The pharmacokinetic parameters of the IgG antibodies calculated after administration of the novel IVIG preparations to patients with CLL and multiple myeloma are in close agreement with data obtained from healthy volunteers and with values of native IgG, suggesting that the production process did not impair clinically relevant characteristics of the viral antibodies.
The new CMG model was established with an advantage for better identification of MGUS patients at low risk.
Background Several models predict the progression from smouldering multiple myeloma (SMM) to therapy requiring multiple myeloma (MM). Three models comprise the assessment of tumour mass by different clinical parameters to stratify in risk groups: 1) the Mayo Clinic model uses bone marrow plasma cells percentage (BMPC) and serum monoclonal protein (M-protein), 2) the PETHEMA model uses immunoparesis and the percentage of abnormal plasma cells by flow cytometry, 3) the Heidelberg group assesses tumour mass by either the percentage of malignant plasma using iFISH or the Mayo assessment depicted above, and the presence of chromosomal aberrations associated with adverse prognosis. Besides tumor mass, they find the number of focal lesions in whole body MRI (>1) as strong prognostic factor. Aim To assess a combination of easily accessible clinical factors identifying patients at ≥ 80% risk of progression to MM requiring treatment within two years from the diagnosis of SMM. Methods Data for this study were obtained from the Registry of Monoclonal Gammopathies (RMG) acquired from hematologic centers of the Czech Republic for 287 SMM patients enrolled from May 2007 to June 2013. A cohort comprising 240 SMM patients from Heidelberg, Germany was used for validation (Neben et al. JCO 2013). Results During the follow up period (median 2.4 years; range 0.6 - 18.0) progression to MM was observed in 51.9% (149/287) patients in the study cohort, representing 16% risk of progression at 1 year, 31.2% at 2 years, 54.8% at 5 years and 73.4% at 10 years. In univariate analysis factors significantly associated with progression were as follows: serum free light chain (iFLC/uFLC) ratio > 30 (HR 2.4 [95% CI: 1.4 - 4.1]; p< 0.001) plasma cell infiltration in bone marrow cytology ≥ 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). In multivariate analysis, 3 parameters showed independent predictive value (immunoparesis, serum M-protein quantity ≥ 2.3 g/dL and iFLC/uFLC > 30). Combining these factors, we proposed a new risk model for SMM patients (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 (reference group), 1, 2 or 3 risk factors are present (p< 0.001) (Figure 1) with HR of 1.5 [0.7-2.9]; p=0.283, 2.5 [1.3-5.0]; p= 0.008, 6.8 [3.0-15.2]; p<0.001, n=139), respectively. The CMG model was validated on 240 SMM patients from Heidelberg published in 2013. The risk of progression from SMM to MM at 2 years was 5.3%, 7.5%, 44.8% and 81.3% if 0, 1, 2 or 3 risk factors were present, respectively (p< 0.001) (Figure 1) with HR of 4.2 ([0.5-36.1]; p=0.189), 21.5 ([2.9-159.1]; p= 0.003, HR 38.6 [4.7- 317.7]; p<0.001, n=113). Conclusion We propose and validate a new risk model for SMM patients with prediction of 80% (78.7% on our CMG model; 81.3% on data from Heidelberg) risk of progression to therapy requiring myeloma within two years based on easily accessible clinical parameters (CMG model). The model could especially be used to identify high-risk patients to be included in early treatment clinical trials. Acknowledgments: This work was supported by grants NT13492-4, NT14575-3 and by EU FP7/2007-2013; grant n°278570 and “OverMyR”, as well as the Deutsche Forschungs-Gemeinschaft (DFG) SFB/TRR79. Figure 1: CMG risk model: CMG cohort of patients and validation cohort of Heidelberg patients Figure 1:. CMG risk model: CMG cohort of patients and validation cohort of Heidelberg patients Disclosures Seckinger: Novartis: Research Funding.
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. Disclosures No relevant conflicts of interest to declare.
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