Paul G. Richardson, MD: Saad, there was a nice abstract from Dickran Kazandjian, MD. The work is by Ola Landgren, MD, PhD, and Dickran from the NIH [National Institutes of Health] group looking at an aggressive approach for KRd [carfilzomib, lenalidomide, dexamethasone]. Nonetheless, the data were quite compelling. What did you think?

Saad Z. Usmani, MD: The key elements that I took away from that experience, it was a good data set. I believe there were 52 patients treated with this approach. Initially, I think Ola had started this trial when he was still at the NIH and carried it over to Memorial Sloan Kettering Cancer Center. They have over 7 years of follow-up now. They treated patients with 8 cycles of KRd [carfilzomib, lenalidomide, dexamethasone], specifically the 20/36 mg dose of the K [carfilzomib] given twice weekly, and then continued patients on LEN [lenalidomide] maintenance. He showed that at that 7-plus year follow-up, only around 20% of the patients had progressed to active disease. I believe it was 6 or 7 patients who progressed within the first 5 years, demonstrating that you can get good, deep responses in these patients. There was a high percentage of MRD [minimal residual disease]-negative CRs [complete responses] on this study.

Regarding the age range, there were younger patients on that study as well as older patients in their early 80s. I think this approach obviously needs to be validated compared to the standard of care where we are right now, but it’s compelling. If you can identify those high-risk patients early, it would be a reasonable approach to offer to patients in a clinical trial setting.

Paul G. Richardson, MD: I completely agree. In fact, I follow a patient who participated in that study and she’s doing extremely well. We harvested or collected the cells, she’s on lenalidomide maintenance alone and she’s in CR. To your point, Saad, the MRD-negative rate was 70%, and what Dickran did was a cross-trial comparison with GEM-CESAR, that’s Maria-Victoria Mateos, MD, PhD’s abstract from a year ago. In that study, her MRD rate was around 56%, and in Ola and Dickran’s work, it’s 70% with all the caveats of cross-trial comparison. I think it’s a fascinating new area.

I really like the point that was made by David and suggested by Nina, that observation is key and manipulating the microenvironment makes sense. For example, I’m very comfortable offering periodic infusion of bisphosphonate if there’s bone mineral density loss or a clue that might help with the microenvironment. From a protocol point of view, which is where we tend to go, we do not tend to treat patients with smoldering multiple myeloma [SMM] outside of the protocol at this stage. We’re looking at immune strategies, be they antibody, vaccine-based, something that addresses the milieu question that David just mentioned. Saad, is that your approach at your center, Levine Cancer Institute?

Saad Z. Usmani, MD: I think we must be good clinicians first, and these criteria are only serving as a guideline and they’re giving us a snapshot answer. They do not tell us what to do with our patients who were diagnosed 5 years ago, who had at that time met the 2/20/20 [International Myeloma Working Group risk stratification]criteria, but instead of treating them, we continued to observe them, and they have yet to progress to active disease. So, these criteria don’t apply to that. I think the clinical gestalt stays. However, if you see the kinetics of those numbers moving as we follow patients, then you can make a very good case about treating them early. You have data now that support it. Observation is always OK, but I think enrolling them on a clinical trial or at least discussing treating them with lenalidomide is not an unreasonable thing.

Paul G. Richardson, MD: Regarding lenalidomide use, that I think is the only caution I have because obviously there’s a price tag to that. As you know, in the pivotal trial that was led by Sagar Lonial, MD, FACP, there was a high rate of discontinuation, there was this second primary signal and so forth. Does that influence your thinking in that regard?

Saad Z. Usmani, MD: It certainly does, especially as many patients with MM are Medicare-age patients, so they have that 20% co-pay that they have to give every month with lenalidomide, and that would also influence that decision-making. But you’re right, that is going to be an important part of the discussion. I know David is itching to get into this debate about early treatment, and I would welcome his thoughts and ideas here, too.

David Siegel, MD, PhD: I find it very surprising that you couch this in terms of, “This is reasonable.” Yes, we can prevent a certain percentage, but in the large randomized lenalidomide trial, we treated 80 patients with no advantage, to prevent progression of disease in 10% of patients. The reality is, we would never take a real patient with MM today and just treat them with lenalidomide. You’re using a suboptimal, extremely expensive therapy to prevent an end point that may not need to be prevented in most of those patients. Moreover, even if that end point was to evolve, we’re treating them suboptimally.

If you go back to the Memorial Sloan Kettering/NCI [National Cancer Institute] data, it’s even more complicated. Once again, they treated a lot of patients who probably didn’t need to be treated. Whether long-term KRd [carfilzomib, lenalidomide, dexamethasone] is an optimal therapy or not, you’re committing a population of patients to long-term therapy, some of whom will never need to be treated, and you’re committing them to a strategy that is today’s strategy.

We are evolving as a community incredibly quickly. We just talked about Irene Ghobrial, MD’s data. Nina is publishing constantly about very sophisticated molecular tools that are going to lead us to CAR [chimeric antigen receptor] T cells and other kinds of therapeutics that may be curative. And if there’s an advantage to treating those patients early, once we start to gain those kinds of tools, and to say, “OK, let’s treat patients who are likely to have MM early with those kinds of things,” then I find this is reasonable. But the idea that I have to treat a patient today because they might progress over the next 2 to 5 years to MM; they might also not. I think it is, I don’t want to use the word irresponsible, but I will nonetheless. Why treat patients with suboptimal therapies that are toxic and very expensive when Nina may cure them a couple years from now with treatments that we haven’t thought about today?

Paul G. Richardson, MD: I love the optimism, David.

Saad Z. Usmani, MD: I just want to make sure we’re talking about the same thing, because I thought we were talking about high-risk SMM, not active myeloma requiring treatment. No one is saying to treat patients with active MM with lenalidomide. The discussion that we’ve had is about analyzing the data, we are preventing these patients from progressing to active MM and having that discussion with your patients or put patients on clinical trials. I made that statement very clear. I’m not a Sagar surrogate, so maybe you can have this debate with him later?

But the data are the data, and we must enroll on clinical trials to see it. I didn’t say treat them…the Spanish myeloma way either. But all those questions are important questions to ask in clinical trials.

David Siegel, MD, PhD: But I think we must remember who the audience is now. I think it’s a very dangerous message to leave with the general population of oncologists, that it is a reasonable approach to take their patients with SMM and treat them. It has another pitfall that is a very important one, that when they relapse, they have never met the diagnostic criteria for MM, they’re not going to be eligible for certain kinds of clinical trials, and they may not be eligible for payment for other strategies later on because they never met the diagnostic criteria. They won’t get CAR T cells; they won’t get a lot of things.

Paul G. Richardson, MD: I think to bring this together as we move on to the next phase, it’s a perfect segue to how do we diagnose newly diagnosed disease. I think the construct of participation in clinical trials, careful observation, the use of nontoxic approaches, targeting microenvironment, and the reality to your point, Saad, the data are the data from the ECOG study. But the huge caveats that are raised are so well put by David, I think our audience can appreciate that this is an area in evolution, and as we said at the very beginning, ask 4 myeloma specialists about smoldering disease and you’ll get 5 opinions is being beautifully captured. My comment would simply be for our audience, think clinical trials and recognize high-risk SMM, I would predict in a few years, is going to be defined as active MM, and we can think of it in those terms. But there may be viable strategies that we can use much earlier in the precursor setting that may not burn any bridges later, and at the same time, generate meaningful clinical benefit, but this is an area of very active research.

I do think it is worth saying one thing about eligibility for trials, because it’s a great point David made. We’re very careful that any of our patients who participate in a SMM trial are clearly defined as that, so it doesn’t in any way prejudice them for participation later. I think that’s a very important point, and thank you, David, for raising it. Saad, thank you for taking on a challenging area so nicely.

Transcript Edited for Clarity