Here is an article I found in this week’s Clinical Oncology newsletter. No new news, but some insight into how stats effect progression free surivival (PFS).
In Multiple Myeloma, Maintenance Therapy After Transplant Improves PFS
Chicago—Maintenance therapy with lenalidomide (Revlimid, Celgene) greatly improves progression-free survival (PFS) in patients with multiple myeloma (MM) after autologous stem cell transplantation (ASCT), according to two large, multicenter Phase III trials. The similarity of the outcomes, which are considered to have immediate relevance to clinical practice, was remarkable. In one study, investigators identified a 54% reduction in the risk for PFS (hazard ratio [HR], 0.46; P<0.00000001). The other found a 58% reduction in time to progression (TTP; HR, 0.42; P<0.0001).
“We have just heard two of the most practice-changing presentations that have happened in myeloma in the last couple of years,” said Sergio Giralt, MD, chief, Adult Bone Marrow Transplant Service, Memorial Sloan-Kettering Cancer Center, New York City. Speaking at the 2010 meeting of the American Society of Clinical Oncology (ASCO), where these data had just been presented, Dr. Giralt emphasized that the benefit of maintenance therapy with lenalidomide after ASCT was observed regardless of β2 microglobulins, cytogenetics, type of induction or response to the initial therapy.
The two studies had similar designs and asked the same question. Can a maintenance therapy after ASCT reduce or delay the high rates of relapse that are presumably due to residual disease? Lenalidomide, an oral therapy, was an attractive choice because it is reasonably well tolerated and has demonstrated substantial activity in MM in the past. There were a few design differences between the two studies, one conducted by the International Myeloma Foundation (IMF 2005-02) and the other by Cancer and Leukemia Group B (CALGB 100104), but the consistency of the outcomes were mutually reinforcing. The expert invited by ASCO to discuss the studies, Dr. Giralt, concurred with the authors that the results support maintenance lenalidomide as a new standard after ASCT.
In the IMF 2005-02 trial, 614 MM patients younger than age 65 years who had received ASCT within the previous six months and had nonprogressive disease were randomized to lenalidomide or placebo (abstract 8018). Those in the lenalidomide arm received a two-month consolidation course at 25 mg per day for 21 days for each of the two induction months followed by 10 to 15 mg per day of maintenance lenalidomide until progression. In CALGB 100104, 568 MM patients younger than age 70 years were randomized to placebo or 10 mg per day of maintenance lenalidomide for three months, at which time the dose was escalated to 15 mg per day.
At the end of 24 months of follow-up in the IMF trial, 68% of patients receiving lenalidomide maintenance had not progressed compared with 35% of those on placebo, generating the 54% relative improvement. The overall survival estimated at three years was 88% in patients receiving lenalidomide maintenance compared with 80% for those given placebo, a relative 12% improvement that approached statistical significance (HR, 0.88; P=0.08). Compared with previous rates of PFS after ASCT, these outcomes were characterized as “unprecedented” by the senior author of the IMF 2005-02 trial, Michel Attal, MD, Department of Hematology and Biostatistics, Hôpital Purpan, Toulouse, France. However, he emphasized that the results were preliminary, that the survival figures are not meaningful with this amount of follow-up and a much more complete analysis will be presented at the American Society of Hematology meeting at the end of this year.
In the CALGB 100104 study (abstract 8017), the median TTP was 25.5 months in patients receiving placebo but had not yet been reached in those randomized to receive lenalidomide. This outcome, recorded after a median of 12 months of follow-up, generated the reported 58% risk reduction. There was no difference in overall survival between the arms, but the lead investigator, Philip L. McCarthy, MD, Roswell Park Cancer Institute, Buffalo, New York, explained that placebo patients were permitted to switch to lenalidomide at progression, diluting the ability to show a survival advantage.
Lenalidomide was well tolerated in both studies. The major difference was the higher rate of hematologic toxicities, which were generally asymptomatic. In IMF 2005-02, grade 3 or 4 neutropenia was recorded in 7% of lenalidomide patients and 1% of patients randomized to placebo (P<0.001). There were no significant differences in any other grade 3 or 4 hematologic outcomes. In CALGB 100104, grade 3 or higher neutropenia was observed in 42% of lenalidomide patients and 7% of those on placebo (P<0.0001), whereas anemia (6% vs. 1%; P=0.0028) and thrombocytopenia (12% vs. 3%; P=0.01) also were significantly higher on lenalidomide. Grade 3 or 4 nonhematologic side effects, including neuropathy, were uncommon and relatively few patients dropped out of either study for adverse events.
In his review of this data, Dr. Giralt expressed concern about the potential risks for significant hematologic toxicities among patients, indicating that some routine form of monitoring may be appropriate. Although he advocated lenalidomide maintenance, he said there is a new set of questions to answer, including how long patients should be maintained on treatment and whether a single ASCT before lenalidomide maintenance is the best approach. These questions may be answered by a 750-patient trial called CTN 0702. In this study, described by Dr. Giralt, patients completing melphalan induction and ASCT will be randomized to a second round of the same therapy, lenalidomide maintenance alone, or four cycles of the combination of bortezomib, dexamethasone, and lenalidomide. All will be followed by three years of lenalidomide maintenance.
Although he commented that “today, we leave knowing that lenalidomide does prolong PFS,” Dr. Giralt called for a better dissection of what it means to achieve or preserve a complete response (CR) with induction or maintenance therapies. In particular, he expects future work to look at specific definitions of CR as established by polymerase chain reaction or flow cytometry, to determine the relationship of the quality of the CR to prolongation of remission.
I’m anxious to see how 750-patient, CTN 0702 trial turns out. Study results may help us better understand how best to time a patient’s SCT.
Feel good and keep smiling! Pat