EHA 2015
Minimal residual disease in multiple myeloma
Dr Bruno Paiva - University Clinic of Navarra, Pamplona, Spain
You are looking at multiple myeloma and you acknowledge the fact that better treatments are available but I gather that here at the haematology meeting you were explaining this puts more demands on clinicians. What is it doing?
Absolutely and I think it’s mandatory also for us in the laboratory to really keep the pace with the improvement that has been observed in recent years for both treatment and diagnosis of multiple myeloma.
What are the challenges?
The challenge is that now increasing response rates are being observed with the incorporation of novel novel agents, depth of response is increasing. We also know that depth of response is clinically relevant in multiple myeloma, particularly the achievement of complete response, but we know that complete response is also a sub-optimal criteria and the criteria is based in ’98 and has not yet evolved like the treatment has evolved. In fact there are some technical limitations: the criteria doesn’t have the sensitivity to compare two very effective treatment strategies; the criteria, the CR criteria, fails to identify patients with very elderly relapses plus it has never been a marker of curability in myeloma. This is why there is the need to incorporate nowadays an MRD assessment in myeloma.
Could you tell me about minimum residual disease and how to incorporate that into myeloma monitoring?
Minimal residual disease is just that residual disease that you couldn’t detect using conventional criteria or the technologies that define conventional criteria. So minimal residual disease is usually one tumour cell in at least 10,000 normal cells, that would be like 10-4, but you can actually monitor today even residual disease at 10-6.
And how are you doing this at your centre in Navarra?
Well, before going to what we are doing in our centre, generally speaking there are two different approaches to monitor MRD inside the bone marrow, that would be flow cytometry or molecular, nowadays based on next generation sequencing, and then there are also imaging techniques such as PET-CT to monitor MRD outside of the bone marrow. In our institution, as well as within the Spanish Myeloma Group Network, we have always worked more with flow cytometry even though also molecular approaches such as previously ASO PCR and nowadays NGS are also being evaluated.
If you apply these to monitoring your patient, how much of a clinical advantage can you get, bearing in mind the new treatments that are now available?
That is perhaps the ultimate question, the most important question, but because it’s so important because it’s when a biomarker moves from a simple prognostic marker into something that can tailor or optimise or make a fine tune of the patient management. Because it is so important, the answer to that question should rely on evidence based medicine and evidence based medicine can only derive from data obtained from prospective and well-randomised controlled clinical trials. We are only now collecting that data from clinical trials in which the question of, for example, the duration of therapy is being placed according to the MRD status of the patient. Before that, because there is no evidence yet, there is only evidence that it is a better biomarker than CR, but there is yet no evidence on the basis of clinical trials, you cannot yet make clinical decisions based on MRD assessment. I think that this is very important to emphasis.
So it’s an objective criterion but one that holds a lot of promise. What about circulating myeloma cells, where do they come into this?
That’s a side benefit of really developing the technologies to monitor disease in a very sensitive fashion. So the same technology that has been developed over the years to monitor MRD can certainly be applied to also monitor circulating tumour cells. Now, I think it’s important to really emphasise that the monitoring or measurement of circulating tumour cells, CTCs, at the moment it’s not possible using the technology that we are using to monitor MRD in the same setting. Therefore, after treatment CTCs in the blood is not a marker for MRD. By contrast, in all the spectrum of disease, that is MGUS, smouldering myeloma, newly diagnosed myeloma, relapsed refractory myeloma patients, in all the four settings it has been shown using very low sensitive techniques that detecting circulating tumour cells is of high clinical significant prognostic value.
What should doctors think, if you could summarise this, about the potential for diagnosis and, indeed, prediction using these techniques? What should doctors take home from this?
Well, they should take home that currently many groups are really working to implement prospectively the detection of CTCs with very sensitive techniques. This, for sure, will make an impact, perhaps even in some sort of laboratory differential diagnosis. By that I mean really those patients because of different risk of progression that might be candidates or not to early treatment intervention, that’s on the one hand. Patient risk stratification, also differential diagnosis for treatment intervention but this needs to be demonstrated prospectively and in independent patients CTCs is crucial. The second part is learning from our colleagues in solid tumours to also take advantage that these cells are in the blood, you can actually sort them, for example using flow cytometry, and then also to perform genetic or cytogenetics on these cells. So perhaps not in all patients but in a subset of patients to perhaps offer the patient the possibility to perform genetic characterisation in a known invasive fashion. If this promise holds true then I think this would be a great improvement in patient management in multiple myeloma.
