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Combination Melphalan/Arsenic Trioxide/Ascorbic Acid Active and Well Tolerated in Relapsed/Refractory Multiple Myeloma: Presented at EHA

By Chris Berrie

AMSTERDAM, THE NETHERLANDS -- June 19, 2006 -- Results of a large, prospective, multicentre, single-arm, phase 2 trial show that combination therapy with melphalan, arsenic trioxide and ascorbic acid (MAC) is active and well tolerated in patients with relapsed/refractory multiple myeloma.

In addition, patients with renal insufficiency who were treated with this combination had improvements in serum creatinine (SCr) levels, researchers reported here at the 11^th Congress of the European Hematology Association (EHA) here on June 16^th.

Multiple myeloma remains an incurable disease despite the expanding array of treatment options. Nearly all patients develop resistance, and most develop renal insufficiency.

In presenting this study, principal investigator James R. Berenson, MD, medical and scientific director, Institute for Myeloma and Bone Cancer Research, West Hollywood, California, United States, said that following their recent phase 1/2 trial of bortezomib/melphalan therapy for patients with relapsed/refractory multiple melanoma, "we had patients who were sick enough but ineligible for the trial, and we knew arsenic had a similar effect on [nuclear factor kappa B (NF-kappa B)], which is important in chemoresistance, so we thought that if we knocked out NF-kappa B with arsenic, as you can do with [bortezomib], we could accomplish the same thing".

Addition of arsenic trioxide to melphalan treatment has been shown to overcome resistance to this alkylating agent, while ascorbic acid is known to enhance the cytotoxic effects of arsenic trioxide.

Therefore, Dr. Berenson and colleagues conducted a study to determine response rates, time to progression, and safety and tolerability of this MAC regimen. The secondary objectives were for time to response, progression-free survival (PFS), overall survival (OS), and effects on renal function.

The inclusion criteria were: > 18 years of age; measurable disease (monoclonal immunoglobulin spike >1 g/dL and/or urine monoclonal immunoglobulin spike greater than or equal to 200 mg/24 hours); relapsed and/or refractory following chemotherapy; Karnofsky performance greater than or equal to 60; baseline platelet count greater than or equal to 50x 109/L (if bone marrow extensively infiltrated, greater than or equal to 30x 109/L); haemoglobulin greater than or equal to 8.0 g/dL; and absolute neutrophil count greater than or equal to 1x 109/L.

Prestudy disease assessment included Karnofsky performance status, skeletal survey and/or bone magnetic resonance imaging, bone marrow aspirate and biopsy, beta2-microglobulin, C-reactive protein, and serum and urine protein electrophoresis. Prior to the start of each subsequent cycle, disease assessment included adverse events, vital sign assessment, review of concomitant medications and other supportive therapies, clinical laboratory tests, history, and physical examination.

The treatment schedule consisted of oral melphalan 0.1 mg/kg/day on days 1 to 4 of each 6-week cycle, IV (2 hours) arsenic trioxide 0.25 mg/kg followed by IV (15 minutes) ascorbic acid 1.0 g during days 1 through 4 of the first week of cycle 1. This was then modified to IV (1 hour) arsenic trioxide 0.25 mg/kg followed by IV ascorbic acid 1.0 g twice weekly for weeks 2 through 5 of cycle 1 and weeks 1 through 5 of cycles 2 to 6. Week 6 of each cycle was left free of study drugs. Patients received a maximum of 6 cycles.

The demographics and baseline characteristics of the 65 patients enrolled were as follows: median age, 66 years (range, 29-89); median number failed therapies, 4 (range, 1-8), including melphalan (n = 25), thalidomide/lenalidomide (n = 40), bortezomib (n = 21) and peripheral stem cell transplant (n = 11); mean serum M-protein, 3.8 g/dL (range, 0.1-11.0); mean urine M-protein, 4.4 g/24 hours (range, 0.01-100.6); and mean beta2-microglobulin, 5.5 mg/dL (range, 0.5-25.9).

Overall patient response was 48%, comprising 3% complete, 23% partial, and 22% minimal. According to the prior therapies, the objective responses were similar (melphalan, 44%; thalidomide/lenalidomide, 55%; bortezomib, 57%; peripheral stem cell transplant, 46%).

Median PFS was 7 months (range, 0.25-25+), and median time to response was 1.5 months (range, 1-6); median duration of response was 12 months (range, 1-16+). Median OS was 19 months.

Of 23 patients (35%) with baseline SCr levels greater than or equal to 1.5 mg/dL, 74% had improvements, 71% of which also showed at least disease control with this treatment. "So I think this is an impressive story, when you get reversal of renal failure in late stage myeloma," he said.

This MAC regimen was well tolerated, with few serious adverse effects (mainly fever/chills; 15% of patients). Mild cytopenias were reversible, fluid retention responded to diuretics and/or steroids, there was no induction of neuropathy, and pre-existing neuropathy did not worsen.

Dr. Berenson said that this study provides another option for patients with multiple myeloma, and indicated his team's intention to follow up with further investigations into similar regimens in the future.

This study was sponsored by Cephalon.


[Presentation title: Efficacy and Safety of Melphalan/ Arsenic Trioxide/Ascorbic Acid Combination Therapy (MAC) in Patients With Relapsed/ Refractory Multiple Myeloma: a Prospective, Multicentre, Phase 2, Single-Arm Study. Abstract 0230]

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