番茄社区

CHICAGO -- In a preliminary trial, the novel agent plitidepsin -- derived from the sea squirt -- showed activity among relapsed/recurrent multiple myeloma patients, researchers reported here.

Among the 18 patients treated with plitidepsin plus bortezomib (Velcade) and dexamethasone, 10 of them -- or 55% of the group -- responded to the treatment, said , consultant hematologist at the University Hospital Salamanca, Spain.

"Initial efficacy results show promising activity in heavily pretreated patients with relapsed or recurrent multiple myeloma, even in bortezomib and lenalidomide (Revlimid)-refractory patients," Mateos said in her oral presentation at the annual meeting of the American Society of Clinical Oncology. "These results support the continued development of plitidepsin in patients with multiple myeloma."

Progression-free survival was 8.3 months, she reported. She said that two of the patients had achieved a stringent complete response; one complete response; four very good partial responses and three partial responses. She said that three patients achieved minor responses and one patient had stable disease. Four of the 18 patients progressed on treatment. The median duration of response has not yet been reached; some patients have been treated for 18 months.

Mateos said that plitidepsin appears to work by inducing oxidative stress and causing cell death through apoptosis. Previous studies with the drug showed promise in preclinical trials. She said one trial showed a synergistic relationship between bortezomib and plitidepsin in xenografts. In a phase II trial, as a single agent or combined with dexamethasone, there was modest activity.

"This is an interesting compound. We just need a bit more data," said , of the Winship Cancer Center at Emory University, Atlanta.

"The mechanism of action is not entirely clear. I think it may work through a cytotoxic mechanism, not dissimilar from conventional chemotherapy," he told 番茄社区. "We don't know what it attacks."

Lonial said that "the synergy data with bortezomib is not a surprise because bortezomib makes a lot of other drugs better. They did have patients with bortezomib resistance who responded to this treatment."

The researchers recruited patients who had been diagnosed with relapsed/recurrent multiple myeloma who had already been treated with at least one line of therapy and had progressive disease. Patients were eligible if they had undergone autologous stem cell transplantation and had recurred after that therapy. Bortezomib therapy was also allowed but not if the the patients was shown to be refractory to bortezomib. The goal of the phase 1 trial was to determine the recommended dose for further studies -- in this case settling on the third dosing level of 5 mg/m² of plitidepsin on day 1 and day 15; bortezomib 1.3 mg/m² subcutaneously on day 1, day, 4, day 8 and day 11; and oral dexamethasone 40 mg on days 1, 8, 15, and 22. There were not enough severe adverse effects to identify a maximum tolerated dose of plitidepsin.

The mean age of the patients in the study was 65; they were divided evenly by sex. Most were in ECOG performance status 1; the others were performance status 0. About 59% of the patients had more than three lines of therapy before being treated with the plitidepsin combination.

She said 16 of the 18 patients had previously been treated with bortezomib; 16 had previously been treated with lenalidomide; 14 patients had undergone autologous stem cell transplantation; two patients had undergone allogeneic stem cell transplantation; six patients had been treated with thalidomide; four patients had been treated with pomalidomide. Mateos said 61% of the patients were refractory to their last line of treatment.

"Data from this phase 1 trial suggest this combination has an acceptable safety profile and tolerability profile," Mateos said. Grade 3-4 thrombocytopenia was observed in eight of 18 patients; Grade 3-4 anemia and neutropenia was experienced by two patients each. Other Grade 3-4 events were two cases of fatigue and one case each of diarrhea, vomiting, and elevated liver enzymes.