Case 2: Molecular Risk Stratification in Myeloma

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARDNina Shah, MD:So this brings us to a really good tumor board discussion. I talked about what my feelings are on maintenance therapy. I tend to offer it to most patients. I think this idea of how long and when is a really good clinical question and clinical trial question. Pei, maybe we can start with you. I want to talk about the patient’s cytogenetic risk status. How you would assess that? Do they meet criteria? And, if you think that affects this case, can you talk about the role of MRD [minimal residual disease] testing and what kind—FISH [fluorescence in situ hybridization], NGS [next-generation sequencing], or flow cytometry?

Pei Lin, MD:Sure. This particular patient has a translocation involving 4;14, which involvesFGFR3and immunoglobulin. This is known to be an adverse prognostic factor. It used to be considered high risk, but there’s literature saying that this could be intermediate risk. Regardless, it’s considered to be an adverse prognostic factor. As far as MRD testing goes, flow cytometry is definitely very important. Both flow cytometry and next-generation sequencing tests are very useful. Many studies have demonstrated utility of MRD testing in prognostication and risk stratification.

In our institution, we do flow cytometry. We also send out the NGS studies for the MRDs. For our flow cytometry, we use the test that has been validated against the EuroFlow standard. The flow cytometry test has the advantage of being fast. The turnaround time is about 24 to 48 hours. However, it does require fresh tissue. That’s a disadvantage. NGS is 1 log more sensitive and does not require the fresh tissue. So, both have pros and cons. For this patient, MRD testing is clearly indicated.

Nina Shah, MD:Great. I think it’s really important. This issue of MRD is like the star issue sometimes, because it’s becoming such a great useful tool for prognostication. Ola, I know that you’re very interested in making this something that the FDA looks at, as well. I wanted to get your opinion, Ola and Ajai, about the prognosis for this patient. It’s a lot to unpack, in this case, because they had transplant and did well. But they technically also have this adverse risk factor, with the translocation. So, what do you think about in the prognosis of this patient?

C. Ola Landgren, MD, PhD:Well, when we talk about prognosis, we have to keep in mind that these models were developed in the light of given therapies. Many of the studies that are kind of underlying on these current models we have are therapies that we don’t necessarily use today. I think that the number of patients who truly have an adverse prognosis is a shrinking species, if you give the best therapies that we have. Five years back or so, maybe a quarter of the patients who I saw had an adverse outcome. Maybe 15% or so of patients who I treat today have an adverse outcome, and I think that’s a reflection of the better drugs that we have.

The reason I bring it up is because I think telling a patient “You have this adverse outcome” is something the patient will have to live with for the rest of their life. If you tell someone “You have a bad outcome,” if they live for a very long time, that is still something that is going to overshadow the patient. These are my personal reflections on that topic. On the other hand, you don’t want to not tell patients about what’s known. Usually, the way that I address that is to say, “Based on the literature, your workup indicates that you have this feature. This is what it is. The good thing is that you have had a good response, and there are also emerging data showing that if you reach MRD negativity, that seems to be the strongest prognostic factor. If you can maintain your MRD negativity, even if you have this t(4;14) translocation, there are pretty strong data from multiple studies showing that this seems to kind of wash out the adverse impact of a t(4;14) translocation.” Again, these are kind of personal reflections. That’s how I usually deal with that in my clinic.

Ajai Chari, MD:I echo your comments. Risk really needs to be thought of in the context of therapy, both for the ISS [International Staging System] as well as FISH and molecular data. My pet peeve is when there’s a phase II study that says that a particular molecular risk is being overcome. You can’t do that. First of all, when we’re talking about risk, we should not be talking about response rates. We should be talking about survival-based endpoints, because high-risk patients can’t respond well. It’s the durability of response that’s limited and whether that translates into overall survival. So, with that said, if we agree that we don’t look at response rate and we look at progression-free survival and overall survival, we really should be looking at these Kaplan-Meier curves. We really should have conventional therapy and novel therapy. Really, every risk-based study discussion should have 4 curves: standard risk, standard therapy; standard risk, novel therapy; high risk, standard therapy; high risk, novel therapy.

Nina Shah, MD:And maybe, in addition, who got MRD negativity and who didn’t.

Pei Lin, MD:Right.

Ajai Chari, MD:Even before we get to MRD, because that’s even more complicated, you need to see all 4 of these curves. If you’re really saying that something is high risk, you want to know if novel therapy is improving or overcoming that risk. What’s interesting about the t(4;14) translocation, as Pei alluded to, is that unlike in some other high-risk cases, proteasome inhibitors seem to bring the t(4;14) translocation curve right up next to the standard-risk patients, which suggests that we are not only improving but may be overcoming t(4;14), which is why it’s been moved out, in some classifications, from high to intermediate risk. However, to your point, I think MRD is really important. What we also don’t talk about but have to think about is the patient’s osseous disease. What if you’re MRD negative? If you have osseous disease…

Nina Shah, MD:PET negative, right.

Ajai Chari, MD:Right. So, we need to integrate the rest of the patient’s data along with MRD. Also, I believe that 15 out of the 16 studies that have been done with high-risk patients and MRD show that high-risk patients who are MRD negative still perform worse than patients who are standard risk and MRD negative. So, MRD means different things in high risk and standard risk. To that point, if you’re going to talk about MRD negativity with high-risk status, it shouldn’t just be at a single time point but at a second time point, as well. It’s sustained MRD negativity. So, I think there’s a lot of subtlety that needs to be talked about more clearly when we talk about risk and MRD, particularly in this kind of patient who has a lot of treatment options.

Transcript edited for clarity.