Minimal Residual Disease in Multiple Myeloma: Past, Present, and Future
Abstract
:Simple Summary
Abstract
1. Prognostic and Clinical Relevance of Minimal Residual Disease in Multiple Myeloma
1.1. Definition of Minimal Residual Disease
1.2. Baseline and Post-Treatment Outcome Predictors
1.3. Assessment of Treatment Responses in Multiple Myeloma Patients
2. Alternatives for the Detection of Minimal Residual Disease
2.1. Immunophenotypic Approaches
2.1.1. Molecular Basis, Potential Targets, and Technical Considerations
2.1.2. Traditional and Next-Generation Flow Cytometry Approaches
2.1.3. Evidence
2.2. Molecular Approaches
2.2.1. Molecular Basis, Potential Targets, and Technical Considerations
2.2.2. Allele-Specific Oligonucleotide Quantitative PCR
2.2.3. Evidence
2.2.4. Next-Generation Sequencing
2.2.5. Evidences
2.2.6. Digital PCR
2.2.7. Evidence
2.3. Overall Comparison of Contemporary MRD Strategies
3. Future Perspectives
3.1. Liquid Biopsy: Circulating Tumor DNA and Circulating Tumor Cells
3.2. Imaging Techniques
3.3. Mass Spectrometry
4. Open Questions in the Field of MRD
- (a)
- Which patients should be evaluated?
- (b)
- What is the optimal time point for MRD evaluation?
- (c)
- How can we use MRD information?
- (d)
- Which strategy is the best?
5. Conclusions
- (1)
- MRD studies should be performed in the bone marrow, using validated and standardized procedures capable of assessing high sensitivity thresholds, ideally 10−6, which currently includes only NGF and NGS. Each institution may choose the most appropriate based on availability, expertise, and other aspects.
- (2)
- Bone-marrow-based MRD analyses should be performed using the first pull of the aspirate to prevent hemodilution. Evaluating MRD outside the bone marrow is an appealing and complementing option; incorporation of liquid biopsies and imaging techniques in prospective clinical trials would be very helpful to avoid invasive procedures, although more evidence is needed.
- (3)
- The evaluation of MRD should be performed in parallel with other clinical routine assessments at relevant time points, at least including post induction, post transplantation in candidate patients, post consolidation, post maintenance, and periodically during the subsequent follow-up. Single-time-point MRD may be prognostic and informative, but consecutive assessments in order to characterize MRD kinetics should be the goal.
- (4)
- If available, we recommend performing MRD studies for all patients diagnosed with multiple myeloma, in and outside of clinical trials. Results must be interpreted in the particular clinical–biological context of each patient and used for prognostic purposes. Interventional strategies based on MRD should be limited to clinical trials designed with that aim.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Risk Marker | Prognostic Impact | References |
---|---|---|
Classical | ||
Age | Survival decrease with each decade of life | [12] |
Baseline HR cytogenetics | OS < 3 years | [13] |
ISS, OS (months) | [14] | |
I | 62 | |
II | 44 | |
III | 29 | |
R-ISS, 5-year OS rate | [15] | |
I | 82% | |
II | 62% | |
III | 40% | |
Novel | ||
R2-ISS, OS (months) | [16] | |
I | NR | |
II | 109.2 | |
III | 68.5 | |
IV | 37.9 | |
Double-hit, OS (months) | 20.7 | [17] |
Study | Sensitivity (Median) | Treatment Algorithm | MRDneg Rates |
---|---|---|---|
ASCT-eligible | |||
Myeloma XI | 4 × 10−5 | ASCT + R vs. | 65.6% |
(NCT01554852) [55] | no maintenance | 34.4% | |
GEM2012MENOS65 | 3 × 10−6 | VRd + ASCT + VRd | 50.2% |
(NCT01916252) [52,53] | |||
CASSIOPEIA | 10−5 | Part 1: Dara − VTd + ASCT + Dara − VTd vs. | 64% |
(NCT02541383) [57] | VTd + ASCT + VTd | 44% | |
10−5 | Part 2: Maintenance with Dara vs. | 66% | |
observation | 55.2% | ||
EMN02/HO95 | 10−5 | Consolidation with VRd vs. | 9.8% |
(NCT01208766) [54] | No consolidation | 8.2% |
Study | Sensitivity (Median) | Treatment Algorithm | Mrdneg Rates |
---|---|---|---|
ASCT-eligible | |||
IFM2009 | 10−6 | VRd, 8 cycles vs. | 20% |
(NCT01191060) [89] | VRd + ASCT | 30% | |
CASSIOPEIA | 10−5 | Part 1: Dara − VTd + ASCT + Dara − VTd vs. | 57% |
(NCT02541383) [57] | VTd + ASCT + VTd | 37% | |
10−6 | Part 2: Maintenance with Dara vs. | 49.5% | |
observation | 36.7% | ||
GRIFFIN | 10−5 | Dara − VRd + ASCT + Dara − VRd vs. | 51% |
(NCT02874742) [96] | VRd + ASCT + VRd | 20.4% | |
ASCT-non-eligible | |||
ALCYONE | 10−5 | Dara − VMP vs. | 22% |
(NCT02195479) [97,98] | VMP | 6% | |
MAIA | 10−5 | Dara − Rd vs. | 24.2% |
(NCT02252172) [98,99] | Rd | 7.3% | |
Relapsed/refractory | |||
CASTOR | 10−5 | Dara − Vd vs. | 15% |
(NCT02136134) [100] | Vd | 1.6% | |
POLLUX | 10−5 | Dara − Rd vs. | 33.2% |
(NCT02076009) [101] | Rd | 6.7% | |
IKEMA | 10−5 | Isa–Kd vs. | 29.6% |
(NCT03275285) [102] | Kd | 13% |
Standard MFC | NGF | ASOqPCR | NGS | ddPCR | |
---|---|---|---|---|---|
Applicability | 90–100% | 90–100% | 40–75% | ~90% | Comparable to qPCR |
Sensitivity | 10−4–10−5 | 10−5–10−6 | 10−4–10−5 | 10−5–10−6 | At least 10−5 |
Standardization | No | EuroFlow | EuroMRD | ClonoSEQ * | Ongoing |
Turnaround time | 1 day | 1 day | ≥1 week | 4 days–1 week | ≥1 week |
Specific primers/probes | Not applicable | Not applicable | Yes | No | Yes |
Standard curve | Not applicable | Not applicable | Yes | No | No |
Influenced by SHM | No | No | Yes | Yes | Yes |
Baseline BM | No | No | Yes | Yes | Yes |
Fresh sample (processing time) | Yes (24–48 h) | Yes (24 h) | No | No | No |
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Medina-Herrera, A.; Sarasquete, M.E.; Jiménez, C.; Puig, N.; García-Sanz, R. Minimal Residual Disease in Multiple Myeloma: Past, Present, and Future. Cancers 2023, 15, 3687. https://doi.org/10.3390/cancers15143687
Medina-Herrera A, Sarasquete ME, Jiménez C, Puig N, García-Sanz R. Minimal Residual Disease in Multiple Myeloma: Past, Present, and Future. Cancers. 2023; 15(14):3687. https://doi.org/10.3390/cancers15143687
Chicago/Turabian StyleMedina-Herrera, Alejandro, María Eugenia Sarasquete, Cristina Jiménez, Noemí Puig, and Ramón García-Sanz. 2023. "Minimal Residual Disease in Multiple Myeloma: Past, Present, and Future" Cancers 15, no. 14: 3687. https://doi.org/10.3390/cancers15143687