Estimated Glomerular Filtration Rate Calculated By The CKD-EPI Formula Has Improved Prognostic Ability Over MDRD Formula In Patients With Newly Diagnosed, Symptomatic, Multiple Myeloma: Analysis In 1937 Patients

Renal impairment (RI) is a common complication of myeloma and is associated with increased risk of early death. Accurate assessment of glomerular filtration rate (GFR) in patients with myeloma is important for evaluation of renal function, for drug dosing and for prognostic purposes. The method of assessment of RI and calculation of GFR is important since serum creatinine alone underestimates renal dysfunction, especially in patients of advanced age. The MDRD formula has been widely used for the calculation of GFR but the CKD-EPI formula has been increasingly used among nephrologists since 2009 (Levey et al, Ann Intern Med 2009;150:604-12). However, the performance of these two equations for the estimation of GFR and their relative prognostic ability has not been assessed in large numbers of patients with myeloma. Thus, in order to evaluate the prognostic significance of GFR as calculated by two different formulas, the MDRD and the CKD-EPI, we analyzed the data of 1937 newly diagnosed patients with symptomatic myeloma who were treated within the centers of the Greek Myeloma Study Group.

The median age of the patients was 66 years (range 20-96 years); 54% were >65 years of age and 23% >75 years of age; 55% were males and 53% had an ECOG performance status ≤1. Anemia (Hb <10 g/dl) was present in 44% of the patients, low platelet counts (<130x10⁹/l) in 13% and hypercalcemia (Ca ≥11.5 mg/dl) in 14.5%. ISS: 27% were ISS-1, 37% were ISS-2 and 36% were ISS-3, while serum LDH was elevated (≥300 IU/L) in 11.5%. Significant Bence Jones proteinuria (≥2 g/day) was present in 19%, while serum creatinine was ≥2 mg/dl in 20.5% of the patients. Frontline therapy was based on conventional chemotherapy in 64% of the patients and 36% received primary therapy with novel agents (22% IMiD-based and 14% bortezomib-based regimens). Median eGFR by the MDRD formula was 63 ml/min/1.73m² (range 2.94-201.4 ml/min/1.73m²) vs. 61.4 ml/min/1.73m² (range 2.51-140.4 ml/min/1.73m²) by the CKD-EPI formula (p<0.001). According to CKD stage disposition, per eGFR calculated by the MDRD 18.6%, 34.5%, 28% , 11% and 8% of patients had stage 1, 2, 3, 4 and 5 RI, respectively, while when GFR was calculated by the CKD-EPI 16.6% , 34%, 28%, 12% and 8.5% of patients had stage 1, 2, 3, 4 and 5, respectively. The difference in the disposition between the two calculation methods was significant (p<0.001): the concordance in stage disposition was 90.3%; thus, 9.7% of patients were allocated in different stages by the two methods of calculation, mainly because with CKD-EPI formula resulted in lower estimated GFR: in 19.5% of the patients the eGFR by MDRD was ≥10% higher and in 0.4% was ≥10% lower than with CKD-EPI equation, but resulted in re-classification in advanced stage of CKD in 8% of patients and in lower stage in 2% of patients. The difference in classification resulted in the downgrade of 42 patients from stage 2 to stage 3 RI, when CKD-EPI equation was used to calculate eGFR.

We examined the prognostic significance in univariate analysis per CKD stage for each calculation formula: median survival for patients with CKD stage 1, 2, 3, 4 and 5, according to MDRD formula was 61, 54, 36, 30 and 23 months, respectively (p<0.001), while the respective median survival per CKD-EPI formula was 64 months, 54, 37, 25 and 23 months (p<0.001). In univariate analysis, eGFR by CKD-EPI formula resulted in higher chi-square values (χ²: 127 vs. 97 for eGFR by MDRD formula) indicating improved prognostic ability for overall survival. We also examined the predictive ability for each of the formulas of eGFR for early death at 2 months, 6 months and 12 months. Harrell’s C statistic, a measure of the discriminating ability of a model was higher for eGFR by the CKD-EPI than for eGFR by the MDRD formula, either for overall survival (p=0.028) or for early death at 2 months (p<0.001), at 6 months (p<0.001) or 12 months (p<0.001) after initiation of therapy.

In conclusion, for the first time we evaluated two different formulas of estimation of GFR, both based on serum creatinine, age and gender, in a large number of patients with symptomatic myeloma and we found that GFR calculated by the CKD-EPI formula reclassifies the stage of renal impairment of about 9% of patients and has better prognostic ability for survival and predictive ability for early death than the MDRD formula. We propose the broad use of CKD-EPI formula for the estimation of GFR in patients with myeloma.