Purpose: This study was aimed at comparing the efficacy and tolerability of an arsenic trioxide/bortezomib/ascorbic acid/dexamethasone (ABCD) regimen with efficacy and tolerability of a bortezomib/dexamethasone (BD) regimen in patients with newly diagnosed myeloma.
Patients and Methods: Fifty-seven and sixty-four patients were treated with the ABCD and BD regimens, respectively. Eligible and agreeable patients received autologous hematopoietic stem cell transplantation followed by consolidation.
Results: The response rates (above VGPR) were 74.1% and 32.8% in the ABCD- and BD-treated groups, respectively (P = 0.000). Compared to BD regimen, ABCD regimen significantly improved PFS (P = 0.026) and OS (P = 0.000) in newly diagnosed patients. Patients with a high tumor burden, low or standard risk, and without auto-HSCT seemed to especially benefit compared to the same group with BD regimen. ABCD also showed better tolerability with lower bone marrow suppression (P = 0.026). Furthermore, complete response or near CR after induction therapy was a good prognostic factor for ABCD-associated OS and PFS.
Conclusion: ABCD is an effective and tolerable regimen compared with BD regimen in newly diagnosed myeloma patients. ABCD regimen could be an economical, effective, and tolerable choice in low- and standard-risk patients.

Keywords: multiple myeloma, arsenic trioxide, bortezomib, overall survival, treatment response

INTRODUCTION


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Multiple myeloma (MM) is a disease that typically requires multiple lines of therapy because many patients have a relatively long survival and relapse and gradually develop resistance to the treatment drugs.1,2 Many novel drugs are emerging for the treatment of MM, such as bortezomib, lenalidomide, pomalidomide, carfilzomib and daratumumab, clinicians tried to single administration or in combination of these drugs have improved responses and outcomes.3–5 Bortezomib and bortezomib-based therapies, including bortezomib plus dexamethasone, are now a cornerstone of treatment for both newly diagnosed and relapsed/refractory MM.6 A third agent added to the bortezomib and dexamethasone regimen has proven effective for the treatment of relapsed/refractory MM in a number of studies,7–10 and three-drug regimens are increasingly recommended for MM patients.11,12

Arsenic trioxide (ATO) is a promising antineoplastic chemotherapeutic agent, it has been approved to the treatment of acute promyeloid leukemia (APL), now it is tried in the treatment of MM. In preclinical studies, ATO induced apoptosis, reduced viability, and caused growth arrest in myeloma cell lines at concentrations low enough for safe use in patients.13–15 ATO exert its antitumor effects in part by generating reactive oxygen species (ROS).16 The cytotoxic effects of ATO in myeloma cell lines are markedly enhanced by the addition of ascorbic acid, as reported both in vitro and in vivo.17 intracellular glutathione (GSH) will neutralize the ROS generated by ATO, ascorbic acid could deplete GSH, which makes a contribution to the synergy of ATO and ascorbic acid. This supposition is supported by the findings of a small Phase I study in patients with stage III relapsed or refractory MM. The study showed ascorbic acid administration decreased intracellular GSH levels and increased the sensitivity of patients’ myeloma cells to ATO.18 Some in vitro studies showed that the sensitivity of myeloma cells to bortezomib is negatively associated with beta-catenin protein levels. After proteasome inhibition, ATO can reduce cytoplasmic beta-catenin accumulation and enhance the sensitivity of myeloma cells to bortezomib.19

Preclinical studies have also shown that ATO combined with bortezomib at low concentrations has synergistic antiproliferative and antimyeloma activity in xenograft animal models,17 suggesting the combination may have the potential to treat MM. Phase I/II trials of ATO and bortezomib have been conducted in heavy pretreatment, relapsed or refractory MM patients, while the addition of ATO has limited success in relapsed/refractory MM.20

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In clinical trials conducted thus far, the combination of ATO, ascorbic acid, bortezomib, and dexamethasone for the treatment of MM has been evaluated in patients with relapsed MM and MM patients showing treatment resistance. The mechanism of ATO in MM treatment relies heavily on GSH level and the ROS system. Patients with relapsed MM and MM patients showing treatment resistance may show changes in levels of GSH and apoptotic regulators.21 However, all previous studies assessed the safety and tolerability of ATO/bortezomib/ascorbic acid (ABC) combination therapy in MM patients. Therefore, we conducted a retrospective study with an aim to evaluate the efficacy and safety of ATO/bortezomib/ascorbic acid/dexamethasone (ABCD) combination therapy in comparison with those of bortezomib/dexamethasone (BD) regimen for newly diagnosed MM patients at three medical centers in China.

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