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Proteasome Inhibitor PS-341Called ‘Very Promising’ in Relapsed or Refractory Multiple Myeloma

Proteasome Inhibitor PS-341Called ‘Very Promising’ in Relapsed or Refractory Multiple Myeloma

CAMBRIDGE, Massachusetts—The proteasome inhibitor PS-341 produced
objective durable responses in multiple myeloma patients with relapsed and
refractory disease in a phase II multicenter trial (ASCO abstract 40).
"The activity of the drug seems very promising. We have an overall 77%
stable disease or response rate, and a 47% objective response rate with
decreased malignant M paraprotein," reported Julian Adams, PhD, from
Millennium Pharmaceuticals, Inc., in Cambridge, Massachusetts. "The
durability of this response is significant, and the drug is well tolerated
with very manageable side effects."

PS-341, formerly known as LDP-341, is the first in its class of
proteasome inhibitors representing a novel pathway for targeted anticancer
therapy. The drug blocks the activity of a cell-signaling pathway regulated
by the proteasome enzyme complex, which controls cancer cell growth despite
stressors that would normally promote apoptosis.

While PS-341 is a potent and selective inhibitor of the proteasome, it
also has numerous effects on regulatory proteins, including blockade of
activation of NF-kB, a transcription factor that upregulates the expression
of IL-6, VEGF, cell adhesion molecules, and antiapoptotic factors.

Preliminary studies with PS-341 suggested antimyeloma effects in vitro
and in xenografts, and a favorable safety profile and impressive
anti-myeloma activity in patients with very poor prognosis.

Two Cohorts Enrolled

For the trial, 202 outpatients were enrolled in two cohorts to receive
PS-341, 1.3 mg/m² by IV push on days 1, 4, 8, and 11 of a 21-day cycle for
up to eight cycles. Patients could also receive dexamethasone (Decadron)
after four cycles if they had stable disease or after two cycles if they had
progressive disease.

Among the first cohort of 78 patients, the median number of prior
therapies was five (range 2-14), median number of years from diagnosis was
4.4, and previous therapies included thalidomide in 74% and stem cell
transplant in 54%.

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