Role for MRD in Myeloma Evolves as Novel Agents Increase Response

Shaji Kumar, MD

In multiple myeloma, the FDA approval of numerous novel agents has resulted in an increasing number of patients achieving deeper responses than what was previously defined as a complete response.

Due to this advancement, a need has emerged for more sensitive imaging techniques to identify the residual tumor cells within and outside of the bone marrow, and new technologies are being increasingly utilized.

OncLive: How has the use of MRD testing evolved in multiple myeloma?

To clarify best practices, the International Myeloma Working Group recently released updated consensus criteria for response and minimal residual disease (MRD) assessment in multiple myeloma. A paper outlining these criteria was published in Lancet Oncology. OncLive spoke with Shaji Kumar, MD, the lead author on the paper and a professor of Medicine at Mayo Clinic, to understand the roles that the new criteria and MRD testing will play going forward in multiple myeloma.Kumar: The concept of MRD testing has been around for a long time in hematological malignancies, mainly in chronic myeloid leukemia, which has a very defined disease-related genetic change. It has been different in other diseases that are more heterogeneous. The second important aspect as to why it has been so late coming to myeloma is that we have had extremely effective treatments that can take patients to an extremely low level of residual disease.

Now, we have very effective treatment combinations that can give us very high response rates, so that kind of immediately brought out the understanding that the current response criteria does not adequately give us the ability to understand and measure those deep responses and compare them between trials.

We had to come up with criteria that could be implemented across different trials, so we could actually compare the results of those studies. To that end, we looked at all the data that are out there, and recently the International Myeloma Working Group came up with updated consensus criteria for response in myeloma that incorporated MRD testing. The way that we have redefined the criteria is by incorporating next-generation sequencing, or the flow-cytometry—based assessment, of MRD. This looks at MRD in the bone marrow, but we also know that myeloma can occur outside of the bone marrow, so we’ve incorporated PET scanning as a way to assess that.

Are there any other methods of determining MRD negativity that are being investigated?

Essentially what we are looking for is the ability to get patients into bone marrow MRD-negative state as defined by 1 of the 2 molecular techniques, and a PET-scan disease state, which tells us that there is no more disease outside of the bone marrow.Clearly, we know that there may be MRD that we are not picking up with these techniques, so there is going to be a lot of improvements on the horizon, in terms of looking at more sensitive ways of sampling the bone marrow.

You mentioned new effective treatments that can take patients to an extremely low level of residual disease. Can you expand on what those are?

One of the most exciting possibilities is looking at these myeloma cells, or cell-free DNA in the peripheral blood, which obviously will eliminate the need to do a bone-marrow biopsy, but could also overcome one of the big problems we have, which is the heterogeneity. In addition, there are new imaging techniques, such as PET MRI, and there is also going to be a certain isotope specifically targeted to myeloma cells that could also be a beneficial new companion with the PET scan.There have been several new classes of drugs that have come up in the last few years and, within each class, there have been several very effective drugs. A good example is the combination of carfilzomib (Kyprolis), dexamethasone, and lenalidomide for newly diagnosed myeloma. In the phase II studies, it looks like it is quite effective and almost one-third of patients can get a stringent complete response using that regimen.

How do you see the use of MRD evolving in the future?

We also see high MRD-negativity rates in some of the relapsed trial settings, such as the combinations including the monoclonal antibody daratumumab (Darzalex). A couple of the phase III trials have looked at this drug recently, and the MRD-negative rate in those studies—despite them being relapsed patients—were still very high.The way we are going to use MRD in the future is that we are going to look at it in 3 different perspectives. The first one is how we use it day to day—basically looking at it as a single marker for response—and determine how deep we can take the response using some of these new regimens. This way we can really compare these effective regimens against each other and see if we are able to get a higher MRD-negativity rate or what. To that end, the new redefined response criteria is pretty critical.

The other use of MRD, which is an important goal that we have not yet achieved, is the ability to use the MRD rate as a surrogate endpoint for long-term outcomes, such as progression-free survival (PFS) and overall survival (OS). This is very important because we have treatments now that will keep people alive for a long time, and clinical trials with very long-term endpoints become impractical. If we can define that X percentage of MRD negativity translates into X percentage in terms of OS, then that can become a surrogate endpoint.

What research should be done in order to use it as an endpoint for PFS?

The final thing is using it as a clinical tool. What do we do with an MRD-negative result? Does it allow us to change therapy or add therapy? These are the questions we need to be asking and to study.We have a lot of data; most of it has been from retrospective trials showing that MRD negativity demonstrates a pretty good outcome. What the regulators are really looking for is this kind of data coming from prospectively designed trials, so we can eliminate some of the bias that comes from retrospective studies.

Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-346.