Validation Of Criteria For Renal Response In Patients With Multiple Myeloma (MM) Who Present With Severe Renal Dysfunction

Severe renal impairment (RI) in MM patients is a medical emergency. Immediate antimyeloma therapy and appropriate supportive measures are needed because these patients are at high risk for early death and other complications associated with their renal dysfunction. Antimyeloma therapy may improve renal function in a significant proportion of patients and the choice of treatment may also be guided by the degree of RI. For the evaluation of the recovery of renal function IMWG has proposed specific criteria (Dimopoulos et al, JCO 2010), which are based on changes of calculated GFR. A new formula for the estimation of GFR has been used by nephrologists as a more accurate method of renal function assessment (CKD-EPI formula). In order to evaluate the currently available IMWG criteria, by using the new CKD-EPI formula, we assessed renal response in patients with newly diagnosed MM who presented with severe RI. We also evaluated simplified criteria for renal response and compared patient outcomes with the IMWG criteria. We analyzed the outcomes of 105 consecutive patients who presented with severe RI (eGFR <30 ml/min/1.73m²) from 1995 to 2012. GFR was calculated using two different equations: the MDRD and the CKD-EPI. Per IMWG criteria, renal response was defined as complete (CRrenal, when GFR ≥60 ml/min), partial response (PRrenal, when GFR from <15 ml/min to 30-59 ml/min), or minor (MRrenal, with GFR increase either from <15 ml/min to 15-29 ml/min or from 15-29 ml/min to 30-59 ml/min). We also applied simplified criteria in which patients who presented with stage 5 RI (eGFR<15 ml/min or on dialysis) should double their eGFR and improve to at least stage 4 RI (eGFR 15-29 ml/min) or become independent of dialysis and patients with stage 4, increase their eGFR by at least 50% and improve to at least stage 3 (eGFR 30-59 ml/min).

Most patients (68%) were >65 years of age; 36% were >75 years, while 92% had ISS-3 disease. Primary therapy with bortezomib-based regimens was given in 38% of patients, 43% received IMiD-based therapy (34% thalidomide- and 9% lenalidomide-based) and 19% high dose dexamethasone and conventional chemotherapy (CC) regimens. When GFR was calculated by the MDRD formula then 51% had stage 4 and 49% had stage 5 RI, while by the CKD-EPI formula, 49% had stage 4 and 51% stage 5 RI. Thus, RI stage change between stage 4 & 5 occurred in only 2% of patients with the use of CKD-EPI vs. MDRD equation. According to the IMWG criteria, with GFR calculated by the MDRD formula, 36 (34%) patients achieved CRrenal, 8 (7.5%) PRrenal and 33 (31%) MRrenal. When GFR was calculated by the CKD-EPI formula, then 35 (33%) patients achieved a CRrenal, 8 (7.5%) PRrenal and 34 (32%) MRrenal; only in 3 patients (3%) there was a discrepancy in the quality of renal response between the two equations. Major renal response (CR+PRrenal) was more frequent with bortezomib (57.5% vs. 34% for IMiDs vs. 26% for high dose Dexa+CC, p=0.034). When we applied the proposed simplified renal response criteria, then 47 (45%) patients were considered responders; responses were more frequent in patients treated with bortezomib (62.5% vs. 35% for IMiDs vs. 32% for high dose Dexa+CC, p=0.016). The median survival for all patients who presented with severe RI was 31 months (95% CI 16-46). Early death (<2 months from initiation of therapy) occurred in 15 (14%) patients; in only 3% of patients ≤65 years vs. 20% of patients >65 years (p=0.022). The median survival of patients who presented with stage 4 vs. stage 5 RI was similar (31 vs. 38 months, p=0.230). For patients who survived at least 2 months, the median survival of the patients who achieved ≥PRrenal was 53 months (by MDRD and CKD-EPI) vs. 43 months for patients who had minor renal response vs. 42 months for patients who did not have a renal response, by the IMWG criteria. Among patients who survived at least 2 months, median survival of the responders according to the proposed simplified renal response criteria was 53 vs. 44 of the non responders (p=0.3). There was no difference in the performance of either criteria for overall survival, risk of death at 6 or 12 months, with either of the formulas for eGFR calculation.

We conclude that in unselected MM patients with severe RI, the criteria for the improvement of renal function can be simplified without any significant change in their prognostic significance. The GFR calculated by the CKD-EPI can also be used for the assessment of renal response in patients with MM.