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Multiple myeloma gammopathies

Cytogenetic abnormalities in monoclonal gammopathy of undetermined significance

Leukemia volume 32, pages 2717–2719 (2018)Cite this article

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Multiple myeloma (MM) is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS), and patients with MGUS have a 1% per year risk of progression into MM [1,2,3]. Recently, colleagues from the Mayo Clinic in Rochester analyzed for the first time the prognostic significance of cytogenetic abnormalities detected by interphase fluorescence in situ hybridization (iFISH) in MGUS [1]. They showed that most cytogenetic abnormalities occur less frequently in MGUS compared to MM and identified t(4;14) as well as del(17p) as risk factors for progression from MGUS to MM. Authors concluded that cytogenetics provide a powerful tool for risk stratification in MGUS, and underlined that their results need to be validated in an independent cohort of patients. Therefore, we searched our iFISH database for patients, who were diagnosed with MGUS between 2002 and 2017 at the University Hospital Heidelberg, Germany. FISH analysis was performed on CD138-purified plasma cells as described previously using probes for: 1q21, 4p16, 5p15, 5q35, 8p21, 9q34, 11q23, 13q14.3, 15q22, 17p13, and 19q13 [4]. We also investigated immunoglobulin H (IgH) translocations t(11;14), t(4;14), and t(14;16). Hyperdiploidy (HD) was assessed by the score of Wuilleme et al. (gains of at least two of the chromosomes 5, 9, and 15) [5]. Statistical analyses were carried out according to the manuscript by Lakshman et al., with time to progression (TTP) being defined by the period from iFISH testing to progression into smoldering MM (SMM) and MM [3]. The study was approved by the local ethics committee review board (numbers S-337/2009 and S-096/20), and carried out in accordance with the Declaration of Helsinki.

We identified 155 patients with MGUS and cytogenetic abnormalities detected by iFISH. Median age was 62 years compared to 64 years in the Mayo Clinic cohort and 51% were male (Mayo Clinic 56%). The most frequently detected cytogenetic abnormality in our and the Mayo Clinic cohort was del(13q) (Heidelberg 23.9% and Mayo Clinic 28.0%). We identified del(17p) in 1.3% (Mayo Clinic 1.8%) and t(4;14) in 5.2% (Mayo Clinic 2.9%). Although we investigated different odd numbered chromosomes than the colleagues from Mayo Clinic, rates of HD were comparable between both groups (Heidelberg 18.4% and Mayo Clinic 22.5%). The most significant discrepancies between the groups were the occurrence of t(11;14) (Heidelberg 5.8% and Mayo Clinic 22.5%) and proportion of patients with normal cytogenetics. While after the exclusion of patients with insufficient plasma cells 26.2% of patients in the Mayo Cohort harbored a normal karyotype, only in 11 patients (7.1%) from our cohort cytogenetic abnormalities were detected in less than 10% of purified cells. This difference might be explained by the fact that in Heidelberg iFISH is performed on purified plasma cells isolated by magnetic-activated cell sorting with anti-CD138 microbeads [4]. Afterwards purity is confirmed by CD38/CD138 phenotypes by using flow cytometry resulting in a high purity of plasma cells even in MGUS or SMM [6]. Table 1 summarizes frequencies of cytogenetic abnormalities detected by iFISH in the Heidelberg and Mayo Clinic cohorts.

Table 1 Summary of cytogenetic abnormalities in MGUS
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References

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Acknowledgements

The authors thank Maria Dörner, Ewelina Nickel, Hendrike Seidt, and Marie-Louise Brygider for technical assistance in the enrichment of CD138-positive plasma cells and Michaela Brough, Michelle Ebentheuer, Stephanie Pschowski-Zuck, and Annekathrin Borowski for performing interphase FISH analysis. This work was supported by grants from the German Federal Ministry of Education (BMBF) “CLIOMMICS” (01ZX1309) and “CAMPSIMM” (01ES1103), the Deutsche Forschungsgemeinschaft (SFB/TRR79), the Dietmar Hopp Stiftung “Heidelberger Konzept zur Optimierung der Diagnostik und Therapie des Multiplen Myeloms”, and the 7th EU-framework program “OverMyR”.

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  1. Department of Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany

    Maximilian Merz, Korbinian Hoffmann, Anja Seckinger, Dirk Hose, Marc S. Raab & Hartmut Goldschmidt

  2. Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany

    Thomas Hielscher

  3. Max-Eder Research Group Experimental therapies for hematologic malignancies, DKFZ, Heidelberg, Germany

    Marc S. Raab

  4. Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA

    Jens Hillengass

  5. Institute of Human Genetics, Heidelberg, Germany

    Anna Jauch

  6. National Center for Tumor Diseases (NCT), Heidelberg, Germany

    Hartmut Goldschmidt

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Merz, M., Hielscher, T., Hoffmann, K. et al. Cytogenetic abnormalities in monoclonal gammopathy of undetermined significance. Leukemia 32, 2717–2719 (2018). https://doi.org/10.1038/s41375-018-0202-1

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