The role of minimal residual disease measurement in multiple myeloma

Introduction

Multiple myeloma is a plasma cell dyscrasia characterized by the monoclonal proliferation of plasma cells. It is the second most common hematological malignancy, with rising global incidence (1). The therapeutic landscape of multiple myeloma has changed significantly over the last years, with many patients now achieving deep and durable responses (2,3). The introduction of novel therapeutics in combination with CD38 targeting monoclonal antibodies and autologous stem cell transplantation in upfront therapy results in very good partial response (VGPR) and complete response (CR) in up to 90% of patients (4-6). Yet, most patients will eventually relapse, indicating that residual and likely resistant cells remain that are below conventional detection limits. Response assessment has traditionally relied on measuring alterations in the monoclonal protein levels in serum and urine, bone marrow plasma cells, and changes in the serum free light chains. However, recently “minimal residual disease” (MRD) assessment has been incorporated in the response assessment, with patients achieving significantly better outcomes if they are MRD-negative (7). Next-generation flow cytometry (NGF) and next-generation sequencing (NGS) enable MRD detection with high sensitivity and specificity and have become treatment goals for nearly all multiple myeloma patients as well as useful endpoints in prospective clinical trials. The use of MRD assessment has expanded rapidly over the last few years and is increasingly being used to guide management, including therapy intensification or de-escalation. In the present review, we discuss several aspects of MRD response assessment, along with endpoints for clinical trials, and highlight future directions.

Methods of assessing MRD and standardization of MRD detection thresholds in multiple myeloma

MRD measurement has emerged as an important tool in assessing response to treatment and predicting outcomes in patients with multiple myeloma. Traditional response criteria based on serum and urine M proteins, bone marrow plasma cells, and serum free light chain assay are insufficient to detect low levels of residual disease, necessitating more sensitive techniques. These include multiparametric flow cytometry (MFC) and molecular methods like allele-specific oligonucleotide quantitative polymerase chain reaction (ASO-qPCR) and NGS of the VDJ sequences (8-11). These methods allow the examination of several hundred to millions of cells or assay their DNA sequences, providing a quantitative estimate of the tumor burden.

Bone marrow-based techniques

Flow cytometry-based methods of MRD detection

MFC-based techniques have gained paramount importance for MRD evaluation in patients with hematological malignancies. Flow cytometry works based on the principle of identification of surface markers to distinguish normal cells from cancer cells. The most commonly employed surface markers that help us differentiate normal plasma cells from malignant cells are CD138, CD38, CD45, CD56, CD19, CD27, CD81, and cytoplasmic κ and λ immunoglobulin light chains (12). Additional markers which tend to be aberrantly expressed on multiple myeloma plasma cells are CD20, CD28, CD117, and CD200, as well as CD54, CD229, CD319. Given significant heterogeneity using these markers, attempts have been made to standardize flow-based MRD assessment in multiple myeloma (13).

Initial flow cytometry-based MRD assessments used a limited number of antibody markers and carried a sensitivity of 10⁻⁴ to 10⁻⁵ (Ability to detect 1 abnormal plasma cell in 10⁴ to 10⁵ cells). However a lack of standardization in staining protocols and data analysis lead to variability in results between different laboratories (14-16). In more recent years, the EuroFlow consortium developed the “Next Generation Flow Cytometry (NGF)” that uses standardized protocols, including antibody panels and data analysis for more reproducible results. Furthermore, NGF uses higher cell acquisition numbers (up to 10⁶) to achieve a higher sensitivity of up to 10⁻⁶ (12).

Molecular methods of MRD detection

The use of ASO-qPCR-based genetic alterations in Immunoglobulin heavy chains (IgH) allows the detection of clonal plasma cells with a sensitivity of 1 in 10⁵ to 10⁶ cells. Therefore, ASO-qPCR provides an accurate quantification of MRD. ASO-qPCR makes primers complementary to the junctional region of the rearranged IGH genes, which are used to interrogate bone marrow samples at different times to determine the response depth. This step requires the availability of the baseline diagnostic sample. Despite its high accuracy in detecting MRD, it is very time-consuming in nature and applicable in only around 42–75% of patients with multiple myeloma. This is because the technique requires personalized primers for each patient which is hindered by the high rate of somatic hypermutation and hence inability to create individualized primers (9,17). Due to the rather low applicability and high labor intensity and given the evolution of other MRD methods, ASO-qPCR is only rarely used.

NGS MRD testing overcomes some of the disadvantages of the ASO-qPCR technique, particularly higher applicability of up to 93% and a standardized approach (18). During initial assessment, NGS identifies the unique V(D)J rearrangements in the IgH gene to create a unique “fingerprint” for that patient. On subsequent assessments, tumor cells can be traced using the patient-specific clonotype. An initial bone marrow sample is needed to identify clones during follow-up assessments. Importantly, although MM cells undergo clonal evolution over time, their V(D)J rearrangements remain typically constant. In rare cases where there are newly emerging clonal sequences over time, NGS will be able to identify those once detection limits of >2% are reached (19). The Food and Drug Administration (FDA)-approved the ClonoSEQ assay, which is the most commonly employed NGS assay for MRD detection and has the highest limit of detection at 6.8×10⁻⁷ (20).

To date, NGS and NGF are the most commonly used techniques to assess for MRD in myeloma. NGF does not require a baseline sample, is faster, and can assess for hemodilution. However, it can be performed only on the fresh sample. On the other hand, NGS requires a baseline clone to track, takes longer time than NGF, and cannot assess for hemodilution, but can be performed on frozen samples as well (21).

Peripheral blood-based techniques

Though bone marrow estimation of MRD is the standard of care, there have been some limitations with the same. Some of the limitations of the bone marrow-based methods are the need for a painful bone marrow aspiration procedure, interference by hemodilution, and false negatives in patients with patchy marrow involvement and those with extramedullary disease (EMD) in the absence of marrow involvement. It has been postulated that peripheral blood testing might hence provide a less painful and more universal milieu for MRD estimation, particularly in those patients with patchy bone marrow involvement and/or those with EMD.

Flow cytometry-based methods of MRD detection

The presence of circulating tumor plasma cells using peripheral blood NGF at the time of diagnosis has been shown to be associated with adverse outcomes (22) prompting further analysis of this technique during or after treatment. In a retrospective study, using 6mL of peripheral blood (≥10⁷ cells per sample), the detection of circulating plasma cells showed to be a less sensitive method compared to bone marrow MRD assessment, with 40% of cases being negative on peripheral blood, but positive in the bone marrow (23). Owing to this rather low sensitivity, further modifications in the technique are being studied (e.g., ‘BloodFlow’); one of the main modification is to increase the extracted peripheral blood volume to levels of around 50 mL (≥10⁸) (24). While this approach can improve sensitivity, it still lags behind conventional bone marrow MRD assessment.

Molecular methods of MRD detection: NGS assessment of the peripheral blood is also limited by low sensitivity. It was found that peripheral blood clonal plasma cells were 2 logs lower than the corresponding bone marrow samples (25). In their totality, NGF and NGS performed on peripheral blood are less sensitive compared with bone marrow methods. Although a peripheral blood MRD-positive result might circumvent the need for bone marrow assessment, a negative result does not.

Mass spectrometry: conventional serum protein electrophoresis has a sensitivity of 0.1 g/dL, and serum immunofixation electrophoresis (IFE) has a sensitivity of 0.05 g/dL (26). The sensitivity of measurement can be increased by mass spectrometry (27). In a study of 447 sequential samples from 56 patients analyzed using clonotypic peptide-based mass spectrometry by Fan et al., using a DOTP score >0.9 as the MS-MRD positive; sensitivity was 99.6% versus IFE and 100.0% versus MFC and NGF (28). Matrix-assisted Laser Desorption-Ionization-Time of Flight (MALDI-TOF) MS and liquid chromatography-mass spectrometry (LC-MS) are the other two types of mass spectrometry that are available for MRD assessment (29,30).

Taken together, one of the main challenge encountered in peripheral blood MRD testing is its lower sensitivity compared to bone marrow MRD testing. In that sense a positive result on a peripheral MRD test is indicative of residual disease and might save the patient from the painful procedure of a bone marrow biopsy. However, a negative MRD result on peripheral blood would still need to be confirmed with a bone marrow biopsy. It is also to be emphasized, that peripheral blood MRD testing is currently available only in a research based setting, with none of these tests having FDA approval yet.

Extramedullary myeloma and focal bone MRD assessment

Functional imaging, such as positron-emission tomography (PET) scan and diffusion-weighted whole body imaging (DWI), is useful to identify extramedullary and focal bone disease and can hence detect active residual disease even in patients where there is no infiltration of multiple myeloma cells on random bone marrow or peripheral blood (31,32). The CASSIOPET study found that 10% of patients that were MRD-negative (<10⁻⁵ using NGF) at the iliac crest were found to have PET-positive focal lesions (33). Similarly, DWI can detect residual focal bone lesions and tends to be more sensitive compared to PET imaging. Rasche et al. showed that 12% of the patients who were in first-line MRD-negative CR had focal lesions on either PET or DWI imaging. These patients had worse progression-free survival (PFS) than those with MRD-negative CR with negative imaging. This number was as high as 50% in patients achieving MRD-negative CR following salvage therapy for relapsed multiple myeloma (34). It is hence to be emphasized that MRD assessment from the bone marrow can be negative despite the presence of active disease, particularly when there is patchy bone marrow involvement and isolated plasmacytomas and/or EMD. In that sense, functional imaging with PET or DWI complements bone marrow or blood-based MRD assessments to look for residual disease during and after treatment in myeloma. Some limitations of functional imaging need to be considered: PET activity depends on high glucose uptake and might be falsely negative if the multiple myeloma cells have low metabolic activity (35,36). DWI signals can be affected by bone marrow hyperplasia, fat content and post-treatment fibrosis/necrosis. Furthermore, small lesions (<5 mm) might be missed by both imaging modalities (37). In these cases future follow up and/or more sensitive imaging studies (as conventional MRI) are necessary to detect growing multiple myeloma cells.

MRD as a strong prognostic marker

Achieving and maintaining MRD-negative status has been consistently shown to be associated with improved outcomes (38-40). Studies have shown that while different treatment regimens can be associated with different rates of MRD-negativity, outcomes after attaining it do not appear to depend on the regimen that led to the development of MRD-negativity (41). Yet other factors play a role when interpreting MRD results, one of them being high risk disease. It has been shown that patients with ≥2 high-risk cytogenetic abnormalities still do poorly even if achieving MRD negativity (3,42). This is probably because patients with high-risk disease tend to have resistant and proliferative cells that rapidly lead to loss of MRD negativity and clinical relapse. In that sense, the achievement of “sustained MRD-negativity” (at least 2 MRD-negative tests a year apart) has been shown to improve the prognostic impact of MRD testing and can overcome some of the high-risk features (43).

MRD assessment has conventionally been done at 100 days post autologous stem cell transplantation, where it has been shown that patients who achieve MRD negativity have significantly better PFS and also overall survival (OS) (11). A study by Muronova et al. found a significantly increased median PFS of 49.2 months in the MRD-negative group compared to 18.4 months in the MRD-positive group. The median OS was not reached among MRD-negative patients and was 74.9 months in the MRD-positive group (44). While MRD is generally measured in patients in CR, MRD-negativity can precede achievement of CR due to delay in clearance of M protein in the blood (45). When this study was stratified according to IMWG uniform response criteria, it was found that MRD-negativity significantly increased median PFS and OS even in VGPR groups compared to MRD-positive patients (44).

The Medical Research Council Myeloma IX study involved patients randomly assigned to receive CTD (cyclophosphamide, thalidomide, and dexamethasone) or CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) therapy, melphalan, and autologous stem cell transplant (ASCT) with the goal of measuring PFS and OS and comparing treatment outcomes. An independent retrospective analysis of this study carried out by Rawstron et al. found that while the choice of induction therapy affects the MRD level achieved, the prognostic value of this level is independent of the induction treatment chosen. Ultimately, the patients who achieved an MRD of less than 0.01% had the same outcome regardless of whether they received CVAD or CTD induction (46). Furthermore, each log depletion in MRD was associated with significantly better OS, highlighting that deeper responses correspond to better outcomes.

Role of MRD in guiding/customizing therapy

It is unclear if MRD status can be used to customize therapy in patients with multiple myeloma. This is being tested in the SWOG S1803 trial, where patients after 2 years of post-ASCT maintenance will be randomized to either continuing or stopping maintenance depending on their MRD status (no further maintenance if MRD is negative at 10⁻⁵) (47). The MASTER trial assigned patients with two consecutive MRD assessments with <10⁻⁵ by NGS to discontinue all therapy. Half of enrolled patients remained off therapy, with the majority of relapses occurring in patients with two or more high-risk cytogenetic abnormalities. An updated analysis found that sustained MRD negativity at 10⁻⁶ was associated with improved PFS compared to sustained MRD negativity at 10⁻⁵, suggesting that the deeper the level of MRD negativity achieved, the better the outcome (48). A phase II study of MRD-adapted elotuzumab, carfilzomib, lenalidomide, and dexamethasone (Elo-KRd) showed that MRD by NGS 10^-6 could be used to effectively guide de-escalation of carfilzomib (49). The phase III randomized ATLAS trial comparing carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide for post-ASCT maintenance allowed patients receiving KRd with standard-risk disease and MRD negativity (<10⁻⁵ if not available) after 6 cycles to de-escalate to lenalidomide; patients who received all 36 cycles of KRd had similar outcomes to those who underwent early de-escalation (50). The ongoing MRD2STOP study (NCT04108624) is using MRD by NGS 10⁻⁶ to guide discontinuation of maintenance therapy; preliminary data showed that maintenance discontinuation in MM patients with a MRD <10⁻⁶ led to low rates of disease resurgence with an estimated 3-year PFS of 85% (20).

Status of MRD testing in multiple myeloma guidelines

The current guidelines were built on the existing International Myeloma Working Group (IMWG) response criteria by adding additional assessments for the detection of MRD in the bone marrow. A comprehensive approach to detect very small amounts of disease both inside and outside of the marrow will require several tests assessing different tumor compartments and probably use different technologies. Furthermore, the added criteria should allow researchers to define a response state that reflects a higher degree of tumor eradication than is possible with the current definition of CR or stringent CR. At this time, the IMWG recommends the use of NGS or next-generation flow for the detection of MRD in the bone marrow based on the availability of the two techniques at each center and the feasibility of individual clinical trials. The comparison between the National Comprehensive Care Network (NCCN) and the European Hematology Association European Society of Medical Oncology (ESMO) is depicted in Table 1 (7,51).

MRD as an end-point in multiple myeloma clinical trials

For years, researchers have been searching for newer and more efficient parameters to help measure the efficacy of various treatment modalities. A previously used hard stop to treatment, like OS, is no longer feasible as the sole endpoint, as it carries the burden of time needed to analyze response to treatment (52). PFS has been a standard treatment endpoint in multiple myeloma for nearly two decades (53). It has contributed to the approval of at least 13 new therapies for patients with multiple myeloma in the United States by cutting down the length of the clinical trial. With the availability of such therapies, patients with multiple myeloma can now live more than 10 years after diagnosis and can have a median PFS of over 5 years (54,55).

Relying on PFS or OS in myeloma can slow ongoing and future trials for newer therapies for newly diagnosed multiple myeloma patients by increasing the period between administration of therapy and the assessment of its risk or benefit. MRD has now consistently been shown to be independently associated with prognosis and large scale meta-analysis have indicated that MRD assessment could be used as a clinical end point in clinical trials (56,57). With these available results, the FDA Oncologic Drugs Advisory Committee voted unanimously in favor of using MRD as a new clinical trial endpoint for accelerated therapy approval in multiple myeloma in April 2024 (58).

Since its recognition and success as a biomarker in studies involving acute lymphoblastic leukemia and chronic myeloid leukemia, MRD has been used as a supplementary endpoint along with PFS in multiple studies (59,60). While better PFS overwhelmingly leads to an increased OS, rarely there can be a discordance between the two (61). This is commonly due to drug toxicity (61,62). For example, initial analysis of the BELLINI trial showed that the addition of venetoclax to a pre-approved treatment for multiple myeloma therapy led to a prolonged PFS but surprisingly decreased OS due to adverse effects of venetoclax (when compared to a placebo group) (63). Subgroup analysis afterwards showed that the toxicity causing decreased OS was seen specifically in the non-t(11;14) population, while patients with t(11;14) or BCL2 high expression benefited from treatment. While accelerated approval based on MRD is essential, the final approval should still depend on the traditional endpoints like OS, underscoring that long-term follow-up is essential.

Numerous trials are evaluating the role of MRD in determining consolidation and maintenance strategy, duration of maintenance treatment, and early rescue therapy in patients who turn from MRD-negative to MRD-positive (see Table 2).

Conclusions and insights

Taken together, MRD assessment is a highly useful tool in patients who have achieved at least a VGPR. While timing and frequency of MRD assessment can depend on the patient’s individual circumstances, including treatment stage, disease status and risk factors, it has been recommended to assess MRD within 6 months post-transplant and then every 6–12 months for patients in a CR or VGPR (64,65). Achieving MRD negativity and sustaining this deep response over a prolonged period of time is one of the best prognostic markers for long-term remission in current multiple myeloma practice and can be used to de-escalate therapy in selected patients. Conversely, the inability to achieve MRD negativity or the conversion from MRD negativity to MRD positivity is significantly associated with worse PFS and tend to herald an impending relapse (66). While sole MRD conversion from a negative to positive status should not necessarily trigger a change of therapy, close observation is usually mandated, particularly in patients with high-risk disease, where clinical relapse or disease progression can occur promptly due to the highly proliferative characteristics. Furthermore, a comprehensive assessment of residual disease also involves the use of functional imaging, such as PET and/or DWI, to rule out focal bone lesions or EMD, which can occur in the absence of a monoclonal protein or even in patients that have no detectable MRD in random bone marrow aspirates from the iliac crest.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://actr.amegroups.com/article/view/10.21037/actr-25-66/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://actr.amegroups.com/article/view/10.21037/actr-25-66/coif). C.S. reports receiving consulting fees from Janssen, Pfizer, OncLive, and Arcellx; payment or honoraria from Janssen and Pfizer; and participation on the Data Safety Monitoring Board or Advisory Board of Janssen and Pfizer. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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References

1. Malard F, Neri P, Bahlis NJ, et al. Multiple myeloma. Nat Rev Dis Primers 2024;10:45. [Crossref] [PubMed]
2. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 2014;28:1122-8. [Crossref] [PubMed]
3. Mohan Lal B, van Rhee F, Al Hadidi S. Current State of Evidence on Definitions and Management of High-Risk Multiple Myeloma. Curr Oncol Rep 2025;27:258-77. [Crossref] [PubMed]
4. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood 2020;136:936-45. [Crossref] [PubMed]
5. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, Carfilzomib, Lenalidomide, and Dexamethasone With Minimal Residual Disease Response-Adapted Therapy in Newly Diagnosed Multiple Myeloma. J Clin Oncol 2022;40:2901-12. [Crossref] [PubMed]
6. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma. N Engl J Med 2024;390:301-13. [Crossref] [PubMed]
7. Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016;17:e328-46. [Crossref] [PubMed]
8. Rawstron AC, Davies FE, DasGupta R, et al. Flow cytometric disease monitoring in multiple myeloma: the relationship between normal and neoplastic plasma cells predicts outcome after transplantation. Blood 2002;100:3095-100. [Crossref] [PubMed]
9. Puig N, Sarasquete ME, Balanzategui A, et al. Critical evaluation of ASO RQ-PCR for minimal residual disease evaluation in multiple myeloma. A comparative analysis with flow cytometry. Leukemia 2014;28:391-7. [Crossref] [PubMed]
10. van Dongen JJ, Langerak AW, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia 2003;17:2257-317. [Crossref] [PubMed]
11. Martinez-Lopez J, Lahuerta JJ, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood 2014;123:3073-9. [Crossref] [PubMed]
12. Flores-Montero J, Sanoja-Flores L, Paiva B, et al. Next Generation Flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia 2017;31:2094-103. [Crossref] [PubMed]
13. Stetler-Stevenson M, Paiva B, Stoolman L, et al. Consensus guidelines for myeloma minimal residual disease sample staining and data acquisition. Cytometry B Clin Cytom 2016;90:26-30. [Crossref] [PubMed]
14. Roshal M, Flores-Montero JA, Gao Q, et al. MRD detection in multiple myeloma: comparison between MSKCC 10-color single-tube and EuroFlow 8-color 2-tube methods. Blood Adv 2017;1:728-32. [Crossref] [PubMed]
15. Takamatsu H, Yoroidaka T, Fujisawa M, et al. Comparison of minimal residual disease detection in multiple myeloma by SRL 8-color single-tube and EuroFlow 8-color 2-tube multiparameter flow cytometry. Int J Hematol 2019;109:377-81. [Crossref] [PubMed]
16. Riebl V, Dold SM, Wider D, et al. Ten Color Multiparameter Flow Cytometry in Bone Marrow and Apheresis Products for Assessment and Outcome Prediction in Multiple Myeloma Patients. Front Oncol 2021;11:708231. [Crossref] [PubMed]
17. Sarasquete ME, García-Sanz R, González D, et al. Minimal residual disease monitoring in multiple myeloma: a comparison between allelic-specific oligonucleotide real-time quantitative polymerase chain reaction and flow cytometry. Haematologica 2005;90:1365-72.
18. Hultcrantz M, Rustad EH, Yellapantula V, et al. Capture Rate of V(D)J Sequencing for Minimal Residual Disease Detection in Multiple Myeloma. Clin Cancer Res 2022;28:2160-6. [Crossref] [PubMed]
19. Singh RR. Next-Generation Sequencing in High-Sensitive Detection of Mutations in Tumors: Challenges, Advances, and Applications. J Mol Diagn 2020;22:994-1007. [Crossref] [PubMed]
20. Derman BA, Major A, Cooperrider J, et al. Discontinuation of maintenance therapy in multiple myeloma guided by multimodal measurable residual disease negativity (MRD2STOP). Blood Cancer J 2024;14:170. [Crossref] [PubMed]
21. Yee AJ, Raje N. Minimal residual disease in multiple myeloma: why, when, where. Hematology Am Soc Hematol Educ Program 2021;2021:37-45. [Crossref] [PubMed]
22. Bertamini L, Oliva S, Rota-Scalabrini D, et al. High Levels of Circulating Tumor Plasma Cells as a Key Hallmark of Aggressive Disease in Transplant-Eligible Patients With Newly Diagnosed Multiple Myeloma. J Clin Oncol 2022;40:3120-31. [Crossref] [PubMed]
23. Sanoja-Flores L, Flores-Montero J, Puig N, et al. Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy. Blood 2019;134:2218-22. [Crossref] [PubMed]
24. Notarfranchi L, Zherniakova A, Lasa M, et al. Ultra-Sensitive Assessment of Measurable Residual Disease (MRD) in Peripheral Blood (PB) of Multiple Myeloma (MM) Patients Using Bloodflow. Blood 2022;140:2095-7.
25. Vij R, Mazumder A, Klinger M, et al. Deep sequencing reveals myeloma cells in peripheral blood in majority of multiple myeloma patients. Clin Lymphoma Myeloma Leuk 2014;14:131-139.e1. [Crossref] [PubMed]
26. Morrison T, Booth RA, Hauff K, et al. Laboratory assessment of multiple myeloma. Adv Clin Chem 2019;89:1-58. [Crossref] [PubMed]
27. Woods AG, Sokolowska I, Ngounou Wetie AG, et al. Mass Spectrometry for Proteomics-Based Investigation. Adv Exp Med Biol 2019;1140:1-26. [Crossref] [PubMed]
28. Fan H, Wang B, Shi L, et al. Monitoring Minimal Residual Disease in Patients with Multiple Myeloma by Targeted Tracking Serum M-Protein Using Mass Spectrometry (EasyM). Clin Cancer Res 2024;30:1131-42. [Crossref] [PubMed]
29. Barnidge DR, Krick TP, Griffin TJ, et al. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry to detect monoclonal immunoglobulin light chains in serum and urine. Rapid Commun Mass Spectrom 2015;29:2057-60. [Crossref] [PubMed]
30. Derman BA, Stefka AT, Jiang K, et al. Measurable residual disease assessed by mass spectrometry in peripheral blood in multiple myeloma in a phase II trial of carfilzomib, lenalidomide, dexamethasone and autologous stem cell transplantation. Blood Cancer J 2021;11:19. [Crossref] [PubMed]
31. Zamagni E, Tacchetti P, Barbato S, et al. Role of Imaging in the Evaluation of Minimal Residual Disease in Multiple Myeloma Patients. J Clin Med 2020;9:3519. [Crossref] [PubMed]
32. Moreau P, Attal M, Caillot D, et al. Prospective Evaluation of Magnetic Resonance Imaging and [18F]Fluorodeoxyglucose Positron Emission Tomography-Computed Tomography at Diagnosis and Before Maintenance Therapy in Symptomatic Patients With Multiple Myeloma Included in the IFM/DFCI 2009 Trial: Results of the IMAJEM Study. J Clin Oncol 2017;35:2911-8.
33. Kraeber-Bodéré F, Zweegman S, Perrot A, et al. Prognostic value of positron emission tomography/computed tomography in transplant-eligible newly diagnosed multiple myeloma patients from CASSIOPEIA: the CASSIOPET study. Haematologica 2023;108:621-6. [Crossref] [PubMed]
34. Rasche L, Alapat D, Kumar M, et al. Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia 2019;33:1713-22. [Crossref] [PubMed]
35. Rasche L, Angtuaco E, McDonald JE, et al. Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood 2017;130:30-4. [Crossref] [PubMed]
36. Barker DW, Zagoria RJ, Morton KA, et al. Evaluation of liver metastases after radiofrequency ablation: utility of 18F-FDG PET and PET/CT. AJR Am J Roentgenol 2005;184:1096-102. [Crossref] [PubMed]
37. Torkian P, Mansoori B, Hillengass J, et al. Diffusion-weighted imaging (DWI) in diagnosis, staging, and treatment response assessment of multiple myeloma: a systematic review and meta-analysis. Skeletal Radiol 2023;52:565-83. [Crossref] [PubMed]
38. Mateos MV, San-Miguel J, Cavo M, et al. Daratumumab Plus Bortezomib, Melphalan, and Prednisone (D-VMP) Versus Bortezomib, Melphalan, and Prednisone (VMP) Alone in Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of the Phase 3 Alcyone Study. Blood 2022;140:10157-9.
39. Cavo M, San-Miguel J, Usmani SZ, et al. Prognostic value of minimal residual disease negativity in myeloma: combined analysis of POLLUX, CASTOR, ALCYONE, and MAIA. Blood 2022;139:835-44. [Crossref] [PubMed]
40. Korde N, Roschewski M, Zingone A, et al. Treatment With Carfilzomib-Lenalidomide-Dexamethasone With Lenalidomide Extension in Patients With Smoldering or Newly Diagnosed Multiple Myeloma. JAMA Oncol 2015;1:746-54. [Crossref] [PubMed]
41. Avet-Loiseau H, San-Miguel J, Casneuf T, et al. Evaluation of Sustained Minimal Residual Disease Negativity With Daratumumab-Combination Regimens in Relapsed and/or Refractory Multiple Myeloma: Analysis of POLLUX and CASTOR. J Clin Oncol 2021;39:1139-49. [Crossref] [PubMed]
42. Guerrero C, Puig N, Cedena MT, et al. Predictors of unsustained measurable residual disease negativity in transplant-eligible patients with multiple myeloma. Blood 2024;143:597-603. [Crossref] [PubMed]
43. Goicoechea I, Puig N, Cedena MT, et al. Deep MRD profiling defines outcome and unveils different modes of treatment resistance in standard- and high-risk myeloma. Blood 2021;137:49-60. [Crossref] [PubMed]
44. Muronova L, Soucek O, Zihala D, et al. Real-World Evidence on Prognostic Value of MRD in Multiple Myeloma Using Flow Cytometry. Eur J Haematol 2025;114:155-63. [Crossref] [PubMed]
45. Paiva B, San-Miguel J, Avet-Loiseau H. MRD in multiple myeloma: does CR really matter? Blood 2022;140:2423-8. [Crossref] [PubMed]
46. Rawstron AC, Gregory WM, de Tute RM, et al. Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction. Blood 2015;125:1932-5. [Crossref] [PubMed]
47. Dhakal B, Usmani S. Daratumumab and Lenalidomide Maintenance Guided by Minimal Residual Disease in Multiple Myeloma. The Hematologist 2021;18.
48. Costa LJ, Chhabra S, Medvedova E, et al. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol 2023;10:e890-901. [Crossref] [PubMed]
49. Derman BA, Kansagra A, Zonder J, et al. Elotuzumab and Weekly Carfilzomib, Lenalidomide, and Dexamethasone in Patients With Newly Diagnosed Multiple Myeloma Without Transplant Intent: A Phase 2 Measurable Residual Disease-Adapted Study. JAMA Oncol 2022;8:1278-86. [Crossref] [PubMed]
50. Dytfeld D, Wróbel T, Jamroziak K, et al. Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial. Lancet Oncol 2023;24:139-50. [Crossref] [PubMed]
51. Dimopoulos MA, Moreau P, Terpos E, et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2021;32:309-22. [Crossref] [PubMed]
52. Avet-Loiseau H, Ludwig H, Landgren O, et al. Minimal Residual Disease Status as a Surrogate Endpoint for Progression-free Survival in Newly Diagnosed Multiple Myeloma Studies: A Meta-analysis. Clin Lymphoma Myeloma Leuk 2020;20:e30-7. [Crossref] [PubMed]
53. Mohyuddin GR, Koehn K, Abdallah AO, et al. Use of endpoints in multiple myeloma randomized controlled trials over the last 15 years: A systematic review. Am J Hematol 2021;96:690-7. [Crossref] [PubMed]
54. Al Hadidi S, Ababneh OE, Schinke CD, et al. Curability of multiple myeloma (MM) based on relative survival rate (RSR) in patients (pts) treated on earlier total therapy (TT) protocols. J Clin Oncol 2023;41:8059.
55. Usmani SZ, Facon T, Hungria V, et al. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: the randomized phase 3 CEPHEUS trial. Nat Med 2025;31:1195-202. [Crossref] [PubMed]
56. Landgren O, Prior TJ, Masterson T, et al. EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical end point for multiple myeloma. Blood 2024;144:359-67. [Crossref] [PubMed]
57. Shi Q, Paiva B, Pederson LD, et al. Minimal Residual Disease-Based End Point for Accelerated Assessment of Clinical Trials in Multiple Myeloma: A Pooled Analysis of Individual Patient Data From Multiple Randomized Trials. J Clin Oncol 2025;43:1289-301. [Crossref] [PubMed]
58. Costa LJ. MRD accelerating myeloma drug development. Blood 2024;144:345-7. [Crossref] [PubMed]
59. Savona MR. Molecular monitoring and minimal residual disease in the management of chronic myelogenous leukemia. J Community Support Oncol 2014;12:171-8. [Crossref] [PubMed]
60. van Dongen JJ, van der Velden VH, Brüggemann M, et al. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood 2015;125:3996-4009. [Crossref] [PubMed]
61. Usmani SZ, Schjesvold F, Oriol A, et al. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol 2019;6:e448-58. [Crossref] [PubMed]
62. Schjesvold FH, Dimopoulos MA, Delimpasi S, et al. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study. Lancet Haematol 2022;9:e98-e110. [Crossref] [PubMed]
63. Kumar S, Harrison SJ, Cavo M, et al. Final Overall Survival Results from BELLINI, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma. Blood 2021;138:84.
64. Ramasamy K, Avet-Loiseau H, Hveding Blimark C, et al. Measurable Residual Disease Testing in Multiple Myeloma Routine Clinical Practice: A Modified Delphi Study. Hemasphere 2023;7:e942. [Crossref] [PubMed]
65. Burgos L, Puig N, Cedena MT, et al. Measurable residual disease in multiple myeloma: ready for clinical practice? J Hematol Oncol 2020;13:82. [Crossref] [PubMed]
66. Mohan M, Kendrick S, Szabo A, et al. Clinical implications of loss of bone marrow minimal residual disease negativity in multiple myeloma. Blood Adv 2022;6:808-17. [Crossref] [PubMed]