Biochemical Progression of Stage II High-Risk Multiple Myeloma - Episode 4
Ajai Chari, MD:Maintenance therapy after transplant is, again, guided by evidence, and we had 2New England Journal of Medicinepapers (1 from the United States, 1 from France), where everybody who had transplant was then randomized post-transplant to either lenalidomide or placebo. Those studies were both quite consistentthe PFS (progression-free survival) without maintenance therapy was approximately 2 years, and with the addition of maintenance therapy with lenalidomide, that increased to about 4 years. And so, that’s pretty clear data and it’s consistent between both studies.
The OS (overall survival), of course, is interesting and important. The OS in the American study showed an improvement, but the French version did not. Interestingly, you probably would have expected the opposite, because it was the American study that allowed crossover. If patients were randomized to placebo, they could cross over to lenalidomide maintenance at the time of progression (which would clearly decrease your ability to detect an OS difference). But, the fact that the American study didn’t show that really does suggest that the PFS benefit does eventually translate into an OS benefit, which is what we usually think about in oncology. The whole reason we use these surrogate endpoints is because response rate typically correlates with PFS, and PFS typically correlates with OS. That’s why the FDA has allowed PFS to be used as a surrogate endpointnot just in myeloma, but in other tumors. That would support that premise.
Now, the push back some people have for maintenance therapy is, are you bringing out resistant clones? By using lenalidomide maintenance, might you be selecting myeloma clones that are difficult to treat? My response to that would be, if that were truly the case, then how are we seeing an OS benefit with lenalidomide maintenance in the United States study? And, secondly, we need to also be mindful that when you’re looking at OS, this is not the primary endpoint of the study. The study only defines that initial therapy. The minute the patient progresses, you lose all the randomization and controlling for confounding variables, and that’s where access to the drug is differentiated from across the Atlantic.
In the United States, when patients were progressing on lenalidomide maintenance, a lot of them could be salvaged appropriately with bortezomib maintenance, etc. In France, some of those patients who progressed on lenalidomide maintenance went on to get more IMiD (immunomodulatory drug) maintenance which, in 2015, was either more lenalidomide or more thalidomide. I’m sorry, from 2005 to 2012when these were done. I think it’s important to remember that OS depends not only on the initial randomization, but on subsequent salvages. And so, you may lose that benefit of the initial randomization.
And then, the last important point to make about lenalidomide maintenance is toxicity. Generally, it’s well tolerated. There are studies that show that patient reported outcomes and quality of life measures don’t seem to drop significantly. However, we do know that there is a slight increase in secondary malignancies. Both studies showed thatthe French study and the United States study. The rates can be anywhere from 1% to 3% in the control arm, and up to 6% to 8% in the interventional arm.
And so, what do we do with that data? Again, the PFS and OS data from lenalidomide maintenance speaks for itself. However, we also do recognize that patients need to be keeping up with age appropriate cancer screening procedures like mammograms and colonoscopies, because the malignancies that the patients got were all over the board. They could be hematologic- or solid tumor-related. But, in the end, many of us feel that the lenalidomide maintenance benefit does seem to override the minor risks of lenalidomide maintenance. However, at the end of the day, it’s always a patient-specific decision.
Lenalidomide maintenance probably has the most data, and there is now a recent meta-analysis showing that, across several studies, the OS benefit was maintained. And now, lenalidomide maintenance is on-label, per the FDA, because of this OS benefit. Are there other alternatives to lenalidomide maintenance? There are some smaller studies with bortezomib maintenance. Some of them have a complicated study design because rather than just a maintenance randomization, they also deferred in the induction part of the therapy. But, certainly, bortezomib maintenance is another option.
One of the limitations is, because it’s a parenteral drug, it can be challenging to administer on a long-term basis. There are numerous studies coming out looking at ixazomib, which is the oral proteasome inhibitor (PI), in maintenance settings (given the convenience of the drug). Also, daratumumab, the monoclonal antibody, will be studied in the maintenance setting. Even now, we feel that lenalidomide maintenance, while important, may not be enough for high-risk patients, because those patients still seem to do worse compared to their standard risk counterparts.
The Emory group presented a retrospective study that showed that combined maintenance with lenalidomide, bortezomib, and dexamethasone can actually result in much better PFS outcomes. Admittedly, we don’t have a randomized prospective study to support that. But, if somebody is really high-risk, consideration should be given to doing more than lenalidomide maintenance in combination therapy.
So, going back to our 61-year-old female, she had the triplet therapy, stem cell transplant consolidation treatment. She did have translocation t(14;16), which is considered to be a high-risk feature. Therefore, lenalidomide maintenance would be appropriate. One might also consider PI-based maintenance to also be appropriate, if somebody had translocation t(4;14), given the data that PIs may be better or may be able to overcome that high-risk finding. But, for this patient, lenalidomide maintenance would be a very reasonable approach.
Transcript edited for clarity.
Biochemical Progression of Stage II Myeloma