Minimal Residual Disease Assessment in the Context of Multiple Myeloma Treatment

Abstract

With contemporary therapeutic strategies in multiple myeloma, heretofore unseen depth and rate of responses are being achieved. These strategies have paralleled improvements in outcome of multiple myeloma patients. The integration of the next generation of proteasome inhibitors and antibody therapeutics promise continued improvements in therapy with the expectation of consistent depth of response not quantifiable by current clinical methods. As such, there is a growing need to develop adequate tools to evaluate deeper disease response after therapy and to refine the response criteria including the minimal residual disease. Several emerging techniques are being evaluated for these purposes including multi-parameter flow cytometry, allele-specific oligonucleotide polymerase chain reaction, next-generation sequencing, and imaging modalities. In this review, we highlight the recent developments and evaluate advantages and limitations of the current technologies to assess minimal residual disease. We also discuss future applications of these methodologies in potentially guiding multiple myeloma treatment decisions.

Noninvasive Molecular Monitoring in Multiple Myeloma Patients Using Cell-Free Tumor DNA

“…34,35 The use of a PB-based assay for MRD analysis has numerous advantages over any method relying on invasive BMBs. 36 In our study, results obtained analyzing MRD by MFC on BM samples using consensus antibody panels 37 showed complete concordance with cfDNA analysis in all cases. Of note, patients defined as MRD negative by MFC (<5 Â 10 À5 BM PCs) were also characterized by very low frequencies of the tumor-associated clonotype in plasma samples (<10 À5 ) and had a significantly longer PFS than patients with >10 À5 BM PCs.…”

Enumeration and characterization of circulating multiple myeloma cells in patients with plasma cell disorders

“…While promising, the use of NGS for clone tracking‐based detection of MM does not provide clinicians with information about genetic abnormalities associated with disease in a particular patient. Moreover, evolving clonal heterogeneity of the disease and/or clonal processes that often accelerate with age (such as monoclonal B‐cell lymphocytosis, or clonal haematopoiesis of indeterminate potential) may complicate interpretation of results obtained with clone‐tracking techniques, such as NGS (Mailankody et al , ; Szalat & Munshi, , ; Nishihori et al , ). Finally, current NGS testing works best with invasive bone marrow aspirates and may not have sufficient sensitivity to detect MRD in serum, plasma or peripheral blood (Mailankody et al , ).…”

Diagnosis of Plasma Cell Dyscrasias and Monitoring of Minimal Residual Disease by Multiparametric Flow Cytometry

“…Before NGS, ASO-qPCR was regarded as one of the most sensitive assays to detect PCDs with a sensitivity limit of 10 −5 to 10 −6 . 127 ASO-qPCR involves the design of specific primers complementary to the clonal rearrangement in the CDR genes of mature B cells. Puig and colleagues 143 analyzed data from three consecutive myeloma trials that utilized both ASO-qPCR and 4-color MFC to evaluate the MRD negativity and clinical outcome in 170 patients.…”

“…In most clinical laboratories, the detection sensitivity of MFC to identify neoplastic PCs in the bone marrow ranges from 10 −4 (1 in 10,000 cells) to 10 −5 (1 in 100,000 cells). 127 Even though multicenter data has demonstrated that a minimum detection sensitivity of 0.01% is of clear prognostic value for MRD monitoring by MFC, it is evident that as assay sensitivity has increased, so has the correlation between MRD status and clinical outcomes. Today a minimum sensitivity of 0.001% is the accepted norm and the threshold for abnormal PCs used in the determination of MRD ranges from 20 – 100 cells.…”