The introduction of several classes of effective novel drugs over the past 2 decades has extended median survival for patients with multiple myeloma (MM) to 8 to 10 years. The goal of contemporary therapy for MM is to achieve not only a complete response (CR) but the deepest possible remission, says Alessandro Gozzetti, MD, associate professor of hematology at the University of Siena in Italy. 

Dr. Gozzetti is the lead author of a review article on the state of the art and applications in clinical practice of minimal residual disease (MRD) approaches in MM therapy, published in the Journal of Personalized Medicine in September. 

“Since most patients relapse even after achieving CR,” Dr. Gozzetti and his coauthors write, “it became obvious that better techniques are needed to identify [MRD] at the lowest possible level.” Bone marrow or bone core biopsy analysis can detect residual disease with a specificity of only 10–2, which is insufficient considering the depth of response that can be achieved with novel agents. 

Several recent studies evaluating MRD in MM have shown that depth of response is directly correlated with survival improvement, the authors write. For example, a retrospective analysis published in 2019 found that “independently of cytogenetics, all patients (n=123) had better survival if MRD-negative (n = 31) when [compared] with those who were MRD-positive (n=92; NR vs. 26 months).”

Dr. Gozzetti and his colleagues state that “[it] is now obvious that MRD is a surrogate for” progression-free survival (PFS) and ultimately for overall survival (OS). They conclude, however, that in clinical practice, making therapeutic decisions on the basis of MRD status cannot currently be recommended. 

Dr. Gozzetti spoke with Nucleus about the current place and future direction of MRD in MM. Our conversation has been edited for clarity.

Nucleus: Is there a “best” method of determining MRD status in MM?

Gozzetti: According to the International Myeloma Working Group (IMWG) 2016 consensus criteria for assessment of response and MRD in MM, MRD negativity can be defined by either multiparameter flow cytometry–based or molecular-based assays with a sensitivity of at least 10−5. It is crucial to test for MRD in a sample of bone marrow aspirate that is not hemodiluted, as hemodilution can lead to false-negative results.

Nucleus: Is there “gold standard” data – i.e., data from large randomized clinical trials – demonstrating that MRD is a surrogate for PFS and ultimately for OS in patients with MM?

Gozzetti: While we do not have data from large randomized trials, multiple small trials and a meta-analysis have demonstrated that MRD status can be used as a surrogate for PFS and OS. Again according to the 2016 IMWG consensus criteria, patients who achieve sustained MRD negativity for 1 year have a greater probability of becoming long-term survivors.  

Nucleus: What questions need to be answered before MRD can be used to make therapeutic decisions in MM?

Gozzetti: We identify three outstanding questions: 

Is it sufficient to evaluate MRD at a single time point? 
Are 3 months after autologous stem cell transplant and 1 month after nontransplant therapy the optimal time points for a first evaluation of MRD? 
Should MRD be evaluated at 1 year or later after therapy or during maintenance to determine sustained negativity?
 
Nucleus: Why do you recommend that MRD detection in the bone marrow be accompanied by skeletal evaluation?

Gozzetti: MM can present as patchy interstitial localization in the bone marrow. Even in the presence of MRD negativity in the bone marrow, relapse can occur because of skeletal lesions that contain active disease. Several studies have shown that the detection of positive lesions on FDG-PET/CT scanning, both at diagnosis and recurrence, has prognostic significance.

Nucleus: Where do you see MRD playing a role in the management of MM? 

Gozzetti: We are in an exciting era for MM management. Although it is premature to use MRD status to make therapeutic decisions in clinical practice, many trials are exploring consolidation or maintenance therapy based on MRD status. Another exciting development is the potential for MRD to be used as a surrogate endpoint that would allow novel agents to be approved for the treatment of MM. The utility of the technique is undeniable. With tools that enable detection of the disease at the deepest possible level, as well as better knowledge of the disease, better prognostic ability, and better therapies, we may allow ourselves to begin thinking of MM as a curable disease. 

References

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. 2020;10(3):E120. doi:10.3390/jpm10030120

Kumar S, Paiva B, Anderson KC, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016;17(8):e328-e346. doi:10.1016/S1470-2045(16)30206-6

Li H, Li F, Zhou X, et al. 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;98(5):1185-1195. doi:10.1007/s00277-019-03609-x
 

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