Study Finds Limits to sCR Compared With MRD in Tracking MM Response

Minimal residual disease (MRD) is a more valuable tool than stringent complete response (sCR) when it comes to measuring disease response and prognosis in patients with multiple myeloma (MM), according to a new study.

The International Myeloma Working Group has established 4 categories of deep response to treatment for MM. sCR was first developed in 2006. It includes normalization of the kappa and lambda serum free light chain (sFLC) ratio plus the absence of clonal plasma cells in bone marrow as measured by immunohistochemistry (IHC) or immunofluorescence with a sensitivity of 10^-3.

However, a group of investigators including Joaquin Martinez-Lopez, PhD, of Spain’s Complutense University, previously found that sCR had significant limitations, including a limited ability to identify patients with a poor prognosis.

Their new study, published in the journal PLOS One, sought to directly compare the prognostic value of sCR and MRD monitoring by using multiparametric flow cytometry (MFC) or next generation sequencing of immunoglobulin genes in patients with conventional complete response (CR).

The study included 193 patients who achieved CR at 1 of 2 institutions. All of the patients included in the study had available bone marrow aspirates and biopsies. Four out of 5 were transplant eligible, and a similar number underwent maintenance therapy, typically with lenalidomide (Revlimid).

Their results showed sCR had a limited value. Neither sFLC, clonality by IHC, nor cell bone marrow infiltration was able to identify patients at the highest risk, Martinez-Lopez and colleagues wrote.

“Patients with sCR had slightly longer progression-free survival,” they said. “Nevertheless, persistent clonal bone marrow disease was detectable using MFC or NGS and was associated with significantly inferior outcomes compared with MRD-negative cases.”

The investigators said their data found that kappa-lambda ratios have little clinical relevance, and they reported an absence of PFS and OS differences in patients in the conventional CR and sCR groups. This suggests that sFLC does not provide additional relevant information when defining conventional CR.

“This affirmation does not mean that sFLC is not an adequate method to follow MM patients,” they said. “sFLC might be considered as an alternative method to define CR, but it is not superior.”

They said more study of other methods, such as mass spectrophotometry to identify monoclonal proteins in serum, are needed.

More broadly, though, Martinez-Lopez and colleagues said MFC appears to be a sufficient technique to capture differences in patient response and prognosis.

“The MRD methodology described in this study, although using 4-color MFC, has an intermediate sensitivity above 10⁻⁴ due to the acquisition of more events (approximately 2 million),” they wrote. “This sensitivity is much higher than that achieved by IHC, which is approximately 1%.”

While they did not find evidence that sCR outperforms MRD status, Martinez-Lopez and colleagues said another step forward could be next-generation sequencing of immunoglobulin genes. They found that such sequencing was capable of accurately differentiating patients with different prognoses who achieved sCR and CR.

“These results confirm our previous findings and strengthen our suggestion that the sCR category should be rethought for the future classification of MM response,” they concluded.

Reference

Cedena MT, Martin-Clavero E, Wong S, et al. The clinical significance of stringent complete response in multiple myeloma is surpassed by minimal residual disease measurements. PLoS One. Published online August 31, 2020. doi:10.1371/journal.pone.0237155