Sagar Lonial, MD, FACP: Nina, you raised a really important point, and that’s the GEM-CESAR trial and isatuximab were presented at the American Society of Hematology 2019 annual meeting. Very different approaches in terms of how you go. Response rate to MRD [minimal residual disease] negativity, all of that for GEM-CESAR, was better than what you’d expect from myeloma.

Isatuximab was more in line, probably a little bit better than LEN [lenalidomide] alone. I think the point I would make is the 3-year PFS [progression-free survival] that showed for GEM-CESAR is identical to lenalidomide alone in the ECOG [Eastern Cooperative Oncology Group] trial. Depth of response and overall response rate may not be all that important.

Nina Shah, MD: For smoldering, I agree, by definition it is a different disease.

Paul G. Richardson, MD: I think that raises a critical question, and I’d love Amrita’s thoughts on this. When you think about this, do you feel that you’re potentially burning a treatment option earlier that may be more valuable later? How do you think of this construct?

Amrita Y. Krishnan, MD: It’s sort of the 2 camps; if you’re going to treat smoldering, treat it all the way, or do you take a more measured approach? Even during a transplant, I tend to be into the measured approach for the points that Sagar mentioned, that you can still get a very good PFS with a less intensive therapy and save that therapy, and not all patients may need that therapy at that point.

Paul G. Richardson, MD: I agree, Ajai, any additional thoughts to that point?

Ajai Chari, MD: I think if we’re going to start treating smoldering, we need to agree on who should be treated and then go to the treatment. Who should be treated; we looked at this. Even FLC [free light chain ratio] greater than 100, which a bunch of experts, many of whom are here, decided that this should be myeloma, that was with the understanding that the predictive value was at least 80% at 2 years. In our hands when we looked at it, it was 40%, and the only prospective study that’s been done, which was published by the Danish in European Journal of Hematology, it was only 30%. There’s a danger of using retrospective studies to determine models, especially as you alluded to, at a single point. I always say, aren’t movies more interesting than photographs? Like why do we need to make decision on day 1 when you meet the patient?

Paul G. Richardson, MD: I couldn’t agree more.

Ajai Chari, MD: We need to think about the kinetics of the disease, and then we need to think about PFS too. I think whenever you’re treating somebody who doesn’t need treatment, you need to make sure that that next line of therapy is not being compromised. We know now for example in newly diagnosed myeloma, when patients progress on lenalidomide maintenance or any kind of lenalidomide exposure, that subgroup does worse in the next line of therapy. I think these are all important issues. Discontinuation of therapy, secondary malignancies. These were all things that came up, and I think we need to really be thoughtful. If we can’t agree on who should be treated, it’s hard to start treating everybody in the real world. We don’t discuss stem cell collection when you start these treatments. We’re adding a lot of toxicity—financial, medical—without clearly justifying them.

Paul G. Richardson, MD: I think that’s very well said. Ken, in your practice, how do you embrace what you’ve seen at the meeting and at the same time, what Sagar so nicely framed earlier?

Kenneth H. Shain, MD, PhD: All the points made so far have been fantastic, and they’re all spot on. I think the big thing for me was that these studies have demonstrated that we can do this, and it’s a good outcome in terms of changing hopefully outcomes down the road. But the adoption of it I think is a little bit, on my side, I still say these are places we’re going to watch a little more closely. The 20/2/20 criteria, I don’t embrace treating right away, outside of a clinical trial. As Amrita mentioned, that there are 2 camps, and I’m kind of more of a camp, if I’m going to treat somebody with high-risk smoldering, I want to see if I can get them myeloma therapy and change it long term. We don’t know if that’s the right answer yet. These are all things that we have to worry about.

Right now to me, it’s still treat, watch right now at this point; on trial we’ll do some treatments. Otherwise it’s, can we use this for patients, keep learning, and who are those right people? We don’t know who all those people really are.

Paul G. Richardson, MD: One additional point to that and as part of observation certainly, what I embrace is if patients have early bone loss, I’m very comfortable using bisphosphonates. It also provides a nice rationale for monitoring the patient carefully, and it provides a sense to the patient that you are being proactive and simply not just saying, “see you in 6 months,” which is probably entirely the wrong thing.

Sagar, 1 last comment if I may, and ask you to comment. The phase II single-arm trial of isatuximab, obviously presented at this meeting by Elizabet Manasanch, MD, what do you think?

Sagar Lonial, MD, FACP: I think it’s taking more of the immunologic approach, and I think one of the things that distinguishes smoldering from symptomatic myeloma is not the genetics and the genomics, those are identical. It’s immune regulation of the clone, which is the reason why I think less is actually more. If you come in and hit hard and wipe out immune regulation, you may make things worse, similar to when patients have myeloma. I think the isatuximab data are very intriguing because it focuses on that immunologic overall response. Its response is not as good as GEM-CESAR. Nothing’s response, short of induction therapy for myeloma, is as good as GEM-CESAR. I don’t consider that a negative point, I think it’s an interesting topic.

Ajai Chari, MD: I would add that it’s a very high response rate, but again, one of the things that’s really lacking in this whole discussion is the biology. Who are the patients that are responding, and do we need to go to MRD negativity? Because if you have an MGUS [monoclonal gammopathy of undetermined significance] clone, we know that some of the patients do very well for a long term. I think, what is the right end point for those patients? And I think it would be nice to marry the biology to the treatment, so that we’re really understanding what should be the end point and who should be treated.

Sagar Lonial, MD, FACP: As an example, in the ECOG trial, the longest patient we have on the study was the first patient we put on—5-1/2 years, never responded, and has been stable for 5-1/2 years. She fit in to the 20/2/20 high-risk criteria. There’s a reasonable chance she was going to progress.

Paul G. Richardson, MD: I think it’s very well said too that this construct of stable disease with excellent quality of life and no toxicity, that’s true success.

Kenneth H. Shain, MD, PhD: These are patients who would get nothing and have great quality of life, so we have to make sure that whatever we do from a treatment perspective is not encumbering that aspect of their life.

Amrita Y. Krishnan, MD: I think that’s the interesting thing in the ISA [isatuximab] trial, their quality of

life apparently improved because in part less cancer concern.

Nina Shah, MD: It was a concern. She’s actually doing more correlative analysis that’s pending to understand that, to Ajai’s point.

Paul G. Richardson, MD: The isatuximab study is relative early in its course right now, it’s only about 24 patients or so strong. At the same time, I think that initiative has been impressive. That’s great.

Transcript Edited for Clarity