Circulating tumor cells predict myeloma outcomes in patients treated with daratumumab, bortezomib, lenalidomide, and dexamethasone Open Access

• CTC are an independent prognostic factor in transplant-eligible NDMM patients treated in the PERSEUS trial,

• D-VRd improved MRD negativity rates and depths in both CTC-high/low patients compared to VRd, with longer PFS in CTC-low patients.

Circulating tumor cells (CTC) represent a high-risk biomarker in newly diagnosed multiple myeloma (NDMM); however, their prognostic value among transplant-eligible (TE) patients receiving daratumumab with bortezomib/lenalidomide/dexamethasone (D-VRd) remains unknown. Here, we analyzed CTC in the phase 3 PERSEUS trial (EMN017/NCT03710603). TE patients with NDMM were randomized (1:1) to D-VRd with daratumumab/lenalidomide maintenance (D-VRd group) or VRd with lenalidomide maintenance (VRd group), both with transplant. A subset of 451/709 patients from PERSEUS (D-VRd, 231/355; VRd, 220/354) had screening blood samples collected for CTC analysis by flow cytometry (median follow-up, 47.6 months). CTC were detected in 370/451 (82%) patients (median limit of detection, 0.0004%). CTC were prognostic of progression-free survival (PFS), independently of other factors, as a continuous (HR, 1.36 [95% CI, 1.15-1.60]; P<0.001) and categorical variable (≥0.175% CTC-high, optimal threshold). D-VRd improved PFS versus VRd in CTC-low patients (4-year rates: 88% vs 74%; HR, 0.42 [95% CI, 0.25-0.70]; P=0.0013). Regardless of study treatment, minimal residual disease (MRD)-negativity rates were lower in CTC-high versus CTC-low patients (10-5: 52.2% vs 66.2%; 10-6: 34.8% vs 52.4%). D-VRd significantly increased MRD-negativity rates versus VRd among CTC-high (10-5: 69.4% vs 33.3%; 10-6: 47.2% vs 21.2%; both P<0.05) and CTC-low patients (10-5: 74.4% vs 57.8%; 10-6: 65.6% vs 38.5%; both P<0.001), with similar observations for sustained MRD negativity. CTC levels are an independent prognostic factor in TE-NDMM patients treated with standard-of-care frontline quadruplet. D-VRd improved overall and sustained MRD-negativity rates in CTC-high and CTC-low patients, and improved PFS for CTC-low with a positive trend in CTC-high patients. NCT03710603