Haematologica 2003 - Supplements

improve patient outcome in MM. Importantly, gene array and
proteomic evaluation samples from patients treated with these
novel agents on will define molecular mechanisms of tumor cell
sensitivity versus resistance, thereby providing the framework for
developing next generation more potent, selective, and less toxic,
targeted MM therapies.
P12.1.2
THE ROLE OF ARSENIC TRIOXIDE IN MULTIPLE
MYELOMA
Mohamad Hussein, MD
Multiple Myeloma Research Program, Cleveland Clinic Cancer
Center, Cleveland, OH, USA
Introduction
In recent years the delineation of the different cytokines and
cellular interactions influencing plasma cells has provided the
drug industry with a rationale to develop target specific
molecules. Multiple Myeloma is incurable as a result of the
complex, redundant and effective mechanisms maintaining the
plasma cell’s survival. Effectively influencing the malignant
plasma cell microenvironment to modulate and/or reset to a
normal level of activity could change the disease into a chronic
process. Molecules that act on different levels of the immune
system, or a combination of such agents will be needed to
overcome the redundancy and positive feedback loops in the
myeloma cell support system. These molecules have diverse
effects and activities; therefore toxicity tends to be a global
byproduct of treatment. Clinical trials that are well designed and
conducted are critical in the development of therapy for
myeloma.
Trisenox ® (arsenic trioxide) is a novel anticancer agent with
unique, multifaceted mechanisms of action. At clinically relevant
concentrations, it causes apoptosis in various tumor cell lines and
has anti-angiogenic effects in vitro and in vivo. Human myeloma
cell lines and freshly isolated cells are particularly sensitive to
Trisenox ® and there is no apparent cross-resistance to the drug in
myeloma cell lines that are resistant to other agents such as
dexamethasone or doxorubicin.
Preclinical effects of arsenic trioxide when used as a single agent
Results from preclinical studies show that arsenic trioxide, when
used as a single agent, appears to act directly on mitochondria to
induce apoptosis. This activity is unlike conventional cytotoxics,
which trigger pro-apoptotic signal transduction pathways
upstream of mitochondria. The induction of apoptosis by arsenic
trioxide is thought to occur by several mechanisms that involve
generation of reactive oxygen species (ROS) and inhibition of the
glutathione (GSH) cellular redox system. These activities appear
to directly damage the mitochondria leading to apoptosis of the
myeloma cells.
Other preclinical work indicates that the effects of arsenic
trioxide treatment also occur at the cell surface. The results from
this work show myeloma cell destruction through modulating
integrins and caspase activation and through the over expression
of CD38 and its ligand on plasma and LAK cells, respectively.
Preclinical effects of arsenic trioxide when used as a combined
agent
Depletion of cellular levels of GSH with agents such as ascorbic
acid (AA) or buthionine sulfoximine (BSO) can enhance
apoptosis of human myeloma cells by arsenic trioxide. Through
different mechanisms, AA and BSO reduce GSH levels and
accentuate mitochondrial damage and apoptosis of myeloma
cells. Investigators observed that AA could potentiate arsenic
trioxide-mediated increases in the production of superoxide and
increase disruption of mitochondrial membrane potential in
myeloma cell lines. The investigators also found that when
myeloma cells from patients are treated with AA and arsenic
trioxide, the cells are more sensitive to the apoptotic effects of
arsenic trioxide. The combination of arsenic trioxide with AA or
BSO also affected drug-resistant myeloma cell lines known to
express various mechanisms of drug resistance.
Clinical effects of Trisenox ® when used as a single agent
PHASE 2 STUDY
In a phase 2, multicenter study, 24 heavily pretreated myeloma
patients received treatment with Trisenox ® (0.25 mg/kg, Mon-Fri,
2 weeks on/2 weeks off). Of the 24 patients, 15 were refractory to
previous treatments and 9 relapsed. Thirteen of the 24 patients
were evaluated for efficacy and 12 of those patients had an
objective response or achieved stable disease. The response to
Trisenox ® in this study was durable with one patient maintaining
stable disease at 22+ months after starting Trisenox ® therapy.
Neutropenia and leukopenia were the only common grade 4
toxicities in this study.
Clinical effects of arsenic trioxide when used as a combined
agent
PHASE 1 STUDY
Preclinical work with arsenic trioxide and AA has led to clinical
studies including a phase 1, NCI CRADA study at the University
of Miami. This study was conducted to assess the combined
treatment of Trisenox ® and AA on the toxicity profile and
pharmacokinetics of Trisenox ® , and on AA-mediated depletion of
intracellular GSH. Six patients with stage IIIA relapsed/
refractory multiple myeloma were treated daily with Trisenox ®
(0.25 mg/kg) and AA (1000 mg) for 25 days. Two patients, both
with thalidomide-refractory myeloma, achieved PR and 4 patients
had stable disease. The combined treatment had acceptable
toxicity and no affect on the pharmacokinetics of Trisenox ® .
Elevated levels of AA were associated with decreased
intracellular GSH.
Additional clinical studies with Trisenox ® when used as a
combined agent
PHASE 2 STUDY
A phase 2 clinical trial was initiated at the Cleveland Clinic
Cancer Center to test the effect of Trisenox ® -AA-dexamethasone
(TAD) in the treatment of 15 patients with active, progressive
multiple myeloma who failed no more than 2 prior treatments.
This study and its treatment regimen are based on the results
others have reported from previous clinical studies with
Trisenox ® as a single agent and in vitro work. The in vitro studies
showed that Trisenox ® sensitizes myeloma cells to
dexamethasone (Dex) or that AA enhances the effect of
Trisenox ® on plasma and human cell lines.
Treatment regimen for phase 2 TAD study Cycle 1: Week 1, load
with Trisenox ® 0.25mg/kg IV days 1-5, AA 1000mg IV within 30
minutes after each Trisenox ® infusion, and Dex 40 mg orally
days 1-4. Weeks 2-12, Trisenox ® 0.25 mg/kg IV twice weekly,
AA 1000 mg IV within 30 minutes after each Trisenox ® infusion,
and Dex 40 mg orally days 11-14, 29-32, 39-42, 57-60, and 67-
70. Weeks 13-15, rest period. Trisenox ® and AA regimens are the
same during cycles 2 and 3, but the frequency of Dex is reduced
to Dex 40 mg orally days 1-4, 29-32, 57-60, and 67-70.
The most current results from this phase 2 TAD study show that 6
patients (42%) achieved >50% reduction in M-protein and 1
patient had near CR after 1 cycle of therapy. Seven patients had
stabilization of their disease process with 1 of these patients
progressing during the second cycle. Preliminary results show
that this combination of drugs is active in the group of relapsed
myeloma patients tested and that the regimen was well tolerated.
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