David S. Siegel, MD, PhD
If a patient with multiple myeloma progresses on a lenalidomide (Revlimid)-based regimen, it does not mean oncologists should completely forgo the class of immunomodulatory (IMiD) agents, according to David S. Siegel, MD, PhD.
When patients become refractory to certain drugs, physicians may believe they need to move on to a different class of agents, he added. However, a study presented at the 2018 ASH Annual Meeting challenged this hypothesis.
In the trial, patients who progressed on lenalidomide were treated with a pomalidomide (Pomalyst)-based regimen. Results showed that the overall response rate (ORR) was 77.7%, with 33.9% of patients demonstrating a very good partial response or better. The clinical benefit rate was 85.7%. The ORR was 80.6% in the efficacy-evaluable population, 75.0% in lenalidomide-refractory patients, and 76.2% in patients with 2 prior lines of therapy. The 9-month progression-free survival (PFS) rate was 86.3%.
Patients received pomalidomide at 4 mg daily on days 1 through 21, low-dose dexamethasone 40 mg daily (20 mg/day if aged >75 years) on days 1, 8, 15, and 22, and daratumumab (Darzalex) at 16 mg/kg intravenously on dexamethasone-dosing days of cycles 1 and 2, days 1 and 15 of cycles 3 through 6, then day 1 of cycle 7 and beyond.
In an interview with OncLive
during the 2018 ASH Annual Meeting, Siegel, chief of the Division of Myeloma at John Theurer Cancer Center and Hackensack University Medical Center, further discussed the potentially practice-changing trial.
OncLive: Please provide some background to this study.
: This is a very interesting trial. One of the big dilemmas we have in multiple myeloma is this notion that it is imperative that we change classes of drugs when we see progression of disease. This is sort of the impression that community oncologists and so-called myeloma experts seem to have. One of the questions that has risen is, “Is this is really true? And if it is true, for which drugs is it true?”
This clinical trial grows out of a previous experience with the combination of pomalidomide and dexamethasone in patients who are progressing on lenalidomide-containing regimens; this was the first cohort of the study. What those data suggested is that there really is no letdown in terms of efficacy to pomalidomide when it immediately follows lenalidomide-based regimens.
This is a practical issue—having a large number of drugs that are active in myeloma—but the reality is that there are 3 main classes we are dealing with: proteasome inhibitors, IMiDs, and monoclonal antibodies. If we accept this dogma that we have to switch classes, we are very much limited in what we can do. The first cohort [of this trial] suggested there was no drop-off in staying within class.
This particular trial is relatively early; these are patients after first and second relapse. We’re seeing that there is a higher response to the combination of pomalidomide, daratumumab, and dexamethasone in this trial than we have seen in other trials; this is somewhat unexpected because the patients are progressing on lenalidomide. Ultimately, the moral of the story is that becoming refractory to a certain drug in a class doesn't mean you have switch to a different class. A patient progressing on lenalidomide should not impact your expectations for pomalidomide or pomalidomide-based regimens.
Biologically, this is a very important question. Why should being refractory to lenalidomide not impact response to another immunomodulatory agent? We presume the mechanism of action is largely the same, so it offers us a very enticing question that needs to be addressed.
Why was there a preconceived notion about switching classes of drugs?
It is just instinctive. If you look at the chemical structure of lenalidomide and pomalidomide, you would not be able to tell the difference. These are very similar molecules; they are engaging the same receptor. Why should it not impact one after the other? Therefore, this is a very interesting question we have to figure out. Perhaps there are ulterior mechanisms that we aren't aware of, or perhaps it is just has to do with dosing.
What are the next steps for this research?
We will have continued follow-up on these patients. We will have more mature data as we move forward. The median PFS wasn't met in this trial, so we hope to report that within the year. As we move around the drugs we have and start to use them in different situations, this is going to very important. We will start to use many daratumumab-based regimens in the frontline setting and so on.
What is the key takeaway from this study?
The most important take-home message for the community is that the idea that we have to say, "This patient was just on lenalidomide, so we have to go to a non-IMiD agent-based regimen," is not necessarily true. We have said this about other classes as well. For example, exposure and response to bortezomib (Velcade) probably has nothing to do with carfilzomib (Kyprolis). We have to teach oncologists who are treating [patients with] myeloma that there are other factors to take into consideration.
Siegel DS, Schiller GJ, Samaras CJ, et al. Pomalidomide plus low-dose dexamethasone plus daratumumab in relapsed/refractory myeloma after failure on lenalidomide-based treatment. In: Proceedings from the 2018 ASH Annual Meeting; December 1-4, 2018; San Diego, CA. Abstract 3271. ash.confex.com/ash/2018/webprogram/Paper111920.html.