The use of highly effective, sequential therapies in multiple myeloma has led to significant improvements in overall survival (OS), with a median survival of over 5 years for newly diagnosed patients.1,2 Triple- and quadruple-drug therapy regimens are now standard of care for primary therapy for both transplant and nontransplant candidates,3 improving the rate of both complete response (CR) and minimal (sometimes called measurable) residual disease (MRD) negativity (Figure 1).4-11 However, despite high rates of CR, most patients eventually relapse.12
Historically, response criteria for multiple myeloma are based on serum and urine monoclonal protein and bone marrow assessment.12 These measures are relatively insensitive for predicting which patients will have a long duration of remission after therapy for multiple myeloma. “When it comes to detection of MRD, the field has evolved over time,” observed C. Ola Landgren, MD, PhD, Professor of Medicine and Chief of the Myeloma Program at Sylvester Comprehensive Cancer Center in Miami. Assessment of MRD status, either by a validated 10-color flow cytometry assay or by a validated next-generation sequencing (NGS) assay, is able to further stratify patients achieving a CR and is predictive of progression-free survival (PFS) and OS in all phases of multiple myeloma.13 MRD testing is recommended by the National Comprehensive Cancer Network (NCCN) Guidelines panel and the International Myeloma Working Group (IMWG) consensus criteria in patients with multiple myeloma who have achieved a CR (Figure 2).3,12
Clinical trials show that achievement of MRD negativity—defined as 1 tumor cell in 100,000 nucleated cells (10-5)—confers PFS and OS benefits.13 At least six different meta-analyses using a variety of regimens have reported improvements in PFS and OS in patients who attain MRD negativity compared with those who remain MRD-positive.14-20 In 2020, Munshi et al published the third meta-analysis focusing on the association between MRD status and PFS/OS. In this study, the authors included all studies published between 1990 and 2016 that enrolled patients with newly diagnosed multiple myeloma receiving any type of therapy except allogeneic stem cell transplantation with MRD assessed by flow cytometry or DNA sequencing.16 Compared with MRD positivity, achieving MRD negativity improved PFS (hazard ratio [HR] = 0.33; 95% confidence interval [CI] = 0.29–0.37; P < .001) and OS (HR = 0.45; 95% CI = 0.39–0.51; P < .001) in patients with newly diagnosed multiple myeloma.16 A recent pooled analysis assessed MRD at 10-5 via NGS in prospectively collected samples of patients with transplant-ineligible newly diagnosed multiple myeloma who were enrolled in two phase III studies (ALCYONE and MAIA).21 The analysis demonstrated patients who achieved greater than or equal to a CR and MRD-negative status had improved PFS compared with MRD-positive patients, and sustained MRD negativity was associated with improved PFS.21
Most of the evidence supporting MRD assessment is derived from patients with newly diagnosed multiple myeloma; however, studies in relapsed/refractory multiple myeloma have recently been published. A large, pooled analysis of prospectively collected samples from patients with relapsed/refractory multiple myeloma enrolled in the POLLUX and CASTOR phase III randomized controlled trials assessed MRD at 10-5 via NGS.19 The study found patients who achieved MRD-negative status had improved PFS compared with MRD-positive patients, and sustained MRD negativity was associated with improved PFS compared with patients who obtained MRD-negative status but did not have a durable MRD-negative response.19 Even among heavily pretreated patients with relapsed/refractory multiple myeloma, MRD negativity was observed in those receiving chimeric antigen receptor (CAR) T-cell therapy.4,22 Achievement of MRD-negative status before the best response according to IMWG criteria was predictive of subsequent development of CR in patients receiving idecabtagene cilolecluecel.22
MRD negativity is associated with significantly improved survival outcomes regardless of disease setting (newly diagnosed or relapsed/refractory multiple myeloma), cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and MRD assessment either premaintenance or 12 months after the start of maintenance therapy. The use of MRD as a surrogate for a clinically significant endpoint in multiple myeloma is being evaluated by a few international groups which include members from academia, pharmaceutical industry, and patient groups.23 Dr. Landgren said, “I have worked with the U.S. Food and Drug Administration (FDA) for over 10 years to investigate the role of MRD as a surrogate endpoint. For a long time, we have been waiting for data to mature. We are approaching the point where data will be mature enough for us to complete the work that we initiated many years ago—I am very excited about that.” The primary objective of these initiatives is to evaluate and validate MRD as a surrogate endpoint for PFS through prospectively planned meta-analytic surrogacy analysis based on patient level data to allow its use as a regulatory endpoint for drug approval. Regulatory approval of MRD negativity as a surrogate endpoint for OS would facilitate more rapid new drug approval, exposure of fewer patients to potentially toxic therapy, and reduced clinical trial duration and cost.23
MRD is a very powerful tool in the clinic.…I think you could intensify or deescalate therapy based on MRD—for me, that is precision medicine for multiple myeloma in the future.C. Ola Landgren, MD, PhD
Dr. Landgren shared, “There are two major avenues I am very excited about. One is that there are more and more datasets showing there is a correlation between MRD negativity and longer PFS. In the coming year, we will hopefully reach a point where the FDA could agree that MRD could be used for regulatory approval for drugs. For patients, using MRD as a regulatory endpoint for drug development would mean much quicker access to new medications.…The second part I am very excited about is that MRD is a very powerful tool in the clinic. More and more people will realize this as they start using it, and treatment decisions will be driven by MRD. I think you could intensify or deescalate therapy based on MRD—for me, that is precision medicine for multiple myeloma in the future.”
“We have used MRD in our clinics every day for about 10 years,” noted Dr. Landgren. There is no consensus on whether patients with multiple myeloma with evidence of reemergence of disease based on MRD assessment should be treated immediately or managed with a watch-and-wait approach.24 While it remains an area of controversy, surveys of practice patterns reveal MRD assessment is used when making clinical decisions by more than one-third of prescribers.25 A retrospective analysis of multinational, multicenter, real-world evidence found changes in multiple myeloma treatment were made based on serial MRD testing of 67 of 400 patients with at least a very good partial response (VGPR) to front-line therapy.26 In patients who achieved MRD negativity during maintenance on at least one occasion, discontinuation of maintenance was not associated with a detriment in PFS (median PFS was 120 months in patients discontinuing maintenance vs 82 months in patients who continued therapy; P = .1). Similarly, in patients who were MRD-positive, changing therapy in 34 patients was associated with improvement in median PFS compared to 171 patients who had no change in therapy (not reached vs 39 months; P = .02).
[If a patient] receiving maintenance therapy has lots of side effects and is seriously considering stopping therapy, a negative MRD test would have added value with other disease information in terms of making that final decision.Shaji Kumar, MD
Shaji Kumar, MD, Professor of Medicine at the Mayo Clinic in Rochester, Minnesota, highlighted two settings outside of clinical trials where MRD is used to guide patient care. One scenario is shared decision-making in patients with high-risk disease after completion of induction and transplant, or at 8 to 12 months in patients not undergoing transplant, to determine whether the patient is MRD-negative. “If not, then certainly an argument can be made for changing or intensifying therapy to achieve MRD negativity,” he said. The other scenario Dr. Kumar noted when such information might guide care is when “someone receiving maintenance therapy has lots of side effects and is seriously considering stopping therapy. A negative MRD test would have added value with other disease information in terms of making that final decision.”
Quantitative, accurate, standardized, and sensitive MRD determinations may improve assessment of tumor biology and likelihood of relapse when performed sequentially over multiple timepoints to establish trends and the pace of changes in tumor burden.27,28 “When patients achieve MRD negativity and they sustain that for 2 years, that is a very strong predictor of PFS. This tells us that MRD tests are important, but the repeat tests are even more important to understand the dynamic of the disease biology,” explained Dr. Landgren.
When patients achieve MRD negativity and they sustain that for 2 years, that is a very strong predictor of PFS. This tells us that MRD tests are important, but the repeat tests are even more important to understand the dynamic of the disease biology.C. Ola Landgren, MD, PhD
A retrospective study examining serial assessments of MRD by NGS found that patients with persistently undetectable MRD at 10-6 or declining levels of clones had significantly better PFS than those with a stable or growing number of clones.28 In addition, MRD testing was able to predict clinical relapse in 9 out of 10 cases when molecular relapse by MRD was defined as a rise of at least 1 logarithm. There is currently no consensus regarding the optimal time points for MRD assessment in myeloma after initial achievement of MRD-negative status. Practice patterns for timing of MRD assessment vary. In a worldwide survey including 84 respondents, 62% of respondents who use MRD assess MRD with standard response assessment, 18% evaluate MRD after induction therapy, 51% after autologous stem cell transplant (ASCT), and 30% after years 1 and 2 of maintenance.25
Clinical trials are ongoing to address the question of how often to monitor for MRD and when to change therapy based on changes in MRD status. Dr. Kumar noted, “There are multiple ongoing trials looking at the questions of whether we need to intensify therapy in patients who are still MRD-positive after a given period of therapy, and also deescalate therapy in those who have achieved MRD negativity.” Close to 50 phase III clinical trials assessing MRD as a primary or secondary endpoint or using MRD to direct treatment are accruing patients.27 Trials incorporating MRD into the study design in multiple myeloma highlighted by Dr. Kumar and Dr. Landgren include EQUATE (ClinicalTrials.gov identifier NCT04566328), OPTIMUM (NCT03941860), SWOG S1803/BMT CTN 1706 (NCT04071457), MASTER (NCT03224507), and ADVANCE (NCT04268498).
MRD can be assessed by multiparameter flow cytometry of surface markers on plasma cells, multiplex polymerase chain reaction (PCR) on DNA derived from the bone marrow or peripheral blood, or NGS. The NCCN Guidelines and IMWG criteria recommend assessment of MRD on bone marrow samples for patients in complete remission.3,12 Samples obtained from the first pull of the bone marrow aspirate should be used to determine MRD to avoid hemodilution.19,29 The volume of marrow aspirate may vary with the assay being utilized and should match the analytical validation of the assay.29 Assessing MRD based on circulating plasma cells, cell-free DNA, or mass spectrometry in peripheral blood is convenient and may be used to guide timing of bone marrow MRD assessment or indicate an early relapse.29 In addition, peripheral blood MRD may overcome limitations due to extramedullary disease or patchy marrow involvement seen with bone marrow MRD assessment. The IMWG response criteria consider both NGS of VDJ (variable, diversity, joining) sequences in bone marrow DNA samples and next-generation flow (NGF) cytometry of surface markers on bone marrow plasma cells to be acceptable methods of MRD assessment.12
To assess MRD by NGS, DNA from a baseline tumor sample is amplified by multiplex PCR, and VDJ rearrangements in the immunoglobulin heavy chain, and kappa and lambda genes are identified.29 Dr. Landgren explained, “Every B cell has a unique ‘fingerprint’ in the three immunoglobulin genes. For reasons we don’t understand, cancers of B cells such as multiple myeloma and other lymphoid malignancies also have these distinct genomic sequences associated with the malignancy, and it’s different from patient to patient, but it is identical within a patient. In multiple myeloma, if you do whole-genome sequencing, the rest of the genomic profile is drastically different from cell to cell. A newly diagnosed patient with multiple myeloma might have 5,000 to 6,000 mutations detectable in the myeloma cells. These mutations are unevenly distributed across the tumor cells, reflected in parallel genomically defined multiple myelomas present at the same time. Despite a striking genomic heterogeneity, all myeloma cells will have the same VDJ sequence in a given patient. This makes VDJ sequencing a very useful tool for MRD tracking.” A baseline tumor sample or an archived sample from a timepoint with detectable disease suitable for capture is needed for NGS sequencing.12 A single platform (clonoSEQ, Adaptive Biotechnologies) has been clinically and analytically validated and cleared by the FDA for assessment of MRD by NGS.30 Successful baseline clonal identification was documented in over 90% of patients with multiple myeloma in recent studies of this assay.29 The LymphoTrack (Invivoscribe) assay is another NGS-MRD evaluated in patients with multiple myeloma. It has similar level of detection/limit of quantification and DNA input requirements to the clonoSEQ assay, but it is not yet approved by the FDA.29
In multiple myeloma, if you do whole-genome sequencing, the rest of the genomic profile is drastically different from cell to cell. A newly diagnosed patient with multiple myeloma might have 5,000 to 6,000 mutations detectable in the myeloma cells. These mutations are unevenly distributed across the tumor cells, reflected in parallel genomically defined multiple myelomas present at the same time. Despite a striking genomic heterogeneity, all myeloma cells will have the same VDJ sequence in a given patient. This makes VDJ sequencing a very useful tool for MRD tracking.C. Ola Landgren, MD, PhD
NGF has been standardized through the EuroFlow consortium to comprise an eight-color, two-tube assay that evaluates differential expression of 10 antigens to identify clonal plasma cells.29 Dr. Kumar noted that in some centers using NGF, including his, “the lab does a sequential approach to use low-sensitivity flow first to see if there are plasma cells, and if they clearly find plasma cells, then they don't do MRD testing. But if they don't clearly find plasma cells, they can reflex on to the higher sensitivity EuroFlow assessment.” In the United States, flow cytometry-based MRD assays have been further improved by using 10-color single-tube assays that allow more efficient workflows.31 Under optimal conditions for flow cytometry and NGS, there is over 90% concordance between the two tests, and the choice of test may be based on more practical considerations (Table 1).31 “One of the limitations of flow cytometry is that everyone does flow cytometry a little differently,” noted Dr. Landgren. “If flow is done in small groups, it will underperform and be very operator-dependent, and NGS will be a much more robust platform to use.”
|Next-Generation Flow Cytometry||Next-Generation Sequencing|
|Availability||Worldwide||clonoSEQ assay (Adaptive Biotechnologies) is FDA-cleared in bone marrow for patients with multiple myeloma|
|Need for baseline sample||Not required||Baseline sample or a stored sample from a time point with detectable disease required|
|Sample requirements||1.8–5.6 mL bone marrow||1 mL first pull bone marrow or 2 mL of peripheral blood|
|Sample processing||Requires fresh sample and analysis within 24–36 hours||May be deferred; can use both fresh and stored samples|
|Sensitivity||1 in 10-5 to 10-6||1 in 10-5 to 10-6|
|Turnaround and complexity||3–4 hours
Flow cytometry skills required
Automated software available
Bioinformatic support required
The NCCN and IMWG guidelines recommend use of MRD assessment after induction, ASCT, consolidation, and maintenance for patients achieving a CR to therapy. Achievement of MRD negativity is associated with improvements in PFS and OS in multiple meta-analyses using a variety of treatment regimens for both newly diagnosed multiple myeloma and relapsed/refractory multiple myeloma. Despite a lack of consensus on the optimal timing for assessment of MRD status or how to tailor therapy based on MRD status, practice patterns reveal real-world use of MRD status to guide decision-making. Clinical trials are ongoing to define the role of MRD assessment in multiple myeloma and how to optimize therapy based on MRD.
Dr. Landgren has received honoraria from Amgen, Bristol Myers Squibb, Celgene, Medscape, Onyx, and Adaptive Biotechnologies; has served in a consulting or advisory role for Bristol Myers Squibb, Celgene, Onyx, and Adaptive Biotechnologies; has received research funding from Amgen, Celgene, Janssen, and Takeda; and has been reimbursed for travel, accommodations, or other expenses by Celgene, Millennium, and Onyx.
Dr. Kumar has received research funding (institutional) from AbbVie, Amgen, Bristol Myers Squibb, Carsgen Therapeutics, Janssen, AstraZeneca, Novartis, Genentech/Roche, Takeda, TeneoBio, and Molecular Templates; has served in a consulting or advisory role (with no personal payments) for AbbVie, Amgen, Bristol Myers Squibb, Janssen, Genentech/Roche, Takeda, AstraZeneca, Bluebird Bio, Epizyme, Secura Biotherapeutics, Monte Rosa Therapeutics, and Trillium Therapeutics; and has served in a consulting or advisor role (with personal payments) for Oncopeptides, BeiGene, Antengene, and GLH Pharma
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