Patients dislike frequent MRD bone marrow testing because it is so invasive and painful. MRD testing in peripheral blood could overcome this limitation, but is it as sensitive as its bone marrow counterpart?

A study presented at ASH 2022 showed that the blood-based versions need to become significantly more sensitive before they can replace the bone marrow versions. New MRD testing methods are in development to spare patients the pain of frequent bone marrow biopsies.  

Just last year, at the 2021 ASH conference, investigators were trying to develop new (and less invasive) methods to keep track of myeloma status. A lot was said about circulating plasma cells in peripheral blood and how they can potentially be used in the future. This year, Dr. Laura Notarfranchi presented an update on Minimal Residual Disease (MRD) testing in peripheral blood at the 64th Annual Meeting of the American Society of Hematology (ASH 2022).

The Spanish investigators in this study aimed to investigate the prognostic value of MRD assessment using current methods and to develop a new method with increased sensitivity.

First, MRD was evaluated using next-generation flow in peripheral blood of 138 patients with myeloma (enrolled in the GEM2014MAIN trial).

The peripheral blood samples were collected after the second year of maintenance. At that point, if patients were MRD negative (by bone marrow biopsy) they stopped treatment; but if they were MRD positive they continued therapy for three additional years. 

As you can see in the table below, of the 138 patients enrolled in the GEM2014MAIN trial which had MRD assessed in peripheral blood, 12% were MRD positive after two years of maintenance. Their median progression-free survival (PFS) since MRD testing was 22 months, which was significantly inferior vs those with undetectable MRD in peripheral blood. 

If the patients were MRD negative in the blood, the researchers then performed MRD testing in the bone marrow. For these 123 patients who were MRD negative in the blood, 27% were indeed MRD positive in the bone marrow. The blood-based test was just not sensitive enough to pick it up.

Importantly, if patients were MRD negative in both the bone marrow and blood, they had significantly longer progression free survival. 

Comparing A New Ultra-Sensitive Circulating Plasma Cell Test vs. Next Generation Flow

 To avoid high staining costs and impractically long acquisition periods, a new method was developed, known as BloodFlow (MACS® MicroBeads).  The performance of BloodFlow vs next-generation flow in peripheral blood was compared in 353 samples collected in different treatment scenarios. The new BloodFlow test was 82x more sensitive compared to the next generation flow MRD test. 

BloodFlow detected MRD in 33/353 (9%) of samples. The lowest MRD level was 10-8. Of the 33 positive samples using BloodFlow, 19 (58%) were negative by next-generation flow, showing that the next-generation flow is not as sensitive as the newer test. All negative cases, according to BloodFlow, were also negative by next-generation flow.

To reinforce the findings, they compared an additional 199 blood and bone marrow samples using BloodFlow vs. next generation flow. The two tests agreed for 137 (69%) double-negative and 19 (9.5%) double-positive samples.

BloodFlow showed a negative predictive value of 77% when compared to next-generation flow in bone marrow. Negative predictive value is the likelihood that a person having a negative test results doesn't have the disease.  

Two of the four patients who were MRD positive using the BloodFlow test have progressed while the 29 patients who were MRD negative have not relapsed. 

In conclusion, it may be possible in the future to use blood-based MRD testing if the sensitivity of the test is increased. The new BloodFlow test is a significantly more sensitive test (MRD down to 10⁸) which opens the door to further progress in moving to blood-based tests. 

To learn more about MRD testing, click here and here.