Philip McCarthy, MD, explains the significance of the updated CALGB 100104 study results.
Philip McCarthy, MD
A recent update on the CALGB 100104 trial, which examined lenalidomide (Revlimid) versus placebo in patients with multiple myeloma, found that at 65 months median follow-up, lenalidomide maintenance resulted in improved time to progressive disease (TTP) of 53 months versus 27 months with placebo (HR = 0.54; P <.001).
At the time of the analysis, median overall survival (OS) had not been reached for the lenalidomide arm and was 76 months for placebo (HR = 0.60; P = .001). The TTP and OS benefit with lenalidomide was observed regardless of whether patients were in a complete response or not at randomization.
OncLive spoke with one of the study authors, Philip McCarthy, MD, professor of Oncology and director of the Blood and Marrow Transplant Center at Roswell Park Cancer Institute, who explained the significance of these results.
OncLive: How do the results of this study impact the treatment paradigm for myeloma?
Dr McCarthy: We are now considering lenalidomide maintenance as the standard of care. One thing we have noticed is that patients who are in complete remission and those who were not in complete remission at day 100 after transplant both benefited from lenalidomide maintenance. This was an unplanned subset analysis, so we have to take this with a big grain of salt. However, we were impressed that both complete response and non-complete response patients benefited. We need to see if this will translate into long-term control of the disease.
Now, we need to have different endpoints because the studies are so long term. That is great for the patients, but we would like to have an early endpoint. Early endpoint options include complete response rate at 1 year, 3 years, and the use of molecular testing for minimal residual disease for a surrogate for long-term disease control.
Were any concerning toxicities observed?
The major toxicities that we saw were hematologic-related, including neutropenia. We controlled it by stopping the drug and restarting it at a lower dose. There were some patients who had to come off of it, despite being at the lowest dose. The other important toxicity observed was secondary primary malignancies. We saw an increase in that with mostly hematologic malignancies. We need to understand this better so we can predict risk versus benefit of lenalidomide maintenance. However, the incidence of these toxicities was low.
What effect did the crossover have on the study findings?
This study was designed initially as a progression-free survival (PFS) study. Patients were randomized either to placebo or lenalidomide. The Data and Safety Monitoring Board told us in December 2009 that there was a major difference in the two arms, and that the lenalidomide was favored for PFS. The results were then unblinded. It was decided that patients who were on placebo and had not progressed would be allowed to cross over into the lenalidomide arm if they desired and their treating physician allowed it.
Approximately 86 out of 128 patients crossed over from placebo to lenalidomide. That made the analysis a little more complicated. Based on the intent-to-treat population, you would want to examine the lenalidomide arm versus the placebo arm, but many in the placebo arm had crossed over.
Despite this, we still saw a PFS and OS benefit on an intent-to-treat basis. We tried to analyze differently by looking at patients who had crossed over at 6 months and at 12 months, and we still saw the benefit. We are now trying to analyze this in a little more detail to figure out if patients can still still maintain the benefit if they start late. If a patient is on placebo and they progress, they cannot cross over. This also makes the analysis difficult.
What questions remain unanswered?
When we opened the study, we did not mandate cytogenetic analysis and, at the same time, CD138 selection of plasma cells from the marrow for fluorescence in situ hybridization (FISH) was not routinely done. Now it is.
We really need to know which cytogenetic abnormalities benefit the most from this. There have been hints from IFM 0502, which is a French study asking a similar question but designed a little bit differently with a different patient population. However, those results have not yet been published. We really need to see if the benefit applies to all cytogenetic abnormalities and if it will be higher in some patients than others.
Another major unanswered question is the addition of other drugs. Some patients on lenalidomide still progressed. Monoclonal antibodies offer a possibility and could potentially be added to lenalidomide. We know that lenalidomide actually potentiates the action of antibodies. Therefore, it depends on whether or not you will get synergy in terms of long-term control of this disease.