Доказательства для мониторинга динамики минимальных остаточных заболеваний с целью руководства клинической практикой у пациентов с множественной миеломой.

Key Points

Introduction

Multiple myeloma (MM) arises through clonal plasma cell proliferation in the bone marrow and is the second most common clonal plasma cell cancer [ 1 , 2 ]. In China, the age-standardized incidence rate is 0.8/100,000 persons [ 3 ]. New cases occur most commonly in the 65–69-year-old age group and the highest prevalence rate is among individuals aged 70–74 years (13.0/100,000 persons) [ 3 ]. Given the population size of China, MM represents a substantial disease burden to the national healthcare system, with an estimated disability-adjusted life years rate of 338,359/100,000 persons [ 3 ].

MM is a highly heterogenous and genetically complex cancer. Most patients with MM become refractory to treatment and relapse (refractory/relapsed MM; RRMM) [ 2 ]. Relapse is due to residual myeloma clonal cells that persist after treatment (also known as minimal residual disease [MRD]) [ 4 ]. Indeed, treatment-resistant clones may remain dormant over many years of follow-up, and relapse can occur even after 10 years in remission from a single-cell clonal expansion [ 5 ], highlighting the source of relapse as residual disease. MRD has been established as one of the strongest prognostic factors in MM [ 6 – 11 ] and is an accepted MM clinical trial endpoint [ 12 , 13 ].

Highly sensitive assays have been developed to detect MRD. This is because of the depth of treatment response achieved with the availability of revolutionary treatments for MM [ 14 ], such as proteasome inhibitors, immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibodies (mABs). Therapeutic advances have also been made for patients with RRMM, including anti-B-cell maturation antigen (anti-BCMA) therapies, such as the antibody–drug conjugate (ADC) belantamab mafodotin and the bispecific antibodies teclistamab, talquetamab, and elranatamab, as well as T cell–directed therapies (chimeric antigen receptor T cell [CAR-T]), such as idecabtagene vicleucel and ciltacabtagene autoleucel [ 2 ]. The 5-year survival rate of MM is now close to 50% [ 1 , 2 ].

Given that MRD indicates the depth of treatment response and is a strong predictor of survival, researchers have turned their attention to how MRD assessment might be utilized in routine clinical practice [ 12 , 15 ]. However, the relevance of assigning prognostic value to results of a single MRD assessment is questionable, since some patients with MRD-negative (MRD−) status may relapse quickly, whereas others with MRD-positive (MRD+) status may not relapse during extended follow-up [ 16 ]. Indeed, MRD status may not be sustained and can change (i.e., transitioning from MRD+ to MRD− and vice-versa) during the course of treatment and during changes in disease state [ 15 ]. Therefore, changes in MRD status can be predictive of clinical relapse [ 17 ]. Evidence now suggests that sustained MRD negativity may be associated with better survival [ 14 , 15 ]. This highlights the importance of monitoring MRD dynamics in clinical practice. There is currently no international consensus on the definition of monitoring MRD dynamics, but for the purposes of this article, it can be defined as periodic or regular MRD assessment to screen for longitudinal changes in MRD status. Several questions remain regarding the role of MRD dynamics in predicting early relapse and assessing prognostic risk. There are also knowledge gaps around implementing monitoring of MRD dynamics in routine clinical practice to assist in making therapeutic decisions, specifically, for example, regarding the frequency, timing, and methods of MRD monitoring.

In this narrative review, we provide an overview of the role of monitoring MRD dynamics in the management of patients with MM in the era of modern treatment strategies, with a focus on the evidence for its use in clinical decision-making and the current gaps associated with implementing MRD risk management into standard clinical practice. The identification of literature for inclusion in this review is summarized in the Online Resource.

The Clinical Value of MRD Dynamics

Monitoring of MRD dynamics can be used to assess the duration and direction of treatment response in patients with newly diagnosed MM (NDMM) or RRMM, and thus may help to predict treatment outcomes [ 18 ]. With newer immunotherapy combination regimens enabling achievement of deep remissions, as evidenced by a patient’s MRD− status (clearance of MRD), the relationship between longitudinal MRD dynamics and survival or risk of relapse/progression becomes important to understand, particularly if these MRD dynamics are to be used to guide clinical decision-making.

Superior Prognostic Value of MRD Dynamics Versus One-Off MRD Test

Patients with NDMM

The importance of monitoring MRD dynamics (i.e., to determine any changes in MRD status over time) on prognosis was shown in a landmark analysis of two 2-year phase 3 studies in patients with NDMM (TOURMALINE-MM3 and -MM4; Table 1 ) [ 19 ]. In these studies, MRD was assessed at randomization to maintenance treatment with the oral proteasome inhibitor ixazomib and then again at 14 months. Although MRD status at the single time point (randomization) had independent prognostic value, with MRD− status being associated with significantly prolonged median progression-free survival (mPFS) versus MRD+ status (38.6 versus 15.6 months; hazard ratio [HR] 0.47), the monitoring of MRD dynamics at two time points during maintenance treatment provided better risk stratification than the single MRD measurement. Patients with sustained MRD negativity (i.e., MRD− status at randomization and at 14 months) had prolonged progression-free survival (PFS) versus patients who converted from MRD+ to MRD− status during maintenance treatment (2-year PFS rate: 75.0% versus 34.2%) [ 19 ]. Monitoring of MRD dynamics also showed that patients with MRD resurgence (i.e., conversion from MRD− to MRD+ status) had an increased risk of progression or death (HR 3.31; 95% confidence interval [CI] 1.77, 6.20; p < 0.001) [ 19 ].

Multiple studies in patients with NDMM have confirmed that sustained MRD negativity is associated with better survival (or time-to-next-treatment) outcomes [ 18 – 34 ]. Three of these studies were conducted in China [ 25 , 26 , 30 ]. In two of these, PFS and overall survival (OS) were significantly prolonged in patients with sustained MRD negativity versus those who converted to MRD+ status [ 26 , 30 ]. In the third study, there was no significant difference in OS between patients who converted from MRD− to MRD+ and those with sustained MRD positivity during the first year of maintenance treatment [ 25 ]. Notably, a retrospective analysis of data from the multicenter NICHE-MM cohort was the first Chinese study to evaluate the prognostic value of MRD dynamics (Table 1 ) [ 26 ]. In the NICHE-MM cohort, mPFS was significantly longer among patients with sustained MRD negativity (52.7 months, 95% confidence intervals (CI) 44.5, not reached [NR]) than in patients who lost MRD− status (30.8 months, 95% CI 26.8, 38.9; p < 0.0001), as was median OS (mOS; NR versus 71.5 months; 95% CI 64.3, NR; p < 0.001) [ 26 ]. Similarly, Xu and colleagues observed that earlier loss of MRD (within 12 months of achieving MRD− status) had a negative impact on PFS compared with later loss of MRD− status (after 12 months) but had no effect on OS [ 30 ]. The aforementioned studies indicate how MRD resurgence severely hinders the generally favorable prognostic effect of MRD− status. MRD resurgence is thought to depend, at least in part, on the biologic and genetic features of the minimal residual plasma cells, including whether drug-resistant clones can emerge under selective pressure of treatment [ 16 , 35 ].

The International Myeloma Working Group (IMWG) defines sustained MRD negativity as MRD− status in bone marrow and by positron emission tomography computed tomography (PET-CT) imaging at two time points measured ≥ 1 year apart [ 14 ]. However, it is worth noting that a favorable PFS outcome can be observed after a much longer duration of sustained MRD negativity. A retrospective study of patients with MM in remission found that sustained MRD negativity for ≥ 5 years was associated with a 6-year PFS rate of 95.9% (95% CI 0.91, 1.0) and an estimated risk of disease relapse at 9 years of 11% [ 36 ]. At last follow-up, 74% of these patients were no longer receiving MM treatment, indicating that sustained MRD negativity could be used to guide the discontinuation of therapy.

Several studies that monitored MRD dynamics during maintenance therapy have confirmed the benefits of sustained MRD negativity [ 17 , 23 , 25 , 37 ]. One of these studies (phase 3 IMROZ study in transplant-ineligible NDMM) also showed how the monitoring of MRD dynamics can accurately evaluate the expected treatment outcomes of specific regimens (Table 1 ) [ 37 ]. After induction therapy with isatuximab in combination with bortezomib–lenalidomide–dexamethasone (VRd) or VRd alone [ 38 ], two- to three-fold higher rates of sustained MRD negativity were observed during maintenance treatment with isatuximab–VRd versus VRd alone [ 37 ]. MRD dynamics indicated that the quadruple therapy group had sustained long-term MRD negativity (at 1, 2, and 3 years) at sensitivity or limit of detection (LOD) levels of < 10 −5 and < 10 −6 , suggesting the achievement of deep durable remission with isatuximab–VRd [ 37 ]. Quadruple therapy was also associated with a two- to five-fold lower rate of MRD resurgence than VRd [ 37 ]. In contrast, maintenance treatment with lenalidomide monotherapy in a phase 2 study showed a prognostic effect on PFS only with 1 or 2 years of sustained MRD negativity but not after 3 years of MRD negativity (although the 3-year analysis was underpowered) [ 23 ]. Nevertheless, these findings suggested that loss of MRD negativity during maintenance treatment is associated with an increased risk of disease progression [ 23 ].

The potential for poor prognosis among patients with MRD resurgence highlights the importance of detecting loss of MRD− status as early as possible. As such, monitoring of MRD dynamics may have important clinical value for predicting the risk of disease recurrence. This was exemplified in a substudy of the EMN02/HO95 MM trial, which monitored bone marrow MRD dynamics using multiparametric flow cytometry before and during lenalidomide maintenance treatment, as well as serum-free light chain (sFLC) and M-protein levels (biochemical/serological assessments) in patients with complete response (CR) ( n = 20) [ 17 ]. Among six patients with disease progression, MRD resurgence was detected 5.5 months prior to biochemical progression and 12.6 months prior to clinical progression, strongly suggesting the clinical benefits of monitoring MRD dynamics for early prediction of disease progression. This study also confirmed the prognostic benefits of sustained MRD negativity in 13/20 patients, all of whom remained free of clinical progression for 6 years [ 17 ].

Patients with RRMM

The prognostic benefits of sustained MRD-negativity (≥ 12 months) on long-term survival have also been reported in patients with RRMM. For example, the DREAMM-7, DREAMM-8, KarMMA, and other trials have evaluated the effectiveness of newer immunotherapies, including BCMA- or G protein-coupled receptor class C group 5 member D (GPRC5D)-targeting CAR−T therapies [ 39 – 41 ] and the BCMA-targeting ADC belantamab mafodotin [ 42 , 43 ].

The clinical importance of monitoring MRD dynamics is even more significant since these newer immunotherapies are highly effective at clearing malignant plasma cells from the bone marrow. In the KarMMa phase 2 trial in RRMM, sustained MRD negativity for up to 1 year after an anti-BCMA CAR-T (idecabtagene vicleucel) infusion was associated with prolonged PFS (Table 1 ), although PFS was worse in patients with extramedullary disease [ 40 ]. The KarMMa trial highlighted that MRD dynamics after CAR-T therapy should be monitored by highly sensitive MRD assessment (LOD < 10 −6 ) for good PFS outcomes, since any detectable MRD was associated with rapid relapse; however, the method of MRD assessment (i.e., next generation sequencing [NGS] versus next generation flow [NGF]) was less important. Finally, discordance between CR and MRD in the first year after infusion was observed, with early MRD negativity after infusion speculated as better reflecting CAR-T peak expansion and malignant plasma cell clearance [ 40 ]. A retrospective observational study in China reported a mismatch between response and MRD negativity to BCMA-directed CAR-T therapy (equecabtagene autoleucel), with 80.4% of patients achieving CR or stringent CR (sCR), while 96.4% achieved MRD negativity [ 39 ]. Sustained MRD negativity for 1 and 2 years was associated with an mPFS of 58 and 64 months, respectively, with mPFS being NR after 3 years of MRD negativity [ 39 ].

MRD-Guided Treatment Decisions

Induction Therapy Duration

Two prospective trials have used MRD dynamics to guide the duration of induction/initial therapy for patients with NDMM (Tables 2 , 3 ) [ 44 , 45 ]. In a phase 1/2 trial by Korde and colleagues, in which patients received induction followed by autologous stem cell transplant (ASCT), MRD testing was only conducted when patients achieved CR/sCR during induction (with carfilzomib−lenalidomide−dexamethasone [KRd]) [ 45 ]. A subsequent phase 2 trial by Derman and colleagues included routine MRD assessments after cycles 4, 8, and 12 of first-line quadruplet therapy with elotuzumab–KRd (Elo-KRd) [ 44 ]. In the Korde et al. trial, patients who were MRD+ (6/28 patients) continued induction therapy until all 12 cycles of KRd were complete [ 45 ], whereas in the Derman et al. trial, patients who were MRD+ at cycle 12 of Elo-KRd (6/46 patients) completed an additional 12 cycles (total of 24 cycles) [ 44 ].

In the Korde et al trial, patients with MRD− status (12/25 patients) received two further cycles of KRd before stopping protocol therapy and undergoing ASCT (and any subsequent off-protocol therapy) [ 45 ]. In these patients, a median (range) of 8 (2–12) cycles of induction were required to achieve CR/sCR and MRD− status. The reduced duration of induction therapy based on MRD status did not adversely affect PFS, since the 2-year PFS rate was not significantly different between the MRD− group and the patients with MRD+ status who completed all 12 cycles of KRd induction therapy (89% versus 64%; p = 0.3) [ 45 ].

In the Derman et al. trial of quadruplet initial therapy, patients with MRD− status after both cycles 8 and 12 of Elo-KRd (20/46 patients) then received Elo-Rd maintenance therapy from after cycle 12 until disease progression [ 44 ]. In contrast, patients who converted from MRD+ to MRD− status between cycles 8 and 12 (2/46 patients) received six more cycles of Elo-KRd before transitioning to Elo-Rd maintenance therapy after cycle 18 [ 44 ]. Patients with MRD− status from cycle 8 of Elo-KRd had 3-year PFS and OS rates of 92% and 100%, respectively (PFS by treatment decision pathway was not reported). This trial confirmed the results of the previous Korde et al. trial, with the detection of MRD negativity allowing for the de-escalation of treatment, reduction of drug exposure, and potentially reducing adverse effects and healthcare costs, without compromising efficacy [ 44 ].

ASCT Decision-Making

The phase 3 GMMG-HD7 trial ( NCT03617731 ) in patients with ASCT-eligible NDMM showed high rates of MRD negativity (50%) after induction with an Isa-VRd quadruplet regimen (versus 36% with VRd; odds ratio [OR] 1.82; 95% CI 1.33, 2.48; p = 0.00017) [ 46 ]. This MRD response deepened after ASCT, with MRD negativity rates of 66% in the Isa-VRd and 48% in the VRd group (OR 2.13; 95% CI 1.56, 2.92; p < 0.0001) [ 31 ]. MRD status at the end of induction and end of transplant were prognostic of survival, with significantly longer PFS in patients who were MRD− than in those who were MRD+ (regardless of subsequent maintenance therapy) at the induction time point (HR 0.38; 95% CI 0.26, 0.55; p < 0.001) and the transplant time point (HR 0.42; 95% CI 0.28, 0.63; p < 0.001). Isa-VRd also showed PFS benefits over VRd in patients who were MRD+ [ 31 ].

In the MIDAS trial, MRD status was used to guide treatment options after six cycles of Isa-KRd induction (Table 2 ) [ 47 ]. After induction, almost two-thirds of patients (63%) were MRD− (LOD < 10 −5 ) and were therefore randomized to either ASCT plus two cycles of Isa-KRd ( n = 242) or consolidation therapy with six cycles of Isa-KRd ( n = 243). Patients who were MRD+ (33%) were randomized to either tandem ASCT ( n = 124) or single ASCT plus two cycles of Isa-KRd consolidation therapy ( n = 109). Subsequently, MRD was assessed again prior to the start of maintenance therapy, and the MRD negativity rate (LOD < 10 −6 ) was not significantly different between ASCT versus Isa-KRd consolidation (in patients with MRD− at end of induction) or between tandem versus single ASCT (in patients with MRD+ at end of induction) [ 47 ]. This suggests that ASCT is not necessarily mandatory for patients who are MRD− after induction therapy and that tandem ASCT may no longer be warranted in those who are MRD+ if an effective quadruplet induction regimen is used. The lack of MRD negativity benefit with ASCT versus Isa-KRd consolidation was attributed to the high rates of MRD negativity (LOD < 10 −6 ) or deep treatment response after induction with isatuximab-based quadruplet therapy [ 47 ]. Survival data from MIDAS are not yet mature and are needed to confirm whether transplant decisions can be made on the basis of MRD status.

Two ongoing trials (ADVANCE [ NCT04268498 ] and MASTER-2 [ NCT05231629 ]) are also investigating the use of MRD-guided therapy for transplant decision-making after induction therapy with daratumumab-KRd in NDMM patient populations [ 48 , 49 ].

Consolidation Therapy Duration

MRD-guided decision-making to determine the duration of consolidation therapy with the quadruplet of daratumumab-KRd (Dara-KRd) after autologous hematopoietic cell transplantation (AHCT; or after four cycles of Dara-KRd in patients not undergoing AHCT) was investigated in the phase II MASTER trial (Table 2 ) [ 50 , 51 ]. MRD status also guided choice of maintenance treatment, with patients achieving sustained MRD-negativity stopping treatment and entering the follow-up MRD-SURE study (discussed in more detail below) [ 50 , 51 ]. MASTER showed that an MRD-guided approach to consolidation treatment led to a high proportion of patients (71%) having consecutive MRD-negativity (10 −5 ) and that these patients could discontinue treatment and enter treatment-free surveillance; only 16% of patients required lenalidomide maintenance therapy [ 50 ]. Notably, the depth of response had improved over time, since only 38% of patients had achieved MRD-negativity at the end of induction with Dara-KRd [ 50 ]. These data suggest that in selected patients (i.e., those with early and deep treatment responses), a de-escalation of consolidation therapy is feasible.

Maintenance Therapy Duration

Using MRD to guide treatment decisions regarding transition to maintenance treatment or stopping maintenance treatment and entering treatment-free surveillance has been successful in several studies (Tables 2 , 3 ) [ 45 , 51 – 54 ].

In the MRD-SURE trial, patients with two MRD− results during MRD-guided consolidation therapy (as described in the abovementioned MASTER trial) immediately entered treatment-free surveillance after completing consolidation therapy (Table 2 ) [ 51 ]. In contrast, patients in other studies continued maintenance treatment and only entered treatment-free surveillance if they achieved MRD− status, with the specific criteria for MRD− varying between studies (Tables 2 , 3 ) [ 52 – 55 ]. In two of the studies, MRD− at a single time point was used to determine cessation of maintenance treatment, either after 24 cycles (~2 years) in the GEM2014MAIN trial [ 53 ] or after ≥ 1 year in the MRD2STOP trial [ 52 ]. In studies by Korde et al. [ 55 ] and Terpos et al. [ 54 ], sustained MRD negativity for 3 years was required before maintenance treatment could be discontinued. Similarly, in the MRD2STOP trial, patients entered a treatment-free surveillance period after a median of 36 months’ maintenance treatment [ 52 ].

The rates of disease progression after treatment cessation were generally encouraging in the MRD-SURE and GEM2014MAIN studies [ 51 , 53 ]. In MRD-SURE, the cumulative proportion of patients who progressed during 42 months’ treatment-free surveillance was only 9% each in patients with zero or one high-risk cytogenetic abnormalities (HRCAs) [ 51 ]. However, 47% of patients with ≥ 2 HRCAs had progressed [ 51 ], suggesting cytogenetics are an important factor when considering treatment-free surveillance versus maintenance treatment in patients with sustained MRD negativity during consolidation. Likewise, in GEM2014MAIN, a low proportion of patients (17.2%) had progressive disease at 4 years after the discontinuation of maintenance treatment [ 53 ].

Where reported, survival data were also generally positive [ 52 , 54 , 55 ]. The Korde et al. study reported a 2-year PFS rate of 89% [ 55 ], while Terpos et al. reported a 3-year treatment-free survival rate of 75.8% [ 54 ] and MRD2STOP a 3-year PFS rate of 92% (MRD test LOD < 10 −7 ) [ 52 ]. Broadly similar rates of MRD resurgence were reported by Korde et al. and Terpos et al. (17.9% and 23%, respectively) [ 54 , 55 ], and the time to MRD resurgence in the Terpos et al. study was 28 months [ 54 ]. In MRD2STOP, the LOD of the MRD assessment conducted before entering treatment-free surveillance (“baseline”) seemed to influence MRD resurgence rates [ 52 ]. The 3-year cumulative rate of MRD resurgence (defined as MRD detected during maintenance using LOD < 10 −6 ) was 75% among patients with MRD− assessed at baseline at an LOD of ≥ 10 −7 versus 20% in patients with MRD− assessed with higher sensitivity (LOD < 10 −7 ) [ 52 ].

Monitoring MRD Dynamics in Clinical Practice: What Is the Evidence?

Evidence supports MRD status as a vital prognostic tool, and MRD has been widely adopted as an endpoint in clinical trials of novel MM treatments. The next step is the adoption of MRD dynamics to guide clinical decision-making. There appear to be significant clinical benefits in using MRD-guided decision-making, with a retrospective study reporting significantly prolonged mPFS among patients with versus without MRD-guided treatment decisions (104 versus 62 months; p = 0.005), even among patients with MRD+ (Table 3 ) [ 56 ]. In this section, we discuss the key clinical considerations for the application of monitoring MRD dynamics in clinical practice.

We should acknowledge first, however, that if MRD-guided therapy is to be routinely implemented in clinical practice, discussion at a country/regional level is required to address the availability of healthcare resources within and across national healthcare systems. If implemented, the cost of monitoring MRD dynamics across the treatment continuum might be offset against a potential reduction in healthcare resource utilization, as well as short- and long-term treatment toxicity [ 51 ]. However, cost-effectiveness analyses and patient quality-of-life data are limited as these outcomes have generally not been included in clinical trials and represent a significant knowledge gap around monitoring MRD dynamics.

Timing and Frequency of MRD Testing

The European Hematology Association-European Myeloma Network (EHA-EMN) guidelines suggest several time points for mandatory and optional MRD testing [ 57 ]; other algorithms have also been proposed [ 12 ]. The EHA-EMN guidelines recommend mandatory bone marrow MRD testing at diagnosis and treatment response, with optional testing every 12 months in patients who are MRD− and in those with disease relapse [ 57 ]. In a review by Paiva and colleagues, MRD testing in the bone marrow is recommended as standard during the first year of treatment, with periodic testing of peripheral blood samples every 6 months during the early and more intensive stages of treatment, with imaging considered throughout treatment, particularly in patients with extramedullary disease [ 12 ]. Based on these recommendations, Fig. 1 shows our suggestions for when MRD testing should be conducted in routine clinical practice. In general, we suggest conducting bone marrow MRD assessments, along with PET-CT imaging, at all treatment decision points and after 1 year of maintenance, with peripheral blood assessments conducted at 6-month interval during maintenance treatment.

In a study by Martinez-Lopez and colleagues, serial bone marrow MRD testing (i.e., > 3 MRD samples) was conducted in 61 patients with NDMM who achieved CR [ 18 ]. This study identified three categories of MRD status: (A) patients with ≥ 3 MRD− samples (LOD < 10 −6 ; n = 21); (B) patients with continuously decreasing but detectable clonal numbers ( n = 19); and (C) patients with stable/increasing clonal numbers ( n = 21). Of note, mPFS was significantly prolonged in groups A and B versus C (NR and NR versus 55 months; p < 0.001) [ 18 ].

MRD Testing Sensitivity

The current IMWG and EHA-EMN guidelines recommend a minimum sensitivity or LOD of < 10 −5 with either NGS (LymphoSIGHT [Sequenta/Adaptive]) or NGF (EuroFlow) to assess MRD in bone marrow (clonal plasma cells) [ 14 ]. In our clinical experience in China, MRD testing most commonly uses an LOD of < 10 −5 . Multiple studies have investigated the prognostic value of different MRD testing sensitivities [ 16 , 18 , 52 , 58 – 62 ]. Although lower LODs (i.e., < 10 −6 , < 10 −7 ) indicate a greater depth of treatment response and better prognosis in MRD− patients, some clinicians consider that MRD testing at these LODs is too difficult [ 16 , 52 ].

The main barriers to using more sensitive LODs are the amount of bone marrow sample that can be obtained, cost, and the lack of a validated assay with an LOD of < 10 −7 [ 52 ]. Reassuringly, monitoring MRD dynamics at an LOD of < 10 −5 can detect deep molecular responses that correspond to clinically significant prolonged PFS [ 18 ]. Critically, sustained MRD negativity at an LOD of < 10 −5 has been modeled as the best predictor of PFS, as well as MRD resurgence in patients who undergo MRD-guided treatment discontinuation [ 32 ]. Given these considerations, in our view, an LOD of < 10 −5 should remain standard practice for MRD testing. What is not yet known is whether MRD− status at different LODs depth of response may be used to guide treatment decisions. For example, should patients with MRD− at an LOD of < 10 −4 or < 10 −5 receive more aggressive treatment to achieve MRD− at an LOD of < 10 −6 or < 10 −7 ? Further studies are needed to confirm whether testing sensitivity should be considered as part of the MRD-guided decision-making process.

MRD Testing Techniques

According to the EHA-EMN guidelines, MRD testing from bone marrow aspirates should be conducted using either NGF or NGS [ 57 ].

EuroFlow-based NGF is a two-tube, eight-color antibody-based flow cytometry assay that has significantly increased sensitivity over conventional flow-MRD [ 63 ]. NGF can also assess the quality of a bone marrow sample, with hemodiluted samples showing a significant decrease in non-plasma cell bone marrow cell populations [ 63 ]. Although NGF has lower testing sensitivity (2 × 10 −6 ) than NGS (< 10 −6 ), this can be overcome by analyzing a greater number of bone marrow cells (> 4 × 10 7 cells) [ 58 ]. Real-world studies have shown the suitability of EuroFlow-based NGF for implementation in clinical practice, with LODs of < 10 −5 and < 10 −6 , respectively [ 58 , 64 ].

NGS is a molecular method that detects clonal plasma cells by identification of immunoglobulin gene rearrangements [ 60 ]. The commercially available LymphoTrack ® NGS has high correlation with EuroFlow NGF for MRD testing, although patients with MRD negativity by NGF were found to have PFS and OS benefits over NGS-detected MRD negativity [ 60 ]. However, a comparative study of the prognostic value of NGF- versus NGS-based MRD testing found that PFS was similar between MRD− patients determined by NGF (LOD <10 −6 ) versus NGS, and was significantly prolonged in NGF-based MRD− versus MRD+ patients ( p = 0.026) [ 58 ].

Frequent MRD testing may not be feasible in routine clinical practice, particularly owing to the discomfort associated with multiple bone marrow aspirations [ 12 ]. Therefore, patients can also undergo assessment of MRD in the peripheral blood via ultrasensitive, noninvasive methods. These peripheral MRD assessments all have lower sensitivity than that of bone marrow-based MRD analyses and therefore have different biological and clinical relevance [ 12 ]. Circulating plasma cells in the peripheral blood can be detected by EuroFlow-based NGF [ 15 ]. Circulating cell-free DNA (cfDNA)-based methods may also be used to monitor genomic abnormalities in cfDNA isolated from blood samples [ 15 ]. Serum protein electrophoresis (SPEP) can detect M-protein in peripheral blood samples and may be used to monitor disease activity when combined with sFLC analyses [ 65 ]. The sensitivity of these techniques is limited by background polyclonal immunoglobulins on SPEP [ 65 ].

Mass spectrometry (MS) is another form of peripheral blood-based MRD testing that can identify plasma cell clones through its high sensitivity to the mass–charge ratio of secreted paraproteins [ 66 – 68 ]. A study of 76 patients with NDMM showed substantial concordance between MRD testing by matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) MS and NGS at LODs of < 10 −5 to < 10 −6 (80% agreement) or LOD of < 10 −6 (89% agreement), although concordance between liquid chromatography (LC)–MS was lower (60% and 78% agreement, respectively) [ 66 ]. Another study has demonstrated that a multiparametric LC–MS assay could be used to monitor M-proteins, therapeutic antibodies, and polyclonal antibodies in serum samples collected from four patients with MM, with LODs of 3–5 × 10 −5 g/L for M-proteins and 1–6 × 10 −5 g/L for the therapeutic and polyclonal antibodies [ 67 ]. Clonotypic MS has also been used to monitor MRD dynamics in a single-center study of 94 patients with MM for 100 days after undergoing AHCT, with MRD+ status being associated with significantly shorter PFS (mPFS 2.5 versus 8.4 years; P = 0.0002) and OS (mOS 5.0 years versus NR; P = 0.001) compared with MRD− status [ 68 ].

PET-CT imaging can be used to identify hypermetabolic regions outside the bone marrow in patients with sustained MRD negativity [ 57 ]. Diffusion-weighted, whole-body magnetic resonance imaging (WB-MRI) has also been shown to have predictive value for sustained imaging MRD negativity in patients with NDMM after ASCT and during maintenance therapy (at 1 year) [ 69 ]. The EHA-EMN guidelines recommend using PET-CT and diffusion-weighted MRI as complementary techniques to bone marrow testing for MRD negativity [ 57 ].

High-Risk MM

In 2025, the International Myeloma Society (IMS)/IMWG consensus recommendations proposed that Consensus Genomic Staging of high-risk MM (HRMM) relied on the presence of at least one of the following genetic abnormalities: (1) del(17p) with a cancer clonal fraction threshold of ≥ 20% and/or TP53 mutation; (2) an immunoglobulin heavy locus ( IgH ) translocation, including t(4;14), t(14;16), or t(14;20), with concurrent 1q+ or del(1p32); (3) monoallelic del(1p32) (with concurrent with 1q+) or biallelic del(1p32); or (4) high β2 microglobulin (≥ 5.5 mg/L) with normal creatinine (< 1.2 mg/dL) [ 70 ]. This definition takes into account the latest evidence from molecular and genomic assays and updated clinical data to provide a practical definition for use in clinical practice [ 70 ]. The current EHA-EMN guidelines acknowledge the IMS/IMWG updated definition of HRMM and recommend assessment of cytogenetics at diagnosis (in all patients with NDMM) and at relapse (in patients with HRMM) [ 57 ]. The prognostic values of monitoring MRD dynamics may become particularly important in patients with HRMM.

The management of patients with HRMM requires special consideration. These patients may initially have a rapid, deep response to treatment only to experience relapse shortly thereafter [ 14 ]. Multiple studies have shown that sustained MRD negativity, MRD− status, or conversion from MRD+ to MRD− (versus MRD+ status) was prognostic of better survival, even in the presence of HRCAs [ 29 , 71 – 80 ]. In a study of the prognostic impact of MRD status conducted by Wang and colleagues, MRD− status (LOD < 10 −5 ) or sustained MRD negativity for ≥ 12 or ≥ 24 months was associated with deep remission and improved survival outcomes, regardless of the presence of HRCAs [ 29 ]. Several studies have further evaluated the prognostic value of monitoring MRD dynamics in patients with HRCAs [ 50 , 80 – 83 ]. In a large longitudinal retrospective cohort study of patients with MM in China, where data are available from regular MRD assessments, sustained MRD negativity was associated with superior PFS and OS outcomes versus sustained MRD positivity, regardless of cytogenetic risk status [ 82 ]. Notably, the proportion of patients with a del(17p) was higher among patients with sustained MRD− versus MRD+ status (21.3% versus 5.4%; p = 0.015) [ 82 ]. The MIDAS trial found differences in postinduction MRD negativity rates based on type of genetic abnormality, with a negativity rate of 81% in patients with t(4;14) versus 48% in patients with del(17p) [ 83 ]. Finally, an analysis of the phase III GEM2012MEN065 and GEM2014MAIN trials in patients with NDMM and MRD− status after induction therapy reported that the presence of HRCAs was not predictive of MR− conversion to MRD+ status (“MRD resurgence”) and/or progressive disease (PD) [ 81 ]. In contrast, patients with ≥ 2 HRCAs in the MASTER trial had poor PFS and OS despite similar rates of MRD negativity to patients with lower cytogenetic risk [ 50 ].

Other studies have indicated that MRD– status does not necessarily negate the adverse effects of HRCAs on survival outcomes [ 15 , 21 , 84 – 87 ]. For example, a 2025 study in China, conducted by Mao and colleagues, found that patients with NDMM with HRCAs and MRD− status had significantly shorter mPFS and mOS compared with those with standard-risk cytogenetic abnormalities and MRD− status [ 85 ].

Patients with HRMM without HRCAs, so-called functional HRMM, typically have suboptimal response to induction therapy or experience relapse within 12–18 months of treatment initiation [ 88 ]. These patients represent an unmet medical need owing to challenges in the correct identification of baseline and dynamic risk factors associated with a higher risk of early relapse [ 88 ]. MRD status may be a better early dynamic predictor of prognosis than standard biochemical response evaluation, although clinical study validation should be conducted before this strategy is adopted in these patients.

Taken together, these data indicate that further research is needed to confirm the impact of MRD status on clinical outcomes in patients with HRMM, including the tailoring of MRD assessment timing based on cytogenetic risk stratification [ 83 ]. The role of functional imaging or extramedullary disease assessment in refining risk stratification also needs to be clarified, especially in patients receiving individualized response-adapted treatment.

MRD Resurgence

Currently, there is limited evidence regarding the management of patients with MRD resurgence occurring in the absence of biochemical and/or clinical progression. As clinical progression appears to be inevitable, should patients with MRD resurgence in the absence of clinical progression be managed by a treatment change or intensification? In an effort to address this question, the ongoing phase 2/3 Relapse from MRD Negativity as Indication for Treatment (REMNANT) trial ( NCT04513639 ) is evaluating how MRD status can be used to guide pre-emptive therapy in patients with NDMM eligible for ASCT who convert from MRD− to MRD+ status [ 89 ].

Discussion and an Expert Opinion from China

Despite the lack of an internationally recognized algorithm for monitoring MRD dynamics in patients with MM, the current evidence supports its use in MRD-guided treatment decisions in these patients to provide optimal treatment strategies for those at high risk of disease relapse, while enabling treatment de-escalation in patients with sustained MRD negativity. Monitoring MRD dynamics may become essential for future clinical practice, particularly among patients receiving immunotherapy, since much of the evidence supporting the monitoring of MRD dynamics in clinical practice has come from clinical trials of immunotherapy agents (e.g., daratumumab, elotuzumab, and isatuximab) [ 44 , 50 , 51 , 83 ]. However, several knowledge gaps exist with regard to monitoring MRD dynamics in routine clinical practice, specifically in selecting the optimal frequency, timing, and techniques for MRD testing.

Although bone marrow MRD testing with NGF or NGS is recommended by EHA-EMN guidelines [ 57 ], the challenges of these high-sensitivity assays include the practical constraints regarding the amount of bone marrow sample that can be obtained, the lack of a validated assay with an LOD of < 10 −7 , and the costs associated with MRD testing [ 52 ]. Indeed, the use of high-sensitivity MRD testing methods, such as NGS, is often limited by the high cost of these techniques [ 61 , 90 , 91 ]. NGF has lower associated costs than NGF but requires freshly collected samples (processed within 24 h of aspiration) and larger sample volumes than NGS [ 61 , 91 ].

Peripheral MRD testing, such as SPEP, may be needed for effective monitoring of MRD dynamics; however, these techniques have much lower sensitivity than bone marrow-based MRD assessments [ 12 ]. There is increasing interest in the potential use of MALDI-TOF-MS or LC–MS for peripheral MRD testing, which has higher sensitivity than other peripheral MRD methods [ 66 ]; however, these methods have limited availability, as well as high associated costs, that will need to be considered when incorporating the use of MS-based peripheral MRD testing.

In routine practice across China, bone marrow-based MRD testing is most commonly performed at a LOD of ≤ 10⁻ 5 using NGS or NGF, which is broadly aligned with IMWG and EHA–EMN guidelines [ 14 , 57 ]. The short-term priorities for nationwide healthcare delivery of MRD testing include rigorous standardization of testing and quality assurance processes (e.g., minimizing hemodilution, harmonizing NGS/NGF pipelines, use of external quality assessment, and explicit reporting of the assay LOD). While MRD testing with LODs from < 10⁻⁶ to < 10⁻⁷ is optimal for risk stratification, indicating a greater depth of treatment response and better prognosis, there are several constraints with regard to sample volume, cost, and the limited availability of validated 10⁻⁷ assays. These challenges currently limit the routine adoption of < 10⁻⁶ to < 10⁻⁷ LODs, making an LOD of < 10⁻ 5 a pragmatic target for most centers in China. To better identify biochemical relapse early and capture any extramedullary disease, and to mitigate the risk of a false-negative result from a bone marrow sample tested for MRD (because MM infiltration in bone marrow occurs in a “patchy” manner) [ 92 ], we suggest integrating MRD dynamics with PET-CT imaging (and low-dose WB-MRI, where available) to guide treatment decisions, alongside serologic markers (e.g., M-protein and sFLC). We believe that this strategy for MRD testing would be generalizable to other middle-to-high income nations.

We propose a schedule for monitoring MRD dynamics in patients with NDMM in routine clinical practice (Fig. 1 ). MRD bone marrow testing plus PET-CT imaging should be conducted at diagnosis, the end of induction treatment, and when RRMM emerges. MRD bone marrow testing alone is suggested after ASCT and every 12 months during maintenance treatment for 2–3 years, with MRD peripheral testing conducted every 3–6 months or when there is biochemical or clinical suspicion of relapse, and narrower testing intervals adopted in patients who lose MRD negativity. Using MRD dynamics to guide changes in the treatment regimen, such as treatment de-escalation or discontinuation, should only be considered in patients with sustained MRD negativity and a favorable cytogenetic risk profile, and should generally be avoided in patients with ≥ 2 HRCAs outside trial-level surveillance. The national healthcare system may encourage more widespread adoption of monitoring MRD dynamics by providing reimbursement for MRD testing, developing regional referral networks, and establishing central laboratories for complex NGS and prospective registries to generate more robust real-world evidence to support its use in routine clinical practice.

In conclusion, the use of MRD testing in MM clinical trials has increased over the past decade, with the ever-increasing importance of MRD− status as a primary endpoint in assessing novel treatments for patients with MM. Prospective studies have demonstrated the effectiveness of MRD-guided clinical decision-making in this setting, with improved prognosis and a reduced need for maintenance treatment, especially in patients with sustained MRD negativity and low cytogenetic risk. However, further prospective real-world studies are needed to support the widespread use of monitoring MRD dynamics in routine clinical practice.

Acknowledgements

We thank Tracy Harrison, CMPP, of Springer Health+, who assisted in the preparation of the outline and subsequent drafts of this manuscript, and Sarah Greig, PhD, CMPP, of Springer Health+, who assisted with post-submission revisions. This medical writing assistance was funded by Sanofi.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82370192, U24A20680), the 1.3.5 Project of High Altitude Medicine (No. GYYX24003), the West China Hospital, Sichuan University, the Natural Science Foundation of Sichuan Province of China (No. 2025ZNSFSC1692), and the National Natural Science Foundation of China (No. 82500270). Medical writing support for this manuscript was funded by Sanofi.

Declarations

Conflict of interest

Xinai Gan, Linfeng Li, Li Zhang, Yuhuan Zheng, Ting Niu, and Zhengyu Yu declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Availability of data and material

Data sharing is not applicable to this article as no datasets were generated or analyzed during the preparation of this article.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

Author contributions

Xinai Gan and Linfeng Li conceived and designed research, obtained original research data, and analyzed and interpreted the results. Xinai Gan and Zhengyu Yu analyzed the data and wrote the manuscript. Li Zhang, Yuhuan Zheng, Ting Niu, and Zhengyu Yu revised the manuscript and interpreted the results. All authors discussed and provided critical comments and approved the final version for publication.

Footnotes

Publisher's Note

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Xinai Gan and Linfeng Li contributed equally to this work.

Change history

3/14/2026

This article was originally published under the subscription model but it is now published under an Open Access license.

Contributor Information

Ting Niu, Email: niuting@wchscu.cn.

Zhengyu Yu, Email: zhengyuyu@wchscu.cn.

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