Both the EuroFlow™ consortium and researchers at Memorial Sloan Kettering Cancer Center (MSKCC) have developed next-generation flow (NGF) cytometers. The EuroFlow™ NGF uses 2 flow cytometry tubes, each with 8 antibodies, while the MSKCC cytometer uses a 10-color, single tube method. Both of the NGF cytometers have comparable results with limits of detection at 2 x 10-6 for the EuroFlow™ and 6 x 10-6 for the MSKCC 10-color NGF.2

An alternative approach for MRD detection is next-generation sequencing using the clonoSEQ® platform, which was cleared by the US Food and Drug Administration for use in patients with MM in 2018. This platform identifies and quantifies the rearranged immunoglobulin heavy chain and kappa and lambda sequences and has a 6.8 x 10-7 limit of detection.

“Having this new ability to measure disease opens up several opportunities that we didn’t have before — for instance, being able to deploy novel therapies early in the natural history of the disease based on the fact that the patient has not reached a certain depth of remission,” said Dr Costa.

To use MRD to inform patient management, the ideal threshold must be defined. Recent studies have demonstrated that different clinical outcomes are associated with different sensitivity rates. In particular, the Intergroupe Francophone du Myélome (IFM) 2009 trial and the Programa para el Estudio de la Terapéutica en Hemopatías Malignas/Grupo Español de Mieloma (PETHEMA/GEM) 2012 trial both found that higher rates of progression-free survival were associated with higher sensitivity, and patients with MRD below 10-6 were at very low risk for relapse. Therefore, future clinical trials and MRD-based treatment decisions may be more likely to use the most stringent assays that can detect MRD at 10-6.

Dr Costa and colleagues also suggested that MRD quantification can be used to develop alternative response criteria for MM therapy. The stratification would be according to disease burden represented by MRD, delineated as: minor, major (MRD[+]) above a threshold of 10-4, major (MRD[-4]) above a threshold of 10-5, major (MRD[-5]) above a threshold of 10-6, and major (MRD[-6]) below a threshold of 10-6.

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The review authors noted that the most important aspect of the technologic developments for improving MRD sensitivity is their acceptance and use by the MM community. Dr Costa explained that the use of MRD could enable novel clinical trials, some of which are ongoing, and improve the management of patients with MM (for example, by redefining treatment failure as failure to meet recommended MRD milestones).

“We all need to welcome this innovation,” Dr Costa said. “It is a challenge, for sure, but it is also an opportunity to come up with new trial designs so we can instrumentalize MRD for future decision making and patient management.”

However, MM is spatially heterogeneous, with differing densities of disease subclones throughout the bone marrow. Furthermore, extramedullary disease presents an additional challenge, as current protocols sample only the bone marrow. The authors emphasized that concomitant use of functional imaging with fluoro-2-deoxyglucose positron emission tomography should be required for experimental therapy discontinuation and to identify any tumor cells undetected by next-generation sequencing or NGF in patients after initial therapy.

Additionally, although the prognostic value of MRD has been established, no clinical trials have demonstrated that changing therapy after achieving undetectable MRD is superior to conventional management. However, many studies are underway that are using MRD as the primary end point; thus, these data will soon be available to help refine therapy and improve outcomes for patients with MM.

Disclosures: Some authors have declared affiliations with the pharmaceutical industry. Please refer to the original study for a full list of disclosures.

References

  1. Bal S, Weaver A, Cornell RF, Costa LJ. Challenges and opportunities in the assessment of measurable residual disease in multiple myeloma. Br J Haematol. 2019;186(6):807-819.
  2. Roshal M, Flores-Montero JA, Gao Q, et al. MRD detection in multiple myeloma: comparison between MSKCC 10-color single-tube and EuroFlow 8-color 2-tube methods. Blood Adv. 2017;1(12):728-732. 

This article originally appeared on Hematology Advisor