MRD, Biomarkers in Multiple Myeloma

MRD Should Be More Widely Used in Clinical Care of MM, Report Argues

Advances in scientists' understanding of multiple myeloma (MM) and in the ability to assess minimal residual disease (MRD) have made the metric an important method to track the efficacy of therapy in clinical trial settings. Yet, a number of questions remain about how exactly MRD can be used in day-to-day practice.

In an article in the Journal of Hematology & Oncology, corresponding author Jesús F. San-Miguel, MD, PhD, and colleagues discussed challenges to implementation of MRD in patients with MM. San-Miguel is a professor at the University of Navarra in Spain.

The authors explained that traditional methods of testing and defining success in the treatment of MM have become outdated in the new scientific paradigm. They noted that some patients in so-called complete remission (CR) are at a higher risk of progression than others, a problem that can be overcome with modern evaluations like MRD.

“Therefore, the words ‘complete’ [and] ’remission’ are misleading for many patients because they may interpret that, once [they have] achieved such status, the disease has been eradicated,” the authors wrote. “Thus, it becomes evident that more sensitive techniques are needed to detect measurable (formerly called minimal) residual disease persisting below CR.”

In advocating for broader use of MRD in a clinical setting, San-Miguel and colleagues wrote that MRD meets the criteria necessary for broad use.

MRD supersedes the prognostic value of CR, and MRD status appears to be reproducible in different settings and using molecular and immunophenotypic methods.

The techniques for ascertaining MRD can be broadly classified into 2 groups: those focused on finding extramedullary disease, such as positron emission tomography (PET)/CT scans, and those focused on detecting intramedullary disease, either multiparameter flow cytometry (MFC) immunophenotyping or molecular assessment of immunoglobulin gene rearrangements. Next-generation flow (NGF) cytometry and next-generation sequencing (NGS) each represent advances in techniques for detecting intramedullary disease, though the authors said these methods can lead to false-negatives.

“Thus, further improvement in the sensitivity of NGF and NGS are warranted to optimize risk stratification based on patients’ MRD status,” they wrote. “PET/CT is currently the optimal method to evaluate the disease outside the [bone marrow], and there are ongoing efforts for its standardization.”

There are, however, some pitfalls to MRD. One is the potential for false-negative MRD results due to sampling errors. The authors also reported that although an MRD-negative test result is a good prognostic sign, it bodes most well for patients when the negative result can be reproduced after 6 or 12 months.

To bring MRD testing into the clinic, the authors recommended that MRD assessment only be performed when a bone marrow aspirate is collected to confirm complete remission and only when the results of the evaluation could be useful to make specific clinical decisions.

The authors noted that a number of different methods are being considered to evaluate MRD, but they said bone marrow samples remain the “gold standard.”

More broadly, San-Miguel and colleagues concluded that MRD is not only important for its prognostic value, but also because it will better enable precision medicine in an era of rising drug costs.

“We have experienced great progress, and now we need to optimize the use of highly effective drugs developed including immunotherapeutics,” the authors concluded. “This should be implemented early in the course of the disease in order to overcome the poor prognosis of high-risk patients, including those with persistent MRD after optimal frontline treatment.”

Reference

Burgos L, Puig N, Cedena MT, et al. Measurable residual disease in multiple myeloma: ready for clinical practice? J Hematol Oncol. 2020;13(1):82. doi:10.1186/s13045-020-00911-4

Analysis Locates 2 Biomarkers for Multiple Myeloma

A recent study has identifiied new biomarkers that appear to correlate to the clinical characteristics and prognosis of patients with multiple myeloma (MM).

The study appeared in the journal Cancer Cell International. Corresponding author Aili He, MD, PhD, of the Second Affiliated Hospital of Xi’an Jiaotong University in China, and colleagues worked to identify key genes involved in cell adhesion in MM, as cell adhesion plays an important role in the progression of the disease. Their findings could lead to important advances in the diagnosis and treatment decisions of patients with MM.

He and colleagues first set out to find differentially expressed genes (DEGs) using the National Center for Biotechnology Information’s (NCBI’s) mRNA expression profiles from the Gene Expression Onmibus GSE6477 DataSet of bone marrow plasma cells. The authors used the NCBI’s GEO2R to perform the analysis (with cutoff criteria of P < .05 and [logFC] ≥ 1). Next, they performed Gene Ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis to determine the biological pathways and functions associated with the DEGs identified. The authors also screened hub genes and analyzed their prognostic and diagnostic values, among other analyses.

In total, the team identified 1383 DEGs, many of which appeared to be enriched in cell adhesion. A dozen genes were identified as hub genes, and an analysis of receiver operating characteristic curves showed that 8 genes were biomarkers for the diagnosis of MM: ITGAM, ITGB2, ITGA5, ITGB5, CDH1, IL4, ITGA9, and LAMB1.

Of those, further analysis showed that ITGA9 and LAMB1 had prognostic values and clinical implications in patients with MM, the authors said. He and colleagues posited theories about how the 2 genes play a role in MM.

“[Gene set enrichment analysis] and transcription factor (TF) prediction suggested that MYC may bind to ITGA9 and repress its expression and HIF-1 may bind to LAMB1 to promote its expression in MM,” the authors said. “Additionally, pan-cancer analysis showed abnormal expression and clinical outcome associations of LAMB1 and ITGA9 in multiple cancers.”

Specifically, abnormal expression of LAMB1 has been linked with overall survival and disease-specific survival in a number of cancers, the authors said. That may have to do with its role in cancer progression.

“LAMB1 has a high protein level in high-grade gliomas, suggesting a possible correlation with tumor progression,” they said. “What’s more, LAMB1 was identified to take part in cell attachment and have the capacity to inhibit metastasis.”

There are some pitfalls to minimal residual disease (MRD). One is the potential for false-negative MRD results due to sampling errors. The authors also reported that although an MRD-negative result is a good prognostic sign, it bodes most well for patients when the negative result can be reproduced after 6 to 12 months.