Multiple myeloma gammopathies

International harmonization in performing and reporting minimal residual disease assessment in multiple myeloma trials

Abstract

Minimal residual disease (MRD) assessment is incorporated in an increasing number of multiple myeloma (MM) clinical trials as a correlative analysis, an endpoint or even as a determinant of subsequent therapy. There is substantial heterogeneity across clinical trials in how MRD is assessed and reported, creating challenges for data interpretation and for the design of subsequent studies. We convened an international panel of MM investigators to harmonize how MRD should be assessed and reported in MM clinical trials. The panel provides consensus on which MM trials should include MRD, the recommended time points for MRD assessment, and expected analytical validation for MRD assays. We subsequently outlined parameters for reporting MRD results implementing the intention-to-treat principle. The panel provides guidance regarding the incorporation of newer peripheral blood-based and imaging-based approaches to detection of residual disease. Recommendations are summarized in 13 consensus statements that should be followed by sponsors, investigators, editors, and reviewers engaged in designing, performing, and interpreting MM trials.

Introduction

The assessment of minimal/measurable residual disease (MRD) during treatment is one of the most active areas of research in multiple myeloma (MM). There has been significant growth in the volume of MRD literature, and MRD assessment is incorporated in an increasing number of clinical trials as a correlative analysis, an endpoint or even as a determinant of subsequent therapy.

With multiple groups investigating MRD and utilizing different technologies, test schedules and study designs, it is not surprising to find substantial heterogeneity in how MRD is assessed and reported in MM clinical trials. Such heterogeneity creates challenges for data interpretation, for the design of subsequent studies and for the performance of any quantitative meta-analysis. Therefore, we convened a panel of MM investigators to provide consensus guidance on how MRD should be assessed and reported in MM clinical trials.

This consensus effort was presented at the Fourth Blood and Marrow Transplant Clinical Trials Network (BMT CTN) MRD and Immune Profiling Scientific Workshop in the 61st American Society of Hematology Annual Meeting (Orlando, FL, USA) [1]. We solicited volunteers among attending experts and recognized field leaders with the objective of having global representation including those with expertise in different methodologies.

We developed an outline of key MRD aspects in need of consensus and submitted it for review by all panelists. We reached agreement on the final outline and assigned specific sets of questions to groups of 2–3 panelists according to expertise, country, and cooperative group representation. We asked panelists to state their recommendation along with a brief paragraph supporting the recommendation with data from the literature or with a scientifically sound rationale. We researched the literature and consulted regulatory agencies worldwide to provide regulatory context of the different MRD platforms. We assembled the first draft incorporating the input from each group of panelists and ensuring consistency across sections. We resolved points of greater controversy and inconsistencies among sections by sequential rounds of revisions. All co-authors approved the final document.

This document was developed in alignment with the International Myeloma Working Group (IMWG) consensus criteria for response and MRD assessment in MM [2]. It also followed guidance provided by regulatory authorities on use of MRD in development of drugs and biological products for treatment [3, 4].

The panelists acknowledge that while we can provide consensus on timing and methodology of MRD assessment and reporting in MM, the crucial question of whether MRD can be employed as a valid surrogate for clinically significant endpoints cannot be answered by consensus. Determination of surrogacy requires robust and complex analysis utilizing raw data from multiple clinical trials [5, 6]. This endeavor is being pursued by the International Independent Team for Endpoint Approval of Myeloma MRD (I2TEAMM) [7].

Analytical requirements for MRD tests in MM

Analytical validation ensures that the assay measures the analyte that it is designed to measure in the intended tissue type. Analytical validation is concerned with the assay’s technical performance and does not address its clinical application [3]. MRD assay validation should encompass the entire assay system from sample collection to system output and should use relevant clinical samples [3].

The analytical performance of an MRD assay in MM—as in any other diseases—can be determined by its limit of blank (LOB), limit of quantification (LOQ), and limit of detection (LOD). LOB is the highest number of aberrant events measured in a negative sample; 95% of negative values are below this limit. LOQ refers to the lowest absolute number of malignant plasma cells whose frequency can be quantitatively determined by that assay with stated accuracy [8]. LOD refers to the lowest number of malignant plasma cells that can be reliably detected by an analytic procedure (i.e., the level at which 95% of samples with a low level of aberrant cells are reliably distinguished from the LOB). MRD assays employed in clinical trials must have a clearly defined LOD and LOQ, and disclose the LOD and LOQ actually achieved in the samples. Understanding the analytical performance of assays is essential for optimizing the quality of submitted MRD samples and for appropriately evaluating their adequacy and findings [3].

All of the above should be counterbalanced with the extent of hemodilution and sample quality, since analyzing 20 μg DNA or 10 million nucleated cells from peripheral blood (PB) instead of bone marrow (BM) will lead to false-negative results irrespective of the LOD intrinsic to the assay [9].

Consensus statement: MRD assays used in clinical trials must be analytically validated with clearly defined LOB, LOD, and LOQ. Clinical trial reports must include or reference the analytical validation for the MRD assay employed.

Performance of MRD assays utilized in MM

The most common methods for BM MRD assessment include next-generation sequencing (NGS), allele specific oligonucleotide-polymerase chain reaction (ASO-PCR) [2], and multi-parametric flow cytometry (MFC), which includes more recent protocols developed by EuroFlow aiming at higher sensitivity and standardization, coined as next-generation flow (NGF) cytometry. NGS and NGF are both capable of covering most of the logarithmic range of 10−6 (i.e., identifying 1 aberrant plasma cell among 1,000,000 nucleated cells) due to their respective LOD.

There are several iterations of MFC that have each resulted in increasing sensitivity and improved prognostication. MFC is widely available for MRD detection, and a baseline diagnostic sample is typically not necessary, yet may identify patients with macrofocal disease without diffuse marrow infiltration. Most laboratories perform MFC with a LOD of at least 10−4, which has been shown to be prognostic even among patients achieving complete response (CR) [10, 11]. Improvements in MFC MRD LOD to 10−5 and ultimately approaching 10−6 with NGF, have led to further enhancements in prognostication [12,13,14,15]. NGF has been standardized through the EuroFlow consortium [13], with an eight-color, two-tube assay that evaluates differential expression of 10 antigens to identify clonal plasma cells [13]. NGF requires assessment of 10 million events (107), and when performed in an appropriate sample (recommended volume and with minimal hemodilution) has a LOD of 2 × 10−6 (i.e., 20 aberrant plasma cells per 10 million events, respectively) [13]. A recent study with NGF in 458 patients treated on the PETHEMA/GEM2014MAIN trial showed that NGF was successful in determining MRD status in 99.6% samples. The LOD was = 2 × 10−6 in 1% and 2 × 10−6 to 1 × 10−5 in 88% of samples [15].

NGS relies on identification and quantification of VDJ (variable, density, joining) and DJ rearrangements in the immunoglobulin heavy chain (IgH), kappa, and lambda genes, which are unique for a given patient and conserved across the malignant clone. DNA from a baseline sample with evident tumor content is first amplified by multiplex PCR and genes of interest are sequenced. Subsequently, sequences in high abundance (clonotype sequences) are identified that are then tracked and quantified in subsequent, post treatment samples. MRD by NGS is currently available through one platform (Adaptive Biotechnologies, ClonoSeq®) that has been clinically and analytically validated and cleared by the US FDA [16,17,18,19,20]. The European Medicines Agency (EMA) has issued guidance on use of MRD in MM studies, but not adjudicated the use of this or any other method [4]. Baseline clonotype identification has been successful in over 90% of patients [20,21,22]. With an input of 20 μg of DNA (equivalent of 2–3 million nucleated cells), NGS has a LOD of 6.8 × 10−7 [20]. Another NGS-MRD assay called LymphoTrack® (Invivoscribe©) has similar LOD/LOQ and DNA input requirements [23].

ASO-PCR (sensitivity of 10−5) [24] is another molecular method. It is more cumbersome as it requires the development of patient-specific primers to identify baseline IgH rearrangements. It is applicable to no more than 70% of cases, is labor intensive and has not been validated in larger studies [24].

Each log reduction of MRD is associated with improved outcomes [12, 19]. Both the IFM-2009 and PETHEMA/GEM2012MENOS65 studies showed that lower residual disease level were associated with better outcomes compared 10−5 to 10−6 [15, 19]. When comparing at similar levels of sensitivity, MFC and NGS are highly concordant [25,26,27]. In the CASSIOPEIA trial, post-consolidation MRD assessment by MFC (NGF) and NGS (clonoSEQ) at level of 10−5 showed 83.5% agreement overall between the two methods and 94.4% agreement in patients with CR [27, 28]. In the FORTE trial, MRD assessment by both MFC (NGF) and NGS (clonoSEQ)was compared in patients achieving CR. At levels of 10−5, the observed agreement was 86%. In a subgroup of patients evaluable at a sensitivity of 10−6, the observed agreement was 76% [26]. Further research is warranted to understand such discordances with the aim of improving both technologies.

Both NGS and MFC are highly sensitive methods and choosing between the two ultimately depends on feasibility and logistical issues. NGS requires a baseline sample for clone identification, which may not be achievable in a small fraction of patients due to lack of sample availability or DNA quality from the baseline marrow sample; however, samples can be stored (it is possible to batch samples for analysis) and fewer cells are required to achieve the same sensitivity as MFC. On the other hand, MFC does not need a baseline sample, but samples must be analyzed within 24–48 h, with 10 million events per tube required to approach 10−6 sensitivity.

Ultimately, supporting evidence will be required to justify the minimum thresholds (decision point for dichotomic assessment, e.g., “positive” vs. “negative”) of MRD needed to meet regulatory requirements for MRD to be used as a surrogate endpoint or for future trials and clinical decision making. Although a MRD threshold of 10−6 seems optimal, its applicability is limited by volume and quality of BM sample and limited access to assays with LOD < 10−6. Even for the best validated MRD assays the threshold of 10−6 is near the edge of the assay performance raising concerns about utilizing such a threshold for decision making. Indeed, the US FDA states that “the detection threshold of the MRD assay should be at least 10-fold below the clinical decision-making threshold (the definition of MRD). For example, if MRD positive or negative is defined as detection of greater or less than 1 × 10−5 cells, respectively, then the assay should be optimized and validated to have an analytical sensitivity of at least 1 × 10−6 [3].” A minimum threshold of 10−5 is also the one recognized in the IMWG definition [2] and EMA [4].

Lastly, in order to be developed into a clinically useful tool to guide management, MRD needs to be applicable to the vast majority of patients. Even assays with high sensitivity will have limited utility if they cannot be used in a significant proportion of patients for analytical or pre-analytical reasons. We recommend that assays used for MRD in MM must have clinical validation demonstrating applicability in >90% of patients.

Consensus statement: MRD assays utilized in MM trials must have LOD < 10−5 and be applicable to >90% of patients. When possible, based on analytical performance of the assay and quality of samples, MRD < 10−6 should also be reported.

Bone marrow sampling for MRD

The performance of MRD assays can be greatly affected by pre-analytical factors, such as sample quality, quantity and stability. Hemodilution of the BM aspirate sample is the most common pre-analytical problem and may result from fibrotic or heavily infiltrated marrow (“dry tap”) and inexperience of the person performing the aspirate. Traditionally, the first “pull” of a marrow aspiration is sent for morphology, whereas subsequent pulls are sent for cytogenetics and traditional flow cytometry. “Research samples” or samples for correlative tests are often obtained last, and in many centers that includes MRD. Collecting MRD samples last or in an inconsistent sequence can lead to significant hemodilution and add variability to the investigation being performed and may lead to underestimation of MRD [29]. On a treated patient, the burden of MRD is the strongest prognostic information to be acquired from the marrow aspiration across the entire clnica l course of a patient. It is therefore crucial that the first “pull” be sent for MRD testing. If the first “pull” cannot be used for MRD testing, next “pull” should be done with repositioning or redirection of the aspirate needle to reduce the likelihood of hemodilution. In such cases, the laboratory performing MRD testing should be informed and this information should be included in the final report. MFC protocols may include procedures to identify substantial hemodilution by identifying cellular elements only present in the marrow environment. NGS and ASO-PCR lack the capacity to discern cell type, yet hemodilution can be suspected by the low yield of DNA

Different assays have different input requirements in order to reach the intended LOD. Clinical trials employing MRD must specify the volume of marrow to be aspirated and how samples should be handled according to the analytical validation of the specific assay.

Consensus statement: Bone marrow-based MRD test must be performed on a sample obtained from the first “pull” of aspirate. The quantity of marrow aspirate must match the analytical validation of the assay being utilized.

MRD assessment in peripheral blood

MRD in the PB has been investigated with evaluation of circulating plasma cells, cell-free DNA or mass spectrometry (MS). In one study of 274 paired PB/BM samples by MFC (NGF) [30], MFC in PB was less sensitive than in BM, as 40% of patients with BM residual disease had undetectable PB MRD [30]. Early data suggest that NGS evaluation of circulating myeloma cells and cell-free DNA is also less sensitive and does not correlate well with BM MRD assessment [31,32,33]. In one study, the majority of the non-responding/progressing patients were negative by PB NGS [31]. In another study, circulating DNA was undetectable in 69% of patients with detectable BM MRD [32].

MS can identify monoclonal protein by its unique molecular mass [34, 35]. In a prospective trial where BM MRD was evaluated by MFC (NGF) and PB MRD by MS, discordance was seen in 31% of patients (21% MS positive/MFC negative and 10% MFC positive/MS negative) [34]. However, residual disease in MFC positive, MS negative patients was low and close to the LOD at 10−5. Importantly, in over 90% of datapoints with NGF-MRD ≥ 10−5, MRD is also detectable by PB-MS [36]. A comparison of NGS with a LOD of 10−5 to 10−6 to PB MRD by MS at later time points found that discordance was seen in 37% of cases, all of which were MRD detectable by PB-MS but not by BM NGS [37]. Presence of residual protein by MS with no residual BM disease may be due to the long half-life of immunoglobulins or due to patchy marrow or extra-medullary involvement causing false-negative BM MRD [34, 35]. Further research analyzing BM cell-based MRD and PB-MS at later time points (i.e., after clearance of the ancillary paraprotein) is warranted to understand the complementarity between MFC/NGS and MS.

PB MRD assessment is convenient and may overcome limitations of patchy marrow involvement or extra-medullary disease. However, further refinements are required to reach similar sensitivity to BM assessment with MFC and NGS and cross-validation is crucial. PB MRD methods have the potential to be used in a complementary role to determine timing for marrow MRD assessment and as indicators of early relapse.

Consensus statement: MRD assays based in peripheral blood need to be further investigated and cross-validated with bone marrow-based MRD assays.

Imaging tests and MRD

BM MRD assessment can be falsely low or undetectable due to heterogenous plasma cell infiltration and extra-medullary disease. Extra-medullary disease is seen in 5–7% of patients with MM at diagnosis and initial relapse [38, 39], and in up to a quarter of heavily pre-treated patients [40, 41]. Imaging studies, particularly functional imaging modalities like positron emission tomography-computed tomography (PET-CT) can have a complementary role to marrow MRD assessment in patients with MM [2, 42].

PET-CT provides additional prognostic information to BM MRD assessment, with low observed concordance between MRD on BM and resolution of metabolically active disease on PET-CT scans [43,44,45]. Resolution of metabolic uptake has been observed in 35–89% of patients who concomitantly had detectable MRD in BM [43, 44, 46]. Conversely, 11–25% of patients have been noted to have residual PET-CT positivity despite achieving undetectable BM MRD [43, 44, 46]. Data from the IFM-2009 trial showed that patients who were PET-CT negative with MFC MRD < 10−4 before the start of maintenance had superior progression-free survival (PFS) compared to patients who were either PET-CT positive or had BM MRD ≥ 10−4 [43]. Similar results were seen in the CASSIOPET study (sub-study of the CASSIOPEIA trial) where PET-CT and BM MRD (MFC, threshold 10−5) were compared before the start of maintenance therapy [44]. Patients who were PET-CT negative and MRD < 10−5 (PET-CT and BM MRD-negative) experienced longer PFS than those who were PET-CT positive or MRD ≥ 10−5 [44].

PET-CT scan is advantageous over magnetic resonance imaging (MRI) as it can distinguish metabolically active disease and assess real time treatment response. In the IFM-2009 trial, whereas both PET-CT and MRI were sensitive for baseline detection of lesions, only the resolution of uptake on PET-CT was prognostic for survival outcomes [43]. Diffusion weighted MRI is a functional MRI technique that was recently compared to PET-CT and noted to be more sensitive for the detection of residual lesions, though discordant results were seen bidirectionally [46]. Hexokinase deficiency can result in a false-negative fluorodeoxyglucose (FDG) PET-CT scan, however, its clinical implications are not yet well-defined [47]. The use of 89Zr-DFO-daratumumab [48] and 64Cu-DOTA-daratumumab [49] to enable immunologic PET imaging have recently been shown to detect sites of MM disease with potential advantage over FDG PET [48].

Although imaging has a valuable and complementary role to BM MRD assessment, there is a lack of data on the timing of imaging studies in response assessment. MRD and PET-CT imaging have been assessed in prospective trials of newly diagnosed patients undergoing novel induction regimens and transplant, typically before the start of maintenance therapy [43, 44]. Given the low observed concordance of BM MRD and PET-CT findings in these studies, future clinical trials should continue to incorporate simultaneous BM MRD assessment and functional imaging at pre-defined time points to evaluate the prognostic impact of discordant results. This is especially true in clinical trials of relapsed MM, where extra-medullary disease is more likely [46].

Consensus statement: Functional imaging to assess resolution of metabolic uptake provides complementary data to BM MRD assessment in patients with MM. Presently, PET-CT is the recommended functional imaging modality as data on other techniques like DW-MRI and PET-MRI are not available from large prospective studies. Given bidirectionally discordant results between BM MRD assessment and resolution of metabolic uptake on PET-CT scan, both methods should continue to be evaluated in clinical trials at simultaneous pre-defined time points, especially in patients with relapsed MM.

Multiple myeloma trials with MRD assessment

Depth of response correlates with patient outcomes and therefore is often used to appraise novel combinations in the treatment of myeloma [50, 51]. Use of the IMWG response criteria allows for uniform assessment and reporting of response in both newly diagnosed and relapsed myeloma patients [2]. Several studies have reported a link between achievement of CR and overall survival [52, 53]. However, even among patients achieving a CR, outcomes can be further stratified by those who attain MRD below a defined threshold [10, 11, 15, 21]. Therefore, MRD was incorporated into the IMWG response criteria in 2016 [2].

Although the bulk of evidence supporting MRD exists for newly diagnosed MM [11, 17, 19, 28, 54], MRD testing can identify relapsed MM patients more likely to have favorable outcomes. The CASTOR and POLLUX studies evaluating daratumumab-containing regimens demonstrated the benefit of achieving deep MRD responses and subsequent delay in disease progression [55, 56]. Recently, immunotherapeutic strategies such as chimeric antigen receptor T cells and T cell engagers have shown rapid MRD responses that were predictive of outcome independent of traditionally assessed best IMWG response [57, 58].

As a more sensitive iteration of a BM-based response assessment, MRD testing is not far removed from traditional response assessment being performed in all stages of the disease. Therefore, we recommend performing and reporting of MRD in clinical trials for both newly diagnosed as well as relapsed myeloma.

Consensus statement: MRD assessment should be performed in all trials for patients with newly diagnosed multiple myeloma and trials for relapsed and refractory multiple myeloma.

MRD in trials of smoldering multiple myeloma

Smoldering multiple myeloma (SMM) is an intermediate stage between the monoclonal gammopathy of unknown significance (MGUS) and active MM. It is, by definition, characterized by an absence of ongoing or imminent end-organ damage [59]. Early intervention approaches with the goal of “cure” versus “control” are being studied in SMM. Recent studies have evaluated the impact of non-intensive regimens such as lenalidomide alone or with dexamethasone on delaying disease’s progression [60, 61]. In contrast, the ongoing phase 2, single-arm GEM-CESAR study is evaluating an intense strategy akin to transplant eligible newly diagnosed MM patients, including triplet induction, high dose therapy with autologous hematopoietic cell transplantation (AHCT) and consolidation/maintenance with the goal of sustained deep response at 5 years after AHCT using MRD test [62]. Korde at al. [63] also reported efficacy of using combination therapy in a small cohort of SMM as well as the feasibility of MRD testing. In addition, based on the very high efficacy of carfilzomib, lenalidomide, dexamethasone with daratumumab in newly diagnosed MM [22, 64], this combination is being evaluated in SMM in the ongoing ASCENT study (NCT03289299).

The possibility of achieving a functional cure with early intervention before the onset of organ injury is appealing and could justify the risk of potentially toxic therapy, in a well-defined population. Because success in trials of SMM is intrinsically linked to obsolete classic endpoints (e.g., time to progression) that may never be reached because most patients will never develop overt active MM. The reporting of MRD in clinical trials of SMM is therefore even more important to understand the possibility of operational cure and justify the risk-reward balance in this setting.

Consensus statement: MRD assessment must be part of all trials for SMM with curative intent.

MRD-based enrichment strategy in MM trials

Enrichment strategies identify a specific study population most likely to benefit from a medical or clinical trial intervention [65]. Prognostic measures for MM including cytogenetic features and prognostic scoring systems, e.g., revised international staging system (R-ISS) have enhanced the ability to identify and stratify patients with high-risk disease [66,67,68,69]. However, these baseline risk assessment tools lack the ability to predict the timing of relapse with a high degree of accuracy. Incorporation of MRD testing as a dynamic (post therapy) predictor for progression is an enrichment strategy that could inform clinical trials. MRD testing can identify patients at the highest risk of early disease progression irrespective of genetic risk and after a defined therapeutic intervention; clinical trials of further therapeutic augmentation approaches in this context may be used to achieve MRD < 10−5 with the intent to delay disease progression. Alternatively, sustained MRD < 10−5 after the initial intervention can be used to predict and select those at low risk for disease progression and enrich a population that is selected for clinical trials exploring de-escalation of therapy. Given the risk of false-negative results in MRD assessment, approaches to treatment de-escalation should preferentially rely in multiple tests (MS, imaging) and/or multiple datapoints.

MRD enrichment techniques can thus improve the risk-benefit relationship of secondary therapeutic interventions by avoiding unnecessary exposure in lower risk patients (who are least likely to benefit) and exposing to additional therapy only those at high risk of progression. For example, in B-ALL, immunotherapy with blinatumumab has been attempted as an additional augmentation after primary therapy for patients who were persistently MRD positive and shown to correlate with MRD clearance and subsequent superior outcomes [70].

To date, MRD testing for MM has been used predominantly for prognostication purposes. Whether MRD is a modifiable risk factor that can provide therapeutic guidance is as yet unknown. Studies utilizing MRD to guide therapeutic choice at time of consideration for consolidation (including AHCT), maintenance, duration of therapy or observation alone are under investigation in MRD-defined patient subsets (NCT03901963, NCT04071457, GEM2014MAIN, UKMRA Myeloma XV trial) [22, 71, 72].

Consensus statement: MRD assessment informs dynamic risk of progression and should be incorporated into therapeutic trial designs as a population selection strategy to explore treatment augmentation or de-escalation.

Timing of MRD testing in clinical trials

Many trials for newly diagnosed MM (NDMM) patients follow a sequence of induction, AHCT, post-transplant consolidation (in many but not all trials) and maintenance therapy. There is however substantial heterogeneity in the literature in terms of when MRD testing is performed with most data coming from post-AHCT assessment.

As regimens utilized for induction therapy become more effective and achieve response ≥ VGPR in over two-third of patients [22, 28, 73, 74], MRD becomes an essential tool to understand the activity of different agents and combinations before the assessment is confounded by AHCT. Assessment of MRD at the transition between treatment phases (e.g., induction to AHCT or AHCT to consolidation) allows better assessment of the contribution of each stage to the overall treatment approach. Moreover, the assessment of MRD post induction enables future trials addressing deferral of AHCT or utilization of intensification beyond AHCT in MRD-defined subsets.

Assessment of MRD post-AHCT is aligned with most of the existing experience [10], permits appraisal of the impact of AHCT in MRD (by having before and after assessment) and may support MRD-guided experimental approaches for post-AHCT therapy. Similarly, trials including a maintenance/observation phase, should perform MRD assessment at the beginning of maintenance/observation and periodically with increasing separation (e.g., yearly, then every 2 years, then every 3 years). Such an approach will enable understanding and comparison of MRD kinetics, including MRD resurgence, with different maintenance strategies.

We acknowledge that multiple MRD assessments incur cost and discomfort due to the need for a BM aspirate. However, a BM examination is necessary for adjudication of CR and is already performed at most of these milestones. Given that in patient with suspected CR, MRD status provides the strongest prognostic information [10, 11], it becomes crucial to perform MRD testing when performing marrow aspiration for response assessment in clinical trials.

Consensus statement: Clinical trials for NDMM with distinct phases of therapy should assess MRD at end of induction, post-AHCT (when applicable), before initiation of maintenance/observation and periodically thereafter.

Many trials for non-transplant eligible NDMM and trials for relapsed/refractory MM (RRMM) commonly do not have distinct phases of therapy and the initial regimen is continued until progression or intolerance, often with simplification of the regimen after a specified number of cycles. Trials with these characteristics should have defined criteria for BM examination to confirm CR (e.g., after the first or second set of serum and urine markers are compatible with CR). MRD testing should be incorporated in BM examination for response assessment. An alternative approach, particularly with therapies with high rates of response, is to plan for MRD assessment in all patients at an early timepoint (e.g., after 3 cycles). In either case, subsequent MRD assessments (e.g., yearly), should be planned after the initial one. Patients who do not meet serum and urine criteria to undergo bone marrow examination or do not undergo MRD testing for any other reason must be considered as having MRD ≥ 10−5 and included in the denominator of any reporting of MRD endpoints.

Consensus statement: Clinical trials without distinct phases of therapy should include MRD test whenever a marrow examination is performed to assess treatment response, and periodically thereafter as long as patients maintain their CR status.

Proper annotation of MRD results

The value of MRD as a prognostic marker is unquestionable. We expect MRD outcomes to have increasingly higher relevance in clinical trial reports. Both NGS and MFC can provide MRD assessment as a continuous variable. It has however become customary to report MRD as a dichotomic parameter, being above (“positive”) or below (“negative”) a certain threshold. Although that practice carries limitations, it suits the instrumentalization of MRD for disease management since therapeutic decisions are dichotomic (i.e., consolidation vs. no consolidation; limited vs. indefinite maintenance, etc.)

Different methods of MRD assessment have different analytical characteristics and can support different thresholds for “positive”. For example, a given assay may have limit of detection below 10−6 yet the authors may report proportion of patients achieving MRD < 10−5 to align with establish definitions or compare with other trials. Therefore, the threshold must not be assumed to be implicit to the methodology. The threshold utilized must be equal or higher than the LOD for the assay.

Authors must always indicate the methodology and the threshold when reporting MRD results. The use of terms “positive” or “negative” is discouraged and not acceptable without immediate explanation of method and threshold. Editors and reviewers should consider optimal statements such as “X% of patients reached NGS-MRD < 10−5” or “The rate of NGF-MRD < 10−5 was Y%”. Conversely, statements such as “rate of MRD negativity was X%” and “Y% of patients were MRD-negative by flow” are not acceptable.

The threshold of 10−5 has most often been utilized and is embedded in the current IMWG consensus [2] and EMA [4]. More recent data indicates that lower thresholds (e.g., 10−6) expectedly have even greater prognostic impact [15, 19]. Authors are encouraged to report MRD utilizing more than one threshold, including 10−5 and the lowest threshold enabled by the method utilized (e.g., 10−6). In addition, authors may report MRD as a continuous numeric variable scattered across a logarithmic scale [75].

Consensus statement: MRD must be annotated in scientific reports with immediate identification of method and threshold utilized. Thresholds must be equal or higher than the assay’s limit of detection and should not be assumed based on the methodology. It is not acceptable to report “MRD-negative rates” with no immediate clarification of method and threshold.

Reporting MRD outcomes in clinical trials

Reporting of MRD in clinical trials has not been standardized with respect to what level of traditional response mandates MRD testing. The spectrum ranges from testing all patients to testing only those with CR [15, 17, 19, 22, 28, 54, 73]. Data suggests that a proportion of patients with less than CR by traditional response assessment may have undetectable MRD in the BM [76]. Although delayed clearance of monoclonal protein has been proposed as a potential explanation for this finding, sampling error, patchy distribution, and presence of extra-medullary disease (false-negative) may also be contributing [46, 77, 78]. The IMWG 2016 criteria [2] defines “flow MRD-negative” and “sequencing MRD-negative” as subsets of patients in CR. However, if results of MRD testing among patients with less than CR by traditional criteria are available, this may be reported as “% of patients with NGF < 10−5” or “% of patients with NGS < 10−5” to clarify lack of concurrent IMWG complete response in such cases.

The approach of testing for MRD only in patients achieving a certain threshold of traditional response will limit both the financial burden of testing and circumvent unnecessary procedures among those with clear evidence of persistent disease. However, this approach cannot be dissociated from reporting by the intention-to-treat principle and patients not tested for any reason (including not achieving a certain category of traditional response) must be counted as having burden of disease > threshold being reported. Consequently, the proportion of patients with MRD < threshold must not be reported with the denominator composed only of CR patient or only of patients tested. This practice inflates the “MRD-negative” rates and is uninformative as it does not account for patients with a lesser response, and makes it difficult to compare results across trials.

The uniform denominator for MRD reporting in clinical studies should be the intention-to-treat population. Scientific reports must explicitly list the number and percentage of the intention-to-treat population where testing could not be performed. Similarly, dropouts, test failures, and test misses should be reported as a percentage of the intention-to-treat population. The use of the term ‘MRD evaluable’ population should be discouraged. The only acceptable circumstances where patients can be excluded from the denominator are circumstances evident prior to initiation of therapy and not related to a patient’s tolerance or response to therapy. Examples are the absence of trackable clonotype sequence on diagnostic sample preventing use of NGS and impossibility of synthesizing patient-specific primers for ASO-PCR. The unavailability of sample due to missed assessment, sample mishandling, lack of achievement of a certain response category or patient discontinuation due to progression or death do not exclude the patient and data point from being “MRD evaluable”. Figure 1 provides an example of the proper accounting for MRD outcomes in clinical trials.

Fig. 1: Representation of appropriate calculation and reporting of MRD following intention-to-treat principle.
figure1

Similar to any other binary efficacy endpoint in clinical trials, all patients initiating treatment and whose endpoint is assessable must be included in the denominator. When MRD not performed at a specific time point because of death, treatment discontinuation, insufficient response assessed by traditional methods or oversight, the patient should be assumed to have MRD above the threshold of interest (“positive”).

Consensus statement: MRD outcomes must be reported utilizing the intention-to-treat principle. Outcomes to be reported are proportion of patients to reach simultaneously CR and MRD < threshold and proportion of patients reaching MRD < threshold regardless of traditional response category. The exclusion from the denominator of patients with missing or inadequate samples or who did not reach a certain traditional response category is not acceptable.

Future directions

MRD is one of the most dynamic fields of research in MM. The impact of MRD in MM prognosis is irrefutable, yet the literature is confounded by extreme heterogeneity on how MRD is performed and reported. We believe that the consensus of MM investigators reflected in this manuscript will greatly improve the quality and reproducibility of MRD results in future trials and ensure uniform reporting of MRD results. High-quality MRD data and reporting will be the foundation to refine the prognostic role of MRD, support assessment of surrogacy for clinically meaningful endpoints and enable strategies for MRD response-adapted therapy, ultimately bringing MRD from clinical trials to the core of clinical practice.

Sponsors and investigators should follow these recommendations when designing MM trials. Statisticians and authors should ensure MRD outcomes are reported in presentations and manuscripts following the principles here outlined. Lastly, editors and reviewers should expect that future scientific communications are aligned with the consensus statements here listed as requirement for acceptance and publication. A list of consensus statements and corresponding pre-publication checklist items is provided for convenience as a supplement (Supplemental File 1).

Consensus statement: Clinical investigators, sponsors, authors, statisticians, editors, and reviewers engaged in MM trials with MRD assessment should adhere to consensus statements outlined in this manuscript. Compliance with these principles will improve quality of MRD research, interpretation of results, and support future applications of MRD in MM care and research.

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LC: Honoraria (Amgen, Bristol-Myers-Squibb, AbbVie), Research Funding (Amgen, Bristol-Myers-Squibb, Janssen); RS: Honoraria (Janssen); VH: Honoraria (Janssen, AbbVie, Amgen, Bristol-Myers-Squibb, Celgene, Takeda); W-JC: Honoraria (Takeda); ES: Honoraria (Celgene, Takeda, Novartis, Teva, Janssen, Amgen, Sanofi); SG: Honoraria (Celgene, Takeda, Amgen, Jazz Pharmaceuticals, Sanofi, Sanofi, Janssen), Research Funding (Celgene, Takeda, Miltenyi Biotec, Johnson & Johnson, Amgen); AJJ: Honoraria (Amgen, Bristol-Myers-Squibb, Janssen, Takeda, Skyline DX), Consultancy (Abbvie); GJM: Honoraria (Celgene, Bristol-Myers-Squibb, Novartis, Roche, Genentech, Takeda, Amgen, Karyopharm, Sanofi, GlaxoSmithKline, Janssen); AK: Ownership Interest (Celgene, Kite Pharma), Honoraria (Celgene, Onyx, Janssen, Takeda, Kite Pharma, Seattle Genetics), Research Funding (Celgene, Takeda); GHJ: Honoraria (Roche, Amgen, Janssen); MM: Honoraria (Janssen, Sanofi, Jazz Pharmaceuticals, Celgene, Bristol-Myers Squibb, Takeda, Amgen, Roche); MM: Honoraria (Janssen, Sanofi, Jazz Pharmaceuticals, Celgene, Bristol-Myers Squibb, Takeda, Amgen) Research support (Roche); MVV: Honoraria (Janssen, Celgene, Amgen, Takeda, AbbvVie, GlaxoSmithKline, Adaptive, Edo-Mundipharma, PharmaMar); MAD: Honoraria (Amgen, Janssen, Takeda, Celgene, Bristol-Myers Squibb); TF: Honoraria (Celgene, Janssen, Takeda, Amgen, Sanofi, Karyopharm, Oncopeptides, Roche); AS: Honoraria (Takeda, Celgene, Janssen, Amgen), Research funding (Takeda, Celgene, Janssen, GlaxoSmithKline); JSM: Honoraria (Amgen, Bristol-Myers Squibb, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche); PH: Honoraria (Takeda, Prothena, Pfizer), Research funding (Takeda); SU: Honoraria (Bristol-Myers-Squibb, Amgen, Takeda, Sanofi, Janssen), Research funding (Onyx, Janssen, Sanofi, Array BioPharma, Pharmacyclics, Takeda, Celgene, Bristol-Myers Squibb); PM: Honoraria (Celgene, Karyopharm Therapeutics, Bristol-Myers Squibb, Sanofi, Janssen, The Binding Site), Research support (Celgene); SK: Honoraria (AbbVie, Celgene, Kite Pharma). FG: Honoraria (Takeda, Amgen, Celgene, Janssen, Bristol-Myers-Squibb, Seattle Genetics, Roche). BP: Honoraria (Amgen, Bristol-Myers Squibb, Celgene, Janssen-Cilag, Takeda, Sanofi), Research funding (Celgene, Janssen-Cilag, Sanofi, Takeda).

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Costa, L.J., Derman, B.A., Bal, S. et al. International harmonization in performing and reporting minimal residual disease assessment in multiple myeloma trials. Leukemia 35, 18–30 (2021). https://doi.org/10.1038/s41375-020-01012-4

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