Methods for Detection of MRD in Multiple Myeloma

Increasingly sensitive techniques are available for the detection and quantification of MRD in multiple myeloma. Each technique offers advantages and inherent limitations that might differentially affect their use and interpretation of the findings.44

Features of MRD detection methods 12,41,44

Method Process Applicability Sensitivity Important considerations
MFC
(≥ 8 color)
Differentiates between normal and abnormal plasma cells through detection of cell-surface marker expression -100% 10-5-10-6
  • Widely applicable and available
  • Hours
  • Relatively inexpensive
  • Clonal heterogeneity undetectable
  • Standardized by the EuroFlow consortium
  • Requires bone marrow aspirate
  • Fresh sample necessary
  • Does not require baseline sample
ASO-PCR Analysis of VDJ heavy chain regions for detection of myeloma specific Ig rearrangements 60%-70% 10-5-10-6
  • Intermediate applicability and availability
  • Days to weeks
  • More expensive
  • Clonal heterogeneity undetectable
  • Standardized (EuroMRD)
  • Requires bone marrow aspirate
  • Fresh sample not necessary
  • Patient-specific primers necessary
  • Requires baseline sample
NGS Use of high throughput sequencing to detect clonal Ig VDJ gene rearrangements -90% 10-6
  • Limited availability
  • One week or more
  • Expensive, but costs decreasing
  • Limited clonal heterogeneity detected
  • Not yet standardized
  • Bone marrow aspirate or peripheral blood sample acceptable
  • Fresh sample not necessary
  • Requires baseline sample or stored sample from a time point of detectable disease
PET/CT Permits detection of lesions demonstrating metabolic activity together with morphologic information and has advantage of detecting extramedullary disease -100% Variable
  • Intermediate availability
  • Hours
  • Expensive
  • Detects extramedullary disease
  • False-negative and false-positive results with coexisting infection or inflammation

ASO: allele-specific oligonucleotide; CT: computed tomography; MFC: multiparameter flow cytometry; NGS: next-generation sequencing; PCR: polymerase chain reaction; PET: position emission tomography.

Future Applications and Clinical Potential of MRD

A publication from the U.S. Food & Drug Administration (FDA) discussing regulatory perspectives on MRD testing in multiple myeloma concluded that MRD assessment in multiple myeloma has the potential to become a surrogate clinical endpoint that could be used to support regulatory purposes for drug review. Standardization of MRD testing and consensus within the multiple myeloma community as to the role of MRD will be integral steps toward this end.45