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%.

After follow-up of median duration 6.2 months, data on the first 78 patients showed 6-month survival of 70%, either decline or no change in maximal paraprotein in 77%, greater than 90% reduction in maximal paraprotein in 20%, and some complete remissions.

Adverse events led to study discontinuation in 16 patients (21%), but no common adverse events were grade 4. Of 19 deaths, none were judged to be probably or definitely treatment-related. Grade 3 thrombocytopenia occurred in 24% of patients, and grade 3 peripheral neuropathy in 12%. Only four patients without baseline peripheral neuropathy developed treatment-emergent neuropathy. Treatment and data analysis for the second cohort of patients is ongoing.

Optimizing Therapy

"The next step is a randomized phase III trial in a less advanced population, including patients with relapses after one to three prior regimens," Dr. Adams said. An international study planned to begin in June will randomize 600 patients to two treatment arms, PS-341 or high-dose dexamethasone.

"Other pilot studies utilizing combination therapies will help to optimize the best therapy," Dr. Adams added, noting that PS-341 is also being studied in other malignancies.