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Table 2 The role of liquid biopsy in predicting therapeutic responses and disease prognosis in MM and precursor conditions

From: Liquid biopsy by analysis of circulating myeloma cells and cell-free nucleic acids: a novel noninvasive approach of disease evaluation in multiple myeloma

Sample

Detection time

Method

Cut-off

Prognostic value

Reference

NDMM

At diagnosis

Wright–Giemsa-stained PB smears

 ≥ 2% CMMCs per 100 nucleated cells on PB smears

1. A prognostic factor for inferior PFS and OS (not independent)

2. The PFS and OS of MM with CMMCs were comparable with primary PCL

[13]

NDMM

At diagnosis

Wright–Giemsa-stained PB smears

 ≥ 5% CMMCs per 100 nucleated cells on PB smears

A prognostic factor for inferior OS independent of age, Scr, DS stage, and ISS stage

[14, 50, 77]

MGUS

/

Slide-based immunofluorescence

Presence of CMMC

1. An independent prognostic factor for inferior PFS and OS

2. Patients with CMMCs were twice as likely to progress than those without CMMCs

[15]

SMM

/

Slide-based immunofluorescence

CMMCs > 5,000 × 106/L and/or > 5% cytoplasmic Ig-positive PCs

1. An independent prognostic factor for inferior TTP and OS

2. A prognostic factor for higher incidences of 2- and 3-year progression

[16]

NDMM

At diagnosis

Slide-based immunofluorescence

 ≥ 4% cytoplasmic Ig-positive CMMCs

An independent prognostic factor for inferior OS

[17]

NDMM

At diagnosis

MFC (2-color)

Presence of CMMC

An independent prognostic factor for inferior PFS and OS

[22]

NDMM

At diagnosis

MFC (2-color)

 > 10 CMMCs/50,000 events

First demonstration of its independent prognostic value of inferior OS

[19]

NDMM

At diagnosis

MFC (2-color)

 ≥ 41 CMMCs/50,000 events

A prognostic factor for inferior PFS and OS independent of standard-risk cytogenetics

[21]

NDMM

Before ASCT

MFC (2-color)

Presence of CMMC

A prognostic factor for inferior TTP (early relapse after ASCT) and OS independent of cytogenetics and response status after induction therapy

[20]

NDMM

At diagnosis

MFC (5-color)

CMMC ≥ 0.02%

Independent prognostic factor of inferior PFS and OS

[24]

SMM

/

MFC (6-color)

 ≥ 150 CMMCs/150,000 events

1. Independent prognostic factor for inferior TTP and OS

2. A prognostic factor for higher incidence of 2-year progression

[30]

NDMM

At diagnosis

MFC (6-color)

Presence of CMMC and ≥ 400 CMMCs/150,000 events

Prognostic factors for inferior TTNT and OS independent of cytogenetic status

[28, 29]

MM in a plateau, RRMM

After therapy

MFC (6-color)

Presence of CMMC and ≥ 100 CMMCs/150,000 events

1. MM in a plateau with CMMCs had inferior OS (independent)

2. RRMM with ≥ 100 CMMCs/150,000 events had inferior OS (independent)

[25]

NDMM

Before ASCT

MFC (6-color)

Presence of CMMC

1. A prognostic factor for PFS and OS independent of post-transplant sCR

2. A prognostic factor for post-transplant response status

[27]

NDMM

At diagnosis, before ASCT and day 100 post-transplant

MFC (6-color)

1. Presence of CMMC

2. Dynamics of CMMCs at diagnosis and before ASCT

(− / −), (+ / −), (+ / +), (− / +)

1. CMMC (+ / +) or (− / +) were factors for lower incidence of pretransplant ≥ VGPR and post-transplant sCR

2. CMMC (+ / +) or (− / +) was an independent factor for inferior PFS and OS

3. Patients with CMMCs at day 100 post-transplant had inferior PFS and OS

[26]

MM with EM

 /

Combination of MACS and MFC (6-color)

Presence of CMMC

The presence of CMMCs in patients with EM disease had worse OS

[35]

NDMM

At diagnosis

MFC (7-color)

 ≥ 0.10% CMMCs/150,000 events

A prognostic factor for inferior PFS and OS independent of R-ISS stage and age

[32]

NDMM

At diagnosis

MFC (2-tube/7-color)

 ≥ 0.038% CMMCs

1. An independent prognostic factor for inferior PFS and OS

2. A factor for higher incidence of ≥ VGPR and ≥ PR

[33]

Transplant-eligible NDMM

At diagnosis

MFC (2-tube/7-color)

 ≥ 0.07% CMMCs (≥ 5 cells/μL)

1. A factor for lower incidences of MRD negativity and ≥ CR at premaintenance

2. A factor for inferior PFS and OS independent of ISS, cytogenetics, and LDH level

3. A similar prognostic value between the cut-off value and continuous variable

[34]

NDMM

Before ASCT

MFC (7-color)

Presence of CMMCs

1. A factor for lower incidence of VGPR or better

2. A prognostic factor for inferior PFS, independent of ISS stage, cytogenetics, and maintenance therapy

3. The presence of CMMC enhanced the stratification of VGPR or better

[31]

MGUS, SMM, MM

At diagnosis

MFC (8-color)

 > 0.0035% CMMCs

An independent prognostic factor of inferior PFS and OS

[68]

MGUS, SMM, MM

At diagnosis

NGF

 ≥ 0.058 CMMCs/µL (for MGUS)

 ≥ 0.1 CMMCs/μL (for SMM and MM)

1. A factor for MGUS of higher incidence of progression in 30 months

2. A factor for SMM of higher incidence of progression to MM in 2 years

3. A factor for MM of inferior PFS and OS independent of CR status or MRD status

[7]

Treated MM

After therapy

NGF

1. Presence of CMMC

2. Kinetics of CMMCs

1. An independent prognostic factor for inferior PFS

2. The presence of CMMC enhanced the stratification of CR/sCR

3. Patients with CMMC − / − or + / − in sequential monitoring showed better PFS than those with CMMC + / + or − / + independent of sIF status

[38]

NDMM

At diagnosis

NGF

 ≥ 0.01% CMMCs (0.6 CMMCs/mL)

1. A factor for inferior PFS independent of ISS stage, LDH, and cytogenetics

2. A prognostic factor for inferior PFS independent of CR status and MRD status

[6]

NDMM

At remission

CellSearch platform

 ≥ 100 CMMCs/4 mL of blood

A prognostic factor for inferior PFS and OS

[39]

NDMM

At diagnosis and 3 months after HDT for ASCT

ASO-qPCR of IgH rearrangement

Presence of CMMC

1. At diagnosis: a prognostic factor for inferior EFS

2. Three months after HDT for ASCT: a prognostic factor for inferior EFS and OS

[5]

RRMM

Before therapy and in remission

NGS (Ion Torrent) of IgH rearrangement

 ≥ 4.7% of total reads

(before therapy)

10−5 or 10−4 of total reads

(at remission)

1. ctDNA levels before therapy were a prognostic factor for inferior PFS

2. ctDNA levels at remission were a prognostic factor for inferior PFS

[12]

NDMM

At diagnosis

ASO-qPCR of IgH rearrangement

Positive + PNQ > 50

A prognostic factor for lower CR rates

[8]

RRMM

At screening and after two cycles of treatment

LP-WGS

 ≥ 10% TF

1. ctDNA levels at screening were a prognostic factor for inferior PFS

2. ctDNA levels at C3D1 were an independent factor for inferior PFS

3. ctDNA levels at C3D1 enhanced the stratification of SD and PR

[47]

MM

/

/

cfDNA > 25.2 ng/mL plasma

ctDNA levels were a prognostic factor for inferior PFS and OS

[9]

NDMM

/

ddPCR (BRAF, KRAS, and NRAS)

Presence of mutations

VAF > 5% trimmed mean value

The presence of mutations and ctDNA levels were related to inferior OS

[79]

NDMM, RRMM

At screening and on C1D5

OMD and ddPCR

1) ≥ 2 plasma-specific mutations or > 1% FA

2) Presence of TP53 mutation

3) FA of ctDNA decrease on C1D5

1. OS was significantly inferior in MM with a high level of mutations in cfDNA

2. OS was significantly inferior in MM with TP53 mutation in plasma

3. Median PFS: significantly inferior in MM with no change or even increasing ctDNA levels at C1D5

[78, 80]