Part 2:
A question of deferred ASCT

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

What about deferred ASCT? We've heard this morning about whether fit, young patients having deferred ASCT would be disadvantaged. But if we run a randomized study, randomizing between transplant and non-transplant, you'll be surprised how many patients actually would prefer to have the non-transplant pathway.

This is my Padimac study. I conceived this study at the same time as the IFM study was conceived, but in the UK it takes a little bit longer. With some statistical battles, in the end, this was a study we carried out. It was a Phase II study. Patients were treated with PAD and then harvested. Patients in CR and VGPR were stratified to a delayed transplant, whereas patients in PR went ahead to ASCT. We repeated the MRD assay 100 days following harvest, or 100 days following transplant. This is, as far as I know, the only study which has stratified patients to a watch-and-wait approach according to depth of response, which is biochemical. These patients received no further treatment. This study was conceived in the days when consolidation as an alternative to ASCT was just beginning to be thought about.

These are the data, they have been presented at various meetings, and the full manuscript is in preparation. This is the outcome, the PFS for all patients, according to MRD negative or positive response. Here you can see the PFS for patients who are MRD negative, 25.7 months, MRD positive, 15.6. But if you look at all four groups of patients, the patients who achieve VGPR and were delayed a transplant are split into those who are MRD negative in the solid blue, or MRD positive in the dotted blue. For the PR patients, MRD positive after transplant versus MRD negative after transplant.

These are the outcomes according to the MRD at day 100. Interestingly, if you take the MRD post-harvest, that is not as prognostic as taking it at day 100. I do think timing of MRD is important. These are very small numbers, but you might be able to see that patients who are MRD negative, whether you had a transplant or not, seemed to have progression-free survival, 27 months, 23 months here. But they are small numbers. What was interesting with the study is that the PFS2 is even more significantly affected by MRD at day 100 post-harvest. MRD negative versus MRD positive patients with a hazard ratio of 0.32.

The benefit of achieving MRD negative response extends beyond the first relapse. I think there is also data from frontline studies. Should we always aim to achieve MRD negative response for our patients? This is an old study now, but I like showing it because for PFS and OS here, here are the outcomes according to depth of response. This is just biochemical response. But from a long time ago now, we know that there are patients who do not achieve CR, who have extended survival. These patients, some of these patients, in fact, will be in PR, they'll have a measurable paraprotein, and they all have residual disease.

Then we come to the question of cure, because the whole debate about MRD is because we are aiming to cure. Do we need to eradicate all tumor cells for cure? Achieving cure is synonymous with achieving and then maintaining the best possible response, but if you can maintain a good response with residual tumor cells, for example in patients who have an MGUS signature, and this has been shown by the Little Rock group. Perhaps that is, in practical terms, good enough. There may be persistent MGUS-like clones after therapy, and the role of the immune system is something we've heard already today at this meeting, and I think that we have not paid enough attention to immune surveillance.

You've heard Bruno Paiva talk already about the nature of the residual cells. The nature of the residual clones might be what's important. If CR is not always essential for long term survival, maybe the same also applies to MRD negative disease, and we need to understand the genetic and biological risk. Some patients may not need to achieve a deep response. What about the question of immune surveillance and what about the question of persistent MRD? This, again, is data from Bruno using flow cytometry. Here you see MRD positive, patients with MRD positive disease, and patients with MRD positive disease with high normal plasma cell recovery and a favorable immune profile seem to cluster together with MRD negative patients. Certainly, their outcomes in terms of time-to-progression do not appear to be different. There are very few of these patients, of course.

But we need to pay more attention to the immune contexture of residual disease in order to understand the true implication of MRD negative or positive disease response. Then we ask the question, is MRD negative response independent of treatment? Does it mean the same if you achieve MRD negativity after transplant or after chemo? The data from the studied randomizing patients between transplant and chemo seems to suggest this is the case, but this may not always be the case.