MRD Potential in MM Undeniable, Even if Not Ready for Use Yet, Review Says

As therapy for multiple myeloma (MM) has improved, life expectancy has lengthened, and the goals of therapy have become more optimistic.

In a new review article, published in the Journal of Personalized Medicine, corresponding author Alessandro Gozzetti, MD, PhD, of the University of Siena, in Italy, and colleagues explain how complete remission (CR), but also the deepest possible remission, have become the new goal of modern therapies. They explain how techniques including next-generation sequencing (NGS) and next-generation flow cytometry (NGF) are being used to evaluate minimal residual disease (MRD), and how that has translated into real-world use.

Until recently, the authors said, the definition of CR was insufficient, with most patients relapsing even after achieving CR. Recently, though, NGS and NGF have made it possible to get much more specific understandings of a patient’s disease. The International Myeloma Working Group (IMWG) now suggests a specificity cutoff of 10^-5 as the target for MRD.

Gozzetti and colleagues wrote that NGF can be a good option, and is included in the IMWG’s recommendations based on local availability, but they noted that it still has some drawbacks. First, there is heterogeneity in terms of how NGF is applied.

“Some groups prefer to use an in-home antibody mix, many do not determine BM [bone marrow] sample quality before processing, and there might be many differences in the way in which data are processed and analyzed, leading to a lack of reproducibility,” they said.

Another problem is that the anti-CD38 monoclonal antibody therapy daratumumab (Darzalex) can lead to CD38 masking and a limit in plasma cell (PC) determination.

As for NGS, it suffers from issues of availability and cost. As a result, digital polymerase chain reaction (dPCR) was proposed for daily MM patient management.

“dPCR does not require a standard curve, leading to the absolute quantification of the target gene, and it is also less laborious than NGS regarding data interpretation,” they wrote. “On the other hand, its applicability is not yet standardized, and further studies are needed to confirm it.”

MRD has been the subject of significant study, but Gozzetti and colleagues said it is still not possible to clearly identify which patients will have long-term survival. Some recent research has suggested redefining response categories, including MRD. Investigations have shown that MRD negativity correlates with progression-free survival, but the authors said MRD evaluation in the bone marrow ought to be paired with skeletal evaluation, since detection of positive lesions can affect prognosis.

The investigators then discussed MRD in clinical practice. While the potential of the technique is “undeniable,” they noted that the current recommendation is that it’s too early for clinicians to make therapeutic decisions based on MRD status.

In conclusion, the authors say this is an exciting time for MM management.

“Although MRD detection is not recommended for clinical therapeutic decisions, real-world practice can be very informative to test depth and duration of response in patients treated with novel drugs or autotransplant,” they said.

They say the development of new drugs and deeper ability to determine their effect could mean that a cure is finally a realistic possibility.

Reference

Gozzetti A, Raspadori D, Bacchiarri F, et al. Minimal Residual Disease in Multiple Myeloma: State of the Art and Applications in Clinical Practice. J Pers Med. Published online September 10, 2020. doi:10.3390/jpm10030120