Initial Treatment with Bortezomib (Velcade®), Doxil®, and Dexamethasone (VDD) Is Superior to Thalidomide and Dexamethasone (TD) as Initial Therapy Prior to Autologous Stem Cell Transplantation (ASCT) for Multiple Myeloma (MM)
Authors: Jakubowiak Andrzej , Kendall Tara , Al-Zoubi Ammar , Khaled Yasser , Mineishi Shin , Brozo Christine , Campagnaro Erica , Talpaz Moshe , Kaminski Mark S. 
Published: October 2019

Abstract
A number of novel combinations used in initial therapy of myeloma show improved overall response (OS) and complete and near complete response (CR/nCR) rates. However, it is not clear if improved responses impact the results after the subsequent ASCT and the overall outcome of MM therapy. To address this issue, we performed a retrospective analysis of patients with symptomatic myeloma who were initially treated with TD (N= 31) or VDD (N =30) followed by ASCT, as part of 2 consecutive clinical studies conducted at the University of Michigan Cancer Center. From July 2003 to May 2005, 31 pts were enrolled in a phase II study of treatment of newly diagnosed myeloma with initial therapy using three 5-week cycles of TD. Thalidomide was given daily starting at 50 mg/d up to 400 mg/d and dexamethasone at 40 mg on days 1–4, 9–12, and 17–20. The outcomes were compared with 30 pts who were enrolled from July 2005 to January 2007 in a phase II trial of initial therapy with six 3-week cycles of VDD regimen. VDD included Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone at 40 mg on days 1–4 in the first 10 pts and 40 mg (cycle 1) then 20 mg (cycle 2–6) Dexamethasone on days of Velcade and the day after in the remaining patients. There were no significant differences in eligibility criteria between both studies. The characteristics of pts in the TD vs. VDD trial were as follows: median age 57 (26–65) vs. 58 (38–71), stage III in 23 vs. 27 pts, ch13 del in 12 vs. 13 pts, and median beta2-microglobulin 3.1 vs. 4.6. Best response to initial therapy (≥PR by modified EBMT criteria) was observed in 80% of pts treated with TD vs. 93% with VDD, CR/nCR in 10% treated with TD vs. 40% with VDD, ≥ very good partial response (VGPR) in 29% treated with TD vs. 63% with VDD (P < 0.01). Grade 3–4 toxicities related to TD included DVT/PE in 5 pts, constipation in 2, CHF in 2, and diabetes in 2. Three pts were removed from the TD study due to toxicities, and 1 died of unexplained cause. Grade 3–4 toxicities during VDD therapy included 4 pts with fatigue, 2 with DVT/PE, 2 with hand-foot syndrome, 1 with pneumonia. There was no death on VDD therapy. In the TD group, 27/27 patients collected median 8.8 × 106 CD34+ cell/kg and 27 completed at least a single ASCT (21 tandem, 6 single). In VDD group, 30/30 collected median 7.5 × 106 CD34+ cell/kg and 28 completed at least a single ASCT (17 tandem, 12 single, 1 single then reduced intensity allo). For pts initially treated with TD, 74 % achieved ≥PR, 48% ≥VGPR and 29% CR/nCR at 3 months after the completion of ASCT. For patients initially treated with VDD, response rates at 3 months post transplant were significantly better with ≥PR in 87%, ≥VGPR in 77%, and CR/nCR in 57% of pts (P ≤ 0.01). After a median follow-up of 49.75 (TD) and 23.8 (VDD) months, progression-free survival (PFS) is 27 months in TD group and not reached in VDD group, with 2 year PFS 53% in TD group and 83% in VDD group (P < 0.01). OS is not reached in both groups with 2 year OS slightly better (NS) in VDD (92%) compared to TD (85%). Based on these observations, it appears that high CR/nCR and VGPR rates in response to initial treatment with VDD persist post transplant, resulting in an improved probability of longer progression-free survival and possibly overall survival. Updated survival curves will be presented at the meeting.