Sequential Administration of Bortezomib, Liposomal Doxorubicin and Dexamethasone (BDD) Followed by Thalidomide and Dexamethasone (TD) Results in Rapid Control of Untreated High-Risk Multiple Myeloma (MM) and Improves Depth of Response
Authors: Landau Heather , Hassoun Hani , Cohen Adam , Hoover Elizabeth , Kewalramani Tarun , Boruchov Adam , Klimek Virginia , Reich Lillian , Riedel Elyn , Pandit-Taskar Neeta , Nimer Stephen D. , Comenzo Raymond L. 
Published: October 2019

Abstract
Background: Doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective, well-tolerated regimen for pts with MM. We previously reported an overall response rate (ORR) of 90.5%, with 35% achieving nCR/CR in 45 newly diagnosed pts, the majority of whom were ISS I (62%). Despite similar ORR, a survival analysis demonstrated inferior outcomes for pts with ISS II, ISS III or softtissue involvement by disease. Based on our experience, we designed a phase II study incorporating bortezomib and liposomal doxorubicin into the upfront treatment of pts with high-risk MM (ISS II, III or ISS I with soft-tissue disease). The aims of the study were to determine the safety and efficacy of bortezomib, pegylated doxorubicin and dexamethasone followed by thalidomide and dexamethasone (with or without bortezomib) in pts with untreated poor-risk or primary refractory MM. We correlated disease response with PET response to determine if there was concordance (or discordance) in these pts.
Methods: 34 pts with high-risk MM have been enrolled. Treatment includes BDD (bortezomib 1.3mg/m2 IV days 1, 4, 8, and 11, liposomal doxorubicin 30mg/m2 IV on day 4, and dexamethasone 20mg PO on the day of and the day after bortezomib) for three 21-day cycles followed by 2 cycles of TD (thalidomide 200mg PO daily and dexamethasone 40mg PO on days 1–4, 9–12, 17–20) every 28 days for patients achieving at least PR, or BTD (less than a PR after BDD). Prophylactic use of acyclovir, fluconazole, and pyridoxine was implemented throughout the study. Aspirin 81mg or low molecular weight heparin (in patients with increased risk for VTE) was mandated during the TD portion of the study. Response was assessed using International Myeloma Working Group (IMWG) uniform response criteria. PET scans were performed at baseline, following BDD and at end of study (EOS) to determine the role of functional imaging in pts with high-risk MM.
Results: At the time of this analysis, 28 pts have completed study and are evaluable. Baseline characteristics include median age of 58 years (range 41–80), 61% male, 43% (12/28) ISS II, 46% (13/28) ISS III, and 11% (3/28) ISS I with soft-tissue disease. Sixty-four percent of pts have abnormal cytogenetics: 39% (11/28) del 13q, 11% (3/28) t(4;14) and 7% (2/28) loss of p53 gene. Following BDD (1–3 cycles) the ORR was 79% with 25% CR/nCR and 36% ≥VGPR. At the EOS, the ORR remained 79%, however there is a significant improvement in the quality of response with 43% of pts achieving CR/nCR (p = 0.03) and 61% ≥VGPR (p = 0.008). Only 1 pt progressed on study based on skeletal survey findings despite achieving a serologic VGPR and improving clinically. Poor-risk cytogenetics (del 13q, t (4;14) or loss of p53) or soft-tissue disease did not affect response (p = 0.20 and p = 1.0, respectively). Of 11 pts with del 13q, 82% had ≥VGPR. Of the 5 pts with t (4;14) or loss of p53, 100% achieved ≥VGPR. There was poor agreement between EOS and PET response in the 19 pts who had PET data available, Kappa 0.11. The majority of pts (15/19) had PR by PET and 3 pts had SD. In the only pt that had progression by PET, IMWG response was VGPR and biopsy confirmed granulomatous disease rather than MM. Grades 3/4 neutropenia and thrombocytopenia occurred in 18% and 36% of pts, respectively. The incidence of neuropathy was 28%, but was grade 3 in only 1 pt (4%). Five pts developed DVT. Two pts developed asymptomatic decline in LVEF that improved with medical therapy. Fifty-seven percent of pts (16/28) have had successful stem cell harvest and have undergone ASCT. Three more pts have ASCT planned.
Conclusions: BDD followed by TD (or BTD) results in rapid disease control with manageable toxicity in a poor-risk group of pts with MM. The depth of response is significantly improved with the sequential administration of novel agents, as has been demonstrated by other investigators (Jagannath ASH 2007). The 79% ORR is modest, however the ≥61% VGPR and 43% nCR/CR rates seen in these very high risk pts are comparable to initial therapy with VTD and Rev/Vel/Dex (Rajkumar ASH 2007 and Richardson ASH 2007, respectively) and are encouraging. High-quality responses were seen independent of cytogenetic abnormalities or the presence of soft-tissue disease. BDD followed by TD represents a promising therapeutic option for these pts. PET response does not correlate with IMWG response, perhaps due to the high sensitivity and lack of specificity of functional imaging.