cox Edmund , Westphal Sandy , Fenton Robert , Meisenberg Barry 
Published: October 2019

Abstract
In vitro data suggest that the addition of bortezomib to chemotherapy can enhance the anti-myeloma activity achieved with either therapy alone. We hypothesized that combining bortezomib and DT-PACE in newly diagnosed MM can increase the CR rate and serve as a new mobilization regimen. The primary objective of the study is to determine the MTD of bortezomib (3 dose levels: 0.7, 1.0, 1.3 mg/m2 days 1, 4, and 8) in combination with thalidomide-based regimen (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). G-CSF 10 ug/kg/day was given from day 5 until stem cell collection or ANC > 2000, G-CSF was held on day 8 for Bortezomib dose. The secondary endpoint was to evaluate the effects of the mobilization regimen on the cellular composition of the graft and subsequent engraftment after high-dose chemotherapy. Five Pts have been enrolled on the study, median age 55 (range: 55–69), all had received 1–2 cycle of thalidomide based therapy, 2 had PD and 3 had PR. Three Pts were enrolled on dose level I; one Pt had grade III diarrhea and DVT with cycle one and tolerated cycle 2 well. One Pt had syncope with cycle 2. Two additional Pts were enrolled at dose level I with no grade III toxicity. After cycle 1, Pts underwent stem cell collections on day 13 (2 Pts had 1 collection and 3 had 2-day collection). Four Pts had a median of 21.7x 106 CD 34+/kg (range: 18.8–33.3) collected. One Pt continued thalidomide after day 4 through mobilization; he collected 4.3 x 106 CD 34+/kg. These collections compares favorably to those obtained from 14 Pts who collected stem cells after DT-PACE at our center in the past yr. This retrospective control group had a median of 14.5 days to collection (range: 11– 22d) with a median 17.8 x 106 CD 34+/kg (range: 9– 35). All 5 Pts responded to therapy; 3 had near CR and 2 PR after cycle 2. To date, 3 Pts received melphalan 200 mg/m2 followed by 4.3–5 x 106 CD 34+/kg and GCSF 5 mg/kg/day SC from day 5 until ANC > 1000 x 2 days. The first patient developed CMV antigenemia treated with ganciclovir. He received a boost of 5 x 106 CD 34/kg on day 21 and engrafted ANC > 1000 on day 25 and Plt > 20000 by day 49. The second patient reached ANC > 1000 on day 24 and plt > 20,000 by day 31. He developed autologous GVHD clinical grade II (skin and gut) upon engraftment, biopsy proven. He responded to steroids. The third patient whose cells were collected on thalidomide, engrafted ANC> 1000 by day 12 and Plt> 20000 by day 21, he has Plt < 30000 at day +35. The other 2 Pts await transplant. In comparison, control Pts mobilized with DT-PACE Pts (n=14) reached ANC > 1000 at a median of 12 days (range: 11-20) and plt > 20000 at 18 days (range: 13–25). Colony counts from DVT-PACE collections yielded a median CFU-C of 525 x 104/kg (range: 118–1000) compared to 540 (range: 153–1388) for DT-PACE. The effects of Bortezomib on the mobilized stem cells is unclear at this time, the delayed engraftment is concerning and will be better defined after additional Pts are treated on this protocol. Theoretically Bortezomib could affect stem cell adhesion molecules resulting in adequate stem cell collections and CFU-C in vitro that later affect stem cell homing and subsequent engraftment.