Deep dive into shallow myeloma cell pool Free

In this issue of Blood, Lasa et al¹ describe BloodFlow, an ultrasensitive method that combines immunomagnetic enrichment of CD138⁺ plasma cells with next-generation flow cytometry, enabling the detection of 1 tumor cell among 10 million leukocytes in patients with multiple myeloma (MM).

A novel combination of quadruplet treatments, rapid development in immunotherapies, and long-term maintenance approaches has transformed the management of multiple myeloma. Recent studies have reported more than 90% to 95% overall response, with most patients maintaining sustained response. In those studies, investigators also reported that two-thirds of patients achieved undetectable minimum residual disease.^2,3 

Bone marrow aspirate remains the standard for minimum residual disease assessment in studies and clinical care, but its invasive nature makes it impractical and less preferable for frequent surveillance.^4,5 Liquid biopsies from blood draws represent an attractive alternative. However, it also has shown limitations in detecting circulating tumor cells, particularly when the disease is confined to the bone marrow microenvironment. This technical barrier has hindered the adoption of peripheral residual disease assessment.⁶ 

The BloodFlow method developed by Lasa and colleagues addresses this challenge through immunomagnetic enrichment of CD138⁺ plasma cells from large volumes of peripheral blood prior to next-generation flow analysis. This preenrichment step significantly magnifies the detection capability over conventional next-generation flow sensitivity. When tested across 644 peripheral blood samples, BloodFlow detected the peripheral residual disease in 8.5% of samples, with half of these positive samples being undetectable by the standard next-generation flow. The authors further validated this through bone marrow-peripheral blood correlation studies, demonstrating a high positive predictive value when using bone marrow minimum residual disease assessment as the reference standard. BloodFlow’s independent prognostic value for progression-free survival alongside established risk factors proves the implications of this work beyond technical achievement.

However, there are still cases where the 2 methods do not overlap. The authors have listed several factors contributing to such differences, such as peripheral blood cellularity, depth of minimum residual disease in the bone marrow, and treatment phase, all of which impact the likelihood of detecting circulating tumor cells in patients. Several questions await further investigation. Will sequential monitoring using BloodFlow detect residual disease resurgence prior to conventional methods? Could the technique be combined with other minimally invasive approaches to improve sensitivity and specificity further? How might the peripheral residual disease dynamics in different biological subsets of MM inform monitoring strategies?

As MM treatment paradigms evolve, the ability to monitor disease kinetics noninvasively addresses a critical clinical need.^7-9 While acknowledging limitations, BloodFlow is a powerful new tool for minimally invasive disease surveillance, addressing the clinical need with a sensitivity threshold previously unattainable with flow cytometry-based methods.

Conflict-of-interest disclosure: M.K.S. is a consultant for AbbVie and K36 and is on the advisory board of the Neuberg Center for Genomic Medicine.