Evaluation of Ultrasensitive Chromosomal Aneuploidy Detection for Detecting Minimal Residual Disease in Multiple Myeloma

Study Overview
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Brief Summary
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Despite the significantly higher complete remission rates and improved survival achieved over the last decade，multiple myeloma (MM) patients continue to relapse due to persistence of minimal residual disease (MRD). Currently, numerous studies have evaluated the prognostic value of MRD by detecting immunophenotypic and immunoglobulin (Ig) gene rearrangements from bone marrow aspiration samples. Here the investigators intend to study the clinical utility of Ultrasensitive Chromosomal Aneuploidy Detection (UCAD) as an MRD assay, which is based on plasma cell-free DNA(cfDNA) low-coverage whole-genome sequencing. UCAD is non-invasive and applicable for tumors with high heterogeneity and extramedullary invasions.

Detailed Description
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In multiple myeloma, Minimal Residual Disease (MRD) refers to myeloma cells that are present in the bone marrow after a clinical response has been measured and the patient is in remission. A patient who tests MRD negative after treatment for myeloma has less than one myeloma cell per million bone marrow cells. Data from recent clinical trials suggest that patients with such a low level of disease may be less likely to experience a relapse of their condition than patients with higher levels. In recent years, MRD testing is now be applied in the management of patients receiving standard therapies for the disease. Chromosomal instability(CIN) results from errors in chromosome segregation during mitosis, leading to structural and numerical chromosomal abnormalities. It will generate genomic heterogeneity that acts as a substrate for natural selection. Furthermore, it is proved that tumors with aneuploidies and polyploidy resulting from whole-genome doubling are related with metastasis, treatment resistance, and decreased overall survival. It is estimated that 60%-80% of human tumors exhibit chromosomal abnormalities suggestive of CIN. CIN positively correlates with tumor stage and is enriched in relapsed as well as metastatic tumor specimens. Due to the ubiquity of CIN in cancer cells and cancer cell releasing DNA into peripheral blood (PB) when apoptosis, it is a potentially non-invasive way to detect CIN in PB cfDNA from the MM patients to character MRD level. UCAD is a new method to detecting CIN in the DNA sample from patients, including extracting cfDNA from PB, analyzing DNA by low-coverage whole-genome sequencing, processing the data by bio-information techniques, and finally optimizing the management of MM patients.

Official Title
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Application of Ultrasensitive Chromosomal Aneuploidy Detection (UCAD) as a Surrogate Biomarker of Minimal Residual Diseases for Multiple Myeloma Patients

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Diagnostic Test: The level of plasma cfDNA CINs


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients new diagnosed with MM and with the curative effect at least VGPR. Male or female patients aged >= 18 years. Participants signed informed consent form. Exclusion Criteria: Age under 18 years Individuals unwilling to sign the consent form or unwilling to provide PB for test or unwilling to provide the medical record. Individuals unwilling to participate in this trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| MM patients have curative effect at least VGPR<br>We will detect cfDNA CIN of multiple myeloma patients who have the curative effect at least very good partial response (VGPR) after front line therapy, and then monitoring cfDNA CIN every two treatment cycles or every three months during follow up，the result will be compared with bone marrow aspiration MFC. | Diagnostic Test: The level of plasma cfDNA CINs<br>* The extracted cfDNA from PB will be analyzed by UCAD to determine the level of CINs<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of the prognostic of the MRD negative and MRD positive defined by UCAD | The patients' prognostic was evaluated with the median time of progress free survival (PFS) and overall survival (OS) | 36month | 
| The concordance rate analysis between UCAD and multiparameter flow cytometry(MFC) | number of patients declared MRD positive or MRD negative with the UCAD and MFC test simultaneously among the patients being tested successfully with both | 36month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The applicability analysis of UCAD | number of patients being tested successfully with the UCAD among the patients included in this cohort | 36month | 
| The MRD negative rate analysis among VGPR patients | The MRD negative patients accounted for the total enrollment | 24month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Multiple myeloma, Minimal residual disease, Chromosomal aneuploidy detection, Chromosomal instability