Myeloma. Measurable residual disease in multiple myeloma and light chain amyloidosis: more than just what you see

An article published in the journal Leukemia & Lymphoma in July 2021 introduced the progress in the treatment of multiple myeloma (MM) and light chain (AL) amyloidosis.
The emergence of high-efficiency treatments has changed the cure Possible
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The key is the need for a highly sensitive measurable residual disease (MRD) technique to replace traditional response assessment
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More and more studies use MRD as the research endpoint, confirming that MRD is not only a predictive marker of treatment response, but also a prognostic marker of disease recurrence
.

This review focuses on the analysis of the relevant content of MRD, including the current evidence supporting the use of MRD in clinical practice, the advantages and disadvantages of various methods of detecting MRD, and pointing out the indications for detecting MRD and the problems that need to be resolved in current clinical trials
.

What is the specific content, I will take you to find out
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Background The treatment of MM and AL amyloidosis is constantly progressing, and the emergence of new treatment methods has improved the treatment outcome
.

The introduction of new therapies has brought a very high complete response rate (CR), triggering thinking about the possibility of curing the disease
.

Assessing the depth of response requires highly sensitive methods to detect residual tumor cells
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Minimal Residual Disease (MRD) is defined as the number of tumor cells that persist after treatment and cannot be detected by conventional serological methods
.

MRD detection methods 1.
Bone marrow (intramedullary) MRD current standardized methods for bone marrow MRD detection include second-generation flow cytometry (NGF) and next-generation sequencing (NGS) (Table 1)
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NGF is a standardized method for evaluating MRD, with high sensitivity and a wide range of applications
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NGF can distinguish between normal and abnormal plasma cells by cell surface markers, and based on Euroflow guidelines and IMWG consensus standards, using 2 tubes of 8-color antibody panels (CD138, CD27, CD38, CD56, CD45, CD19, CD117, CD81, κ and λ Light chain) for testing
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NGS is a set of methods that use DNA sequencing to evaluate MRD [deep sequencing, allele-specific oligonucleotide quantitative PCR (ASO-qPCR), high-throughput sequencing, etc.
]
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Deep sequencing has been verified, and it is in good agreement with NGF and ASO-qPCR.
The OS and next treatment (TTNT) time of MRD-negative patients is longer
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2.
Extramedullary MRD (imaging and peripheral blood) Although intramedullary MRD is negative, there may still be extramedullary diseases
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PET-CT for MRD detection has been included in the IMWG guidelines and can predict progression-free survival
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PET-CT has recently been standardized for MRD detection after MM and anti-plasma cell therapy, local lesions and bone marrow FDG uptake is lower than the liver background value (Deauville scale <4), which can predict longer OS and PFS
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Diffusion-weighted magnetic resonance imaging (DW-MRI) is a type of functional magnetic resonance imaging that shows the contrast between tissues based on the difference in water molecule motion (as opposed to PET-CT, which assesses metabolic activity)
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Its main advantage is that diffuse bone marrow infiltration can be detected, and the false positive rate due to bone marrow hyperplasia is relatively low
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Immuno-PET is a promising new MRD imaging method
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Its effect was evaluated in 10 patients, and the results showed that it was sensitive, but its clinical role in MRD assessment is still unclear
.

MRD in MM 1.
NDMM (Newly Diagnosed Multiple Myeloma) Several studies have evaluated the role of MRD in the treatment of NDMM patients receiving triple therapy and quadruple therapy (Table 2)
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Triple therapy ENDURANCE trial: MRD was used as a secondary endpoint of the study.
The negative rate of MRD (NGF, LoD <10-6) was 7% in the VRd group and 10% in the KRd group (p=0.
079)
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FORTE trial: Phase 2 FORTE trial is a study with MRD as a secondary endpoint
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This trial compared 76 patients' KRd, KRd/ASCT and KCd/ASCT, and used two methods for MRD assessment: NGS (LoD <10-5) and NGF (LoD <10-5)
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The negative rates of MRD obtained by the two methods of NGS and NGF are inconsistent, being 14% (LoD <10-5) and 21% (LoD <10-6), respectively
.

MAIA trial: For patients who are not suitable for transplantation of NDMM, MRD (NGS, LoD <10-5) was tested in patients with CR at 12, 18, 24 and 30 months.
The negative rate of MRD in the DRd group was higher than that in the control group ( 24.
2 vs.
7.
3% )
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MRD has a predictive effect on PFS
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CLARION test: There was no difference in the negative rate of MRD between KMP and VMP (15.
7% vs.
15.
5%)
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The Quadruple Therapy GRIFFIN Study: A pivotal Phase 3 study evaluating Dara-VRd and VRd
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MRD (NGS, LoD<10-5) was used as the secondary end point of the study
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The negative rate of MRD in the D-VRd group was significantly higher, and the rate further increased after ASCT
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CASSIOPEA trial: Dara-VTd and VTd were compared among 1085 eligible patients for transplantation, and it was found that the MRD-negative rate (NGF, LoD<10-5) of the Dara-VTd group was higher (64% vs.
44%), and There is a good correlation between NGS and NGF
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MASTER study: The first reported study using quadruple therapy to adjust the treatment of NDMM based on MRD
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Use NGS (LoD<10-5) to assess the MRD of multiple endpoints
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Patients who reached MRD negative after ASCT/4 cycles of consolidation therapy/8 cycles of consolidation therapy stopped treatment and were monitored by MRD
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The negative rate of MRD after ASCT increased (42% after induction, 73% after ASCT), but longer follow-up time is needed to verify whether the remission will continue
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ALCYONE study: 706 patients who were not eligible for transplantation were randomly assigned to Dara-VMP and VMP.
The MRD negative rate in the Dara-VMP group was higher (28% vs.
7%)
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The persistent MRD negative rate (assessed at 6 and 12 months) [NGS (LoD<10-5)] was also higher in the Dara-VMP group
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MRD has a predictive effect on PFS and OS
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Autologous stem cell transplantation (ASCT) ASCT is considered to be the standard treatment for NDMM patients eligible for transplantation.
Phase 3 trials all support that transplantation can improve PFS in patients compared with conventional new therapies
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In the era of high-efficiency induction programs, the use of MRD negative to guide the decision to postpone ASCT is currently being evaluated in clinical trials, such as the Phase 2 ADVANCE trial (NCT04268498), which randomly selects early or delayed transplantation treatment based on the MRD status after initial treatment
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2.
Several RRMM studies have evaluated the role of MRD in RRMM
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POLLUX test: The negative rate of MRD in the DRd group was higher (30.
4% vs.
5.
3%).
As the follow-up time prolonged, the reaction deepened
.

CANDOR test: The DKd group has a higher rate of negative MRD at 12 months (NGS, LoD<10-5).
ICARIA test: In the Isatuximab, pomalidomide, and dexamethasone (Isa-Pd) groups, MRD is negative The rate was 5%, and 0% in the pomalidomide and dexamethasone (Pd) groups
.

BELLINI trial: Patients treated with Venetoclax, bortezomib, and dexamethasone have a higher MRD negative rate (NGS, <10-5) (15% vs.
2% ), and a higher continuous 1-year MRD negative rate ( 7% vs.
0% )
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CASTOR test: Compared with the Vd group, the MRD negative rate of the DVd group is higher
.

3.
SMM (Smoking Myeloma) is currently studying the early intervention methods of SMM, evaluating intensive treatment programs with the goal of cure, rather than less proactive treatment programs with disease control as the goal
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In the GEM-CESAR study, 90 high-risk SMM patients eligible for transplantation were included, and the primary endpoint was MRD negative (NGF)
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The negative rate of MRD was 30% after induction therapy, 52% after ASCT, and 57% after consolidation therapy
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After a median follow-up of 32 months, 2% died and 93% survived without progression
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  Light chain (AL) amyloidosis MRD data is currently lacking MRD data for AL amyloidosis, but there are data showing that the depth of response is related to the outcome
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The results of clinical trials based on risk adaptation and trials evaluating the effects of continuous or intensive treatment on MRD-positive patients have found that there is a correlation between MRD and organ response
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MRD should also be explored as an alternative test endpoint for AL amyloidosis.
In the future, MRD may be included in the evaluation of the response criteria for AL amyloidosis
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  Indications for MRD evaluation in clinical practice and future research The use of MRD in clinical practice can predict patient prognosis
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Although MRD is included in the IMWG response criteria, there is no random data to support the use of negative MRD to change the duration of maintenance treatment, delay ASCT, or adjust treatment based on MRD results
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The issues to be further addressed in clinical trials are MRD evaluation time, the best MRD combination to obtain predictive results, and whether MRD can be used as the primary research endpoint for regulatory drug approval (Table 4)
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  Conclusion The application of MRD in MM and AL amyloidosis is still under development, and more and more trials use MRD as the research endpoint
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MRD has been proved to have higher prognostic value, the deeper the test, the stronger the predictive ability
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In order to avoid overtreatment and undertreatment, the literature on MRD needs to be interpreted carefully, and applicability, reproducibility, and cost need to be considered
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Researchers need to collaborate to collect data and change treatment patterns
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MRD is only a factor that should be considered comprehensively when formulating a treatment plan for a specific patient, while other factors include patient characteristics (such as comorbidities and performance status), disease biology (such as FISH, rISS, extramedullary disease), and treatment toxicity (such as Bone marrow suppression and neuropathy) are equally important
.

References: 1.
Vaxman I, Gertz MA.
Measurable residual disease in multiple myeloma and light chain amyloidosis: more than meets the eye.
Leuk Lymphoma.
2021 Jul;62(7):1544-1553.
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