The updated analysis of the Intergroupe Francophone du Myelome (IFM) 2005-02 trial in newly diagnosed multiple myeloma patients showed that lenalidomide (Revlimid) maintenance prolongs progression-free survival after stem cell transplantation, but does not improve overall survival, according to Michel Attal, MD, of the Centre Hospitalier Regional Universitaire Hôpital Purpan in Toulouse, France.1
The fact that the new analysis does not support the findings of an overall survival benefit demonstrated in the Cancer and Leukemia Group (CALGB) 100104 trial2 spurred a lively debate among myeloma researchers at the 2013 American Society of Hematology (ASH) Annual Meeting.
Also presented at the session, a meta-analysis of four key randomized controlled trials showed only a “modest improvement” in overall survival for maintenance, according to the abstract, though the benefit in progression-free survival was clear.3
More Data Needed
“Where this leads us in my view is that we need more data—further studies and more maturity of current studies will be vital, and in the United States, the answer will hopefully be provided by the currently open randomized trial IFM/DFCI 2009, which is now endorsed by both the CTN [Blood and Marrow Transplant Clinical Trials Network] and the Alliance [for Clinical Trials in Oncology],” said Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Boston. “The obvious difference between IFM 2005-02 and the other trials discussed was that lenalidomide was continued until disease progression in all of these except the IFM study (where patients got lenalidomide for a median of 24 months and were then stopped),” he told The ASCO Post.
“Whilst possible resistance is always a worry, the opposite appears to be the case with continuous therapy utilizing our best novel agents in multiple other phase III trials reported to date. I am also struck that different salvage strategies are a key factor here, as a high proportion of the patients in the IFM study on prior lenalidomide (and who then had disease progression) got immunomodulatory drug–based therapy and did worse, perhaps not surprisingly. Importantly, those who got bortezomib [Velcade] did just as well in both arms,” added Dr. Richardson.
“All in all, I was left with the impression that the results of the IFM study were the real outlier in the debate, although obviously some provocative questions were raised, which I do think will be answered as the field evolves and ongoing studies are completed.” Dr. Richardson commented.
The Mayo Clinic meta-analysis showed a significant survival benefit for lenalidomide maintenance until the newest analysis from IFM was added just prior to the meeting. Once this was done, there was still an overall survival benefit, but its significance was more marginal, as reported by Preet Paul Singh, MD, at the ASH meeting. The methodology used to assess second progression-free survival for the IFM findings was then called into question by Shaji K. Kumar, MD, from the Mayo Clinic at the session, which in itself raised some concern regarding the validity of such a last minute change to the results presented.
Other Theories
Philip McCarthy, MD, of Roswell Park Cancer Institute, Buffalo, New York, who was principal investigator of CALGB 100104, proposed some theories for the different findings.
He noted that there are several differences between IFM 2005-02 and CALGB 100104, including the duration of continuous lenalidomide, different induction regimens, the use of consolidation or not, the use of DCEP (dexamethasone, cyclophosphamide, etoposide, cisplatin) or not, and the use of double transplants or not.
“There’s enough heterogeneity between the trials that we are comparing apples and oranges,” he suggested. He noted that the most important difference is a median of 2 years of maintenance on the IFM trial and maintenance until progression in the CALGB study. This strongly suggests that continued maintenance is the preferred approach, especially in light of the RV-MM-PI209 study, which shows both a progression-free and overall survival benefit for lenalidomide maintenance.
In addition, half the patients in the IFM study received VAD (vincristine, doxorubicin, dexamethasone), which is no longer a standard regimen, whereas the majority of the CALGB study patients received an immunomodulatory drug (thalidomide [Thalomid] or lenalidomide) or bortezomib, Dr. McCarthy pointed out.
Dr. Attal responded, “This is an important debate and these are good questions,” but he maintained that intertrial heterogeneity is not the cause. His study failed to show that differences in induction regimens, DCEP, or double transplant were independently associated with overall survival, he said.
“I do agree with your observation regarding consolidation,” he continued, though he further suggested that “2 months of consolidation would not abrogate an overall survival benefit of 3 years of maintenance.” Dr. Attal also speculated that the lack of crossover in the IFM study, and the make-up of the placebo arm, could well influence the outcomes.
“The major difference is not between our lenalidomide arms, but in our placebo arms,” he said. “The IFM placebo arm is probably better than the CALGB trial’s.”
‘A Complex Problem’
The trial investigators and others who commented agreed with Gareth Morgan, MD, who called this “a complex problem” and indicated that the ongoing Medical Research Council (MRC) lenalidomide maintenance study, which is randomizing 2,500 patients to maintenance or no maintenance, will help “resolve this argument.” Dr. Morgan also emphasized the point about lenalidomide being stopped at 2 years in the IFM trial vs being given until disease progression in other studies, calling this a key difference in the maintenance strategies that could explain the divergent findings.
Dr. McCarthy said there will continue to be analysis of the landmark CALGB 100104 trial. Even though the 100104 study has met the primary endpoint of progression-free survival, there is also an overall survival benefit, and this study is quite valuable in allowing us to continue analyzing the outcome, he commented. He emphasized, “In our last analysis, we were still seeing an overall survival benefit on an intent-to-treat basis, despite crossovers in the study.” ■
Disclosure: Drs. Kumar, McCarthy, Attal, and Morgan reported no potential conflicts of interest.
References
1. Attal M, Lauwers-Cances V, Marit G, et al: Lenalidomide maintenance after stem-cell transplantation for multiple myeloma: Follow-up analysis of the IFM 2005-02 trial. 2013 ASH Annual Meeting. Abstract 406. Presented December 9, 2013.
2. McCarthy PL, Owzar K, Hofmeister CC, et al: Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med 366:1770-1781, 2012.
3. Singh PP, Kumar S, LaPlant B, et al: Lenalidomide maintenance therapy in multiple myeloma: A meta-analysis of randomized trials. 2013 ASH Annual Meeting. Abstract 407. Presented December 9, 2013.
