High Rate of Complete and near Complete Responses (CR/nCR) after Initial Therapy with Bortezomib (Velcade®), Doxil®, and Dexamethasone (VDD) Is Further Increased after Autologous Stem Cell Transplantation (ASCT).
Authors: Jakubowiak Andrzej J. , Al-Zoubi Ammar , Kendall Tara , Friedman Judah , Ahmed Asra , Khaled Yasser , Mineishi Shin , Kaminski Mark S. 
Published: October 2019

Initial therapy with novel combinations including bortezomib, lenalidomide or thalidomide show a superior overall response rate (80–90% range) and high CR/nCR rate (20–30% range). Although a number of studies demonstrated that achieving CR/nCR after ASCT prolongs survival, it is not clear whether improved quality of response after initial cytoreduction impacts on overall outcome of treatment of myeloma. Recently, we completed accrual to a phase II trial of initial therapy with VDD for patients with active myeloma. The primary objective was to determine the rate of CR/nCR in response to VDD. Secondary objectives included overall response, safety, and feasibility of collection of peripheral blood stem cells. The regimen was given for six 3-week cycles as follows: 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 for the first 10 patients and for the remaining patients at 20 mg per on days 1, 2, 4, 5, 8, 9, 11, 12 (same total dose of 160 mg dexamethasone per cycle). The study opened in July 2005 and enrolled 30 patients. Presently, 28 of 30 patients are evaluable for response of which 18 completed 6 cycles. The characteristics of the evaluable patients included: median age 61 (range 39–83), stage III disease in 26 patients (stage II in 2), chromosome 13 deletion in 12, t(4;14) in 2, median beta2-microglobulin 4.4. CR/nCR was observed in 9 patients (32%), very good partial response (VGPR) in 6 (21%), partial response (PR) in 10 (36%) and minor response (MR) in 1 (4%) for an overall response (≥ PR) of 89%, and ≥ VGPR of 53%. The change of dexamethasone schedule did not appear to affect response rates. There was no grade 4 hematological toxicity and grade 3 was limited, with thrombocytopenia in 2 patients and neutropenia in 1. There were no episodes of neutropenic fevers. Grade 3–4 non-hematological toxicities included 4 patients with fatigue, 3 patients with pneumonia, 2 with DVT/PE, 2 with hand-foot syndrome, 1 with partial small bowel obstruction, and 1 with diarrhea secondary to Cryptosporidium sp. Fatigue was significantly reduced after the change of dexamethasone schedule. Peripheral neuropathy was limited to grade 1–2 and observed in 9 patients. All patients are alive. To date, 18/18 patients had successful harvesting of peripheral blood stem cells (median 8.2 x 106 CD34+ cell/kg, range 3.2 to 41.2) and 17 completed at least a single autologous stem cell transplant using melphalan 200 mg/m2 as the preparative regimen (12 single, 5 tandem). Responses were further improved in 11 of these 17 patients bringing overall response rate (≥ PR) to 96%, with 79% of patients achieving ≥ VGPR and 54% achieving CR/nCR. These results indicate that initial treatment with VDD is very effective and well tolerated and does not adversely affect stem cell harvest. Moreover, it appears to improve probability of achieving CR/nCR and VGPR after transplant compared to results from randomized studies with single or tandem transplantation. Considering that achieving CR/nCR or VGPR after ASCT has been associated with improved survival, VDD appears promising as an initial treatment strategy to improve survival.