Professor Cai Zhen: The clinical significance of MRD in MM treatment

Multiple myeloma (MM) is a disease characterized by the malignant proliferation of clonal plasma cells, with the second highest incidence among hematologic malignancies and still incurable
.

With the application of a variety of new drugs, the prognosis of MM patients has been significantly improved, but almost all patients will eventually relapse
.

The persistence of minimal residual disease (MRD) is thought to be the root cause
of relapse.

Therefore, MRD detection has attracted more and more attention
from researchers.

There is substantial global evidence that MRD testing is important in the assessment of prognosis in MM patients, and may also replace progression-free survival (PFS) and total survival (OS) as clinical trial endpoints, and has a positive effect
on dynamic risk stratification and guided treatment in MM patients.

Professor Cai Zhen of the First Affiliated Hospital of Zhejiang University School of Medicine was invited to share the clinical significance
of MRD in MM treatment.

Mitigation assessment of MM has traditionally relied on the use of serum protein electrophoresis (SPEP) and/or immunofixation electrophoresis (IFE) to determine the proportion of M protein in serum and urine, bone marrow detection of plasma cell ratio, and the presence of soft tissue plasma cell tumors ^[1].


MRD represents a persistent disease that cannot be detected by the above techniques and may lead to relapse
.

The International Myeloma Working Group (IMWG) efficacy standard ^[2] defines MRD testing as a test based on the absence of clonal plasma cells in patients with complete remission (CR) with a sensitivity reduction of ^10-5
.

Figure 1.
Myeloma cell count vs.
disease burden

MRD detection includes NGF, NGS, mass spectrometry (MS), immunohistochemistry, and PET-CT/MRI
.

Among them, NGS used multiple primers to sequence overlapping immunoglobulin gene fragments, and applied reference genomes as scaffolds for recombination, and the highest sensitivity < 1×^{106 [3,4]}; NGF distinguishes between normal and abnormal plasma cells in bone marrow specimens with sensitivity of 2–4×^{106 [5,6,7]} depending on the expression of markers on the cell surface; MS is a minimally invasive and bone-marrow (BM) specimen test, and evaluation of blood MS-MRD has been shown to replace bone marrow NGS/NGF-MRD evaluation, but requires clinical validation ^[2].


Systemic PET-CT/MRI is also a minimally invasive assay that does not require a BM specimen and as a complementary method of NGS/NGF that can overcome patchy bone marrow infiltration and detection of extramedullary lesions, as well as limitations of flow/molecular techniques such as heterogeneity ^[8
].

The IMWG efficacy standard defines MRD negative as detectable by NGF or NGS technology with a minimum detection sensitivity of¹⁰⁵ cloned plasma cells
.

Among the recommendations of the IMWG MRD efficacy criteria, NGS and NGF are the most commonly used techniques for assessing MRD status ^[2
].

A pooled analysis of three PETHEMA/GEM trials for the newly diagnosed multiple myeloma (NDMM^)[9] showed that a negative MRD provided a better prognostic outcome than traditional efficacy assessment (Figure 2).


MRD-negative status assessment PFS and OS are more sensitive
than achieving CR.

Figure 2.
Pooled analysis of three PETHEMA/GEM trials in NDMM (n=^609)[9].

A meta-analysis exploring the prognostic value of MRD for PFS ^[10] showed that patients with MRD-negative PFS had a greater benefit in the course of the disease compared with MRD-positive patients in patients with NDMM who were eligible for transplantation and those who were not eligible for transplantation, as well as in patients with R/R MM
.

It can be seen that MRD negative is an effective predictor of the benefit assessment of PFS in the above categories of patients
.

Figure 3.
Meta-analysis of the prognostic value of PFS by MRD (n=8098)^[10].

Myeloma XI test ^[11] is performed by testing for MRD status and relevance of PFS and OS at 3 and 9 months after autologous hematopoietic stem cell transplantation (ASCT), showing that MRD negative for both 3 and 9 months after ASCT or MRD negative at 3 months after ASCT to 9 months after ASCT is most beneficial for the patient's prognosis, MRD-negative loss at 9 months after ASCT is comparable to the prognosis in patients with persistent MRD positivity (Figure 4).

Figure 4.
Effect of MRD status on PFS and OS in patients receiving lenalidomide maintenance therapy at 3 months after ASCT (n=750) and 9 months after ASCT (n=326) ^[11].

Longitudinal studies of MRD evolution pattern prediction prognosis in transplant-eligible NDMM patients^[12] found that loss of MRD negative within 24 months had similar adverse outcomes to patients with persistent MRD positive; Continuous MRD negative for 24 months significantly improved PFS and OS (Figure 5)
compared with patients who lost MRD-negative or MRD consistently positive.

Thus, a "persistent" MRD negative can be defined as a patient who is persistent with a negative MRD for more than 24 months and remains until the last follow-up
.

In addition, the study suggests that consistent and regular MRD testing for 24 months after transplantation may help detect early recurrence
.

Figure 5.
Effect of MRD status on PFS and OS ^[12].

The Phase 3 CASSIOPEIA study ^[13] has shown that patients who achieve MRD negative after induction therapy and maintain an MRD-negative state after ASCT and consolidation therapy are more likely to achieve PFS regardless of the treatment they receive, compared with those who achieve MRD negative after induction therapy but achieve MRD negative after consolidation therapy (figure below).


It can be seen that patients who reach MRD negative early have a better prognosis
.

Figure 6.
MRD negative PFS ^[13].

For patients with high-risk cytogenetic abnormalities (HRCA), achieving MRD negative as early as possible (before ASCT) is an independent prognostic marker
.

A small retrospective study ^[14] showed that patients who achieved MRD-negative early treatment (before ASCT) had a better prognosis than those with positive MRD (Figure 7).


However, patients with multiple HRCA factors are at highest risk of MRD regain and early disease recurrence ^[15].

Figure 7.
MRD-related PFS (N=155) in patients with cytogenetic risk before ASCT ^[14].

Data from the PETHEMA/GEM2012MENOS65 trial ^[16] showed that after 36 months of induction/consolidation therapy, MRD-negative patients with HRCA had a comparable prognosis with patients with negative MRD, and MRD-negative or overcame the poor prognosis in high-risk MM patients (Figure 8).

Figure 8.
Effect on PFS and OS according to MRD status in standard-risk and high-risk patients (N=390) ^[16].

Patients with ≥ 2 HRCA factors lose MRD negative earlier than patients with 1 or 0 HRCA factors, resulting in a poor prognosis ^[15].


However, patients with ≥ 2 HRCA factors maintain a negative MRD for 1 year, which is comparable to the prognosis of patients with 1 HRCA factor ^[17] (Figure 9).

Figure 9.
High-risk (n=243) and double-strike (n=105) patients in the FEFEDE study had a 4-year PFS profile of continuous MRD-negative for one year ^[17].

MRD is the small amount of tumor cells that remain in the body after MM therapy reaches CR and is closely related
to the patient's poor prognosis.

Currently, NGS and NGF are commonly used detection techniques for MRD status assessment, but other non-invasive operating techniques such as peripheral blood mass spectrometry are also being actively explored
.

Multiple studies have shown that a positive prognostic value for MRD is higher than that of CR and is an effective predictor of PFS benefit, and that achieving and maintaining a negative MRD early is associated with an optimal outcome and may overcome the poor prognosis in high-risk patients, but loss of a negative MRD is also associated
with a poor prognosis.

Professor Cai Zhen

• The First Affiliated Hospital of Zhejiang University School of Medicine

• Doctor of Medicine, Qiushi Distinguished Physician of Zhejiang University, Grade II Professor, Chief Physician, Doctoral Supervisor

• Director of the Multiple Myeloma Treatment Center, Deputy Director of the Department of Hematology, and Bone Marrow Transplant Center

• High-level health innovation talents in Zhejiang Province

• Chairman of the Hematological Lymphoma Committee of Zhejiang Anti-Cancer Association

• Vice Chairman of Hematology Branch of Zhejiang Medical Association

• He is a member of the Hematology Branch of the Chinese Medical Association and the deputy leader of the plasma cell disease group

• He is a member of the Hematology and Tumor Committee of the Chinese Anti-Cancer Association and the deputy leader of the multiple myeloma group

• Deputy Leader of CSCO China Autologous Hematopoietic Stem Cell Transplantation Working Group

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MAT-CN-2223119

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