Ian W. Flinn, MD, PhD: Let’s turn now and talk a little bit about the R² regimen. Lenalidomide and rituximab has been tried in a variety of settings; relapsed, frontline now. Nathan, you’ve chaired and have been part of a lot of these studies. How do you see your R² being used in the coming years?

Nathan H. Fowler, MD: R², which is lenalidomide and rituximab, there were several studies that were done a long time ago in different malignancies; for example, in CLL and in preclinical models that suggested that lenalidomide and rituximab were synergistic. This mainly was due to increased ADCC (antibody-dependent cellular cytotoxicity) when you combined a drug like lenalidomide with a monoclonal antibody such as rituximab. The good thing about follicular lymphoma is that we know this disease is very sensitive to drugs that use ADCC as a main mechanism, things like rituximab. So, we’ve seen data now, as you mentioned, from several different trials, both in the relapsed setting and the frontline setting. These are mainly phase II trials which showed response rates upwards of 80% in both lines, frontline and in relapsed. At this ASCO, I’m presenting the data from a study called RELEVANCE, which stands for Revlimid versus any chemotherapy.

This study was again based upon some phase II trials that we did at MD Anderson several years ago. But the study enrolled around 1000 patients and randomized them to receive lenalidomide plus rituximab. These were untreated follicular lymphoma patients with GELF criteria who were randomized to receive lenalidomide/rituximab versus rituximab plus chemotherapy. Although the study was built as a superiority trial, it did not meet its primary endpoint, in that we didn’t see a difference, honestly, in long-term progression. When I say long-term, I mean 3-year progression-free survival with 2 arms. They were essentially identical with lenalidomide/rituximab or rituximab plus chemotherapy. I think that data like that would suggest that that’s a real viable option for patients, especially patients who are going to be looking for a regimen that doesn’t include traditional chemotherapy. Because, again, the disease control appeared to be very similar. We do have a study out soon, which I think John is very involved in, called the AUGMENT trial, which is going to look at lenalidomide/rituximab versus rituximab in the relapsed setting, and that data has yet to be announced.

Ian W. Flinn, MD, PhD: So, you see a lot of uptake in the frontline with R²? Do you think people are still going to be using it in second- or third-line treatment?

Nathan H. Fowler, MD: I’m obviously a little biased. I think it’s a great option for people in the frontline. Again, with a lot of these new therapies—and we talked about this with idelalisib and copanlisib—there is a learning curve. Once physicians understand the common toxicities of lenalidomide, it’s very manageable. Many of our patients, including patients who have very high tumor burden, go into complete remission or very good partial remission, with a long duration of response with the regimen. I have patients that, for example, are college students who have continued throughout the semester, or played sports, or done things well on therapy and achieved the same remission as if they had been on R-CHOP or rituximab/bendamustine. So, again, I’m a bit of a believer, and I know I’m clearly biased because of the work that we’ve done in Houston.

Ian W. Flinn, MD, PhD: Before I get other people’s opinion, let me ask you though. With myeloma, there’s an issue with second malignancies. Any signal in that in these studies?

Nathan H. Fowler, MD: We saw no difference. So, if we look at the second primary malignancies, there was no difference with lenalidomide/rituximab compared to rituximab chemotherapy in the randomized trial.

Ian W. Flinn, MD, PhD: Matt, in Nebraska, are you as bullish on R² in the frontline setting?

Matthew Lunning, DO: I think it’s going to just make the discussion longer, because you have another option to discuss. Because it’s getting back to where we are in CLL when we’re discussing things. You now have something that would be considered a longer treatment, months, to a finite duration therapy. People are going to self-select out which one they want and you’re going to tell them the advantages and the disadvantages. I worry about the cost of lenalidomide/rituximab long term because I do see patients in myeloma until toxicity, progression, or they don’t want to take it anymore or can’t afford to take it anymore. That needs to be kept in mind, also, because one of the things you don’t want to do is be half-treating people even in the frontline. I know you probably are going to say, “Okay, if they get a relapse, it’s probably not going to matter into the second and the third.” But, again, we don’t have long-term data in how this could change the disease from that standpoint.

Ian W. Flinn, MD, PhD: How do others feel, John?

John P. Leonard, MD: Yes, I think it’s certainly a longer discussion. The data certainly are suggesting that R² could be useful for patients, even if they have adverse prognostic features or bulky disease, which honestly is a little bit surprising to me. So, in those patients that you might be giving the rituximab to, or R-CHOP to, for a nontransformed setting, this might be an option to consider. In follicular lymphoma, the good news is, it’s another option for people. While we’d like to see better efficacy, having the same efficacy with a different toxicity profile allows a patient to choose that issue. The hard part is these are quality-of-life things, and patients and doctors have impressions about what’s going to give somebody a better quality of life. That’s one of the messages probably throughout all of our discussion today, and that is that since most people with follicular lymphoma are not going to die of their disease, it’s all about quality of life. We help patients make these choices. But the tools that they have to make those choices are limited. This is one example, well, for some people that they would have a very good quality of life and others they wouldn’t, because it would be an ongoing therapy with some nagging toxicities. That’s something that people just are going to navigate in these ever-elongating discussions.

Ian W. Flinn, MD, PhD: Sonali, are you thinking the same way here?

Sonali M. Smith, MD: Well, as part of the Alliance trials, and John is the person who wrote all these studies, we also had some frontline studies with lenalidomide and rituximab. When you see some of these responses and then you see the data that Nathan showed, I think it’s absolutely an appropriate option. The nice thing about the way the Alliance trials, and the MD Anderson trials, and now this international trial, is that it’s not indefinite lenalidomide. I think that’s a really key point. When we think about the myeloma world, people are on this drug for years and years and years, until, like Matt said, they have progression, or toxicity, or something like that. Here, it’s 18 months at most. In the Alliance trials, it was 12 months. So, that makes me more compelled to think about this as a biologic therapy that induces deep remissions and allows a good quality of life. Yes, there is this concern about second primary malignancies, but I think people who have one cancer already have an increased risk of second cancers. How much more a year of lenalidomide adds, I really don’t know. So, I’m glad to hear that it wasn’t any different in the randomized setting.

Transcript Edited for Clarity