Multiple Myeloma and NHL Patients Respond to LDP-341

CHICAGO—Eight out of nine patients with advanced multiple myeloma responded to LDP-341, a proteasome inhibitor formerly called PS-341, during a phase I clinical trial in patients with advanced hematologic malignancies, according to preliminary results reported at the American Chemical Society’s annual meeting.

The announcement by Robert Orlowski, MD, of the Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, was so upbeat—one woman had a complete response—that by October 2001, a multicenter phase II trial of LDP-341 in multiple myeloma reached full enrollment ahead of schedule. Dr. Orlowski also reported partial responses in two patients with non-Hodgkin’s lymphoma who had been enrolled in the phase I study.

"To have this number of responses, even if partial, and to have any complete responses, is very unusual and very encouraging," Dr. Orlowski told ONI. He noted that the phase I study was supported in part by the Leukemia and Lymphoma Society.

The drug’s developer, Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts, has also initiated a phase II trial of LDP-341 in patients with chronic lymphocytic leukemia (CLL) and phase I trials in conjunction with chemotherapy agents for solid tumors.

While multiple myeloma patients have had the best results to date, Julian Adams, PhD, senior vice president for drug discovery at Millennium, said that the company was encouraged by early work with solid tumors, particularly prostate, lung, colon, breast, and pancreatic cancers.

"The LDP-341 trials are the first time a proteasome inhibitor has been used in humans in any type of disease, and it is uniquely designed to work in cancer," he told ONI. It has been well tolerated in about 200 patients treated to date, he said.

Proteasome inhibitors block an enzyme that degrades unwanted proteins tagged with ubiquitin. Blocking the enzyme causes these proteins to accumulate in the cell, interfering with normal function and promoting cell death. Apoptosis also appears to be advanced by interference with cellular signaling.

Empirical testing has shown cancer cells to be more sensitive to proteasome inhibition than normal cells, Dr. Adams said. In working out an intermittent dosing regimen, the investigators are seeking to inhibit between 70% and 80% of proteasome function. "We need 20% to 30% of proteasome function for normal housekeeping," he said.

In the phase I multiple myeloma trial, patients received LDP-341 intravenously twice a week for 4 weeks followed by a 2-week break. In phase II, they will be treated twice a week for 2 weeks, followed by a 1-week break. Usually, patients receive at least two cycles, Dr. Orlowski said.

Also used in the solid tumor trials, the new dosing schedule was adopted, he said, because the researchers found that most side effects occurred during the third and fourth weeks of treatment.

Dr. Adams listed the main side effects as mild fatigue, diarrhea, thrombocytopenia, and peripheral neuropathy. He said the neuropathy may have originated with thalidomide (Thalomid) treatment, which many patients had received before entering the trial.

All the patients had been treated previously for multiple myeloma, and several had undergone transplantation, Dr. Orlowski said. "We were particularly fortunate because the first patient with multiple myeloma that we treated had what would be described as a complete response," he said.

One measure of response was based on detection of multiple myeloma cells in bone marrow. In the complete responder, plasma cell count went from 41% prior to treatment to 1% after a single cycle, Dr. Orlowski said.

Another measure, he said, was a monoclonal protein produced by multiple myeloma: IgG kappa. It disappeared after three cycles in the complete responder, and treatment was stopped after four cycles. The protein reappeared after 6 months and has remained at a low level for 6 months since then without any additional treatment, Dr. Orlowski said.

Updated results were presented at the 43rd Annual Meeting of the American Society of Hematology (ASH) in Orlando, Florida, in December, 2001.

The investigators speculate that LDP-341 could be most effective in combination with other therapies. One arm of the phase II multiple myeloma trial will receive the drug in combination with dexamethasone, and many of the other trials also involve combination therapies.