Part 1:
Utilization of MRD assessment in
real-world practice

Kwee Yong, PhD, FRCP, FRCPath
University College London, UK

Here are my disclosures. I will start with just a couple of slides with a brief overview of the platforms and technologies, and I will start by saying I will only talk about bone marrow based MRD because Dr Mateos will cover very nicely the more global assessment of disease using cross-sectional imaging. This flow cytometric based assessments, you get a liquid bone marrow biopsy and by applying a panel of antibodies, as you can see here, we can identify B-cell precursors, the different B-cells, populations, matures, as well as plasma cells and other important immune populations like mast cells.

But we can also use next-generation sequencing to assess MRD, looking for the unique DNA sequences that are generated by VDJ recombination in the malignant clone. We do this using multiplex PCR using forward and reverse primers. We use primers for each of the V and each of the J families so that we can amplify all of the rearranged sequences of the malignant clone or clones. The way this is quantified is to express the dominant sequences, you can see here in red, as a percentage of the locus-specific sequences that are amplified. We can also express the dominant sequences as a percentage of all viable nucleated cells, by enumerating amplifiable DNA.

There are two different methods of assessing MRD. They give us different types of information about the disease status in the patient. Let's look at what information we have from clinical trials about MRD and try and answer the question whether any of this information is helpful for us in managing our patients. What can we use MRD to do? We can monitor the response to treatment. As you will probably hear more during the meeting, sometimes for multiply relapse patients or for more experimental therapies, it's important to get an early biomarker of effectiveness.

More commonly, I suppose, we try and use MRD to inform treatment decisions, how long you should treat someone. Protocols today are extended therapy. Should we escalate, should we change treatment, or perhaps, more importantly, can we deescalate therapy? Finally, all the discussions about MRD have to be done in the context of sensitivity, how deep a sensitive assay do we need? Do we need deep-sensitivity analysis in every situation? Are there particular patient groups in whom it is important?

You will have seen this already, this study today. It has been discussed several times. This is the randomized study, the IFM study, where newly diagnosed patients are treated with RVd and then randomized to a transplant or chemotherapy. Marivi will also show this data, so I will go through it really quickly just to set the scene and to make the point. You know already, and it's been published, that patients in the transplant arm had a superior progression-free survival compared to patients in the RVd arm.

Patients who are MRD negative, seem to fair similarly, whether they have a transplant or not. We've heard this theme already. Can we take this into the real world and tell our patients that if they achieve MRD negative response, they can be deferred ASCT? I have a case study, and in case you think the rest of the presentation has lots, this is the only case study I have. This is a 56-year-old man who we diagnosed a few years ago, lambda light chain myeloma. Standard risk with high lambda light chain set diagnosis. He entered my Cardamon study, you've heard about this already from Graham Jackson this morning. This is a study where patients receive carfilzomib, cyclophosphamide and dexamethasone induction, and then after harvest, they are randomized to have a transplant or consolidation with KCD times four. They have an MRD assessment here after harvest, and then again, post-ASCT or post-consolidation.

This patient achieved stringent CR very quickly after two cycles of KCD. He went on to have a harvest, but during the harvest he developed some problems with arrhythmia. During the cyclophosphamide priming, we see this now and again, but it's not very common. He was randomized to ASCT. His MRD at this time point was positive, but this episode really psychologically damaged him and he refused to take up his randomized treatment and withdrew from the study. What would you advise him to do now?

Perhaps the people who feel very strongly that he should have an ASCT, could you raise your hands? Nobody feels strongly. Do you think it would be all right to defer ASCT for this patient? Perhaps we should take into account the fact that he has no high-risk features, and maybe genetic risk matters. What if his genetics showed 1q gain and 14;16 translocation? Would that make a difference to the advice one would give him? This is about three years ago now. He keeps coming back. His second MRD test was also positive, but it was just at the border of positive, at 10-5.

Here again is the same study I showed you before, but here we split the patients according to genetic risk and MRD status regardless of transplant or not transplant. Here you can see the patients who fair worse are those who are MRD positive and high risk, but that the MRD negative, high-risk patients, actually seem to do reasonably well, and certainly the benefit of being MRD negative is much greater if you're high risk than if you are standard risk. This is generally borne out by other data. Marivi will also show this later, so I will just show you the top-line data. This indicates that patients who are MRD negative, whether they are high risk or standard risk, appear to have similar outcomes.

But I would caution you about the numbers, so the numbers of patients who are high risk and MRD negative, are really quite small. But if you look at these numbers already, we begin to get a sense that if you have high-risk genetics, it's more difficult for you to achieve MRD-negative response. So, perhaps there is an interaction of risk in MRD.