Abstract
Simple SummaryAlthough the majority of patients with myeloma who achieve undetectable minimal residual disease show prolonged survival, some of them relapse shortly afterwards. False-negative results due to hemodiluted bone marrow samples could explain this inconsistency, but there is no guidance on how to evaluate them. We analyzed three cell populations normally absent in peripheral blood in 1404 aspirates obtained in numerous disease settings and in 85 healthy adults. Pairwise comparisons according to age and treatment showed significant variability, thus suggesting that hemodilution should be preferably evaluated with references obtained after receiving identical regimens. Leveraging the minimal residual disease results from 118 patients, we showed that a comparison with age-matched healthy adults could also inform on potential hemodilution. Our study supports the routine assessment of bone marrow cellularity to evaluate hemodilution, using as reference values either treatment-specific or from healthy adults if the former are unavailable.Background: Whereas, in most patients with multiple myeloma (MM), achieving undetectable MRD anticipates a favorable outcome, some others relapse shortly afterwards. Although one obvious explanation for this inconsistency is the use of nonrepresentative marrow samples due to hemodilution, there is no guidance on how to evaluate this issue. Methods: Since B-cell precursors, mast cells and nucleated red blood cells are normally absent in peripheral blood, we analyzed them in 1404 bone marrow (BM) aspirates obtained in numerous disease settings and in 85 healthy adults (HA). Results: First, we confirmed the systematic detection of the three populations in HA, as well as the nonreduced numbers with aging. Pairwise comparisons between HA and MM patients grouped according to age and treatment showed significant variability, suggesting that hemodilution should be preferably evaluated with references obtained from patients treated with identical regimens. Leveraging the MRD results from 118 patients, we showed that a comparison with HA of similar age could also inform on potential hemodilution. Conclusions: Our study supports the routine assessment of BM cellularity to evaluate hemodilution, since reduced BM-specific cell types as compared to reference values (either treatment-specific or from HA if the former are unavailable) could indicate hemodilution and a false-negative MRD result.
Highlights
Measurable residual disease (MRD) is routinely evaluated in multiple myeloma (MM)clinical trials [1,2,3,4,5,6]
There were no differences in the median percentages of the B-cell precursors and nucleated red blood cells (NRBC) when comparing healthy adults (HA) younger and older than 65 years, while the frequency of mast cells significantly increased in the latter (Table 1 and Figure 2)
These findings further supported the evaluation of these cell types to assess hemodilution due to nonreduced numbers with aging and systematic detection in bone marrow (BM) aspirates from HA
Summary
Measurable residual disease (MRD) is routinely evaluated in multiple myeloma (MM)clinical trials [1,2,3,4,5,6]. The uncertainty about the meaning of undetectable MRD at the individual patient level holds back the use of MRD to guide treatment decisions in MM; whereas, in most cases, it predicts a favorable outcome, some patients continue to relapse after achieving MRD negativity in “real-world” studies, as well as in clinical trials [11,12] Such a discordance between laboratory and clinical findings could possibly be attributed to the disease biology (e.g., a high proliferation of residual cells), as well as to low-sensitive assays, extramedullary disease and to nonrepresentative bone marrow (BM) aspirates either due to patchy tumor infiltration or hemodilution [2]. Conclusions: Our study supports the routine assessment of BM cellularity to evaluate hemodilution, since reduced BM-specific cell types as compared to reference values (either treatment-specific or from HA if the former are unavailable) could indicate hemodilution and a false-negative MRD result
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