Effect factors related to a high probability of hemodialysis independence in newly diagnosed multiple myeloma patients requiring hemodialysis

Abstract Background Renal failure is a severe complication of symptomatic myeloma, related to higher mortality. Recovery from dialysis dependence can lead to enormous survival benefits. We investigated the effect factors for probability of dialysis independence. Methods Retrospective data on 45 newly diagnosed MM (NDMM) patients with serious renal impairment and requiring hemodialysis were analyzed. The statistical methods including logistic regression analysis, Kaplan‐Meier survival curves, the log‐rank test and the Cox proportional hazards model for survival analysis were used in our study. Results Twenty‐two of the 45 patients, who were on hemodialysis at diagnosis, became dialysis independence. In the logistic regression analysis, serum level of β2‐microglobulin, kidney disease history, involved free light chain, and achieving at least VGPR were significantly associated with reversibility from dialysis dependence. In addition, achieving hemodialysis discontinuation was related to better survival. The multivariate analyses demonstrated that reversibility from dialysis dependence, proteinuria < 3.5 g/24 h, and achieving at least VGPR were significantly associated with OS among NDMM patients requiring hemodialysis. Conclusion Lower serum level of β2‐microglobulin and lower level of free light chain at diagnosis, achieving at least VGPR, and shorter kidney disease history are related to a high probability of dialysis independence in NDMM patients with serious renal failure requiring dialysis.

mortality, because the majority of patients requiring dialysis are unable to achieve renal recovery. 2,5,6 Due to the little of clinical trials conducted in severe RF requiring dialysis in MM, the effect factors of reversal of renal failure and recovery from hemodialysis dependenceareunknown.
Inthecurrentstudy,weexaminedclinicalfeaturesandresponse to therapy in newly diagnosed MM (NDMM) patients with severe RF requiring dialysis who received initial therapy including novel agents to evaluate the promising factors of recovery from dialysis dependence and investigate the prognostic impact of dialysis independence for survival results.  Table 1.

| Patients and methods
Renal function was assessed using the estimated glomerular filtration rate (eGFR), which was calculated by the simplified Modification of Diet in Renal Disease (MDRD) formula. 7 Renal failure requiring hemodialysis was defined as an eGFR < 15 mL/min/1.73 m 2 and on hemodialysis at initial diagnosis. In order to analyze data in our study, the patients were classified depending on renal function at diagnosis and response treatment: group 1: on dialysis at diagnosis improved to dialysis independence after therapy and group 2: on dialysis at diagnosis and remained dialysis dependence after treatment.
The degree of recovery of renal function was estimated on the basisoftheInternationalMyelomaWorkingGroup(IMWG)criteria: 2,3 AsustainedimprovementofbaselineeGFRto≥60mL/min/1.73m 2 was defined as renal complete response (CRrenal), a sustained improvement of baseline eGFR from < 15 to 30-59 mL/min/1.73 m 2 as renal partial response (PRrenal) and a sustained improvement of baseline eGFR of <15 mL/min/1.73 m 2 to 15-29 mL/min/1.73 m 2 or if baseline eGFR was 15-29 mL/min/1.73 m 2 , improvement to 30-59 mL/min/1.73 m 2 as renal minor response (MRrenal). Treatment response was evaluated at the date of termination of each treatment according to the standard IMWG criteria. 8 From the first day of treatment until the day of first confirmative, renal response (at least MRrenal) was estimated as time to renal response. From the first day of treatment until the day of first confirmative, maximum renal response was estimated as time to major renal response. From the first time of the discovery of renal insufficiency symptoms until the time ofinitialtreatmentofmyelomawasdefinedaskidneydiseasehistory.
The time from diagnosis until date of death or date of last followupwasestimatedasoverallsurvival(OS).Thetimefromtreatment initiation until date of progression, death, or last follow-up was estimatedasprogression-freesurvival(PFS).

| Response to chemotherapy
In the present study, at least very good partial response (VGPR) rate was 46.88% in patients received bortezomib-based regimens, and 23.08% TA B L E 1 Clinical and laboratory characteristics of 45 NDMM patients with severe renal failure requiring dialysis based on dialysis discontinuation or dependence after therapy  Figure 1C).

Dialysis dependence after therapy (n = 23) P-value
Then we analyzed for factors that could be related to probability of dialysis discontinuation among NDMM patients with serious renal impairment requiring hemodialysis (Table 1). In the univari-  (Table 3).
Upon categorizations were on the basis of renal function at diagnosis and response to treatment. After comparison, the median

Multiple myeloma (MM) is a malignancy of malignant plasma cells
and occurs renal insufficiency in 20%-50% of patients. 5 F I G U R E 2 Kaplan-Meierplotcomparing(A)overallsurvival and (B) progression-free survival between groups 1 and 2 based on their renal function at diagnosis and response to therapy: group 1, on dialysis at diagnosis improved to dialysis discontinuation after therapy; group 2, on dialysis at diagnosis and remained dialysis dependence after therapy improved at least VGPR rate distinctly. In addition, achieving at least VGPR (OR 0.394, 95% CI 0.179-0.870, P = .021) was significantly related to reversibility from dialysis dependence. In summary, bortezomib-based regimens were strongly recommended for treatment of MM patients requiring dialysis.
In the meanwhile, the other study from the group of Dimopoulos has recently investigated the outcomes of 52 NDMM patients requiring dialysis. 12 Early mortality (within 2 months from start of therapy) was 16%, in most cases because of infectious complications. In our study, early death occurred in 4 (8.89%) cases on account of infection and heart failure. Early mortality owing to MM with severe renal failure is inevitable, but it may represent a serious confounding effect for the purpose of the planned analysis. and tubular function in adults. 28 However, our study first found the role of β 2 M in the reversal of renal failure and recovery from dialysis dependence.
ItisknowntousthatserumFLCassaysindiagnosticscreening panels were recommended currently by International Myeloma Working Group (IMWG). 29 In addition, Thomas et al illustrated that serum free light chains should be used to evaluate response in light chain multiple myeloma. 30 However, our study found the prognostic value of involved free light chain which was significantly related to reversibility from dialysis dependence. This is possibly associated with the monoclonal light chains on basement membranes of the glomeruli and/or the renal tubule which cause the reason of MM patients with renal impairment. 3,31 In the meantime, Dimopoulos et al suggest that very high levels of FLCs were associated with a lower probability of RF recovery or dialysis discontinuation. 12,13 Inaconclusion,ourdataindicatethattheshorterkidneydisease history, lower serum level of β2-microglobulin and free light chain, achieving at least VGPR is related to a high probability of hemodialysis discontinuation and bortezomib-based regimens were strongly recommended for treatment of MM patients requiring dialysis. In addition, recovery from dialysis dependence, proteinuria <3.5 g/24 h, and achieving at least VGPR can lead to enormous survival benefits in NDMM patients with serious renal impairment requiring hemodialysis. Our study offered instructions for treatment and evaluated prognosis of NDMM patients with severe renal failure requiring dialysis.

ACK N OWLED G M ENTS
This work was supported by the National Natural Science