NEW ORLEANS—Preliminary results from the Phase I/II MM-002 dose-escalation trial of the immunomodulating drug (IMiD) pomalidomide (CC4047), alone or combined with low-dose dexamethasone, show a minimal response rate of at least 38% in heavily-pretreated patients with refractory or relapsed multiple myeloma.
Stable disease was achieved in 43% of patients receiving pomalidomide alone, and in 46% receiving pomalidomide plus dexamethasone.
The responses were very encouraging for this thalidomide-derived IMiD, the researchers said in presenting the results at the ASH Annual Meeting here, considering that patients entered the study with a median of seven prior treatments including lenalidomide and bortezomib (100% of patients) and thalidomide (78% of them). And 59% had also undergone prior stem cell transplant.
In the Phase I dose-finding portion of the trial, patients received pomalidomide at a dose of 2 to 5 mg. All patients received low-dose prophylactic aspirin daily and were monitored for venous thromboembolic events.
“The incidence of serious side effects and discontinuations decreased with increased doses of pomalidomide, with no dose-dependent increase in Grade 3/4 hematological toxicities,” said first author Paul G. Richardson, MD, Clinical Director of the Jerome Lipper Multiple Myeloma Center of Dana-Farber Cancer Institute, and Associate Professor of Medicine in the Department of Medical Oncology at Harvard Medical School.
The maximum tolerated dose of pomalidomide has not been reached to date, he said. “Overall, these data indicate that pomalidomide has an acceptable safety profile and is a clinically active therapeutic option for advanced refractory multiple myeloma,” Dr. Richardson said.
The Phase II randomized portion of the trial comparing pomalidomide-dexamethasone with pomalidomide alone continues, with a total of 192 patients planned to be included.
In the Phase I portion of the trial, pomalidomide was given daily on Days 1 to 21 of a 28-day cycle on a 3x3 dose-escalation plan. During treatment with pomalidomide alone, the overall response rate was 38%, including one complete response, two partial responses, and five minimal responses. The mean duration of response was 11.1 weeks, and the mean time to progression was 8.3 weeks.
During treatment with pomalidomide-dexamethasone the overall response rate was again 38%, including two partial responses and three minimal responses. The mean duration of response was 14.2 weeks, and mean time to progression was 20 weeks.
The incidence of significant adverse events and discontinuations decreased with increased doses of pomalidomide, with no dose-dependent increase in Grade 3/4 hematological toxicities, and the maximum tolerated dose has not been reached to date.
Dr. Richardson said 15 of 32 patients had discontinued therapy at the time of the report, and 17 continue for both safety and efficacy analyses.
There were four dose reductions due to pomalidomide after 108 completed cycles: two due to neutropenia and one with rash at the 5 mg dose, and one for neutropenia at 3 mg. Neutropenia and thrombocytopenia were the most common Grade 3/4 toxicities, with no dose-dependent increase apparent to date.
Twelve serious adverse events occurred in 10 patients. Pomalidomide-related events included venous thromboembolism, syncope, third-degree AV block, asthenia, diarrhea, neutropenia, anemia, and rash. One event was related to the pomalidomide-dexa-methasone combination: sepsis with pharyngeal abscess.
Dr. Richardson reported three deaths on study not attributed to pomalidomide: two from rapid progressive disease, and one from gastrointestinal perforation due to amyloidosis. “We know it wasn't the steroid,” he said of the gastrointestinal perforation, in an interview after his oral presentation, “because at autopsy [the patient's] gut was full of amyloidosis.”
The original Phase I work on pomalidomide, Dr. Richardson noted, was done by colleagues in Britain. Martha Q. Lacy, MD, Associate Professor of Medicine at the Mayo Clinic, then took the work forward with a Phase II combination trial in patients with earlier disease (published as Abstract 866 at the 2008 ASH Annual Meeting and then published as a full study last fall in the Journal of Clinical Oncology [2009;27: 5008–5014]).
Among the 60 patients enrolled in that earlier trial, 38 (63%) achieved a confirmed response, including a complete response in three patients.
Busy Therapeutic Landscape
In the new study, Dr. Richardson explained, “we sought to complete the [pomalidomide] repertoire by doing a Phase I/II study exclusively in relapsed and refractory myeloma, recognizing that the therapeutic landscape for myeloma is now, thankfully, very busy.
“In that context, our most unmet medical need is in relapsed and refractory patients. Even though we've made great progress, no matter how many lines of therapy our relapse and refractory patients have had, their survivals can be as short as six months.”
The study was a three-center effort by Dana-Farber, Hackensack (NJ) University Medical Center, and H. Lee Moffitt Cancer Center and Research Institute, sponsored by Celgene and supported by the Multiple Myeloma Research Consortium.
In the Phase I portion of the study, testing was for doses of 2, 3, 4, and 5 mg. Dose-limiting toxicity was seen at 5 mg, but the 4 mg dose was well tolerated and was used in the Phase II part of the study.
The use of growth factor was not allowed in the first cycle, Dr. Richardson said, “because that allows us to get a clean signal of the drug alone in terms of neutropenia.
“But in Phase I they were permitted G-CSF in subsequent cycles, and going forward into Phase II, GCSF will be allowed, so we think neutropenia will prove manageable.”
What was really interesting, he said, was the low rate of neuropathy—only one case. In addition, there were only two cases of deep vein thrombosis, “and that was with simple antithrombotic therapy with aspirin alone.”
The Chairman and Medical Director of the International Myeloma Foundation, Brian G.M. Durie, MD, was asked in a telephone interview after the meeting to comment on Dr. Richardson's enthusiastic presentation on pomalidomide.
“I think excitement is appropriate for this third-generation IMiD,” Dr. Durie said.
He noted that pomalidomide is different from its predecessors, thalidomide and lenalidomide, in that it does not cause neuropathy, and that its main side effect appears to be myelosuppression, particularly leukopenia. “But most interestingly, it had significant activity in patients who have been previously exposed to thalidomide, bortezomib, and lenalidomide.”
Dr. Durie also pointed to previous reports from the Mayo Clinic on the drug, with the same finding of 20% to 30% response rates in patients who had not responded to prior therapy with immunomodulatory drugs.
Dr. Paul Richardson called the results of the pomalidomide research to date encouraging, including from a regulatory perspective: “If we can convincingly show to the regulatory authorities that we've got a response rate that's robust in about a third of patients, and that it's durable, and that the drug is well tolerated, and that it is taking place in truly relapsed and refractory patients in whom prior lenalidomide and bortezomib have failed them, then we have an approval basis strategy,” he said in an interview.