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Evaluation of Current Clinical Models for Risk of Progression from Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma or Related Malignancies in 2028 Persons Followed in the Czech Republic

Roman Hajek, MD
University of Ostrava
Ostrava, Czech Republic

01.05.15

Program: Oral and Poster Abstracts
Session: 651. Myeloma: Biology and Pathophysiology, excluding Therapy: Poster II

Viera Sandecka, MD1*, Zdenek Adam, prof, MD, PhD1*, Ivan Spicka, Prof. MD, PhD2,3*, Vlastimil Scudla, prof, MD, PhD4*, Evzen Gregora, MD5*, Vladimir Maisnar, As Prof, MD, PhD6*, Lucie Brozova7*, Jiri Jarkovsky, Doc.7*, Lucie Rihova8*, Aneta Mikulasova9,10,11*, David Starostka, MD12*, Lenka Walterova, MD13*, Dagmar Adamova, MD14*, Petr Kessler, MD15*, Martin Brejcha, MD16, Ivan Vonke, MD17*, Jarmila Obernauerova, MD18,19*, Kamila Valentova, MD20*, Ludek Pour, Doc, MD, PhD1*, Jiri Minarik, MD, PhD4, Jan Straub, MD2*, Jakub Radocha, MD, PhD6*, Jaromir Gumulec, MD21* and Roman Hajek, Prof, MD, PhD21,22,23,24

1Department of Internal Medicine, Hematology and Oncology, University Hospital, Brno, Czech Republic
2Department of Internal Medicine, General University Hospital, Prague, Czech Republic
3Clinical Department of Haematology of the First Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic
4Department of Hematooncology, University Hospital, Olomouc, Czech Republic
5Department of Clinical Hematology, University Hospital Kralovske Vinohrady, Praha, Czech Republic
6Department of Clinical Hematology, University Hospital, Hradec Kralove, Czech Republic
7Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic
8Department of Clinical Hematology, University Hospital, Brno, Czech Republic
9Laboratory of Molecular Cytogenetics, Institute of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
10Department of Experimental Biology, Faculty of Science,, Masaryk University, Brno, Czech Republic, Brno, Czech Republic
11University Hospital, Department of Clinical Hematology, Brno, Czech Republic
12Department of Clinical Hematology, General Hospital, Havirov, Czech Republic
13Department of Clinical Hematology, General Hospital Liberec, Liberec, Czech Republic
14Department of Hematology and Transfusiology, Silesian Hospital, Opava, Czech Republic
15Department of Hematology and Transfusion, General Hospital, Pelhrimov, Czech Republic
16Department of Clinical Hematology, J.G.Mendel Oncology Center, Novy Jicin, Czech Republic
17Department of Clinical Hematology, Hospital Ceske Budejovice, Ceske Budejovice, Czech Republic
18Department of Hematology and Transfusion, Claudian Hospital, Mlada Boleslav, Czech Republic
19Department of Hematology-transfusiology, General Hospital, Mlada Boleslav, Czech Republic
20Department of Clinical Hematology, Thomayer Hospital, prague, Czech Republic
21Department of Haematooncology, University Hospital Ostrava and the Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
22Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Brno, Czech Republic
23Babak Myeloma Group, Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic
24On behalf of Czech Myeloma Group, Ostrava, Czech Republic

 
Introduction:

Monoclonal gammopathy of undetermined significance (MGUS) is a non-malignant condition associated with a risk of progression to multiple myeloma (MM) or related disorders. There are currently 2 clinical models predicting progression from MGUS to MM. The Mayo Clinic model uses levels and type of serum monoclonal protein (M-protein) and serum free light chain ratio (sFLC). The Spanish PETHEMA model uses flow cytometry of bone marrow plasmocytes (BMPC) and the presence of DNA aneuploidy.

 

Purpose:  

The primary end point was to estimate the cumulative risk of hematologic disorders occurring during the follow-up of our cohort. The secondary end points were: to validate known clinical models suggested by the Mayo Clinic group and the Spanish PETHEMA group for the risk of progression from MGUS to MM or related malignancies and to establish a new risk model by the Czech Myeloma Group (CMG model) with better prediction of low-risk MGUS group.   

 

Group:

Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic. MGUS diagnosis was made according to IMWG criteria. In total, 2028 persons with MGUS were enrolled in the RMG study from May 2007 to June 2013. A total of 93% (1887/2028) of persons were evaluated.

 

Results:

1887 MGUS persons were followed with median 4 years. Malignancies developed in 8.6% (162/1887) cases; MM occurred in 77.2% (125/162) of persons. The risk of progression was 1.5% at 1 year, 7.6% at 5 years and 16.5% at 10 years after diagnosis. The key predictors factors of progression were as follows: age ≥ 69 years, serum M- protein concentration ≥ 1.5 g/dL, BMPC > 5%, pathological sFLC ratio (< 0.26 or >1.65), immunoparesis of polyclonal immunoglobulins, levels of serum hemoglobin at baseline < 12.0 g/dL and the presence of normal plasma cells (nPC) in bone marrow ≤ 5 %  identified by multiparametric flow cytometry techniques. Distribution of MGUS persons according to risk groups based on the Mayo Clinic model confirmed predictive power of Mayo Clinic model based on our data although isotype of M- protein was not found as independent predictor. At 10 years, no-risk group had 4.9% risk of progression compared to 16.3%, 24.6%, and 54.9% in groups with 1, 2 or 3 risk factors, respectively (p< 0.001). MGUS group with 1, 2 and 3 risk factors in comparison to the reference group without any risk factor had HR( 2.59 [95% CI: 1.39- 4.84]; p= 0.003, HR 4.79 [95% CI: 2.56-8.93]; p< 0.001, HR 12.97 [95% CI: 5.52-30.48];p< 0.001), retrospectively. Immunoparesis instead of DNA aneuploidy was used together with the presence of abnormal plasma cells (aPCs) to validate the modified PETHEMA model. The rates of progression at 3 years were 2.5%, 8.1% and 28.0% for groups with neither, one or both risk factors, respectively (p< 0.001). MGUS group with 1 and 2 risk factors in comparison to the reference group without any risk factor had HR (3.98 [95% CI: 1.60-9.91]; p= 0.003,  HR 14.23 [95% CI: 2.86-70.76]; p< 0.001), retrospectively. Based on the 5 parameters with independent predictive value in the univariate analysis (immunoparesis, serum M-protein quantity ≥ 1.5 g/dL, BMPC > 5%, abnormal sFLC ratio and serum level of hemoglobin < 12.0 g/dL) we proposed a new CMG model. The created CMG model clearly detected MGUS persons at low risk 86.6% (828/956) with the risk of progression 5.6% at 5 years better than previously described models. As expected, the number of MGUS persons with the highest risk of progression was limited to 3.7% only (35/956), with the risk of progression 31.9% at 5 years. The MGUS group with 5 risk factors had 63 times higher hazard of progression compared to reference MGUS group (HR 63.17 [95% CI: 13.99-285.36]; p< 0.001).   

 

Conclusion:

In the large cohort of MGUS persons, we confirmed validity of previously considered clinical models for the risk of progression from MGUS to MM by the Mayo Clinic group and the Spanish PETHEMA group (model used for SMM). New CMG model for the risk of progression from MGUS to MM or related malignancies was established with an advantage for better identification of MGUS persons at low risk (87% of persons with risk of progression below 10% in 5 years) as well as few persons at the highest risk of progression. As a consequence, limited evaluation and visits can be planned in majority of MGUS persons in follow-up.

 

Acknowledgments: This work was supported by grants NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant n° 278570.


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