Abstract
There is an increasing clinical interest in the measure and achievement of minimal residual disease (MRD) negativity in the bone marrow of Multiple Myeloma (MM) patients, as defined equally either by Multicolor Flow Cytometry (MFC) or by Next Generation Sequencing (NGS) technologies. At present, modern technologies allow to detect up to one on 104 or on 105 or even on 106 cells, depending on their throughput. MFC approaches, which have been progressively improved up to the so-called Next Generation Flow (NGF), and NGS, which proved clear advantages over ASO-PCR, can detect very low levels of residual disease in the BM. These methods are actually almost superimposable, in terms of MRD detection power, supporting the lack of unanimous preference for either technique on basis of local availability. However, some technical issues are still open: the optimal assay to use to detect either phenotype (e.g., next generation multidimensional flow cytometry, imaging) or genotype aberrations (e.g., ASO-RQ PCR, digital droplet PCR, NGS) and their standardization, the sample source (BM or peripheral blood, PB) and its pre-processing (red-cell lysis vs. Ficoll, fresh vs. frozen samples, requirement of CD138+ cells enrichment). Overall, MRD negativity is considered as the most powerful predictor of favorable long-term outcomes in MM and is likely to represent the major driver of treatment strategies in the near future. In this manuscript, we reviewed the main pitfalls and caveats of MRD detection within bone marrow in MM patients after front-line therapy, highlighting the improving of the currently employed technology and describing alternative methods for MRD testing in MM, such as liquid biopsy.
Highlights
In Multiple Myeloma (MM), the clonal neoplastic plasma cells (PCs) grow within a microenvironment niche [1, 2], which provide factors promoting their longevity, either within or out of bone marrow (BM) [1,2,3]
minimal residual disease (MRD) has been assessed on BM samples by amplifying the V(D)J clonal rearrangements, first just to gain qualitative information by polymerase chain reaction (PCR) [22, 27, 31] using clonal-size based methods (PAGE, GeneScanning) [17, 32], by allelic specific oligonucleotide PCR (ASO-RQ-PCR), to obtain quantitative information [22, 33, 34]
The sensitivity of MRD detection of quantitative polymerase chain reaction approach depends on several factors, including the type of VDJ rearrangement, the dimension and specificity of the junctional region and the amount of DNA available for each reaction
Summary
In Multiple Myeloma (MM), the clonal neoplastic plasma cells (PCs) grow within a microenvironment niche [1, 2], which provide factors promoting their longevity, either within or out of bone marrow (BM) [1,2,3]. The International Myeloma Working Group (IMWG) has defined a revised criteria of responses for patients with MM, by including minimal residual disease (MRD) [9] (Table 1); several studies [14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30] (Figure 1), confirmed by two meta-analysis [16, 30], consistently showed inferior outcomes in patients remaining MRD-positive, despite the achievement of complete remission (CR). We will review the more recent techniques developed to assess MRD in MM, their limits in sensitivity and applicability and their application in several clinical contexts
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