Arsenic Trioxide (Trisenox® ATO), Ascorbic Acid (AA) and Dexamethasone (Dex) Pulses (TAD) for Relapsed Refractory Progressive Multiple Myeloma (MM) Patients (pts); a Final Report.

ATO is a novel anticancer agent whose unique multifaceted mechanisms of action offer a scientific rationale for investigation in different hematologic malignancies. 2 phase II studies of ATO in advanced, heavily treated MM reported ≥25% decrease(40–50% of treated pts) in serum M-protein concentrations. Data from both studies suggest that long term therapy might result in enhanced quality of responses. It has been shown that ATO sensitizes myeloma cells to Dex in-vitro and AA potentiates the effect of ATO on different myeloma and human cell lines. We therefore initiated a phase II trial combining ATO with Dex & AA. MM pts with active, progressive disease who failed < 2 different regimens were eligible for enrollment. SWOG response criteria was used to assess efficacy to therapy. Treatment regimen consisted of 12 weeks (wks) treatment blocks with the 1^st block considered induction, containing intense steroid schedule, and 1–2 more 12 wks blocks for consolidation with reduced steroid schedule. Regimen details;Cycle 1:Wk 1, loading with ATO at 0.25mg/kg IV d1-5,AA 1000mg IV within 30 minutes after each ATO infusion & Dex 40 mg orally d1-4. Wks 2 through 12; ATO at 0.25mg/kg IV twice weekly,AA 1000mg IV within 30 minutes after each ATO infusion & Dex 40 mg orally d11–14,29–32,39–42,57–60,& 67–70. Wks 13 through 15, is a rest period. Cycles 2 & 3 are the same as cycle 1 except Dex frequency is reduced to once a month (m) as follows;Dex 40 mg orally d1–4,29–32,57–60,& 67–70. Pts achieving SD or better were initiated on maintenance with the regimen administered for 5 wks with a 2m break and steroids given once a month. 20 pts were enrolled & evaluable for response and toxicity. Median age is 64,β2 microglobulin 3.2mg/dl & median serum albumin is 3.85. Six,7,2 & 5 patients were on study for a median duration of 58, 151, 351 and 511 days respectively.17 pts were taken off study;14 for disease progression,1 for grade 4 painful neuropathy,1 for refusal of therapy &1 developed colon cancer. Median survival for the 14 pts alive is 18.3 m (2.5–24.2). The regimen was well tolerated with 6 pts experiencing either grade 3 hyperglycemia, headaches, burning at IV site, neutropenia, dehydration, syncope, or fatigue. 1 patient experienced grade 4 painful neuropathy and was taken off study with the event resolving in 4 wks without any therapy. 3/5 pts who proceeded to maintenance decided against the 3^rd consolidation cycle because of travel logistics, absence of further reduction of protein, or normalization of performance status. The most common cause to reduce the number of loading dose days and the biweekly treatment during maintenance is grade 2 paraesthesia that resolved with dose reduction. 8 pts achieved >50% reduction of the m-protein following cycle 1 of therapy;2CR,1NCR,5PR,10SD & 3PD. None of the pts but 1 showed further improvement in the m-protein after the1^st cycle of therapy. Mean duration of therapy was 1.9 years. TAD results in an over all response rate of 45% & 85% SD or better with a mean survival of 18.3 months. Further expansion of the study to confirm this data is warranted, and utilizing the complementary mechanism of action of other immunomodulatory agents such as thalidomide with this regimen is ongoing.