Monoclonal Antibodies in Relapsed Multiple Myeloma with Ola Landgren, MD, PhD: Case 2 - Episode 2
Ola Landgren, MD, PhD: When the patient relapses, she comes back with fatigue and additional workup is done with imaging showing multiple lesions. So, there’s clearly bone disease. The patient has evidence of both symptoms and probably active measures of relapse disease. She needs to start therapy. Using a 3-drug combination, similar to what we have discussed earlier in the relapse setting, is now considered to be the new standard of care; not to use 2-drug combinations. I think the use of daratumumab with lenalidomide and dexamethasone is a very good option. There are some older studies showing that patients with bone disease would benefit from a proteasome inhibitor, but I do think that with these new combinations with monoclonal antibodies, I’m not so sure that those old ideas will hold up. I think it’s a very reasonable option.
The POLLUX study is a randomized international phase III trial. Again, the highest level of evidence will be used when we assess drugs. It’s based on lenalidomide and dexamethasone in both arms, and the experimental arm has the addition of daratumumab. The results show a median follow-up of 13.5 months. There is a striking difference in terms of progression-free survival. At 12 months, the experimental arm has 83% progression-free survival, and the lenalidomide/dexamethasone control arm has 60% progression-free survival at 1 year. And that translates into a hazard ratio in the range of 0.3. Additional analysis beyond the primary endpoint, which is progression-free survival, show that there are striking differences with regard to minimal residual disease (MRD) negativity. In this study, they have applied MRD testing that can rule out 1 cell in 100,000. They show that in the experimental arm, over 20% of patients are MRD-negative, and in the control arm it’s about 5%. These are patients that are relapsed get treated with 3 drugs. These are very impressive results. Just going back a few years, the newly diagnosed setting studies show that newly diagnosed patients maybe could reach about 30% of MRD negativity. Here, we have patients with 1 to 3 prior lines of therapy having MRD negativity at the rate of over 20%. That’s very impressive.
In my opinion, the POLLUX study changes the treatment landscape in myeloma significantly. It gives us access to a monoclonal antibody for early relapse in combination with well-tolerated oral regimen lenalidomide/dexamethasone. I think a lot of patients that have their first relapse after extended therapy will go on it. I would like to emphasize that the results, in the POLLUX study, are based on patients that have been sensitive to lenalidomide and they’re not allowed to be refractory to lenalidomide. Many patients in the United States are treated on lenalidomide maintenance. So, to switch to a higher dose of lenalidomide with daratumumab and dexamethasone in that setting may not yield the same results as you see in patients who never were treated on lenalidomide. Many patients on the POLLUX study were treated outside of the United States, where lenalidomide is not used and approved for the indication of maintenance therapy.
I do think that lenalidomide does, for sure, not only impact the tumor cells, it also activates the immune cells. When daratumumab goes into the body, finds the myeloma cells, and binds to them, one of the mechanisms of action is to attract activated immune cells. So, we really don’t know what the difference is in a patient who is progressing on lenalidomide maintenance versus a patient who was never really treated on lenalidomide in the past. I guess we could speculate that it works less well in a patient who was on lenalidomide maintenance. But as I tried to point out, the mechanism of action is complicated. There is more than one mechanism of action. It may be good enough to have this activation of the immune cells. The data will show us, going forward, what the answer to this question is.
When it comes to toxicities of the combination in the POLLUX study, daratumumab/lenalidomide/dexamethasone, I have quite a lot of experience. I’ve used this combination a lot, and also the literature, of course, guides us and provides a lot of information from the publication in The New England Journal of Medicine. Lenalidomide and dexamethasone have the typical toxicity profile. Lenalidomide tends to press CBC, the red cells and the white cells, on the platelets. Patients have a high risk of developing blood clots, hypercoagulation, and fatigue. There can be skin rashes, there can be joint stiffness over time; diarrhea is one of the problems. Steroids, as I pointed out before, are not free from toxicities; they have a lot of toxicities. When we treat patients with combinations, many times steroids are actually the worst actors in many patients. They disrupt the sleep, the mood, and how patients are feeling overall.
Daratumumab has mostly infusion reactions as the side effect, and they are attributed to the first infusion. I think around one-third to half the patients that I treat with daratumumab have some type of infusion reactions the first dose. Usually, patients do not have the infusion reaction until later, and patients who did not have the infusion reactions the first time, they rarely have infusion reactions later.
My experience when it comes to the depth of response with the combination of daratumumab, lenalidomide, and dexamethasone that was published in this POLLUX study, is very consistent with the publication. You have deep responses in many patients. The paper says that in this randomized study, over 20% of patients obtained MRD negativity, 10 to -5 with the combination. In my experience, you have a higher complete response rate. And if you look at MRD data, that’s consistent with the publication.
Case Scenario 2: