ASH 2021: Using Circulating Tumor Cells in the Blood to Track Precursor and Active Myeloma Conditions

Circulating tumor cells found in blood samples could be causing the spread of multiple myeloma according to investigators who presented at the recent American Society of Hematology (ASH) meeting. Knowing the number of those cells in the blood could be an important step to know the rate of dissemination and burden of multiple myeloma.

The research reviewed data from multiple studies that included 1157 patients who had smoldering myeloma (316 patients), newly diagnosed myeloma (650 patients) and relapsed/refractory myeloma (191 patients). 

Circulating tumor cells (CTCs) were detected in 78% of smoldering myeloma, 92% of newly diagnosed myeloma and 89% of relapsed myeloma. 

Smoldering Myeloma

Importantly, untreated Smoldering myeloma patients who have more than 0.02% of circulating tumor cells have “ultra high risk of transformation” to active multiple myeloma.

The detection of high CTCs levels resulted in a 4x risk of progression to active myeloma.

This is an interesting finding, because there is currently a widespread debate about when to treat or not to treat a patient with smoldering myeloma. Potentially having a cutoff value of percentage of circulating tumor cells may help decide whether to start therapy or just keep "watching and waiting." CTC levels may also help classify patients with ultra high risk transformation to active myeloma, and therefore, start therapy before it transitions to active disease. Potentially in the future and with the help of more CTC research, we can finally answer the complex question of when to treat smoldering myeloma.

Newly Diagnosed Myeloma

In newly diagnosed multiple myeloma there was an association between an increased percent of circulating tumor cells and high risk cytogenetics, elevated LDH levels and advanced RISS stages (how myeloma is staged at diagnosis). This is important to know because (in theory) if you were diagnosed with RISS III myeloma, you should also have a high percentage of circulating tumor cells. In contrast, if you had a RISS of I, the percentage of circulating tumor cells should be a lot lower.

There were also correlations with CTC levels for newly diagnosed transplant-eligible patients. They were divided into three groups, depending on the number of circulating tumor cells:

1. Undetectable CTCs
2. Low (<0.02)
3. High (>0.02)

The Undetectable CTCs group was associated with an exceptional outcome for stem cell transplant. The green line shows patients with undetectable circulating tumor cells, and the black and red lines are patients who did have detectable tumor cells.

Relapsed / Refractory Myeloma

In relapsed/refractory myeloma, the authors didn’t find any association between the percentage of circulating tumor cells and the number of previous lines of therapy. It didn't seem to matter if you had a single line of Revlimid/Velcade/dex, or multiple lines of different therapies. It seems the number of circulating tumor cells are not affected by prior treatments.

Conclusions

The overall study conclusions are that tumor cells are continuously trafficking in the blood. Evaluating the percentage of circulating tumor cells was a more accurate indicator than the percent of plasma cells in the bone marrow for smoldering and newly diagnosed myeloma, and showed prognostic value in all three-disease stages. This may be important because smoldering myeloma patients may have very low percentages of myeloma cells in the bone marrow (10-19%) and sometimes the sample is suboptimal. Additionally, bone marrow samples can vary, based on where in the body the biopsy is taken. In contrast, the circulating tumor cells are taken from the blood and it is not limited to a single bone marrow area.

The authors suggested that circulating tumor cell assessments should be part of the diagnostic workup of multiple myeloma. As a reminder, the initial myeloma workup today includes kappa and lambda light chains, the m-spike (paraprotein), the % of plasma cells in the bone marrow (by aspirate), the cytogenetic studies, beta 2 microglobulin, LDH and albumin levels.