Table 6 Longitudinal monitoring of therapeutic responses and disease status using liquid biopsy

CMMC

CellSearch

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Patients who achieved remission had much lower CMMCs than at baseline, and who had relapsed had elevated CMMC levels

[39]

CMMC

IgH-qPCR

IgH rearrangement

In 66% of cases with progression, the 2IgH/b-actin ratio increased 4 months earlier than the relapse defined by the EBMT criteria

[5]

cfDNA

Ion Torrent

IgH rearrangement

A similar trend was observed between the levels of ctDNA and tumor dynamics evaluated using the IMWG criteria

[12]

cfDNA

NGS

IgK and IgL rearrangements

cfDNA profiles allowed for the detection of serologically measurable and unmeasurable MM (oligo-/non-secretory myeloma)

[36]

cfDNA

ASO-qPCR

IgH rearrangement

ctDNA levels decreased in response to therapy. The number of samples with undetectable ctDNA significantly increased over time

[8]

cf-mRNA

RNA-seq

IgH and IgL rearrangements

Longitudinal cf-mRNA profiling reflected the therapeutic response following melphalan-based treatment and ASCT

[54]

cfDNA

ULP-WGS

TF via CNA

The dynamics of TF in cfDNA were consistent with those of the FLC ratio in sequential monitoring

[46]

cfDNA

LP-WGS

TF via CNA

1. The dynamics of TF in cfDNA were consistent with those of sFLC in sequential monitoring

2. Sequential cfDNA analysis reflected the clonal evolution in BM clonal PCs when relapse and drug resistance occurred

[49]

cfDNA

ULP-WGS

TF via CNA

1. The kinetics of TF in cfDNA were consistent with those of BMPCs from SMM to MM to 3 months post-induction

2. The kinetics of TF in cfDNA were consistent with the changes in PET-CT

[74]

cfDNA

ULP-WGS

TF via CNA

1. A decline in cfDNA burden was observed as early as 1 week after treatment initiation

2. cfDNA showed robust and early detection of imminent relapse independent of low levels of serological parameters

[47]

CMMC

scDNA-seq

Somatic mutations

The clonal architecture of CMMCs exhibited remarkable similarities between remission and relapse

[51]

cfDNA

TAS

Allele fraction of mutations

The tumor fraction in cfDNA increased in the progression of SMM, which was consistent with the elevation in the FLC and BMPCs

[9]

cfDNA

NGS

Allele fraction of mutations

1. The ctDNA clonal structure was highly heterogeneous before and after six rounds of therapy

2. ctDNA samples from patients with CR and VGPR showed pathways enriched only in the clonal mutations, whereas ctDNA from patients with PR and PD showed pathways enriched only in the subclonal mutations

[73]

cfDNA

ddPCR

Allele fraction of mutations

1. High concordances were observed in ctDNA profiles among serial PB samples and between paired PB and BM samples

2. The serological response and the kinetics of the specific mutation in cfDNA showed discordance during the therapy

3. Clinical disease progression was associated with an increase in VAFs of NRAS and KRAS mutations

[3]

cfDNA

ddPCR

Allele fraction of mutations

The dynamics of the specific mutation in cfDNA showed similar or earlier disease detection than the serum light chain

[59]

cfDNA

WES and ddPCR

Allele fraction of mutations

1. Longitudinal sequencing of cfDNA reflected the clonal evolution during progression

2. In a patient with EM and oligosecretory MM, the VAF of NRAS Q61H in cfDNA continued increasing along with the persisting EM lesion, in contrast to the absence of FLC response, indicating the potential drug resistance of the clone

[91]

cfDNA

(7 years)

ddPCR

Allele fraction of mutations

1. The kinetics of mutated VAF in cfDNA and M protein were highly covariant. ctDNA monitoring identified relapse parallel with or several months earlier than M protein and detected relapse in a case with light chain escape

2. Longitudinal sequencing of cfDNA reflected the change in genetic profile through the disease progress

3. In terminal disease, ctDNA reflected the development of disease better than M protein

[75]

cfDNA

ddPCR

Allele fraction of mutations

The dynamics of tumor-related mutations were concordant with the therapeutic response evaluated using paraprotein in serum, whereas cfDNAs were more sensitive for early detection of disease progression and relapse than sFLC

[108]

cfDNA

ddPCR

Allele fraction of mutations

1. The VAF of ctDNA coincided with or appeared to be better than the changes in sFLC in reflecting disease status and therapeutic response of patients with MM even in cases with light chain escape or nonsecretory MM

2. The longitudinal monitoring of cfDNA revealed the clones with differential therapeutic responses to different therapy

[10]

cfDNA

ddPCR

Allele fraction of mutations

1. Tumor fraction in cfDNA was correlated with changes in serum FLC or paraprotein and clinical progression in 87% of cases

2. Sequential sequencing revealed the clones with differential responses to drug treatment in individuals

[80]