TO THE EDITOR
Multiple myeloma (MM) is an incurable B-cell malignancy that is characterized by both relapsing and refractory disease. Therapeutic strategies are needed to overcome drug resistance and to improve patient outcomes for this difficult-to-treat patient population. Arsenic trioxide has been shown to be effective in the treatment of acute promyelocytic leukemia in newly diagnosed disease,1, 2 as well as in refractory/relapsed disease.2, 3 Arsenic trioxide, which has been clinically studied as a single agent4, 5 and in combination with ascorbic acid,6 has been found to be safe and has shown some antimyeloma activity. In clinical trials, arsenic trioxide at a dose of 0.25 mg/kg given intravenously twice weekly was well tolerated in a recent phase 1/2 clinical trial (Berenson J et al. Blood 2002; 100: 394b, abstract). Oral melphalan has shown significant antimyeloma activity clinically at doses of 0.25 mg/kg/day for 4 days every 4–6 weeks. Ascorbic acid given intravenously at a dose of 1 g following a dose of 0.25 mg/kg arsenic trioxide, also given intravenously, twice weekly, has shown promising early clinical results.6 In this preliminary analysis, 10 patients with MM, who were refractory to their most recent therapeutic regimen, had failed multiple previous therapeutic regimens, and for whom other treatment options were exhausted at the time of initiation of therapy, were administered a combination of melphalan, arsenic trioxide, and ascorbic acid (MAC) therapy (Table 1). Arsenic trioxide was administered intravenously at a dose of 0.25 mg/kg over 1–2 h on a twice-weekly basis. A fixed dose of ascorbic acid (1 g) was administered intravenously for 15 min after each dose of arsenic trioxide. As arsenic trioxide may potentiate the myelosuppressive effects of melphalan, a dose of 0.1 mg/kg (40% of conventional dose) was selected to achieve a balance between the therapeutic benefit and the reduced toxicity of the combination. Of note, six of the 10 patients had received melphalan previously; four of these patients received melphalan as part of their conditioning regimen for autologous peripheral blood stem cell transplantation (SCT), and the other two patients were progressing on melphalan as part of the melphalan-prednisone regimen when MAC was initiated (Table 1). No adjustment in dose or schedule was made for patients with renal dysfunction (n=5). At the time of initiation of MAC therapy, the first six patients were taking ongoing oral glucocorticoids (oral methylprednisolone, prednisone, or dexamethasone) that were continued at the same dose and then discontinued within 6–8 weeks of initiation of MAC therapy. The last four patients who were given this regimen had their regimen modified so that they were receiving arsenic trioxide and ascorbic acid daily on the same 4 days along with oral melphalan during the first week of a 6-week cycle, instead of twice weekly during those 4 days as was done in the first six patients. Treatment duration for these patients was 13–104 weeks. All 10 patients responded to MAC therapy. Serum M-protein levels were reduced by 29–90%, urine M-protein reductions ranged from 34 to 71%, and six of 10 patients exhibited a sustained response, including two patients with continuing responses for more than 1 year (Table 2). These six patients continue to receive arsenic trioxide and ascorbic acid although, after six cycles (36 weeks), melphalan was discontinued, and the combination of arsenic trioxide and ascorbic acid was changed to once weekly. The other four patients had a response followed by disease progression after 13, 21, 26, and 40 weeks, respectively. None of the patients developed new skeletal complications or hypercalcemia during the period of progression-free disease. In the five patients with azotemia, significant reductions in their serum creatinine levels (from 5.1 → 3.0, 6.1 → 1.9, 2.3 → 1.5, 5.1 → 2.1, and 4.0 → 2.2 mg/dl, respectively) were observed. One patient with profound hypercalcemia (despite treatment with zoledronic acid) normalized her serum calcium after 1 week of MAC therapy. To date, six patients remain on therapy and have maintained their response. Overall, MAC therapy was generally well tolerated with only minor treatment delays due to QT interval prolongation, thrombocytopenia, and neutropenia. The most common adverse events noted with this combination were fatigue (n=7, grade 1), marrow suppression (anemia (n=7, grades 1–3), leukopenia (n=7, grades 1–3), and thrombocytopenia (n=4, grades 1–3)), transient prolongation of the QT interval (n=5, grade 1), sensory neuropathy (n=4, grades 1–2), gastrointestinal symptoms (n=4, grades 1–2), pulmonary and peripheral edema responsive to treatment with diuretics and pulse oral glucocorticoids (n=2, grade 3), reactivation of herpes zoster (n=2, grade 2), headache (n=2, grade 1), and skin rash (n=3, grade 2). One patient with fatigue had her arsenic trioxide dose reduced by half, with a marked reduction in her symptoms, and has been on ongoing therapy for 2 years. Another patient with grade 1 neuropathy experienced improvement in symptoms after the arsenic trioxide and ascorbic acid was changed to a once-weekly schedule. Delays in the administration of MAC therapy occurred in seven patients. Delays secondary to hematologic toxicity occurred in two patients for ANC <500 × 109/l and platelets <50 × 109/l, attributable to melphalan. Only one patient required transient G-CSF support for neutropenia. Delays of only a few days occurred in five patients whose QTc intervals were prolonged (>460 ms), attributable to arsenic trioxide. Of note, no grade 4 adverse events were observed and no treatment discontinuations occurred among patients on MAC therapy. In this small series of patients treated, MAC therapy has been shown to be an active new therapeutic regimen for patients with refractory MM. A formal large multi-center phase 1/2 clinical trial is underway to further investigate this novel combination for patients with relapsed or refractory MM, and extend the promising findings of this pilot study.
Duality of interest
Dr Berenson has an ongoing financial relationship with Cell Therapeutics, Inc., which includes research grants, honoraria, speaker's bureau, and consultant work only.
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Borad, M., Swift, R. & Berenson, J. Efficacy of melphalan, arsenic trioxide, and ascorbic acid combination therapy (MAC) in relapsed and refractory multiple myeloma. Leukemia 19, 154–156 (2005). https://doi.org/10.1038/sj.leu.2403541
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