Arsenic Trioxide with Ascorbic Acid and High-Dose Melphalan: A New Preparative Regimen for Autologous Hematopoietic Stem Cell Transplantation for Multiple Myeloma.
Authors: Qazilbash Muzaffar H. , Davis Marilyn S. , Ana Aleman , Roden Linda , Libunao Floralyn , Thall Peter F. , Wang Xuemei , Couriel Daniel , De Lima Marcos , Hosing Chitra , Kebriaei Partow , Weber Donna , Wang Michael , Jones Roy B. , Matthes Steven G. , Champlin Richard E. , Giralt Sergio A. 
Published: April 2020

Abstract
Backround: Arsenic trioxide (ATO), an active agent against multiple myeloma, has been shown to be synergistic with melphalan both in vitro and in vivo. We conducted a phase I/II trial to determine the safety and efficacy of a combination of arsenic trioxide, melphalan and ascorbic acid (AA) as prepaprative regimen in patients undergoing high-dose therapy (HDT) and autologous hematopoietic progenitor cell transplantation (AHPCT) for multiple myeloma (MM). We also assessed the impact ATO levels on melphalan pharmacokinetics (PK), engraftment and toxicity.
Methods: Twenty-five patients with secretory myeloma (11 females, 14 males median age: 53, range: 49 – 69) were treated b/w 4/04 and 1/05. All patient received melphalan 100 mg/m2 IV on days -4 and -3 and AA 1000 mg/day IV on days −9 to −3. Patients were randomized to 3 arms; no ATO (arm 1), ATO 0.15 mg/kg IV on days −9 to −3 (arm 2) and ATO 0.25 mg/kg IV on days −9 to −3 (arm 3). Seven patients had a prior autograft. Median CD34 cells dose infused was 4.4 x 106/kg (range 2.3–10.9). Results: Patients were evenly matched except for a high median β2m level (3.6 vs. 2.4 in arms 1 and 2, p=0.04) in arm 3. With a median F/U of 7.1 months post autograft, no dose-limiting toxicity or non-relapse mortality was seen. Median ATO level on day 0 in arms 1, 2 and 3 were 0.2, 26.3 and 46.2 ng/ml, respectively. Toxicity was limited grade I or II nausea, vomitting and diarrhea. Median time to neutrophil engraftment (ANC &gt;500/dl) was 9 days. There were no engraftment failures or delays in the ATO arms. Response rates (RR) are shown in Table 1. With a median F/U of 7.1 months (range, 6.4 – 8.9 months), the progression-free survival (PFS) and overall survival (OS) are as shown in Figure 1. There was no significant difference in RR, PFS or OS between the 3 arms. Melphalan PK was not altered by ATO pretreatment.
Conclusions: Arsenic trioxide, given in combination with melphalan and ascorbic acid as preparative regimen, is safe and well tolerated. A longer follow up is needed to determine the impact of this combination on survival.
Response Rate at 3-Month Evaluation Response at 3 months CR PR MR SD PD p = 0.55 CR = complete response, PR = partial response, MR = minimal response, SD = stable disease, PD = progressive disease Arm 1 (no ATO) 1 5 0 1 1 Arm 2 (ATO 0.15) 1 5 2 0 1 Arm 3 (ATO 0.25) 0 7 0 0 0 Figure 1. The Kaplan-Meier estimates for progression-free survival probability (N=25). Figure 1. The Kaplan-Meier estimates for progression-free survival probability (N=25). Figure 2. The Kaplan-Meier estimates for overall survival probability (N=25). Figure 2. The Kaplan-Meier estimates for overall survival probability (N=25).