ORLANDO, FL—Lenalidomide maintenance therapy for patients with multiple myeloma increased the median time to disease progression by 20.5 months compared with placebo—42.3 vs 21.8 months, respectively. Data from the randomized Phase III CALGB 100104 trial were reported here at the American Society of Hematology Annual Meeting by Philip L. McCarthy Jr, MD, Professor of Oncology and Director of the Blood & Marrow Transplant Program at Roswell Park Cancer Institute.
Maintenance therapy in the trial (Abstract 37) was initiated at Day 100 to 110 after single autologous stem cell transplant (ASCT), and the trial's primary endpoint was time to progression.
“The study's implication is that there is now an option for patients to continue on a therapy that will allow them to maintain their response,” Dr. McCarthy said.
Eligible patients had Stages I to III myeloma for one year or less from diagnosis and more than two months after induction therapy.
The ASCT regimen was melphalan at 200 mg/m2. Maintenance lenalidomide started at a low dose, 10 mg/day, and escalated to 15 mg/day after three months. Maintenance continued until disease progression.
All patients required some form of anticoagulation including aspirin, warfarin, or heparin compounds, Dr. McCarthy said. There was no consolidation therapy.
A total of 460 patients accrued from 47 centers were randomly assigned to the two study arms. For the lenalidomide arm and the placebo arm, respectively, the median ages were 58 and 57; the percentages of patients who were male were 48% and 52%; and those who had beta-2M greater than 2.5 mg/L were 28% and 27%.
The primary study results for time to progression were released in December 2009, Dr. McCarthy noted, and the data reported at the ASH meeting were from a third interim analysis of time to progression, with a median follow-up of 17.5 months post-ASCT.
A total of 44 of the 231 patients randomized to lenalidomide had adverse events, compared with 91 of the 229 patients randomized to placebo.
Patients receiving lenalidomide had a 61% relative reduction in the risk of disease progression or death when compared with patients receiving placebo.
The number of deaths in the lenalidomide and placebo arms were 19 and 28, respectively, which Dr. McCarthy said was not a statistically significant difference.
Pooled Grade 3 to 5 adverse events for lenalidomide and placebo, respectively, were: thrombocytopenia, 11% vs 3%; neutropenia, 44% vs 8%; anemia 5% vs 1%; and all infections, 16% vs 3%. There were no significant differences in the incidences of fatigue, neuropathy, rash, or thromboembolism.
In an interview after his presentation, Dr. McCarthy said the patients he would be interested in targeting for some form of maintenance therapy long-term are the high-risk patients—“those who have high-risk cytogenetic abnormalities and who are at very high risk for relapse or progression and then developing resistance to treatment.”
Dr. McCarthy said that there are new, preliminary studies showing some potential benefit for using bortezomib in maintenance therapy, both intravenously and subcutaneously. “That may be another option; we have to see how this plays out and in fact, eventually we may want to see a head-to-head study comparing [maintenance with lenalidomide or bortezomib].”
Key Will Be Overall Survival Data
Also in interviews after the session, session co-moderators Edward A. Stadtmauer, MD, Professor of Medicine and Director of the Bone Marrow and Stem Cell Transplant Program at the University of Pennsylvania, and Elena Zamagni, MD, Associate Professor of Hematology, University of Bologna, Italy, were asked to comment on Dr. McCarthy's study for this article.
“They are really impressive results, and very important results, but the main point will be overall survival,” Dr. Zamagni said. “We just know now that lenalidomide is improving in the time to progression, and that can be a very good message anyway because it will be better quality-of-life for the patient.”
Dr. Stadtmauer agreed, saying that if outcome data showed that survival was increased by maintenance therapy over no maintenance therapy, there would be no discussion about the superiority of maintenance with lenalidomide.
“What these studies very clearly show is that the duration of a remission is much better when you take lenalidomide than if you don't take lenalidomide,” said Dr. Stadtmauer, who is one of the authors on CALGB 100104.
“But when you just have that, it's appropriate to weigh in toxicity, and cost, and convenience, and all of those other things. If survival were significantly different, then there would be much less debate.”
On the other hand, he said, myeloma is a disease where progression means more than just a number. When people have disease progression, they have broken bones, kidney failure, infections, and low blood counts. Progression is not a good thing, so if taking this medicine prolongs the duration of remissions, then that is a positive thing.
“But whether it means everyone is required to take maintenance therapy, that still is not the case,” Dr. Stadtmauer said.
An expert not involved in the trial said he thought the CALGB 100104 progression-free survival data were very exciting.
“I think it's something that a lot of people are already incorporating into their practices, just based on some of the early impressions that have already been out in the community,” said Don Benson, MD, PhD, Assistant Professor of Internal Medicine at Ohio State University Medical Center.
He noted that approximately 60 of the patients in CALGB 100104 were treated at Ohio State—“so we were very excited to see these results, because it means a lot to the patients we take care of here.”