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The role of Multidrug Resistance Anti-therapy in the Management of Multiple Myeloma A
major obstacle to the successful treatment of MM is the emergence of
chemotherapy-refractory disease. Although 60% to 80% of patients treated with
Melphalan and prednisone or VAD achieve an objective response to initial
therapy, many patients will relapse. Those patients who relapse within 6 months
of therapy will not respond to subsequent treatment with the same regimen, and
will have a lower response rate to new therapy. The tumor cells in 90% of VAD-refractory
patients exhibit a multidrug resistant (MDR) phenotype resulting from
over expression of P-glycoprotein (P-gp). This protein is responsible for pumping
the active drug out of the cancerous cell, thus compromising its exposure to the
cytotoxic therapy. This in turn renders the myeloma cells resistant to
Melphalan, Vincristine, and doxorubicin.(4-10) Disabling
this active protein pump in these tumors has presented a difficult challenge.
The most widely studied agents include Verapamil, cyclosporine A, and the
second-generation cyclosporine analogue Valspodar (AmdrayÒ;
Novartis Pharmaceuticals Corporation, East Hanover, NJ), also known as PSC 833.
However, the clinical applications of both Verapamil and cyclosporine A have been
limited by severe heart, kidney, and immunosuppression at doses that could
effectively inactivate the active pump. Currently, a variety of
second-generation MDR modulators (pump inhibitors) are being investigated, some
of which may prove to have a more favorable toxicity profile compared with these
first-generation products. In contrast to cyclosporine A, Valspodar is a
nonimmunosuppressive, non nephrotoxic cyclosporine derivative, which is
approximately two- to tenfold more potent than cyclosporine A.(11)
Preclinical and phase I clinical studies have shown that Valspodar reverses MDR
at dose levels that are well tolerated in animals and humans.(12-14) The
principle toxicity associated with administration of Valspodar is moderate,
reversible ataxia (i.e., loss of coordination, unsteadiness, and/or mild
dizziness). Clinical
trials have demonstrated the safety and efficacy of this novel MDR modulator in
chemotherapy-refractory MM patients. Sonneveld et al reported the first phase I
trial (a study evaluating the safety of the drug) of Valspodar in 22 patients
with VAD- or Melphalan-refractory MM. (15) In this study, patients were treated
with three cycles of VAD plus an escalating dose of Valspodar (2.5 to 15 mg/kg).
The dose-limiting toxicities were myelosuppression
(bone marrow suppression) and neuropathy (nerve damage. Because Valspodar
inhibits the normal clearance of some chemotherapeutic agents (e.g.,
doxorubicin) via the liver and kidneys, it increases the drug levels in
patients. Consequently, dose reductions, depending on the specific agent, are
required. This does not, however, compromise the therapeutic efficacy of the
chemotherapy regimen. With
respect to MDR modulation, Sonneveld et al reported partial responses in 10 of 22 (45%) patients, including 4 of 8 assessable
Melphalan-refractory patients and
6 of 12 assessable VAD-refractory patients. Subsequently,
a phase II trial (a trial designed to evaluate the efficacy of the drug) in VAD-refractory
MM patients was conducted and preliminary data are available. Based on a
previous phase I dose-escalation study,(16)
patients on this trial received a reduced dose of VAD plus
Valspodar every 28 days. Patients were treated for up to 6 cycles or until
progression or unacceptable toxicity. As reported at the 1998 meeting of The
American Society of Hematology, accrual to this study is complete, a total of 41
patients have been treated, and 36 patients are evaluable for safety. The
primary chemotherapy-related toxicities were severe low white blood count and
platelets in 36% and 11% of patients respectively. The most common
Valspodar-associated toxicities were mild to moderate unsteady gate (36%), with
no reports of severe symptoms. Objective responses were observed in 4 of 41
(10%) patients. Further more, a recent update has confirmed that another 15% of
the patients have responded for a total of 25%. This study has further
demonstrated that the combination of Valspodar and reduced-dose VAD is safe and
can induce responses in VAD-refractory patients. However, continued follow-up is
necessary to establish the efficacy of this regimen. Based
on these encouraging results, the Eastern Cooperative Oncology Group (ECOG) has
recently initiated a randomized phase III (a study designed to compare new
therapy to the standard) intergroup trial of modified VAD plus Valspodar versus
full-dose VAD alone in patients with relapsing or refractory MM. The primary
objective of this study is to determine if Valspodar improves the objective
response rate and overall survival in this patient population. Event-free
survival, P-gp expression, prognostic variables, and toxicity will also be
assessed. Eligible patients will be those with a confirmed diagnosis of MM, and
with clinical evidence of progression following initial chemotherapy. However,
patients previously resistant to VAD are ineligible. Planned accrual for this
study is 324 patients. The
aim of these studies is to develop an effective strategy to overcome multidrug
resistance and ultimately, perhaps, to prevent the development of drug
resistance in a variety of human malignancies. Valspodar is a prime example of
an agent that has emerged from the culmination of intensive research into the
molecular mechanisms of MDR and novel drug development. References
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