FEATURE
There is no clear consensus on which methodology to use or when to use it .
Regardless of how the samples are analyzed , all methods rely on BM aspirates taken from a single site – typically , the pelvic bone – ignoring the fact that patients can have disease in many other areas of the body . Measuring disease burden in just one area may not give us an accurate picture of the patient ’ s disease .
Dr . Davies : There are a number of tools in development to measure MRD and it seems unlikely that there is just one ideal test . In the long run , we may find that all of the tools are valid and provide clinically useful information . The most important factor to consider is the test ’ s sensitivity . Available tests are able to document tumor cells at levels of 10 ‐4 to 10 ‐6 . I think your concerns about the availability of MRD testing on a large scale are valid . MRD testing has become more commonplace in the setting of acute leukemias , but it has only really been used in the clinical trial setting in myeloma to date . I ’ m certain that transplant centers conduct MRD monitoring with more regularity .
Dr . Usmani : Right , in the clinical trial setting , MRD is more common ; patients who have achieved very good partial response ( PR ) or better will routinely undergo MRD testing . Certain transplant centers are also examining the use of MRD testing in the posttransplant setting – before patients move on to their maintenance phase .
Dr . Davies : Recent data in the non-transplant and relapse settings also supports the wider use of MRD testing . And , as you already mentioned , one of the factors inhibiting its widespread uptake is the limited availability of facilities and laboratories that can handle high volumes of samples and the potential inconsistencies among facilities . We need to be assured that the level of sensitivity will be the same if we send a sample to one laboratory versus another . We also cannot overlook the issue of reimbursement .
Dr . Usmani : Absolutely . Even though the International Myeloma Working Group ( IMWG ) issued consensus criteria defining the role of MRD assessment in 2016 , many hospitals are probably still picking up the tab for the procedure . 2
Regardless , before MRD monitoring becomes part of routine clinical practice , we need to ensure that MRD is being measured and validated uniformly – whether that ’ s by flow cytometry or sequencing .
Unfortunately , there isn ’ t much research comparing MRD testing with other efficacy endpoints head-to-head in different patient settings . There are two large datasets that have looked prospectively at the value of MRD in patients with relapsed myeloma : CASTOR and POLLUX , both of which served as the basis for the FDA ’ s approval of daratumumab for patients with relapsed / refractory myeloma . 3 In those clinical trials , we observed that even high-risk patients were able to achieve MRD negativity when treated with daratumumab ( in combination with either lenalidomide and dexamethasone or bortezomib and dexamethasone ) and , in general , MRD-negative patients had longer PFS in both of those studies compared with MRDpositive patients .
Beyond that , we do not have enough prospective trial data to comment on the value of MRD testing in high-risk patients .
Dr . Davies : I am hopeful that we will have more answers to these questions , particularly concerning high-risk myeloma , when we see results from two research groups that are investigating the use of flow cytometry MRD testing in the upfront setting : GEM-PETHEMA ( the Spanish Myeloma Group ) and the U . K . Myeloma Research Group . A pooled analysis of studies conducted by the Spanish group determined that patients who achieved CR but remained MRD positive had a similar PFS , compared with those who achieved PR ( 27 vs . 29 months ; p < 0.001 ). 4 Achieving MRD negativity , however , was significantly associated with prolonged PFS ( 63 months ; p < 0.001 ), suggesting that MRD status had greater predictive significance than CR status alone . The researchers also noted that this association was particularly strong in patients with high-risk cytogenetics .
“ At this moment , we don ’ t have any data to support what defines ‘ sustained ’ minimal residual disease negativity or at what time point we could consider scaling back treatment .”
— FAITH DAVIES , MD
Results from the U . K . group are forthcoming .
On the other hand , a recent study of 185 patients with myeloma showed that , although MRD negativity was associated with longer PFS and OS than MRD positivity , MRD negativity did not translate to superior survival in patients with del17p or ≥2 cytogenetic abnormalities , suggesting that MRD testing may not be valuable in patients with these risk factors because they have poor outcomes regardless of MRD status . 5
We are also eagerly anticipating updated results from the MRD analysis of the Intergroupe Francophone du Myelome / Dana-Farber Cancer Institute 2009 study , which is measuring MRD with both flow cytometry and NGS techniques ( which can detect myeloma cells to a level of 10 -4 and 10 -6 , respectively ) in newly diagnosed patients , including those with high-risk disease .
Data suggest that achieving MRD negativity is predictive of survival . These results have prompted researchers to question whether MRD negativity could be used as a surrogate endpoint for survival in drug approvals . However , I don ’ t think we ’ re quite ready for that .
Dr . Usmani : I am not prepared to say that MRD status should be used as a surrogate marker either , and I think we should be cautious about using MRD status to drive any treatment decisions given the concerns we discussed earlier – namely a lack of guidance on what constitutes MRD and a lack of standardization in analyzing MRD samples .
The IMWG consensus guidelines established an acceptable sensitivity level of 10 -5 , but I think many hematologists tend to agree that 10 -6 is an ideal MRD negativity sensitivity point . 2
Dr . Davies : The guidelines provide sensitivity cutpoints for both flow cytometry and NGS . These serve as baselines so that investigators can start to report in a more standardized fashion and compare results between different treatment strategies . As MRD monitoring is used more frequently in practice , the IMWG guidelines will need to be updated accordingly , and it will become clear what level of sensitivity is most appropriate for each situation .
In my opinion , the prerequisite for myeloma to be considered “ cured ” is to achieve sustained MRD negativity . We need to be using the best treatments possible for every patient , but , even if a patient reaches an MRD-negative status , it doesn ’ t necessarily mean treatment should be stopped . I would argue that MRD positivity should play a greater role in making treatment decisions ; if a patient reaches MRD positivity after treatment , that ’ s when we need to stop and think , “ Do we change our treatment plan to improve the depth of response ?”
At the moment , though , we don ’ t have any data to support what defines “ sustained ” MRD negativity or at what time point we could consider scaling back treatment . The next series of clinical trials , which many of the cooperative groups are discussing and trying to design , are hopefully going to provide some answers to these questions .
The studies about MRD-guided therapy that we have now are largely retrospective trials ; we need prospective trials to provide guidance . Personally , I would need a patient to be testing MRD negative for at least 1 year , but more likely 3 years , before I would consider de-escalating treatment .
Dr . Usmani : I agree – at least 1 year , but ideally 3 years of sustained MRD negativity before you can say a patient is potentially cured or is going to survive long term .
And , before we can start to develop responseadaptive treatment strategies based on MRD status – either de-escalating treatment if the patient is MRD negative or changing the treatment plan if the patient is MRD positive – we need to better define what “ counts ” as MRD negativity . Sustained MRD negativity should be our treatment goal , but this is an issue that clinical trials are just now starting to address . ●
REFERENCES
1 . Munshi NC , Avet-Loiseau H , Rawstron AC , et al . Association of minimal residual disease with superior survival outcomes in patients with multiple myeloma : a metaanalysis . JAMA Oncol . 2017 ; 3:28-35 .
2 . Kumar S , Palva 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 : e328-46 .
3 . Avet-Loiseau H , Casneuf T , Chiu C , et al . Evaluation of minimal residual disease ( MRD ) in relapsed / refractory multiple myeloma ( RRMM ) patients treated with daratumumab in combination with lenalidomide plus dexamethasone or bortezomib plus dexamethasone . Abstract # 246 . Presented at the 2016 ASH Annual Meeting , December 3 , 2016 ; San Diego , California .
4 . Lahuerta J , Palva B , Vidriales M , et al . Depth of response in multiple myeloma : a pooled analysis of three PETHEMA / GEM clinical trials . J Clin Oncol . 2017 May 12 . [ Epub ahead of print ]
5 . Chakraborty R , Muchtar E , Kumar SK , et al . Impact of post-transplant response and minimal residual disease on survival in myeloma with high-risk cytogenetics . Biol Blood Marrow Transplant . 2017 ; 23:598-605 .
ASHClinicalNews . org ASH Clinical News
43