ASH 2021 | CTCs in myeloma: egression mechanisms, transcriptomics, and prognostic value

I’m Bruno Paiva from University of Navarra in Pamplona, Spain, and this year we’ll be presenting at ASH a very large study on circulating tumor cells in multiple myeloma, focusing on the mechanisms of aggression, clinical significance and therapeutic endpoints. I think that many agree that circulating tumor cells or CTCs may be responsible for myeloma spreading and therefore their numbers in blood could be a surrogate for the rate of dissemination and overall tumor burden in the marrow. And if this hypothesis holds true, then CTCs would be a powerful biomarker of malignant transformation and disease aggressiveness. And this was the rational behind our efforts to investigate the clinical significance of CTCs in patients with smoldering, newly diagnosed and relapsed refractory myeloma.

And also from a biological point of view, to compare the description of profile of CTCs across the disease spectrum, taking as a reference the tumor cell in the marrow from the same set of patients. We used next generation flow cytometry, high sensitivity [inaudible] to quantify the percentage of CTCs in the blood of approximately 1,100 patients–300 smoldering myeloma, 650 with newly diagnosed myeloma, and almost 200 with relapse refractory disease. And we also used FLOW to isolate the CTC, the tumor clone in the marrow, and we performed afterwards RNA seq on these tumor cells from two different spatial locations.

Well, in sake of time, I will skip the detection rate of CTCs. As you would expect it increases with aggressiveness. But we found a surprising result that it peaks in patients with active disease, but in newly diagnosed, not relapsed refractory. And then by performing the transcriptional analysis, we confirmed previous observations by our group that the transcription profile of CTCs is very similar to that of bone marrow tumor cells–only 80 genes truly, differentially expressed between patient maps, CTCs, and bone marrow tumor cells. However, the small differences were not stable across disease stages. Rather, the mechanisms that lead into the aggression of tumor cells in the marrow into the blood may be different as the patient evolves from smoldering to newly diagnosed and relapsed refractory myeloma. From a clinical point of view, we showed that the quantification of CTCs in smoldering myeloma is a biomarker of ultra-high risk of transformation, median TTP of 11 months.

It is more informative when compared to the percentage of bone marrow plasma cells. And we believe that CTCs may have the potential to replace the assessment of bone marrow plasmacytosis in upcoming risk certification models. And then we showed, particularly in transplant-ineligible myeloma, that CTCs may be one of the most powerful biomarkers at diagnosis. And the results were also positive, although not as positive, in elderly newly diagnosed and relapsed/refractory myeloma. Importantly, in untreated smoldering myeloma, as I said before, CTCs high risk biomarker. But if patients were offered early treatment in the scope of Spanish clinical trials for high risk smoldering myeloma, early treatment intervention was able to aggregate the poor prognosis of high the percentage of CTCs.

Therefore, this could be a biomarker to enrich for clinical trials investigating early treatment intervention. As I said before, in sake of time, I skipped detection grades, the cutoff for CTCs. This obviously is available in the abstract and it’ll be described in the oral presentation.

To conclude, this was probably the largest study in myeloma investigating the role of CTCs in smoldering and active disease. Our results show that CTCs are continuously trafficking in blood, possibly through a dynamic mechanism of aggression that peaks in newly diagnosed myeloma. And we believe that this data builds upon other data reported by our and other groups and suggests that CTC assessment should be part of the diagnostic workup of patients with myeloma.