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(Drug information on 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(Drug information on thalidomide) in 74% and stem cell transplant in 54%.
