Search strategy
We conducted a comprehensive literature search in PubMed and Google Scholar for focused on English-language studies published from 2015 to 2025. Search terms included ‘measurable residual disease’, ‘minimal residual disease’, ‘hematologic malignancies’, ‘AML’, ‘ALL’, ‘CLL’, ‘multiple myeloma’, ‘flow cytometry’, ‘next-generation sequencing’, ‘PCR’, and ‘ddPCR’, combined with terms for study types such as ‘clinical trial’, ‘randomized controlled trial’, ‘meta-analysis’, ‘systematic review’, ‘practice guidelines’, and ‘observational study’. We manually screened references of selected articles, reviews, meta-analyses, and guidelines to identify additional studies. Data from this search was integrated into illustrative examples to summarize the clinical utility and scope of measurable residual disease in hematologic malignancies.
MRD as a prognostic tool
MRD status has near-universal prognostic significance across hematologic malignancies. MRD positivity signifies residual disease and worse outcomes, while MRD negativity suggests a lower or absent disease burden (depending on the sensitivity of the MRD test) and a better prognosis. Examples across hematologic malignancies abound.
In acute myeloid leukemia (AML), both adult and pediatric patients who achieve complete remission (CR) or CR with incomplete hematologic recovery show significantly different 5-year overall survival (OS) rates based on their minimal residual disease (MRD) status—68% if MRD-negative versus 34% if MRD-positive. 1 In acute lymphoblastic leukemia (ALL), MRD positivity is the strongest predictor of relapse, and its prognostic significance has been demonstrated in both pediatric and adult ALL. A meta-analysis of 39 studies that included over 13,000 patients found a consistent association between MRD negativity and improved event-free survival (EFS) (Hazard ratio (HR) 0.23 (95% BCI 0.18–0.28) for pediatric patients and 0.28 (95% BCI 0.24–0.33) for adult patients) and OS (HR 0.28 (95% BCI 0.19–0.41) for pediatric patients and 0.28 (95% BCI 0.20–0.39)) for adult patients. 2 Similarly, in chronic lymphocytic leukemia (CLL), a systematic review and meta-analysis of prospective trials including 2765 patients confirmed a strong association between MRD status and progression-free survival (PFS) (HR 0.28 (95% CI, 0.20–0.39; P < 0.001)), particularly in the first-line treatment setting (HR 0.24 (95% CI, 0.18–0.33)) and with time-limited therapy (HR 0.28 (95% CI, 0.19–0.40)). Achieving undetectable MRD translated to a 72% reduction in the risk of progression or death, with this benefit persisting across treatment strategies, therapy durations, MRD assessment methods, cytogenetic risk groups, and patient populations. 3
Multiple myeloma follows similar patterns associating MRD with outcomes, with meta-analyses demonstrating that despite challenges such as small sample sizes, variability in patient populations, treatment regimens, and MRD assessment methods, MRD negativity consistently correlated with superior PFS (HR 0.33; 95% CI, 0.29–0.37; P < 0.001) and OS (HR 0.45; 95% CI, 0.39–0.51; P < 0.001), regardless of sensitivity thresholds, cytogenetic risk, or timing of MRD evaluation. 4 , 5
While MRD negativity has emerged as a powerful predictor of survival and a valuable endpoint in drug development—as demonstrated by agents like blinatumomab in ALL—its role in clinical decision-making remains complex. A binary classification of MRD as positive or negative can certainly inform therapeutic intensification and, potentially, de-escalation. In other contexts, this black-and-white framework may oversimplify a nuanced clinical landscape. In diseases like AML, where patients in CR may share similar baseline risk, MRD testing raises an important question: can it help better identify those individuals truly at greatest risk of relapse? We are still learning how to move beyond categorical MRD assessments toward more individualized strategies that consider MRD depth, kinetics, and other patient- and treatment-specific factors. Importantly, it remains to be proven that targeting the biomarker—i.e., striving to “erase” MRD—consistently translates into outcomes that matter most to patients, such as improved survival and quality of life.
Considerations in MRD assessment
MRD testing is not a one-size-fits-all concept; in general, its clinical relevance is highly dependent on disease- and biology-specific contexts. While many assays are broadly categorized as “MRD”, meaningful clinical application requires careful assessment of the most appropriate testing modality and the necessary depth of detection for each disease at the specific timepoints. The concept of MRD itself is also subject to ongoing refinement, and assays once considered indicative of measurable residual disease are now more accurately understood to be reflective of active disease burden. 6
Two of the most striking examples of successful implementation of MRD in clinical practice have occurred in the management of acute promyelocytic leukemia (APL) and chronic myeloid leukemia (CML), both cancers driven by well-defined and conserved molecular alterations that are, in fact, disease-defining (The PML-RARa translocation in the former, and the BCR-ABL translocation in the latter). In these diseases, MRD assessment by RT-PCR is considered highly reliable and has been successfully integrated into treatment algorithms to guide therapy duration, assess response, predict relapse, and identify when changes in therapy may be appropriate. In APL, PML-RARα detection by RT-PCR was shown to predict relapse as early as the 1990's, during the chemotherapy era of treatment for APL, a finding later confirmed in modern chemotherapy-free regimens. Subsequent evidence of greater concordance between bone marrow (BM) and peripheral blood (PB) detection led to a reduced need for repeated BM biopsies, ultimately leading to the incorporation of MRD assessments into European Leukemia Net (ELN) guidelines. 7 , 8 , 9
Similarly, it has been recognized for decades that CML activity is linked to the detection of its genetic underpinnings. Over the past two decades, strong evidence from the initial randomized trials of tyrosine kinase inhibitors (TKIs) has led to the development of CML MRD guidelines, wherein RT-PCR can reliably guide therapy by assessing response at regular intervals, informing TKI switching when early milestones (BCR-ABL1 > 10% at 3 or 6 months) are not met, and determining eligibility for treatment-free remission after stable deep molecular response (BCR-ABL1 ≤ 0.01% IS) is achieved and maintained for at least three years. 10 , 11
Assay issues
Extending this approach to malignancies with greater genetic and biological heterogeneity presents significant challenges, reinforcing the need for continued refinement of MRD methodologies across different disease contexts. Efforts to harmonize MRD approaches across laboratories have been led by major consortia such as EuroFlow and EuroMRD. EuroFlow established and published standardized multiparametric flow cytometry (MFC) MRD protocols, focusing on ALL, 12 CLL, 13 and multiple myeloma. 14 , 15 For multiple myeloma, the EuroFlow NGF approach is regarded as the MFC gold standard for MRD assessment according to IMWG guidelines. 16 EuroMRD, formerly known as ESG-MRD-ALL, consists of 71 laboratories across 27 countries and focuses on molecular MRD assessment in ALL 17 and lymphoma, 18 aiming for standardized molecular MRD quantification in lymphoid malignancies. The EuroMRD interpretation guidelines currently form the basis for molecular MRD quantification in most non-American clinical trials for ALL in children and adults. 19
Although these consortia have greatly advanced MRD harmonization in lymphoid malignancies, comparable standardization in AML remains an unmet need. For example, MFC is an accepted MRD tool for AML and ALL, its sensitivity is markedly lower in AML. The genetic heterogeneity of AML and the absence of universal MFC markers challenge assay standardization. 20 Specifically, the lack of a standardized panel of AML-associated antigen combinations and the variability in gating strategies across laboratories contribute to significant inter-laboratory differences in MRD detection and quantification. Consequently, the relatively high ELN MRD threshold of 0.1% MFC-MRD reflects these limitations. At this level of detection, MRD positivity after appropriate therapy is a suboptimal tool for disease risk stratification with a high likelihood of false negatives in AML. 21 In other words, the presence of 1%–0.1% residual blasts by MFC is likely consistent with persistent disease, rather than true minimal residual disease, akin to the way SPEP functions in myeloma. 22 In contrast, the relatively uniform immunophenotypic marker profile seen in ALL allows for a standardized, highly sensitive MRD detection threshold (up to 10 −5 ), making it approximately comparable to PCR-based MRD assessments and serving as a more refined, and standardized, prognostic tool. 2 , 12 While this limitation is acknowledged, these low-level MFC detections may be clinically actionable in AML, even leading to modifications in treatment intensification, underscoring the need to refine their interpretation through prospective outcome correlation. 23 , 24
PCR-based assays are considered considerably more effective at monitoring MRD in AML, but are limited to the minority of patients with specific, molecularly defined subtypes of disease, such as NPM1. 25 In AML transplant studies, DNA sequencing of pretransplant blood samples from adults with AML in first remission detected residual FLT3-ITD or NPM1 variants in 17.3% of patients. The presence of these variants was associated with significantly higher 3-year relapse rates (68% vs. 21%) and worse overall survival (39% vs. 63%), demonstrating the prognostic utility of pretransplant MRD assessment by DNA sequencing, 26 and raising the treatment question of the utility of transplant, and of continuing FLT3 inhibitor therapy post-transplant.
The significance of other mutations in AML, however, is much less clear, both pre- and post-transplant. For example, one study showed that patients with persistence of mutations associated with clonal hematopoiesis of indeterminate potential (CHIP) post-transplant, such as DNMT3A , TET2 , and ASXL1 (collectively termed “DTA” mutations), were no more likely to relapse than those without these mutations, though some subsequent studies are starting to dispute this finding. 27 , 28 A significant gap in molecular MRD standardization for AML, beyond NPM1 and FLT3-ITD, is the lack of consensus on the prognostic significance and actionable thresholds for a broader panel of mutations. This heterogeneity in prognostic interpretation further highlights the need for standardized reporting frameworks, a goal currently being advanced by collaborative efforts such as the ELN MRD Working Party and EuroMRD. The ELN MRD Working Party is actively developing consensus recommendations for the interpretation and reporting of molecular MRD in AML, including guidelines for next-generation sequencing (NGS) based approaches, while EuroMRD provides inter-laboratory quality control for molecular targets. These groups are actively working toward consensus definitions for clinically meaningful MRD in molecularly defined AML subtypes, and their recommendations are expected to enhance future MRD evaluation. At present, the ongoing debate surrounding such discrepancies, coupled with the broader challenge of standardizing MRD assessment in the context of disease status has led to continued uncertainty in the application of MRD in clinical decision-making.
In some disease contexts, this uncertainty is exacerbated by the challenge of interpreting MRD detected below established thresholds, in which MRD may still be present at levels lower than what is considered prognostically significant but escapes the assay's technical limit of detection. Advances in assay sensitivity now allow for the detection of residual mutations at levels previously considered undetectable. Empirically, these patients would be classified as “MRD negative” according to conventional thresholds, yet modern assays still identify a mutation—raising the question of how such findings should be interpreted, and how these patients should be managed clinically. One example occurred about a decade ago, when the standard threshold for MRD detection of the BCR-ABL translocation for CML shifted from a depth of 10 3 to a depth of 10 4.5 . 29 Almost overnight, patients and their doctors who were basking in the glow of a complete molecular remission again found themselves in the badlands of measurable disease, which had profound implications for considering cessation of tyrosine kinase inhibitor therapy. Sometimes, these advances resolve long-standing ambiguities—and other times, they bring new questions to the forefront, offering fresh opportunities to refine clinical decision-making.
Choosing the right compartment: where to look
Choosing the right compartment for MRD testing is a critical challenge in hematologic malignancies, as it directly impacts both the accuracy of the assay and its prognostic value. In multiple myeloma, BM evaluation is traditionally the gold standard for MRD detection due to the disease's primary localization site. However, BM assessments are not ideal for frequent and dynamic monitoring, which may be necessary for MRD-adapted treatment strategies. While next-generation flow cytometry and sequencing have improved the sensitivity for detecting residual malignant plasma cells, the concordance between PB and BM remains suboptimal. PB MRD detection methods may reliably identify persistent disease, but their ability to rule out residual disease is less robust, highlighting the need for improved strategies to enhance negative predictive capabilities. 30 , 31 , 32 , 33
Pediatric ALL, largely considered a pediatric oncology success story, has had more robust MRD assessment data compared to many other hematologic cancers for decades, and provides useful context for compartment-specific MRD testing. In T-lineage ALL, concordance studies have shown that leukemia-associated immunophenotypes in PB mirror those in BM, suggesting that PB could be a reliable and accessible alternative for MRD monitoring. 34 , 35 This phenomenon may stem from the thymic origin of T-ALL, which often presents as a disseminated disease with comparable MRD levels in PB and BM.
In contrast, B-cell ALL, which originates in the BM, frequently exhibits undetectable or significantly lower MRD levels in PB compared to BM. 34 , 35 As might be expected, when MRD is detectable in PB, it correlates with a more aggressive disease course and an increased relapse risk. These findings highlight the need to consider the biological differences between compartments when developing MRD monitoring strategies, and the specific purpose of each assessment. At timepoints were the most sensitive test is warranted, BM assessment is ideal. However, although less sensitive overall, PB MRD positivity may represent a biologically high-risk state, and could be leveraged as a trigger for therapeutic intensification.
Consistent with pediatric data, studies in adult ALL using RQ-PCR testing in a central reference laboratory have shown similar differences in MRD levels between PB and BM, though rare instances of higher MRD levels in PB have been observed. 36 Potential explanations for this discrepancy include the presence of extramedullary disease, sampling variability, or patchy leukemia distribution.
In the case of chronic lymphocytic leukemia (CLL), peripheral blood (PB) is a convenient and patient-friendly source for long-term MRD monitoring. MRD detection in PB is associated with much higher risk of progression when compared to the BM and, hence, could potentially be a more reliable tool to intensify according to MRD. A downside to PB testing is that, while practical, it may not reliably reflect disease in lymph nodes or bone marrow, especially in patients with bulky nodal involvement or incomplete tissue responses. BM assessment, though more invasive, provides greater sensitivity (with ∼80–85% concordance to PB at 10 −4 , varying by treatment) and remains the gold standard in clinical trials—particularly after fixed-duration therapies, where residual disease may persist in BM despite PB clearance. 8 , 37 This improved sensitivity is valuable, as it leads investigators, clinicians, and patients down a path of identifying “true” MRD negativity, potentially as a biomarker of cure or prolonged disease-free survival. It should serve as a “north star” for less invasive techniques. This discordance does call into question, though, the value of PB MRD negativity in guiding treatment discontinuation or serving as a surrogate for deep remission expected with fixed duration therapy. In CLL patients on indefinite therapies such as the Bruton's tyrosine kinase inhibitors, persistent nodal disease despite PB MRD clearance creates additional clinical interpretation uncertainty. 38 , 39
While lymph node sampling in lymphomas with extramedullary involvement could provide valuable biological insights, its clinical feasibility remains limited by invasiveness. Residual disease in these sanctuary sites (lymph nodes, spleen, liver) often explains discordant MRD results and late relapses observed in practice. 37 , 40 These MRD detection ‘blind spots’ have accelerated development of hybrid surveillance strategies combining functional imaging (e.g., PET/CT) with liquid biopsy biomarkers—an approach that leverages the complementary strengths of anatomic and molecular assessment. Although standardization is ongoing, such multimodal protocols increasingly represent the frontier of comprehensive disease monitoring, particularly for malignancies with complex compartmentalization.
Blood-based MRD testing using circulating tumor DNA (ctDNA) has more recently entered clinical guidelines for aggressive lymphomas. Notably, the NCCN now includes a category 2B recommendation for ctDNA-based MRD testing in PET-positive DLBCL when biopsy is infeasible, requiring assays with sensitivity below 1 part per million. This precedent reflects growing recognition that integrating molecular surveillance with anatomic imaging may help resolve diagnostic uncertainty—particularly when traditional sampling is not feasible or yields discordant results. 41
Overall, compartment-specific sensitivity must be weighed against patient burden to optimize the utility of minimally invasive testing. The variability in MRD detectability across compartments and diseases underscores the need for a tailored approach—one that prioritizes blood-based testing where validated but acknowledges its limitations in capturing systemic disease burden. This reinforces the importance of disease-specific monitoring strategies, where MRD is neither a standalone tool nor a universal surrogate, but rather a dynamic component of comprehensive disease management that integrates clinical risk factors, therapeutic intent, and ongoing standardization efforts.
Timing of assessment and kinetics of disease clearance
While we have alluded to the importance of timing in MRD assessment, it is worth emphasizing that consistency in MRD evaluation is critical for meaningful comparisons across clinical trials and for accurately determining its prognostic value.
MRD levels can fluctuate over time, and assessments at non-standardized timepoints may lead to misinterpretation of results; fixed time points ensure that MRD measurements reflect true disease biology rather than transient fluctuations. Further, different timepoints can reveal distinct aspects of disease biology and treatment response. As a general rule, earlier MRD clearance indicates more chemotherapy-sensitive disease, which corresponds to a better prognosis. For example, while most evidence comes from adult AML trials, pediatric data similarly support that early attainment of undetectable MRD at the end of intensive induction therapy, compared to delayed MRD clearance, is an independent predictor of improved relapse free survival (RFS) in intensively treated patients. 42 , 43 , 44 , 45 , 46 , 47 Interestingly, while MRD negativity was associated with superior OS, early MRD kinetics did not significantly impact OS, indicating that some patients with slower clearance may still be salvaged. 44 For example, early NPM1 transcript clearance by PCR testing in patients with NPM1-mutated AML is not a prerequisite for improved overall survival, as patients with slower molecular responses may still fare well with continued therapy or salvage strategies. 48
The optimal timing for MRD assessment naturally depends on treatment standard for each disease. For example, in adult NPM1-mutated AML treated receiving intensive chemotherapy, PCR-based testing at defined timepoints—post-intensive induction, prior to allogeneic hematopoietic cell transplantation (alloHCT), and during follow-up—can influence clinical decision-making with respect to the need for alloHCT. 27 , 48 These timepoints are defined for patients receiving intensive chemotherapy regimens, where discrete phases of treatment provide clear opportunities for MRD assessment. For patients receiving less-intensive or continuous treatment regimens, such as venetoclax combined with hypomethylating agents (Ven-HMA)—a standard of care for older or less fit patients that is increasingly being adopted for younger, fitter populations—clear guidelines for MRD assessment are lacking. Data from the Viale-A study, along with additional analyses, now indicate that patients who remain MRD+ after four cycles of Ven-HMA-based combination therapy represent a population most susceptible to relapse. 49 , 50 Yet, specific guidance for how to differentially manage these patients is still being evaluated and will need to be incorporated into formal guidelines. This variation in timing is not unique to AML. In multiple myeloma, for instance, transplant-eligible patients undergo MRD assessment at standardized treatment milestones—post-induction, post-transplant, and post-consolidation—while those on maintenance or ineligible for transplant typically undergo MRD testing at arbitrary intervals (e.g., every six months), often guided by clinician preference. 16 , 51
While these principles of MRD timing and clearance have strong prognostic value in chemotherapy-based approaches, the relationship between treatment efficacy and MRD becomes more complex with novel targeted therapies. In CLL, studies of BTK inhibitors have consistently shown that these agents can provide substantial clinical benefit despite more modest MRD clearance, compared to chemoimmunotherapy. 44 , 52 , 53 Recent data from a phase 3 trial comparing acalabrutinib-venetoclax ( ± obinutuzumab) with traditional chemoimmunotherapy further illustrates this disconnect: despite superior PFS with acalabrutinib-venetoclax compared to chemoimmunotherapy, the percentage of patients achieving undetectable MRD was actually lower in the acalabrutinib-venetoclax group. 54 Even more striking, the acalabrutinib-venetoclax group demonstrated significantly improved OS despite inferior MRD clearance. These results spotlight the impact of both therapy and timing of MRD assessment, which was measured before the completion of the acalabrutinib combinations in this study, 54 and challenge the universal application of MRD as a surrogate endpoint across different treatment modalities, suggesting that its optimal interpretation may need to be treatment, and timing-specific.
Dynamic nature of MRD
In the long term, for diseases such as the acute leukemias, guidelines generally recommend bone marrow (BM) minimal residual disease (MRD) assessments at pre-set intervals—for example, approximately every three months in acute lymphoblastic leukemia (ALL), or more frequently if PB testing is used due to its lower sensitivity—over a two-year period following intensive therapy, when the risk of relapse is highest. 27 , 55 , 56
Critically, the primary goal of these assessments is to detect early signs of relapse before clinical manifestations of disease, with rising MRD levels often indicating the need for preemptive interventions such as immunotherapy (for ALL), salvage therapy (for AML), or alloHCT. 2 , 27 , 57 In ALL, supporting this approach, a study by the German Multicenter Study Group in Adult ALL (GMALL) analyzed ALL patients in first complete remission and found that the median time between MRD detection and clinical relapse was approximately four months. 56 , 58 This has treatment implications: prior studies have shown that blinatumumab is most effective when deployed in the setting of a low disease burden, underscoring the critical nature of early MRD detection in ALL. 59 , 60 , 61 Therefore, in these acute malignancies with shorter-duration monitoring, MRD is being evaluated with a greater focus on therapy intensification for residual disease, though the emergence of longer-term maintenance approaches may ultimately reshape this therapeutic paradigm.
In biologically heterogeneous diseases like multiple myeloma, which also employ diverse treatment algorithms, achieving MRD negativity with upfront therapy is widely accepted as crucial for long-term outcomes. However, a key question remains: at which time point is MRD negativity most valuable—during frontline therapy, after consolidation, or during maintenance?
Increasing MRD sensitivity enhances prognostication, and sustained MRD negativity holds greater significance than a single negative result. 62 , 63 It is still not known, however, how long MRD negativity needs to be sustained to confidently de-escalate therapy or the appropriate duration and frequency of MRD monitoring. A few studies have indicated that the highest risk of conversion from an MRD negative to an MRD positive state is between 2 and 5 years. 63 , 64 , 65
Additionally, a phase II study evaluating MRD dynamics during lenalidomide maintenance therapy highlighted the importance of MRD changes. Patients who lost MRD negativity had a higher risk of progression compared to those with sustained MRD negativity and even fared worse than those who remained persistently MRD positive. This underscores that MRD dynamics—particularly the loss of MRD negativity—are a critical predictor of outcomes, emphasizing the need to consider MRD trends over time rather than isolated results. 66 Additionally, studies have shown that the reliability of MRD monitoring tends to break down for patients with skeletal/extramedullary relapse without biochemical progression, and in those with adverse risk disease. 64 , 65 , 67 , 68 These observations underscore the complexity of dynamic MRD assessment, with the ultimate goal of improved clinical decision making.
MRD-directed therapies
In June of 2023, blinatumomab, an anti-CD19 bispecific T cell engager, became the first U.S. FDA-approved agent with a specific MRD indication in patients with ALL. The approval was based on the BLAST trial, which demonstrated that treating MRD-positive patients (≥10 −3 by MFC) in CR with blinatumomab led to MRD clearance in 78% of evaluable patients after 1 cycle of therapy. 69 , 70
Despite this clear rationale and indication, subsequent findings demonstrate that the relationship between MRD clearance and survival is more complex than initially presumed. A recent trial showed blinatumomab improved outcomes in MRD-negative ALL patients (80% vs. 64% RFS; 85% vs. 68% OS) compared to chemotherapy alone. 71 This suggests either that blinatumomab's mechanisms extend beyond MRD clearance, that the ≥10 −3 threshold lacks sufficient sensitivity compared to the <10 −4 level used in GRAALL-2014, or most fundamentally, that ALL's biological heterogeneity defies simple biomarker interpretation. 72 While MRD remains clinically valuable, these findings caution against overreliance on any single test in treatment decision-making.
Along the same lines, in FLT3 -mutated AML, MRD detectable at any level (10 −4 –10 −6 ) has been shown to negatively impact relapse-free survival. 73 The phase 3 QuANTUM-First study evaluated the FLT3 inhibitor quizartinib in adult AML patients aged 75 and younger with FLT3-ITD mutations combined with remission induction and standard high-dose cytarabine consolidation and/or allogeneic hematopoietic cell transplantation (alloHCT) in CR1. The study demonstrated that, when compared to placebo, the addition of quizartinib significantly improved RFS and OS when added to standard therapy, including alloHCT, followed by up to three years of quizartinib monotherapy. Importantly, the survival benefit with quizartinib was observed regardless of pre-alloHCT minimal residual disease (MRD) status—both MRD-positive and MRD-negative patients experienced improved outcomes. 73 , 74 The findings suggest that MRD may be a more nuanced indicator than previously thought, resisting straightforward clinical algorithms as a singular entity, while emphasizing disease complexity.
In multiple myeloma (MM), MRD-adapted therapy is a central focus of many trials, with a goal of tailoring treatment based on MRD status: intensifying therapy for MRD-positive patients, stopping maintenance for those with sustained MRD negativity, or altering treatment if MRD status converts from negative to positive. Trials like MASTER have shown that MRD-based de-escalation is most appropriate for standard-risk patients, while the GEM2012MENOS65 trial demonstrated that stopping maintenance after achieving MRD negativity led to low progression rates, supporting MRD-guided therapy duration. 65 , 68 These studies underscore the potential of MRD-driven strategies to individualize treatment, though more concrete prospective data are needed.
MRD as a clinical trial endpoint and the ultimate goal of OS
MRD is increasingly used in clinical trials for patient selection, response assessment, and treatment optimization, with established success in CML and ALL. However, regulatory integration remains a challenge. An FDA analysis of 196 drug applications (2014–2021) found that while 28% included MRD data, nearly 40% of proposals to incorporate it into prescribing information were rejected, with acceptance rates declining over time. 75 Challenges such as assay validation, data standardization, and statistical considerations persist, underscoring the need for improved methodologies to fully integrate MRD into regulatory frameworks and drug development. The authors noted that MM had a high number of applications and rejections, reflecting ongoing difficulties in assay validation and regulatory alignment. To address such gaps, the myeloma community is increasingly collaborating to refine MRD criteria, proposing a standardized 10 −5 threshold at 9 or 12 months as an intermediate endpoint to support accelerated approvals in upcoming trials for newly diagnosed and relapsed/refractory MM. 2
While MRD is a valuable regulatory endpoint that can facilitate accelerated drug approval, its impact on long-term survival and treatment optimization remains unproven. Like the CR endpoint in AML that correlates with improved survival, MRD negativity is prognostic, yet it has not consistently translated into better overall survival, as seen in relapsed/refractory AML. The field of CLL is grappling with the same question—Does driving MRD negativity enhance survival or quality of life in a disease with an inherently long natural history? While some trials suggest an association between MRD negativity and longer PFS, it remains to be seen whether patients are living longer or better when MRD positivity is intervened on, as opposed to waiting for a morphologic relapse. 76 In CLL and some other hematologic malignancies, until we have robust prospective data, MRD remains an exploratory marker of avid interest rather than a clinical standard, and current guidelines do not support its routine use in practice ( Table 1 ).
Table 1
Current status of measurable residual disease and selected representative clinical trials in hematologic malignancies.
Abbreviations: CML: Chronic Myeloid Leukemia, PCR: Polymerase Chain Reaction, RT-PCR: Reverse Transcription Polymerase Chain Reaction, ELN: European LeukemiaNet, ESMO: European Society for Medical Oncology, FDA: Food and Drug Administration, EMA: European Medicines Agency, APL: Acute Promyelocytic Leukemia, MFC: Multiparameter Flow Cytometry, AML: Acute Myeloid Leukemia, NGS: Next-Generation Sequencing, ALL: Acute Lymphoblastic Leukemia, ASO: Allele-Specific Oligonucleotide Polymerase Chain Reaction, NCCN: National Comprehensive Cancer Network, COG: Children's Oncology Group, AIEOP-BFM ALL: Associazione Italiana Ematologia Oncologia Pediatrica - Berlin-Frankfurt-Münster Acute Lymphoblastic Leukemia, Ph+: Philadelphia Chromosome Positive, CLL: Chronic Lymphocytic Leukemia, iwCLL: International Workshop on Chronic Lymphocytic Leukemia, BTK: Bruton's Tyrosine Kinase, PFS: Progression-Free Survival, OS: Overall Survival, MCL: Mantle Cell Lymphoma, uMRD: Undetectable Minimal Residual Disease, FL: Follicular Lymphoma, DLBCL: Diffuse Large B-cell Lymphoma, ctDNA: Circulating Tumor DNA, MM: Multiple Myeloma, IMWG: International Myeloma Working Group, IMF: International Myeloma Foundation, i2TEAMM: International Independent Team for Endpoint Approval of Myeloma MRD.
| Disease | MRD methodologies | Detection sensitivity | Guideline integration | Regulatory approvals | Use in clinical settings | Selected trials |
| CML | PCR (RT-PCR) | 10 −3 –10 −6 | ELN, ESMO | FDA (US): routine use EMA (EU): routine use | Post-treatment monitoring, treatment modification | IRIS ( NCT01316250 ), DASISION ( NCT00481247 ), ENESTnd ( NCT00471497 )–establish molecular response thresholds correlating with outcomes EURO-SKI (NCT01592927)–treatment discontinuation with sustained MRD negativity |
| APL | MFC, PCR (RT-PCR) | 10 −4 –10 −6 | ELN | FDA (US): routine use EMA (EU): routine use | Post-treatment monitoring, treatment modification | AIDA ( NCT02688140 ), APOLLO ( NCT02688140 )–MRD as an outcome predictor APL0406 (NCT00813727)–MRD for treatment de-escalation |
| AML | MFC, PCR (RT-PCR), NGS | 10 −3 –10 −5 | ELN | FDA (US): not routine EMA (EU): not routine | Research settings, post-treatment monitoring | HOVON/SAKK AML 42A–MRD negativity after intensive induction correlates to improved outcomes PREMEASURE/MEASURE ( NCT05224661 )–MRD based relapse risk prediction after allogeneic transplantation MORPHO ( NCT02997202 )–MRD based selection & risk prediction for post-transplant targeted maintenance therapy |
| ALL (adult) | MFC, PCR (ASO), NGS | 10 −4 –10 −6 | ESMO, NCCN | FDA (US): routine use EMA (EU): routine use | Post-treatment monitoring, risk stratification, treatment modification | GMALL trials ( NCT02881086 ), GRAALL 2005 ( NCT00327678 )–prognostic value of MRD, set up MRD guided risk stratification for therapy modification BLAST ( NCT01207388 )–treatment modification based on MRD status (benefit subsequently noted in MRD negative as well) |
| ALL (peds) | MFC, PCR (ASO), NGS | 10 −4 –10 −6 | COG, ESMO | FDA (US): routine use EMA (EU): routine use | Post-treatment monitoring, risk stratification, treatment modification | Children's Oncology Group (COG) AALL0232 ( NCT00075725 )–MRD as a prognostic factor COG AALL0331 ( NCT00103285 ), AIEOP-BFM ALL 2000 ( NCT 00430118 / NCT 00613457 )–treatment intensification/de-escalation integrating MRD status EsPhALL( NCT00287105 )– BCR-ABL1 monitoring of MRD status for Ph+ patients, treatment modification |
| CLL | MFC, NGS, PCR (ASO) | 10 −4 –10 −6 | iwCLL | FDA (US): not routine EMA (EU): not routine | Research setting, post-treatment monitoring, risk stratification | ELEVATE-TN ( NCT02475681 )–BTK inhibitor continuous therapy is effective despite lower MRD negativity CLL14 ( NCT02242942 )–deep MRD as a PFS predictor with fixed duration therapy CAPTIVATE ( NCT02910583 ), GLOW ( NCT03462719 )–MRD impact on OS unclear. In diseases with longer survival these raise the question of MRD vs. treatment toxicity with fixed duration therapy |
| MCL | MFC, NGS | 10 −4 –10 −6 | ESMO, NCCN | FDA (US): not routine EMA (EU): not routine | Research settings, post-treatment monitoring, risk stratification | MCL Younger/MCL Elderly (European MCL Network Trials)–prognostic value of MRD in MCL/MRD timelines to define depth of remission AIM ( NCT02471391 )–chemotherapy free regimens can achieve high uMRD rates TRIANGLE Study ( NCT02858258 )–assessing MRD and therapeutic modification |
| FL | MFC, NGS | 10 −4 –10 −6 | ESMO, NCCN | FDA (US): not routine EMA (EU): not routine | Research settings, post-treatment monitoring | SWOG S0016 ( NCT00006721 )–uMRD associated with improved long term PFS GALLIUM trial ( NCT01332968 )–deeper MRD after induction predicts improved PFS/MRD concordance with PET FOLL12 (NCT01287118)–PET/MRD-adapted maintenance strategy- endpoint not met |
| DLBCL | MFC, NGS | 10 −4 –10 −6 | ESMO, NCCN | FDA (US): not routine EMA (EU): not routine | Research settings, post-treatment monitoring | GOYA ( NCT01287741 ), POLARIX ( NCT03274492 ), ZUMA-7 ( NCT03391466 )–ctDNA clearance independently associated with PFS, prognostic benefit REMARC study ( NCT01122472 )–persistent ctDNA predicts chemoimmunotherapy resistance, not designed for MRD guided treatment cessation |
| MM | MFC, NGS | 10 −5 –10 −6 | IMWG, ESMO | FDA (US): not routine EMA (EU): not routine | Post-treatment monitoring, risk stratification, treatment modification, research settings–FDA recognition as a clinical trial surrogate endpoint | IFM 2009 ( NCT01191060 )–MRD as outcome predictor MAIA ( NCT02252172 )–MRD as a treatment goal MASTER ( NCT03224507 )/MRD2STOP ( NCT04108624 )–feasibility of MRD use to stop treatment FDA recognition as a clinical trial surrogate endpoint based on consolidated review by IMF and i2TEAMM |
Future directions and outstanding questions
In conclusion, while measurable residual disease (MRD) testing shows great promise in guiding therapeutic decisions, its role in clinical practice is still evolving. With respect to methodologic evolution, the various hematology disciplines have gained insights into improving MRD practice from each other; Pediatric ALL established rigorous timing, assay standardization, and prognostic use of MRD, which has served as a blueprint for AML and other leukemias. Advances in NGS-based MRD detection in CLL, especially using the clonoSEQ platform, provided a model quickly adopted in myeloma. APL's use of molecular MRD to guide therapy reduction encouraged PCR-based MRD strategies in select AML subtypes. Multiple myeloma also helped shape how MRD can be used to track deep responses to immunotherapies—an insight now informing lymphoma trials. The critical next step is translating technical advances into actionable clinical protocols—ensuring harmonized detection methods yield consistent real-world interpretation and decision-making. MRD's clinical utility hinges on key disease specific considerations: selection of clinically relevant timepoints, test selection, level of detection, sampling and a realistic understanding that MRD negativity does not mean ‘cure’—nor does positivity always predict relapse. Like all laboratory tests, MRD cannot supplant comprehensive clinical assessment; it complements rather than replaces other diagnostic and prognostic tools needed to guide therapy. This multimodality approach remains essential in a rapidly changing therapeutic environment where MRD represents one critical piece—but not the entirety—of the clinical puzzle.
We have progressively improved MRD tools, but we are learning how to use them well to enhance patient outcomes. As with artificial intelligence, which is only as effective as the data it receives, MRD's utility will depend on the quality and relevance of the input data. This requires standardization that bridges technical development and bedside application—where uniform reporting thresholds and validation practices align with therapeutic decision points. Therefore, it is crucial for both clinical trials and physicians-in-practice to approach MRD thoughtfully, ensuring that how data are assessed, reported and interpreted aligns with the larger biological context, and goals of patient care.
Future research will focus on implementing these harmonized standards, defining uniform thresholds, and refining adaptive clinical trial designs to continue evolving MRD as a prognostic and predictive biomarker—ultimately improving patient outcomes in a rapidly changing therapeutic environment. While MRD status is correlated with relapse risk at the sub-cohort level, we are aware it is an imperfect predictor of clinical outcomes in isolation. For most patients, we are still likely to require a multimodality approach. This may require integrating different MRD platforms, correlating MRD evaluation with imaging in a structured way, or combining multi-omic profiling, immune analysis, and real-time monitoring for a more comprehensive approach to risk stratification and therapy guidance tailored to the specific disease. These technological advancements must be balanced with practical, scalable solutions to ensure they are clinically feasible and globally applicable. Successful implementation of MRD-guided care in the right patient could reduce unnecessary therapy for some patients, improving their quality of life, or providing lifesaving interventions for those at risk.
In real-world practice, MRD testing is gaining traction but at present is unevenly implemented across healthcare systems worldwide. Its adoption varies globally, influenced by regulatory frameworks, infrastructure, reimbursement policies, and clinician awareness. In high-income countries, MRD is increasingly incorporated into routine care for diseases such as ALL, where its role in risk stratification and treatment adaptation is well established and often supported by reimbursement. 72 , 77 In myeloma, implementation has accelerated—particularly in the U.S., where the FDA-cleared clonoSEQ assay is reimbursed by Medicare. In Europe, clonoSEQ has obtained In Vitro Diagnostic Regulation (IVDR) certification, with uptake observed in academic centers across Germany, France, Spain, and Italy, although national reimbursement policies are still evolving. 65 , 78 Routine clinical use in CLL and indolent lymphomas remains more limited, as the clinical actionability of MRD in these diseases continues to be evaluated.
Even within well-resourced health systems, disparities persist. Academic centers are more likely to integrate MRD into care, while community practices often face barriers related to infrastructure and reimbursement. 79 Many community settings lack the necessary support to implement MRD testing effectively. 80
Access challenges are even more pronounced in low- and middle-income countries, where foundational diagnostic tools commonly used in high-income settings may be limited or unavailable—leaving little room for adoption of more advanced technologies like MRD. 77
Looking ahead, efforts to harmonize assay validation, expand clinician education, and align reimbursement with clinical utility offer a path toward broader MRD adoption. As evidence grows and technology becomes more accessible, MRD-guided care has the potential to advance precision oncology globally—optimizing treatment, minimizing toxicity, and ultimately improving patient outcomes across diverse healthcare settings.
Contributors
NSC and MAS both contributed to the conceptualization of the study, conducted the literature search, and participated in the writing of the manuscript. Both authors reviewed and approved the final version of the manuscript.
Declaration of interests
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Namrata S. Chandhok receives grant support from the Robert A. Winn Excellence in Clinical Trials Award Program. She has participated in the production of unbranded anemia educational material sponsored by Bristol Myers Squibb and advisory boards for Rigel and Taiho. Mikkael A. Sekeres has received travel support to attend meetings from Daiichi Sankyo and has participated in advisory boards for Bristol Myers Squibb, Kurome, Agios and Geron.
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