EVALUATION OF CURRENT CLINICAL MODELS FOR RISK OF PROGRESSION FROM SMOLDERING MULTIPLE MYELOMA TO MULTIPLE MYELOMA IN 287 PATIENTS FOLLOWED IN THE CZECH REPUBLIC

Background
Two risk stratification models predict the progression from smoldering multiple myeloma (SMM) to multiple myeloma (MM). i) the Mayo Clinic model uses percentage of bone marrow plasma cells (BMPCs) and serum monoclonal protein (M-protein) and free light chain (FLC) ratio, ii) the PETHEMA model uses immunoparesis and the percentage of abnormal PCs (aPCs) by flow cytometry.

Aims
The primary end point was to estimate the cumulative risk of MM occurring during the follow-up of our cohort. The secondary end points were: to validate known clinical models and to establish a new risk model by the Czech Myeloma Group (CMG model) with better prediction of ultra high-risk SMM group.

Methods
Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic. In total, 361patients with SMM were enrolled in the RMG study from May 2007 to June 2013. In total, 79.5% (287/361) of patients were analyzed.

Results
287 SMM patients were followed with median 2.4 years. MM was developed in 51.9% (149/287) of patients. The risk of progression was 16%, 31.2%, 54.8% and 73.4%  at 1, 2, 5 and 10 years after diagnosis, respectively. The key predictors factors of progression were as follows: serum (iFLC/uFLC) ratio >30 (HR 2.4 [1.4 - 4.1], p<0.001), BMPCs  ≥15% (HR 2.1 [1.5-3.0]; p<0.001), immunoparesis (HR 2.0 [1.3-2.9]; p<0.001), M - protein concentration ≥2.3 g/dL (HR 2.00 [1.4-2.7]; p<0.001), beta2 microglobulin ≥2.0 mg/l (HR 1.8 [1.2-2.7]; p=0.001), and thrombocyte count ≤250 x 10⁹/l (HR 1.7 [1.1-2.4]; p= 0.005). Distribution of SMM patients according to risk groups based on the Mayo Clinic model (Dispenzieri 2008) confirmed predictive power of this model based on low and intermediate- risk group, but did not confirm high-risk group. The high-risk group was represented only by 4 SMM patients.  At 2 years, no-risk group had 20.2% risk of progression compared to 23.2%, 45.4% and 25% in groups with 1, 2 or 3 risk factors, respectively (p=0.014) (Fig 1). SMM group with 1, 2 and 3 risk factors in comparison to the reference group had HR( 1.14 [0.54- 2.41]; p=0.732, HR 2.58 [1.25- 5.35]; p=0.011, HR 2.18 [0.47-10.03];p=0.317, n= 146), retrospectively. Immunoparesis and ≥ 95% aPC was used to validate the PETHEMA model (Perez-Persona 2007). The rates of progression at 2 years were 5.9%, 20% and 41.4% for groups with 0, 1 or 2 risk factors, respectively (p=0.058) (Fig 1). SMM group with 1 and 2 risk factors in comparison to the reference group had HR (1.51 [0.40-5.69]; p= 0.546, HR 3.31 [0.78-14.06]; p= 0.104, n=62), retrospectively. Based on the 3 parameters with independent predictive value in the univariate analysis (immunoparesis, serum M-protein quantity ≥2.3 g/dL and iFLC/uFLC >30) we proposed a new CMG model. The risk of progression from SMM to MM at 2 years was 18.5%, 20.9%, 41.9% and 78.7% if  0, 1, 2 or 3 risk factors are present (p<0.001) with HR of 1.4 [0.7-2.9]; p=0.28, 2.5 [1.2-5.0]; p=0.008, 6.7 [3.0-15.2]; p<0.001, n=139), respectively (Fig 1).

Summary
We confirmed the validity of previously considered clinical models by the Mayo Clinic group (except high-risk group) and the PETHEMA group. New CMG model for the risk of progression from SMM to MM was established. Better identification of ultra high-risk group with prediction of 79% risk of progression to MM within two years based on easily accessible clinical parameters is advantage.

Acknowledgments: NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant 278570, IGA MZ CR NT14393.

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