Monoclonal Antibodies in Relapsed Multiple Myeloma with Cristina Gasparetto, MD: Case 2 - Episode 2
Cristina Gasparetto, MD:This patient was treated initially with lenalidomide/dexamethasone, and for some reason, therapy was discontinued after 1 year. I would have probably not discontinued therapy in this patient, but she remained without evidence of myeloma for about 6 months. So, we know that she still can be rechallenged with the lenalidomide. She tolerated the lenalidomide well at the beginning, so why not to institute the same therapy? I think adding the daratumumab based on the results of the POLLUX study is very, very reasonable to improve the overall response of the outcome in this situation.
The POLLUX study was a very similar study to daratumumab/bortezomib/dexamethasone. The POLLUX study was also a phase III randomized study where patients with relapsed or relapsed refractory disease were enrolled and randomized to receive lenalidomide/dexamethasoneso, a different backbone in this situation—plus the daratumumab. Patients had, in this study, failed more than 1 prior line of therapy, but the average, I think, was about 2 lines of therapy. And I think one of the important things to remember is that patients were still sensitive to lenalidomide. Patients with refractory disease to lenalidomide were excluded. So, this patient, now by definition, still has sensitive disease to the lenalidomide.
In the POLLUX study, more than 500 patients were randomized to receive lenalidomide/dexamethasone plus/minus the daratumumab. And the follow-up of the study was a little bit longer than the CASTOR; it was more than 13 months. With a longer follow-up, it was clear that the chance of achieving a more durable response was higher with the addition of daratumumab. The overall response was also higher, including the number of patients achieving a very good partial response or more than a complete remission. And actually in the POLLUX study, MRD was one of the endpoints of the study. If I recall correctly, about 22% of patients in the daratumumab arm were MRD-negative compared to only 4.6% of patients in the lenalidomide/dexamethasone arm. And this is very important because it’s very difficult for a patient with myeloma to achieve a deeper response at time of relapse. Like I mentioned earlier, it’s easier to achieve a complete remission of MRD negativity in the newly diagnosed setting, but more difficult to achieve such a deep response in the relapsed setting. So, the POLLUX study is also very important for that reason, because we have an incredible number of patients in the relapsed setting achieving MRD negativity. Recently, the FDA approved daratumumab in combination with lenalidomide and dexamethasone in first relapse, based on the results of the POLLUX study that we just described.
I think it’s clear that achieving a deeper response in the relapsed setting is also very important to maintain the durability of responses. Daratumumab/lenalidomide/dexamethasone is a great combination. In this setting, it’s very well tolerated. The toxicity profile was very acceptable, not very different from the doublet, lenalidomide/dexamethasone. The addition of daratumumab didn’t cause additional toxicity. So, I think, yes, definitely, the combination is changing and will change how we treat patients in first relapse.
We have a lot of experience on treating patients with lenalidomide/dexamethasone, and the addition of daratumumab really didn’t have too much more toxicity. We have to be a little bit more concerned about pancytopenia, neutropenia, and anemia, but not really excessive with the myelosuppression. There was, in the POLLUX study, an increased incidence of GI toxicity, like diarrhea, and the risk of infection was very similar. The risk of blood clotting was also very similar. If anything, it was a little bit higher without the addition of daratumumab. There was some increased incidence of upper respiratory infection in the daratumumab arm. But, overall, it was not really dissimilar.
With the daratumumab, about 40% to 50% of patients will experience some infusion reaction during the first infusion, but that generally is self-limited. The patients will end up tolerating the daratumumab well with subsequent infusions, and we’re learning. Since the daratumumab was approved in 2015, we have started to use the daratumumab more and more often, and it was clear that that is now a limiting toxicity. So, overall, the safety profile of this regimen is really good.
I would expect to have a very good response with this regimen in this particular patient. The patient has clearly sensitive disease to lenalidomide, so the addition of daratumumab increases the overall response. In fact, in the POLLUX study, the overall response was about 90%, which, in the lab setting, is exceptional. So, I expect a very high response rate, including a very high chance of achieving a complete remission again for this patient.
Case Scenario 2: