Circulating tumor plasma cells as an independent prognostic marker for patients with MM

Monitoring minimal residual disease (MRD) is an important tool to assess disease burden and response to therapy. MRD negativity (defined as less than one myeloma cell per 10^-6 of bone marrow cells) has been associated with improved survival.¹ MRD is used as a prognostic factor, helping to identify high-risk patients and assisting in treatment-making decisions.¹ Read more on MRD here.

However, methods used to detect MRD differ in sensitivity and there is a lack of standardization in sample source and processing. Moreover, sampling of bone marrow (BM) is an invasive procedure with relatively low sensitivity. In contrast, monitoring of blood for circulating tumor plasma cells (CTPC), tumor-derived DNA, RNA, or protein markers have been reported as a less invasive and more precise way of quantifying absolute numbers of CTPC than BM MRD.^2–5

Luzalba Sanoja-Flores, the University of Salamanca, Salamanca, ES, and colleagues investigated CTPC detected in peripheral blood (PB) using next-generation flow (NGF) cytometry as a prognostic factor for patients with multiple myeloma (MM). The study was conducted on behalf of EuroFlow Consortium. This article summarizes the results of the study, recently published in Blood journal.⁶

Methods⁶

• Newly-diagnosed patients with MM (N = 137), after treatment outside clinical trials, were monitored for:
  • BM MRD
  • CTPC in blood by NGF
  • serum immunofixation (sIF)
• In total, 328 samples were analyzed:
  • 274 paired BM and 54 follow-up blood samples
• Samples of ≥ 10⁷ cells were obtained by lysing a median of 6 mL (3–14 mL) of blood and 1.8 mL (0.3–5 mL) of BM sample^5,6
• sIF was measured using the HYDRAGEL kit

Results⁶

CTPC were detected in the post-treatment blood samples of 26% of patients, which was at a similar level to previously reported for allele-specific oligonucleotide polymerase chain reaction (PCR)^7,8 and next-generation sequencing (NGS)^3,9, and 50% higher than previously reported with conventional flow cytometry.^10,11 Among patients who achieved a complete response (CR) or stringent CR (sCR), 17% were CTPC⁺ by NGF versus 0–8%^11,12 by conventional flow cytometry. However, NGF failed to detect CTPC in 55/137 (40%) of BM MRD⁺ and 41/137 (30%) of sIF⁺ paired samples.

In the total MM cohort (n = 137) and in patients who achieved CR/sCR (n = 71), CTPC⁻ and BM MRD⁻ patients had a longer progression-free survival (PFS) compared to those who tested positive, with the biggest differences in outcome seen in patients that became CTPC⁺ after initially being CTPC⁻. In univariate and multivariate analysis, age ≥ 65 years and cytogenetic profile did not have a significant impact on PFS in the total MM cohort or in patients who achieved CR/sCR. The prognostic factors with a significant impact are presented in Table 1.

Table 1. Selected analysis of prognostic factors for PFS in MM

BM, bone marrow; CI, confidence interval, CR, complete response; CTPC, circulating tumor plasma cells; HR, hazard ratio; IF, immunofixation; MRD, minimal residual disease; NGS, next-generation flow; PB, peripheral blood; PFS, progression-free survival; sCR, stringent CR
	Univariable analysis		Multivariable analysis
	Median PFS (months)	p-value	HR	95% CI	p-value
Prognostic factors for the whole MM cohort Serum IF Negative Positive BM MRD status by NGF Negative Positive PB CTPC status by NGF Negative Positive	41 18   46 25   46 9	0.001     < 0.0001     < 0.0001	— 2.4   —     — 5.1	— 1.3–4.4   —     — 2.9–8.9	— 0.004   —     — < 0.0001
Prognostic factors for sCR/CR cohort BM MRD status by NGF Negative Positive PB CTPC status by NGF Negative Positive	50 25   46 9	< 0.0001     < 0.0001	— 6.1   — 7.4	— 1.5–24.4   — 3.0–18.2	— 0.01   — < 0.0001

Additionally, in sequentially followed cases, patients who were persistently CTPC⁻, or became CTPC⁻ after initially being CTPC⁺ (n = 41), had significantly improved PFS compared with cases CTPC⁺ at last study follow-up (n = 13; 50% PFS: not reached vs 19 months; p < 0.0001), independent of sIF status. The statistically significant factors were then combined into a prognostic score to stratify patients into three risk categories (values given below are for the total MM cohort):

• Score 0, sIF^- and PB CTPC⁻(n = 60) — low-risk patients with 50% PFS of 46 months
• Score 1, sIF⁺ or PB CTPC⁺ (n = 56) — intermediate-risk patients with 50% PFS of 26 months
• Score 2, sIF⁺ and PB CTPC⁺ (n = 21) — high-risk patients with 50% PFS of five months and two-year PFS rate of 1% (total MM cohort) and 33% (patients with sCR/CR)

Conclusions⁶

The findings suggest that PB CTPC may be a novel independent prognostic marker for PFS in patients with MM. This less invasive method, compared to BM sampling, may be more suitable for patients who require frequent monitoring and, therefore, more informative than a single time-point BM MRD. A larger study with a longer follow-up is required to confirm these findings.