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Published online November 1999
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Published online November 1999
Although a proportion of patients with multiple
myeloma
(MM) may achieve a long-term plateau phase with intensive therapy
followed
by stem cell salvage,(Attal, N Engl J Med, 1996; 335:91-97; Jagannath,
Blood, 1990; 76:1860-1866) the majority of patients will succumb to
their
disease. In the community, MM patients are usually treated with
conventional-dose
melphalan and prednisone or a regimen consisting of vincristine,
doxorubicin,
and dexamethasone (VAD). With this approach, the median survival of MM
patients is 30 to 36 months; however, therapy will eventually fail in
nearly
all of these patients secondary to drug-resistant disease or infectious
complications.(Alexanian, N Engl J Med, 1994; 330:484-489). 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
overexpression
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.(Grogan, Blood, 1993; 81:490-495; Epstein,
Blood, 1989; 74:913-917; Sonneveld, Br J Haematol, 1993; 83:63-67;
Grogan,
Lab Invest, 1990; 63:815-824; Pilarski, Blood, 1994; 83:724-736;
Cornelissen,
J Clin Oncol, 1994;12:115-119; Dalton, Blood, 1989;73:747-752).
Disabling
this active protein pump in these tumors has presented a difficult
challenge.
The most widely studied agents include verapamil, cyclosporin 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 cyclosporin 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 cyclosporin A,
valspodar
is a nonimmunosuppressive, nonnephrotoxic cyclosporine derivative,
which
is approximately two- to tenfold more potent than cyclosporin
A.(Fisher,
Eur J Cancer, 1996; 32A: 1082-1088) Preclinical and phase I clinical
studies
have shown that valspodar reverses MDR at dose levels that are well
tolerated
in animals and humans.(Ford, Hematol Oncol Clin North Am, 1995;
9:337-361;
Twentyman, Eur J Cancer, 1991; 27:1639-1642; Hausdorff, Proc Am Soc
Clin
Oncol, 1995; 14:181) The principle toxicity associated with
administration
of valspodar is moderate, reversible ataxia (ie, 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.(Sonneveld, Leukemia, 1996; 10:1741-1750) 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 (eg, 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,(Dalton, Blood, 1996; 88:662a) 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.(Case, Blood, In Press). 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.