NCCN endorses MRD testing: what does this mean for patients?

This past week the National Comprehensive Cancer Network (NCCN) endorsed the full new International Myeloma Working Group (IMWG) response criteria, including MRD (minimal residual disease) testing. The NCCN’s endorsement is very good news for patients because it means that the cost of individual MRD testing is more likely to be reimbursed by providers. It signals a broader acceptance for MRD testing in upcoming clinical trials—a critical aspect of the IMF’s Black Swan Research Initiative® (BSRI).

The NCCN endorsement has also drawn attention to the details of MRD testing in myeloma, which can be performed by two different methods: Next-Generation Flow (NGF) or Next-Generation Sequencing (NGS). So, what are the pros and cons of these two options? NGF and NGS have equal sensitivity; each can detect one myeloma cell in one million normal cells. But that’s where the similarities end. Here are the key differences between the methods.

Differences in timing and cost

NGF can be used at any time in the disease course, whereas NGS requires a pre-treatment sample to identify the myeloma clone. NGF must be performed within 36 hours on fresh samples, while NGS has the advantage that samples can be stored for later testing. NGF’s use of fresh samples adds some shipping costs, but because NGF testing itself is much cheaper, the overall processing costs remain less expensive with NGF.

In addition, the advantage of using fresh samples (versus stored samples) is that you know right away if it is a “good sample” (contains adequate bone marrow material). This means there is what is called excellent “internal quality assessment” (IQA). If there is not adequate bone marrow in the sample, then a new sample can be obtained immediately for retesting as needed. For NGS, there is a delay of at least 1-2 weeks to obtain a new sample, and there is no IQA.

NGS fails approximately 15% of the time

Although not frequently discussed, there are important technical issues with NGS. About 15% of the time the test doesn’t work. In addition to the technical difficulties, a negative result can be a “false negative” because the sequences which identify the myeloma clone have been “lost” (deleted from the myeloma cell DNA due to the cancer molecular evolution processes).

In contrast, NGF works for all patients. This is preferable for an “intent to treat” clinical trial, when it is important to achieve results for every patient, especially for FDA review.

A question of standardization

An important question to ask about both methods of MRD testing is: will the result be the same if you send a sample to one lab versus another? The first point is that there is just a single Adaptive®/Sequenta® NGS lab testing system. In contrast, hundreds of different labs around the world can perform NGF testing. This type of cross-lab comparison is called EQA (external quality assessment). EQA for NGF testing is rolling out in Europe and starting in the US, and entails sharing of both samples and computer files for quality checks. Part of the assessment includes double checking exact MRD levels – such as 1 in a million, 10 in a million, or, maybe, negative at 0 in a million. With NGF monitoring, full bone marrow and immune monitoring are feasible. This means that when using immune therapies, levels of B, T, NK, and other types of immune cells present in the bone marrow can be tracked sequentially. Some aspects of this can also be measured with NGS, but the ability to identify, sort, and study further at the molecular level is a major advantage for NGF – the flow cell capture method.

Promise of liquid biopsy

A final point in favor of NGF is about the possibility of blood testing or “liquid biopsy.” NGS has produced limited information with blood testing. Conversely, NGF readily detects myeloma cells in the blood, which can prove to be an excellent indicator of early disease progression both early in the disease (at the MGUS/SMM stages) and later, in the conversion of MRD-negative to MRD-positive, or in the study of persistently MRD positive disease. A recent publication demonstrates molecular analysis of myeloma cells in the blood captured with single-cell micromanipulation using a fluorescent microscope. The new, very sensitive NGF method described above can be used in the same fashion, and far more efficiently.

At this point, you can appreciate that many detailed aspects must be understood to implement MRD testing. Thus, education for both physicians and patients is key and an important goal of the Black Swan Research Initiative.

Bottom line on MRD testing

Both NGS and NGF can be used with the same sensitivity. However, depending upon the needs and circumstances, one method may be preferred, especially if real-time results are a priority. If immune monitoring in parallel can be helpful, and, moving forward, if sequential assessment in blood can provide a less invasive ongoing-monitoring approach, then NGF is clearly preferable.

 

Bottom, bottom line

We are planning to keep an updated list of available labs for NGF testing on our Black Swan web page. In addition, a new booklet is in the works to give patients the day-to-day information they need about MRD testing, including: where to get reliable MRD testing done, how bone marrow samples should be collected and shipped, as well as what to expect when the results come back!

 

Comments

Dr Durie
Thank you for your blog. I always look forward to reading it.
My question is pretty much straight forward. If several successive MRD test are performed all with negative results, is the MM considered cured with no further treatments required.
Thanks
Jim Barendse

Dear Jim,

Thank you for your question.

Your results are definitely very encouraging! Obviously, the details of the MRD testing method are very important as I discuss in the blog. Your doctor will be able to guide you about the sensitivity and reliability of the particular tests used in your case. The best level of MRD negative is with the 10¯ (1/million or better) level of sensitivity repeated at 1, 3 and 5 years. In this case, it is important to have a PET/CT scan to make sure there is no disease outside the bone marrow. Sustained MRD negative plus a negative PET/CT at 5 years is definitely in the “functional cure” category especially for a patient with initial good risk cytogenetics (iFish testing). Our current statistics indicate an excellent chance for such remissions to extend beyond 10 years. At the present time, for patients who received autologous stem cell transplants as part of initial therapy, a subset of patients (14% of total) continue in remission at 20 years. The IMWG paper on this topic will be published very soon.

I hope this is helpful.

Sincerely,
Brian Durie

To this lay person it is not clear: Is the NGF a bone marrow sample and the NGS a blood sample? The technical arguments in favor of NGF seem clear, but if this is the case the practical difference to the patient is substantial.

Many thinks to all these bodies that support research and progress against this nasty disease!

Dear Ann,

Thank you for your question.

Both NGF and NGS are performed on a bone marrow sample for MRD testing. My comparisons are therefore between bone marrow NGF and bone marrow NGS. However, it turns out that the very sensitive NGF method also picks up myeloma cells in the blood. This is an added advantage and with further research may prove to be very useful for disease monitoring in the blood (“liquid biopsy”) and thus avoid the repeated bone marrow sampling!

Sincerely,
Brian Durie

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