Drops in Circulating MicroRNA-451a Could Be Sign of MM Relapse

Investigators may have found a minimally invasive way to predict which patients with multiple myeloma are about to experience a relapse.

MicroRNA-451a expression levels could be used to monitor minimal residual disease (MRD) in patients with multiple myeloma (MM) and potentially give physicians an early warning sign that treatment is warranted, according to a newly published study.

Patients with MM are usually stratified via the revised International Staging System (ISS), and responses to therapy are increasingly measured in terms of minimal residual disease (MRD) using multiparameter flow cytometry(MFC). The problem, according to corresponding author Tao Jiang, PhD, of the University of Electronic Science and Technology of China, is that myeloma cells are not evenly distributed in the bone marrow (BM), a fact that can lead to false negative readings.

“Therefore, identifying a novel marker that is universal for the majority of patients, that reflects the dynamic changes in tumor load and is able to be conveniently assessed is urgently needed,” Jiang and colleagues wrote.

One apparent candidate for a biomarker is circulating miR-451a, a tumor-suppressing microRNA that has been associated with a number of types of cancer. Jiang and colleagues discussed their exploration of miR-451a as a potential biomarker for MM in the journal Oncology Letters.

Interleukin 6 (IL-6) is believed to regulate the growth of MM, and miR-451a has been found to target the IL-6 receptor (IL-6R) in solid tumor types. What has been unknown is whether it has a similar effect in MM, and if so, whether miR-451a levels might be indicative of real-time tumor load.

Jiang and colleagues recruited 66 patients with MM, along with 10 healthy controls. They performed reverse transcription-quantitative polymerase chain reaction (PCR) tests to calculate miR-451a levels in patients’ BM and in circulation. In addition, IL-6 levels and IL-6R levels were measured using enzyme-linked immunosorbent assays (ELISA) western blotting, respectively. Patients were subsequently assessed for MRD using MFC.

The data showed patients with MM had markedly lower levels of circulating miR-451a—just 0.39 times that of the control group. The disparity increased with stage: the 15 patients with R-ISS stage 1 MM had median miR-451a levels that were 0.73 times that of the control group, while 17 patients with stage II MM had levels 0.41 times that of the control group. By stage III, miR-451a levels of the 34 patients were just 0.24 times the levels of the controls. In BM samples, miR-451a levels generally correlated with circulating blood levels, but negatively correlated with IL-6 and IL-6R levels.

Though miR-451a levels appeared to be associated with disease progression, the authors next evaluated whether the levels might have predictive value of prognosis following therapy.

Of the 19 patients who achieved complete remission following consolidation therapy, Jiang and colleagues noticed a split in terms of miR-451a levels during follow-up. Ten of the patients had steady miR-451a levels, while 9 had an abrupt decrease in circulating miR-451a.

The authors found those drop-offs correlated with positive MRD readings approximately 4-8 weeks following the decrease, and clinical relapse 4-16 weeks after the decrease.

The findings raise the hope that a less-invasive technique could be used to monitor patients and potentially predict which patients are likely to experience relapses in the coming weeks. The authors said the exact reason for the apparent correlation is not yet known, though the question has been examined in solid tumors, which may lead to insights for MM and similar malignancies.

In the meantime, Jiang and colleagues wrote that miR-451a decreases could be treated as an early warning system in MM.

“For instance, patients may start treatment if there is a dramatic and rapid decrease in miR-451a,” they said. “However, if the rate of decline is slow, observation is recommended.”


Zhong L, Jin X, Xu Z, et al. Circulating miR-451a levels as a potential biomarker to predict the prognosis of patients with multiple myeloma. Oncol Lett. 2020;20(5):263. doi:10.3892/ol.2020.12126