A new end point for MM treatment?

Multiple myeloma (MM) is a malignant disease in which clonal plasma cells proliferate abnormally.
The incidence is increasing year by year, becoming the second largest malignant tumor of the blood system
.

In recent years, with the introduction of new drugs and the advancement of detection methods, the diagnosis and treatment of MM have been continuously improved and perfected.
The detection of minimal residual disease (MRD) has become a current research hotspot in the field of MM
.

At the Cross-Strait Hematology Academic Conference held on December 11-12, 2021, Professor Bao Li from Beijing Jishuitan Hospital shared the "progress in MRD detection for multiple myeloma"
.

This article organizes its main content for readers' reference
.

PART ONEMRD test is of great significance to MM patients.
With the improvement of MM diagnosis and treatment technology, the medical community is constantly pursuing higher standards of MM efficacy
.

The concept of MRD-negative (MRD-) was first proposed in the International Myeloma Working Group (IMWG) efficacy criteria in 2016, and this concept was introduced in the 2017 Chinese Guidelines
.

A meta-analysis concluded that PFS and OS in MRD-MM patients were significantly better than those in MRD+MM patients
.

Compared with the time-consuming PFS, MRD detection can more quickly reflect the clinical benefits of treatment
.

Therefore, whether MRD- can be used as a new MM treatment endpoint has become a hot spot in current research
.

PART TWOMRD test is an important evaluation endpoint of the study
.
At present, clinical research attaches great importance to MRD- .

Of the 170 ongoing MM clinical trials, 154 indicated that MRD was assessed in the "descriptive information", 41 (27%) had MRD-rate as the primary endpoint, and 104 (67%) were the secondary endpoint
.

In clinical treatment, MRD detection is of great value to the prognosis of patients
.

To this end, Professor Bao Li cited three recent studies to give a detailed description of the choice of treatment options, factors affecting patient prognosis, and MRD status.
The contents are as follows
.

A study published in Blood in 012021 found that MM patients with standard-risk or high-risk cytogenetic abnormalities (CAs) can achieve similar complete remission (CR) rates, but the latter have shorter PFS and OS
.

This result questioned the validity of CR rate as an end point for MM treatment
.

On this basis, the study evaluated the MRD status of 300 standard-risk CAs MM patients and 90 high-risk CAs MM patients using VRD (bortezomib + lenalidomide + dexamethasone) regimen after standard treatment
.

The treatment plan in the study is to first use 6 courses of VRD induction, then autologous hematopoietic stem cell transplantation, then 2 courses of VRD consolidation, after 2 years of maintenance treatment with RD (lenalidomide + dexamethasone), if the patient is MRD-, then stop maintenance treatment, if the patient is MRD+, use the RD regimen for another 3 years
.

This program is more consistent with the current clinical situation, and the current clinical maintenance treatment is mostly 2 years
.

In the study, 49% of patients with standard-risk CAs and 37% of patients with high-risk CAs obtained MRD-
.

The 36-month PFS rate of MRD-MM patients was >90%, while the median PFS of MRD+ MM patients was 3 years and 2 years, respectively
.

The results of the study indicate that MRD can improve the prognostic model of MM and should be used as a clinical treatment endpoint for MM, especially in high-risk CAs MM patients
.

If MRD is still positive or reyang, early treatment intervention may be necessary
.

A total of 1493 MM patients were included in the Phase III EMNO2/HO95 MM trial published in the Blood Cancer Journal in 022021
.

MRD samples are collected during and after the treatment of the patient (as shown in the figure).
A total of 1204 MRD samples can be analyzed
.

After COX multivariate analysis, the study found that patients’ MRD- and cytogenetic abnormalities are the key factors affecting PFS and OS
.

The 03TOURMALINE-MM3 and TOURMALINE-MM4 (MM3/MM4) studies gave MM patients who achieved partial remission (PR) or better efficacy the maintenance treatment with ixazomib or placebo to observe the efficacy of the two and compare the MRD status of the patients
.

The results of the study showed that compared with placebo, ixazomib can significantly improve the PFS of MRD+ patients at the time of enrollment (median PFS 18.
8 vs 11.
6 months, HR: 0.
65, 95%CI: 0.
55-0.
76, p<0.
001), a total of 10 % Of patients were in continuous MRD- state, 5% of patients changed from MRD+ to MRD-, 10% of patients changed from MRD- to MRD+, and 75% of patients were in continuous MRD+ state
.

The median PFS of patients in the ixazomib group and placebo group were 23.
2 months and 19.
3 months, and the median OS were 17.
5 months and 11.
1 months, respectively.
The risk of disease progression and death in patients with continuous MRD+ or MRD-conversion to MRD+ The hazard ratio (HR) for patients with continuous MRD-was 8.
20 (95% CI 5.
49-12.
2, p<0.
001)
.

The research results support the achievement and maintenance of MRD-status as the treatment goal of maintenance treatment, and emphasize the importance of continuous evaluation of MRD status in predicting disease recurrence and guiding treatment strategies
.

The study also proved that ixazomib showed a significant PFS advantage compared to placebo in patients with MRD+ at the time of enrollment
.

PART THREEMRD test results guide the continuous treatment of MM.
The current clinical MRD detection methods are mainly second-generation flow (NGF) and second-generation sequencing (NGS)
.

In addition to bone marrow and blood tests, imaging tests can also show disease progression, and PET-CT is also a powerful tool for assessing the status of MRD
.

In 2016, IMWG established MRD efficacy standards, using NGF or NGS to detect bone marrow MRD-lasting> 1 year as an indicator of long-term survival and even cure
.

China's 2020 version of multiple myeloma diagnosis and treatment guidelines stipulate MRD testing: MRD testing must be performed on the basis of CR, and two consecutive MRD testing must be performed at any time before starting a new treatment plan
.

Professor Bao said that MRD detection has a positive effect on dynamic stratification and guiding treatment
.

If the patient's abnormal phenotype at the MRD level is cleared and no new abnormal phenotype appears, the prognosis is better
.

Although MRD testing to guide MM treatment has gradually become a mainstream trend, more clinical trials are still needed to verify its value
.

The realization of continuous MRD- is also a difficult point in current clinical research
.

Professor Bao pointed out that the longer the medication, the more likely it is for patients to achieve sustained MRD-
.

At present, the continuous medication time of most domestic clinical drugs is short, and the goal of continuous treatment cannot be achieved
.

The treatment regimen based on oral proteasome inhibitor ixazomib has a longer median administration time than other drugs
.

In a double-blind, placebo-controlled phase III study, the combination of ixazomib + lenalidomide + dexamethasone was used to treat relapsed/refractory MM.
The study proved that in patients treated with ixazomib regimen, With the extension of the treatment cycle, the number of people achieving very good partial remission (VGPR) or CR has steadily increased, and even after 14 medication cycles, patients still have a deeper remission
.

Therefore, the longer the ixazomib is administered, the more sustained MRD- can be achieved
.

Summary Professor Li Bao concluded that the continuous update of MRD detection methods makes MRD detection more convenient and feasible
.

The IMWG consensus recommends MRD testing as one of the methods for evaluating treatment remission.
At present, MRD- has gradually become the research endpoint of most studies, and clinical trials are also trying to analyze the correlation between MRD- and patient prognosis
.

Most of the research results show that MRD-as a new end point for the treatment of MM patients is meaningful
.

There are also studies showing that continuous medication can deepen the remission of the patient's condition and contribute to the realization of MRD-
.

At present, the research of MRD detection in the treatment of MM is still in its infancy, and we look forward to more research results in the future! Prof.
Bao Li, Director and Chief Physician, Department of Hematology, Beijing Jishuitan Hospital, Chairman, Hematology Committee, Beijing Perioperative Medical Research Association, Vice Chairman, Myeloma Branch, Chinese Medical Education Association, Standing Committee, Chinese Society of Chinese Medicine, Hematology Branch Committee, Chinese Women Physicians Association, Clinical Oncology Member of the Professional Committee of Medicine, Member of the Hematology Professional Committee of the Chinese Medical Education Association Member of the Lymphatic Disease and Lymphoma Professional Committee of the Chinese Medical Education Association Member of the Lymphatic and Hematological Professional Committee of the Chinese Society of Geriatric Oncology , We make progress together