I have been involved in multiple myeloma since 1980, a long way, and regarding the story of minimal residual disease that is the topic for today I would say that this started with acute leukaemia. When we treated in the ‘70s and in the ‘80s patients with acute leukaemia we were able to achieve complete responses in a good fraction of patients. However, unfortunately many of them relapsed and this was due to the persistence of residual cells that were not detectable with the conventional methods. In multiple myeloma this has not been an important issue, mainly because complete response was rare until ten or fifteen years ago. But with the newer agents the situation has completely changed. Bortezomib, thalidomide, lenalidomide and now more recently the monoclonal antibodies, the second and third generation proteasome inhibitors and IMiDs have been able to demonstrate that a large fraction of myeloma patients can achieve a complete response, a complete response assessed by morphology and cytological methods. But again we have the same problem – when you have 3% plasma cells after treatment you are not sure whether or not these plasma cells are normal cells, if they are normal cells you are really in complete response, or are malignant plasma cells, clonal plasma cells. Then you need more sensitive methods, more specific methods, to assess if the residual plasma cells are clonal, that means malignant, or polyclonal – normal plasma cells. This is the focus of minimal residual disease tests in the bone marrow – to assess the clonal plasma cells, the residual plasma cells, for malignancy.

But the concept of minimal residual disease also goes outside the bone marrow. It’s the new imaging technique methods, particularly the CT-PET, that allows you to identify residual locations of foci of plasma cells that could be associated with late relapses. All this was the reason why the International Myeloma Working Group decided in a recent paper to implement a new concept for response and they are the MRD concept of responses.

Let me expand a bit more because the concept of minimal residual disease is usually associated with depth of response, with quality of response but could help not only to assess the quality of response but also to monitor the treatment efficacy in the long-term follow-up during consolidation and during maintenance. We have a beautiful example about this with CML, chronic myeloid leukaemia. Now, in the chronic myeloid leukaemia patient the treatment is adapted based on the minimal residual disease assessment by molecular techniques. In ALL it’s also adapted by minimal residual disease methods, either by flow cytometry or by molecular methods. Now in multiple myeloma we have started to implement these techniques to evaluate the residual cells in the bone marrow and outside the bone marrow both by flow and molecular methods. The Spanish, the UK, the French, American groups have been able to demonstrate that patients that achieve after induction therapy in newly diagnosed patients after transplant an MRD negative status have significantly longer progression free survival and overall survival as compared to the MRD positive patients. In fact, we have recently shown that the patients that achieve CR, conventional complete response, in this cohort of conventional CR patients you have two cohorts – the ones that are MRD negative and the ones that remain MRD positive in spite of in cytological complete response. The MRD positive ones are similar to the VGPR with the partial responders; the ones that really benefit from the treatment, from this good response, are the MRD negative ones. Then one of the aims currently in myeloma treatment is to put the patient into an MRD negative status.

Due to the pattern of bone marrow infiltration in myeloma different from leukaemia that is a patchy bone marrow infiltration while in leukaemia it’s more diffuse, you may have a situation in which you don’t detect cells, in other words you are MRD negative, but the sample was not representative enough of the whole marrow due to this patchy marrow of infiltration. By contrast, if you detect residual cells by sure the tumour is there. Then I like to tell my patients, ‘Look, good news, you are MRD negative.’ This is good news because to be MRD positive is bad. I know the definition that MRD positive is bad. MRD negative is good but it’s not entirely good since some patients may relapse in spite of being MRD negative because the sample was not representative enough but the news are very good because you are not MRD positive. Then this concept is very relevant to be understood.

Regarding your question about whether or not MRD negativity could mean cure or could become a surrogate marker for cure, the answer is going to be yes. I have just mentioned about the pitfall that you may have with a non-representative bone marrow sample when you do the analysis that is reported as MRD negative but the bone marrow was not the ideal one for this exam, therefore you may have an error in that case. But when we are considering MRD negativity as a surrogate marker for survival we are not going to rely on just one sample. What we want is to maintain an MRD negative status at least for a period of time. If you repeat this bone marrow two or three times just to confirm the MRD negative result the two or three subsequent samples for sure are not going to have this problem in case you have that problem. The demonstration in a sequential fashion that the patient maintains an MRD negative status is becoming a more and more robust indicator of disease free long survival and probably in the near future, and similar to what is being implemented in other malignancies, we are going to have MRD as a surrogate marker for survival.

Professor San Miguel, thank you so much.