Peripheral Blood Genomic Interrogation in Myeloma: Developing a Blood Biopsy to Replace the Bone Marrow Biopsy

A holy grail for cancer diagnostics is the “liquid biopsy” — the ability to diagnose, profile, and follow a patient’s cancer from a sample of peripheral blood rather than an invasive sample such as the bone marrow biopsy. Bone marrow aspiration and biopsy can be inconvenient and uncomfortable, making repeat sampling to follow genetic evolution impractical. In solid tumors, liquid biopsies are starting to become a reality. For example, in lung cancer, Roche’s epidermal growth factor receptor mutation test of circulating-free tumor DNA from plasma is now an approved test.¹  In multiple myeloma, Dr. Jens G. Lohr and colleagues recently presented the early stages of a comprehensive assay of individual circulating myeloma cells isolated from peripheral blood.² 

From a routine sample of only 6 mL of peripheral blood, the authors developed a robust pipeline for isolating very rare circulating myeloma cells (< 1 in 10⁵ cells) using a combination of CD138⁺ CD45^– cell enrichment and single-cell micromanipulation. Using this approach, they could identify at least 12 circulating myeloma cells from 24 patients. They then performed targeted sequencing at 35 loci known to be commonly mutated in myeloma, and found that they could call the same mutations as previously identified by conventional genotyping of the bone marrow. Interestingly, they also detected some mutations in the circulating tumor cells that were not detected in the corresponding bone marrow myeloma cells, suggesting that some bona fide “driver” mutations occur in a greater fraction of the myeloma cells in the blood than in the bone marrow. Circulating tumor cells may therefore be a more accurate representation of the tumor repertoire than the sampling from an individual bone marrow site. Furthermore, the investigators could isolate and genotype circulating tumor cells in patients with low tumor burden, such as those responding to treatment and in a patient with monoclonal gammopathy of undetermined significance (MGUS). Finally, in addition to identifying mutations, the investigators also could perform transcriptome profiling at the single-cell level.

Overall, Dr. Lohr and colleagues have developed a new tool for exploring the complexity of multiple myeloma through circulating myeloma cells, thereby overcoming the logistical burden of bone marrow biopsies and permitting analysis to be performed at multiple time points. This innovation empowers investigators to address a range of fundamental questions in myeloma. Resistance to treatment and relapse are a core problem in myeloma care, and this has been attributed to “clonal tiding,” where multiple heterogeneous clonal populations may evolve with treatment.^2-4  The liquid biopsy described here may enable a more thorough dissection of this problem in real time and identify new mechanisms of resistance. Its sensitivity may also permit a better understanding of the biology behind minimal residual disease. Similarly, it may be used at earlier stages of disease, such as MGUS and smoldering myeloma, prior to the development of symptoms and where treatment may be more effective when the disease burden is lower. Importantly, this technology, in addition to providing a comprehensive profile of disease, also has the added benefit of convenience and comfort — something all patients will welcome. Other options such as circulating DNA assays are simultaneously under investigation and will allow liquid biopsies to be used more broadly.