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

Multiple Myeloma Clinical Trial

— EUCADD  

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04122092
• Other study ID #: cz-pg001
• Status: Recruiting
• Start date: October 20, 2019
• Est. completion date: October 20, 2022

Study information

• Verified date: November 2019
• Source: Shanghai Changzheng Hospital
• Contact: Juan Du, PhD
• Phone: 8615800706091
• Email: changzheng_pg[@]163.com
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 100
• Est. completion date: October 20, 2022
• Est. primary completion date: October 20, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Aneuploidy
• Multiple Myeloma
• Neoplasm, Residual
• Neoplasms, Plasma Cell

Intervention

Diagnostic Test:
• The level of plasma cfDNA CINs
The extracted cfDNA from PB will be analyzed by UCAD to determine the level of CINs

Locations

Country	Name	City	State
China	Juan Du	Shanghai

Sponsors (1)

Lead Sponsor	Collaborator
Shanghai Changzheng Hospital

Country where clinical trial is conducted

China, 

References & Publications (8)

Bai Y, Orfao A, Chim CS. Molecular detection of minimal residual disease in multiple myeloma. Br J Haematol. 2018 Apr;181(1):11-26. doi: 10.1111/bjh.15075. Epub 2017 Dec 19. Review. — View Citation

Bakhoum SF, Ngo B, Laughney AM, Cavallo JA, Murphy CJ, Ly P, Shah P, Sriram RK, Watkins TBK, Taunk NK, Duran M, Pauli C, Shaw C, Chadalavada K, Rajasekhar VK, Genovese G, Venkatesan S, Birkbak NJ, McGranahan N, Lundquist M, LaPlant Q, Healey JH, Elemento O, Chung CH, Lee NY, Imielenski M, Nanjangud G, Pe'er D, Cleveland DW, Powell SN, Lammerding J, Swanton C, Cantley LC. Chromosomal instability drives metastasis through a cytosolic DNA response. Nature. 2018 Jan 25;553(7689):467-472. doi: 10.1038/nature25432. Epub 2018 Jan 17. — View Citation

Berger N, Kim-Schulze S, Parekh S. Minimal Residual Disease in Multiple Myeloma: Impact on Response Assessment, Prognosis and Tumor Heterogeneity. Adv Exp Med Biol. 2018;1100:141-159. doi: 10.1007/978-3-319-97746-1_9. Review. — View Citation

Hieronymus H, Murali R, Tin A, Yadav K, Abida W, Moller H, Berney D, Scher H, Carver B, Scardino P, Schultz N, Taylor B, Vickers A, Cuzick J, Sawyers CL. Tumor copy number alteration burden is a pan-cancer prognostic factor associated with recurrence and death. Elife. 2018 Sep 4;7. pii: e37294. doi: 10.7554/eLife.37294. — View Citation

Li H, Li F, Zhou X, Mei J, Song P, An Z, Zhao Q, Guo X, Wang X, Zhai Y. Achieving minimal residual disease-negative by multiparameter flow cytometry may ameliorate a poor prognosis in MM patients with high-risk cytogenetics: a retrospective single-center analysis. Ann Hematol. 2019 May;98(5):1185-1195. doi: 10.1007/s00277-019-03609-x. Epub 2019 Feb 5. — View Citation

Martinez-Lopez J, Lahuerta JJ, Pepin F, González M, Barrio S, Ayala R, Puig N, Montalban MA, Paiva B, Weng L, Jiménez C, Sopena M, Moorhead M, Cedena T, Rapado I, Mateos MV, Rosiñol L, Oriol A, Blanchard MJ, Martínez R, Bladé J, San Miguel J, Faham M, García-Sanz R. Prognostic value of deep sequencing method for minimal residual disease detection in multiple myeloma. Blood. 2014 May 15;123(20):3073-9. doi: 10.1182/blood-2014-01-550020. Epub 2014 Mar 19. — View Citation

Oberle A, Brandt A, Voigtlaender M, Thiele B, Radloff J, Schulenkorf A, Alawi M, Akyüz N, März M, Ford CT, Krohn-Grimberghe A, Binder M. Monitoring multiple myeloma by next-generation sequencing of V(D)J rearrangements from circulating myeloma cells and cell-free myeloma DNA. Haematologica. 2017 Jun;102(6):1105-1111. doi: 10.3324/haematol.2016.161414. Epub 2017 Feb 9. — View Citation

Rihova L, Vsianska P, Bezdekova R, Kralova R, Penka M, Krejci M, Pour L, Hájek R. Minimal Residual Disease Assessment in Multiple Myeloma by Multiparametric Flow Cytometry. Klin Onkol. Summer 2017;30(Supplementum2):21-28. doi: 10.14735/amko20172S21. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	The applicability analysis of UCAD	number of patients being tested successfully with the UCAD among the patients included in this cohort	36month
Secondary	The MRD negative rate analysis among VGPR patients	The MRD negative patients accounted for the total enrollment	24month