Efficacy and safety of melphalan, arsenic trioxide and ascorbic acid combination therapy in patients with relapsed or refractory multiple myeloma: a prospective, multicentre, phase II, single-arm study

Abstract Background: Both arsenic trioxide and bortezomib as single agents have shown efficacy for patients with relapsed/refractory multiple myeloma (MM). Recently, we have demonstrated synergistic anti-MM effects when these two agents are combined to treat human MM in SCID mice and evaluated in in vitro studies. In addition, we and others have also shown that the addition of ascorbic acid (AA) sensitizes MM cells to the cytotoxic effects of arsenic trioxide both through in vitro and in vivo studies. Thus, the objective of the current Phase I clinical trial was to assess the safety and tolerability of bortezomib + arsenic trioxide + AA treatment for patients with refractory/relapsed MM. Methods: A treatment cycle comprised of intravenous injections of arsenic trioxide, bortezomib and AA on days 1, 4, 8, and 11 followed by a 10-day rest period every three weeks. Bortezomib was given at one of three dose levels (0.7, 1.0, or 1.3 mg/m2), followed by arsenic trioxide at one of two doses (0.125 or 0.25 mg/kg) intravenously followed by AA (1000 mg). Patients were treated for a maximum of eight cycles and were eligible for maintenance therapy with the same treatments given once every other week. Results: Eighteen patients have been enrolled to date, with three patients enrolled in each of the six cohorts. Patients had received a median of three prior therapies (range, 1–6), and five patients had received prior bortezomib therapy. Fifteen patients are evaluable for efficacy to date, and response data are summarized in Table 1. Overall, among the 15 evaluable patients, seven patients responded (2 PR, 5 MR), three patients showed stable disease, and five patients progressed. Among the six patients (in cohorts 1 and 4) enrolled at the lowest (0.7 mg/m2) bortezomib dose level, only one achieved a MR whereas among the nine evaluable patients enrolled at the higher (1.0 and 1.3 mg/m2) bortezomib dose levels six patients responded (2 PR, 4 MR). In general, the regimen was well tolerated. One patient in cohort 3 was removed from study during the first cycle because of the development of an asymptomatic arrhythmia which resolved spontaneously. Other serious adverse events included pneumonia in two patients, chest pain, and abdominal pain (one patient each). Conclusion: These early results from this Phase I/II study indicate that the combination of bortezomib, arsenic trioxide and ascorbic acid has efficacy and is well tolerated in a heavily pretreated population of patients with relapsed or refractory MM. Because of these encouraging clinical results, we plan to further evaluate this combination in a larger group of patients with relapsed/refractory myeloma. Table 1. Dose escalation scheme Cohorts Arsenic trioxide Bortezomib No. of evaluable pts Response *one patient in cohort 3 went off study during cycle 1 (see above), and the other two patients (one each in cohorts 3 and 6) are too early for response evaluation Cohort 1 0.125 mg/kg 0.7 mg/m2 3 1 MR, 2 PD Cohort 2 0.125 mg/kg 1.0 mg/m2 3 1 PR, 1 SD, 1 PD Cohort 3 0.125 mg/kg 1.3 mg/m2 1* 1 PR Cohort 4 0.25 mg/kg 0.7 mg/m2 3 1 SD, 2 PD Cohort 5 0.25 mg/kg 1.0 mg/m2 3 3 MR Cohort 6 0.25 mg/kg 1.3 mg/m2 2* 1 SD, 1 MR

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A Multicenter Phase II Study of Combination Treatment with Melphalan, Arsenic Trioxide and Vitamin C (MAC) for Patients with Relapsed or Refractory Multiple Myeloma.

Blood ◽

10.1182/blood.v106.11.2564.2564 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2564-2564 ◽

Cited By ~ 1

Author(s):

James Berenson ◽

Ralph Boccia ◽

David Siegel ◽

Marek Bozdech ◽

Alberto Bessudo ◽

...

Keyword(s):

Multiple Myeloma ◽

Ascorbic Acid ◽

Vitamin C ◽

Arsenic Trioxide ◽

Phase Ii ◽

Stable Disease ◽

Objective Response ◽

In Vivo Studies

Abstract Background: Despite the recent increase in treatment options for patients with multiple myeloma (MM), the disease remains largely incurable. Both arsenic trioxide (ATO) and melphalan have shown clinical activity in MM. Recent in vitro and in vivo studies in our laboratory have shown that arsenic trioxide sensitizes chemoresistant MM cells to melphalan-induced cytotoxicity; the addition of ascorbic acid (AA) further improves this effect. We conducted a multi-center clinical trial to evaluate the safety and efficacy of this steroid-free combination, melphalan, ATO and vitamin C (MAC), for patients with relapsed/refractory MM. Methods: MM pts who relapsed after responding to 1st-line therapy and/or were refractory to prior treatment were enrolled. During week 1 of each 6-week cycle, pts received ATO, 0.25 mg/kg IV, followed by ascorbic acid (AA), 1 g IV, days 1–4. ATO followed by AA was given twice-weekly for the next 4 weeks of each cycle. Low-dose melphalan (0.10 mg/kg) was administered orally for the first 4 days of each cycle. Pts received a maximum of 6 cycles followed by weekly maintenance treatment with ATO and AA. The primary objectives of this study were to determine response rate and safety and tolerability of MAC therapy. Results: 65 patients have been enrolled and 51 are currently evaluable for response. 26 (1 CR, 10 PR, 15 MR) of the 51 evaluable patients (51%) had an objective response and an additional 14 patients achieved stable disease, resulting in a total of 40 patients (78%) with disease control. Among patients with elevated serum creatinine levels at baseline, renal function improved for those with responsive or stable disease. 20 of the 26 responding patients had failed ≥ 2 prior therapies: 19 pts had received prior thalidomide or lenalidomide therapy and 8 pts had received prior bortezomib. The regimen was well-tolerated with few significant side effects reported. Mild cytopenias occurred infrequently and were reversible. Conclusions: The results from this large multi-center phase II trial show that the MAC regimen is active in a group of MM patients who had either relapsed or were refractory to standard and/or investigational MM treatments. The regimen was well-tolerated even in this heavily pre-treated patient population. These findings are consistent with preclinical studies that showed the efficacy of this combination from both in vitro and in vivo studies.

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A Randomized Phase II Trial of High-Dose Melphalan, Ascorbic Acid and Arsenic Trioxide with or without Bortezomib in Multiple Myeloma.

Blood ◽

10.1182/blood.v114.22.2309.2309 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2309-2309

Author(s):

Manish Sharma ◽

Peter Thall ◽

Xuemei Wang ◽

Chitra Hosing ◽

Floralyn L Mendoza ◽

...

Keyword(s):

Multiple Myeloma ◽

Ascorbic Acid ◽

Arsenic Trioxide ◽

Phase Ii ◽

Phase Ii Trial ◽

High Dose ◽

Randomized Phase Ii ◽

Preparative Regimen ◽

Grade 3 ◽

High Dose Melphalan

Abstract Abstract 2309 Poster Board II-286 Background There is a role for novel preparative regimens in multiple myeloma to improve the outcome after high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto HCT). Bortezomib is an active agent in newly diagnosed or relapsed multiple myeloma, and has synergistic activity with melphalan. We conducted a randomized phase II trial to determine the safety and efficacy of adding bortezomib to a preparative regimen of arsenic trioxide (ATO), ascorbic acid (AA) and melphalan. Methods auto HCT, with preparative regimen melphalan 100 mg/m2 IV on days -4 and -3, AA 1000 mg/day IV on days -9 to -3 and ATO 0.25 mg/kg IV on days -9 to -3. Patients were randomized to 3 arms; no bortezomib (arm 1), bortezomib 1 mg/m2 on days -9, -6 and -3(arm 2), and bortezomib 1.5 mg/m2 on days -9, -6 and -3 (arm 3). Primary endpoints were complete response (CR), NCI grade 4 toxicity, and overall survival (OS). Results In arms 1, 2 and 3, median intervals between diagnosis and auto HCT were 12.2, 9.6 and 8.8 months; median follow up in all surviving patients was 20 months (range 10 to 31). CR+near CR rates in arms 1, 2 and 3 were 35%, 30% and 25%. Grade 3–4 toxicity was seen in 6 patients in arm 1 (mucositis 3, dyspnea 1, acute renal failure 1, pleural effusion 1), 6 patients in arm 2 (mucositis 3, diarrhea 1, pneumonia 1 and hydronephrosis 1) and 6 patients in arm 3 (pulmonary edema 2, mucositis 1, intestinal obstruction 1, low back pain 1, elevated transaminases 1). The most common adverse events were nausea, diarrhea and pedal edema. Grade 1–2 weight gain due to fluid retention was seen in 84%, 70% and 95% of patients in arms 1, 2 and 3. Median time to neutrophil engraftment (ANC >500/dl) was 10 days in each arm. Median OS has not been reached in any of the 3 arms. Median progression-free survival (PFS) times were18.6, 13.2 and 17.5 months. OS was significantly shorter in patients with relapsed disease (0.00001) and cytogenetic abnormalities at auto HCT (0.0002). Conclusions Adding bortezomib to a preparative regimen of ATO, AA and high dose melphalan is safe and well tolerated in patients with multiple myeloma. There was no significant impact of adding bortezomib at either dose on the CR rate, grade 3-4 toxicity or OS. Disclosures: Shah: Celgene, Amgen, Novartis, Elan: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Qazilbash:Cephalon: Speakers Bureau.

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