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