General MM

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 sample5,6
  • 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

 

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

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

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.

References
  1. Perrot A.  et al. Minimal residual disease negativity using deep sequencing is a major prognostic factor in multiple myeloma. Blood. 2018 Dec 06; 132(23):2456–2464. DOI: 10.1182/blood-2018-06-858613
  2. Waldschmidt JM. et al. Comprehensive characterization of circulating and bone marrow-derived multiple myeloma cells at minimal residual disease. Semin Hematol. 2018 Jan; 55(1):33–37. DOI: 10.1053/j.seminhematol.2018.02.010
  3. Oberle A. et al, Monitoring multiple myeloma by next-generation sequencing of V(D)J rearrangements from circulating myeloma cells and cell-free myeloma DNA. Haematologica. 2017 Jun; 102(6):1105–1111. DOI: 10.3324/haematol.2016.161414
  4. Sanoja-Flores L. et al. Next generation flow for minimally-invasive blood characterization of MGUS and multiple myeloma at diagnosis based on circulating tumor plasma cells (CTPC). Blood Cancer J. 2018 Nov 19; 8(12):117. DOI: 10.1038/s41408-018-0153-9
  5. Flores-Montero J. et al. Next generation flow for highly sensitive and standardized detection of minimal residual disease in multiple myeloma. Leukemia. 2017 Jan 20; 31(10):2094–2103. DOI: 10.1038/leu.2017.29
  6. Sanoja-Flores L. et al. Blood monitoring of circulating tumor plasma cells by next generation flow in multiple myeloma after therapy. Blood. 2019 Dec 12; 134(24):2218–2222. DOI: 10.1182/blood.2019002610
  7. Korthals M. et al. Molecular monitoring of minimal residual disease in the peripheral blood of patients with multiple myeloma. Biol Blood Marrow Tr. 2013 Jul 01; 19(7):1109–15. DOI: 10.1016/j.bbmt.2013.04.025
  8. Huhn S. et al. Circulating tumor cells as a biomarker for response to therapy in multiple myeloma patients treated within the GMMG-MM5 trial. Bone Marrow Transpl. 2017 May 15; 52(8):1194–1198. DOI: 10.1038/bmt.2017.91
  9. Mazzotti C. et al. Myeloma MRD by deep sequencing from circulating tumor DNA does not correlate with results obtained in the bone marrow. Blood Adv. 2018 Oct 24; 2(21):2811–2813. DOI: 10.1182/bloodadvances.2018025197
  10. Moor I. et al. Peripheral flow-MRD status at the time of autologous stem cell collection predicts outcome in multiple myeloma. Bone Marrow Transpl. 2018 Jun 08; 53(12):1599–1602. DOI: 10.1038/s41409-018-0245-y
  11. Cowan AJ. et al. Circulating plasma cells at the time of collection of autologous PBSC for transplant in multiple myeloma patients is a negative prognostic factor even in the age of post-transplant maintenance therapy. Biol Blood Marrow Tr. 2018 Jul 01; 24(7):1386–1391. DOI: 10.1016/j.bbmt.2018.02.017
  12. Rawstron AC. et al. Circulating plasma cells in multiple myeloma: characterization and correlation with disease stage. Br J Haematol. 1997 Apr; 97(1):46–55. DOI: 10.1046/j.1365-2141.1997.72653.x
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