Dr Chari reviews the MRD assessment and how he uses it in his practice.
Ajai Chari, MD: Regarding the role of MRD [minimal residual disease] in myeloma, I was privileged to participate in a panel at the 2019 ASH [American Society of Hematology annual meeting] with all the hematologic malignancies. And what’s interesting is that when we look at AML [acute myeloid leukemia], CLL [chronic lymphocytic leukemia], ALL [acute lymphoblastic leukemia], and myeloma, the story is the same in all 4 of these diseases with 1 exception, which is ALL. MRD is a great surrogate end point. In study after study, randomized clinical trials are showing that better MRD negativity translates into the survival end points of PFS [progression free survival] and perhaps OS [overall survival]. The problem though is we have to decide, is this a prognostic or predictive test?
Some of the things that are involved in that discussion are, do we have studies that say if you’re MRD-positive, you need to intensify therapy? Or if you’re MRD-negative, can you discontinue or de-intensify therapy? Those would require risk adapted designs, and right now we don’t have any of those results.
So in 2019, other than ALL where there is MRD-positive/negative alteration in your treatment, in no other hematologic malignancy do we have MRD as a predictive marker. The one other caveat I would like to make for MRD is that myeloma is very different from these other tumors because it is essentially a blend of a liquid and solid tumor. And we know that patients can have osseous disease, and people can have macrofocal disease. So, if you sample a patient’s bone marrow and it’s MRD-negative, but they have residual radiologic disease, what does it mean to be negative from that 1 sample?
Some of the things that we need think about when using MRD in myeloma are the PET [positron emission tomography] scan or MRI [magnetic resonance imaging] to make sure there’s radiologic negativity, making sure that the sample was collected properly and it was a first pull, and making sure there were enough events to count because if you do next-generation flow cytometry and the marrow is essentially empty or cellular, it’s going to be falsely negative. And finally, confirm it’s a sustained MRD negativity. A single time point is not enough. We’ve already seen that in the FORTE study, patients with high-risk disease in particular are relapsing earlier even though they had MRD-negativity. And so I think the sustaining of MRD, particularly for high-risk patients, is important. We have a lot of things to grapple with.
And finally, I would close by saying how I am using MRD right now in 2019 in my practice. Because of the lack of evidence, it’s hard to justify it, but probably the 2 areas I sometimes will consider it in will be a transplant-eligible patient who gets induction therapy and the post-induction marrow is MRD-negative. And if the patient is averse to getting a transplant, it reassures me and the patient that it’s maybe OK to defer the transplant.
Conversely, in a patient who’s low risk and MRD-negative, sometimes I also use it if they’re having difficulty tolerating treatment. And if it’s MRD-negative and they’re a low-risk patient, we have a risk-benefit discussion that maybe it’s appropriate to hold therapy and monitor them. But other than those 2 unique limited settings, I’m not using it routinely in my practice.
The utility of MRD may also differ based on the patient population. For example, in the FORTE study, those patients who were low risk—R-ISS I [Revised International Staging System, stage I]—MRD negativity seemed to be comparable in the 2 arms, which is KRd [carfilzomib, lenalidomide, dexamethasone] for 12 months versus carfilzomib, lenalidomide, dexamethasone with a transplant consolidation embedded into it. However, for those patients who are high risk, R-ISS [stage] II or III, there were more early relapses in the non-transplant arm. And so I think this is an important finding because not all patients are created equal. The risk of a patient may matter.
While some studies are showing that the MRD negativity can make a high-risk patient have a comparable outcome to standard-risk patients, there are also many studies that show that even if you’re MRD-negative, as a high-risk patient you still do worse than standard-risk patients. I think we need more data, and part of that may also be the ability to sustain MRD because if you’re a high-risk patient and you have a single time point of MRD negativity, is that the same as now becoming standard risk? And I think still we need a little bit more information. But I think this is an interesting area of research.