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).
Andrzej J. Jakubowiak, MD, PhD1,
Ammar Al-Zoubi, MD1,
Tara Kendall, PA-C1,*,
Judah Friedman, MD1,
Asra Ahmed, MD1,
Yasser Khaled, MD1,
Shin Mineishi, MD1 and
Mark S. Kaminski, MD1
1 Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA.
Initial therapy with novel combinations including bortezomib,lenalidomide or thalidomide show a superior overall responserate (8090% range) and high CR/nCR rate (2030%range). Although a number of studies demonstrated that achievingCR/nCR after ASCT prolongs survival, it is not clear whetherimproved quality of response after initial cytoreduction impactson overall outcome of treatment of myeloma. Recently, we completedaccrual to a phase II trial of initial therapy with VDD forpatients with active myeloma. The primary objective was to determinethe rate of CR/nCR in response to VDD. Secondary objectivesincluded overall response, safety, and feasibility of collectionof peripheral blood stem cells. The regimen was given for six3-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 at40 mg on days 14 for the first 10 patients and for theremaining patients at 20 mg per on days 1, 2, 4, 5, 8, 9, 11,12 (same total dose of 160 mg dexamethasone per cycle). Thestudy opened in July 2005 and enrolled 30 patients. Presently,28 of 30 patients are evaluable for response of which 18 completed6 cycles. The characteristics of the evaluable patients included:median age 61 (range 3983), 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%), partialresponse (PR) in 10 (36%) and minor response (MR) in 1 (4%)for an overall response ( PR) of 89%, and VGPR of 53%. Thechange of dexamethasone schedule did not appear to affect responserates. There was no grade 4 hematological toxicity and grade3 was limited, with thrombocytopenia in 2 patients and neutropeniain 1. There were no episodes of neutropenic fevers. Grade 34non-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 diarrheasecondary to Cryptosporidium sp. Fatigue was significantly reducedafter the change of dexamethasone schedule. Peripheral neuropathywas limited to grade 12 and observed in 9 patients. Allpatients are alive. To date, 18/18 patients had successful harvestingof 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 autologousstem cell transplant using melphalan 200 mg/m2 as the preparativeregimen (12 single, 5 tandem). Responses were further improvedin 11 of these 17 patients bringing overall response rate (PR) to 96%, with 79% of patients achieving VGPR and 54% achievingCR/nCR. These results indicate that initial treatment with VDDis very effective and well tolerated and does not adverselyaffect stem cell harvest. Moreover, it appears to improve probabilityof achieving CR/nCR and VGPR after transplant compared to resultsfrom randomized studies with single or tandem transplantation.Considering that achieving CR/nCR or VGPR after ASCT has beenassociated with improved survival, VDD appears promising asan initial treatment strategy to improve survival.
* Corresponding author
Disclosures: Use of bortezomib (Velcade) combination in as initialtherapy of myeloma.; Membership of Speakers Bureau.