ALBERT

Description: Irreversible acute renal failure (ARF) is associated with significantly increased morbidity and mortality in multiple myeloma (MM) patients. 10% of MM patients require dialysis support and of these 80% remain dialysis dependent. Cast nephropathy from excess serum free light chains (sFLC) accounts for approximately 70% of dialysis-dependent ARF in this setting. We recently reported preliminary studies demonstrating high cut-off hemodialysis (HCO-HD) as a novel method for FLC removal in MM patients (JASN, March, 2007). The purpose of this subsequent study was to two fold: Firstly, to determine the safety and effectiveness of HCO-HD to result in sustained reductions in sFLC concentrations in cast nephropathy patients. Secondly, to compare renal recovery rates in patients treated with FLC removal HD with a case-matched historical control population. Methods: 25 patients with dialysis dependent ARF and MM were assessed for inclusion. 3 patients were not suitable for renal biopsy. Renal biopsies demonstrated cast nephropathy in 20 of 22 patients. Only 18 patients commenced treatment as 2 were not suitable for chemotherapy. Thalidomide/dexamethasone regimes were used for patients with de novo MM and bortezomib/doxorubicin/dexamethasone for relapsing patients. FLC removal HD was undertaken using the Gambro HCO 1100™, for extended periods of 8 hours/day. Extended dialysis was supported by replacement of albumin, magnesium and calcium by protocol. Historical age matched control patients received standard high flux dialysis (n=18). Results: There were no complications related to FLC removal HD. However, 6 of the 18 patients developed infections requiring intervention. The percentage reductions, in sFLC concentrations, achieved by days 5, 12 and 21 were 54 (0–71), 66 (0–88) and 57 (0–88), respectively. There were no significant differences in presenting serum creatinine, sFLC type or concentration between the treatment and control groups. 13 of 18 patients (72%) in the treatment group became independent of dialysis versus 2 of 18 controls (11%, P

Description: Abstract 3949 Acute kidney injury (AKI) is a common but serious sequela of multiple myeloma. Recently, the International Myeloma Working Group (IMWG) introduced a new renal response criteria with complete (CRenal), partial (PRenal) and minimal (MRenal) responses. This study compares the IMWG criteria with other models to determine their correlation with overall survival (OS). Patients with multiple myeloma and AKI were identified from centers around the world. OS was calculated from the day of AKI. Renal function was assessed by estimated glomerular filtration rate (eGFR) via MDRD method. Hematologic response was the best achieved as assessed by International Uniform Response Criteria for Multiple Myeloma. Only patients with peak serum creatinine (Scr) ≥ 2.0 mg/dl were included. Separate analyses were performed on the newly diagnosed (ND) versus previously treated (PT) patients. A total of 158 patients were collected from centers in United States, United Kingdom, France and Austria. Fourteen patients were excluded for having peak Scr 〈 2.0 mg/dl and one for repeated episodes of AKI. Median age of the 143 patients was 64 (34 – 87) years, 58.7% were male and 115 were newly diagnosed. Median Scr was 5.1 (2.0 to 18.6) mg/dl and median eGFR was 10.6 (2.8 – 36.5) ml/min/1.72 m2. Dialysis was required in 49.3%, and 72.9% were dialysis independent at the end of the study. By IMWG criteria, median OS ranged between 6.0 months (m) in PT patients with no renal response (NRenal) to 23.7m in patients with CRenal, p = 0.34 (Table 1). In ND patients, OS was 31.4m in NRenal vs 73.8m in CRenal (p = 0.08). However, OS was similar between PRenal and CRenal, p = 0.70 (Figure 1). If only patients with a hematologic PR or better were analyzed, the OS range was 6.0m in NRenal to 23.7m in CRenal in PT patients (p = 0.85) and 36.6m in NRenal to 73.8m in CRenal in ND patients, p = 0.73.Table 1.Previously TreatedNMedian SurvivalNMedian Survival (〉PR)    CRenal323.7 m323.7 m    PRenal413.1 m312.8 m    MRenal512.0 m119.2 m    NRenal166.0 m56.0 m    p-value0.340.85Newly Diagnosed    CRenal2273.8 m2273.8 m    PRenal27Not Reached23Not Reached    MRenal2265.6 m1965.6 m    NRenal4331.4 m2136.6 m    p-value0.080.73Figure 1.Overall survival (OS) of 115 patients evaluated by the IMWG renal response criteria. OS was not significantly different by Log-Rank test between patients with CRenal and NRenal, p = 0.08.Figure 1. Overall survival (OS) of 115 patients evaluated by the IMWG renal response criteria. OS was not significantly different by Log-Rank test between patients with CRenal and NRenal, p = 0.08. The best model tested was one that defined renal response (RR) as regaining or maintaining dialysis independence and no response (NR) as dialysis dependence. RR was associated with a superior survival for both PT patients (13.5 m vs 6.0m (NR), p = 0.03) and ND patients (73.8m vs 20.1m (NR), p 〈 0.001). RR increased with the depth of hematologic response, p = 0.04. RR occurred in 75% of the PT patients with hematologic PR or better and 66.7% in those with less than PR, p = 0.64. In ND patients, RR occurred in 85.7% of those with PR or better and 54.6% of those with PR or less, p = 0.003. This may explain the differences in OS when hematologic response was considered. In PT patients with hematologic PR or better, renal response did not improve OS (21m vs 6m, p = 0.28) but it remained beneficial in the ND patients (73.8m vs 35.1m, p = 0.04, Figure 2). Renal response was not significantly associated with OS for any patient with hematologic response that was VGPR or better. In a multivariate analysis, RR (p = 0.001), ND (p

Description: Abstract 3974 Background: An early reduction in serum free light chains (FLC) improves outcomes for patients with myeloma kidney. The purpose of this study was to assess how high cut-off (HCO) dialysers are being used internationally to achieve this target. Methods: Data was collected for 54 patients, from 18 centers in 10 countries. Clinical presentation and treatment parameters, including details of removal of FLCs with high cut off hemodialysis and chemotherapy treatment, were captured using a web-based collection database. Demographics: All patients were Caucasian, median age of 65 years (range 43–81). Median biochemistry at presentation was: GFR of 8mls/min/1.73m2 (1–27). creatinine 633.5μmol (168–2263); calcium 2.3mmol/L (0.91–3.83); albumin 34g/L (14–46) and β2M 9.45mg/L (0–55.7). Baseline monoclonal κ and λ FLCs levels were: 5070mg/L (range 2250–20200) and 4200mg/L (range 300–13300), respectively. Of the patients who received a renal biopsy, 81% had myeloma kidney as their primary diagnosis. For initial chemotherapy prescriptions: 78% received bortezomib and 34% received thalidomide. 68.75% of the patients were treated with the Theralite HCO dialyzer; the other 31.25% received treatment with the HCO1100 dialyzer. There was a total of 626 HCO dialysis sessions recorded, with each patient receiving on average 13 session each (median, range 3–35) treatments per patient. Of the 54 patients, only 3 were treated with HDF. Results: 73.2% of patients demonstrated a decreased serum FLC level over the course of treatment, with 86.7% of these patients demonstrated decreased levels by day 12. The median FLC reduction achieved was 72.96% (15.09–99.62%) by day 12 and 93.03% (40.23–99.96%) by the last dialysis treatment. There was no difference in the percentage FLC reduction achieved between bortezomib (median: total 94.09%, day 12 79.14%) and thalidomide (median: total 77.65%, day 12 66.51%) treatment groups (total p=0.179, day 12 p=0.300). FLC removal was significantly increased in patients receiving Theralite treatment over those receiving HCO1100 at both day 12 (p=0.030) and by the end of treatment (p=0.031) Dialysis independence occurred in 68.2% of patients, median time 32 days (10–249). Patients who became independent of dialysis had significantly greater reductions in serum FLC by day 12 (p=0.032). No significant adverse events related to the study device were reported. Conclusion: Reducing FLC in patients with myeloma kidney is associated with increased levels of dialysis independence. This study adds further evidence that a combination of chemotherapy and FLC removal by HCO hemodialysis improves patient outcomes following acute kidney injury secondary to multiple myeloma. Disclosures: Hutchison: The Binding Site: Honoraria. Bevins:The Binding Site Group Ltd: Employment. Mead:The Binding Site Group Ltd: Employment.

Description: Of newly diagnosed patients with multiple myeloma, 12–20% present with acute renal failure caused by monoclonal free light chains (FLCs). Plasma exchange can reduce the pre-renal load of FLCs but randomised controlled trials have shown no clinical benefit. This disappointing outcome can be explained by the low efficiency of the procedure. A model of FLC production, distribution and metabolism in myeloma patients indicated that plasma exchange might remove only 5–10% of the total body FLCs over a three-week period. To improve removal rates we have used prolonged hemodialysis with a protein leaking dialyser. In-vitro studies indicated that the Gambro HCO 1100 dialyser, with pores of 100kDa, was the most efficient of seven tested. This dialyser was used in 10 patients with myeloma and renal failure, as part of their hemodialysis treatment, to assess FLC removal efficiency. Three of the patients were studied at initial clinical presentation with biopsy proven FLC cast nephropathy. Routine chemotherapy was used, together with prolonged daily hemodialysis and multiple measurements of FLCs in serum, urine and dialysate fluid. Serum FLCs were reduced by 40 to 70% within one hour then reduction slowed as extravascular re-equilibration occurred. FLC concentrations rebounded on successive days until chemotherapy was effective. 1.5kg of FLCs was removed from one patient over 6 weeks and another became independent of dialysis. Prolonged hemodialysis allowed removal of 5–10 times more FLCs than plasma exchange without attendant clotting problems and removal of many serum proteins (Figure 1). Proof of clinical value will require further studies. Simulations of aFLC removal by plasma exchange versus hemodialysis on the Gambro HCO 1100. Simulations: 1) 100% tumor kill on day one with only reniculoendothetial removal; 2) 10% tumor kill per day reniculoendothetial removal alone; 3) 10% tumor kill per day with plasma exchange (3.5 liters exchange in 1.5 hrs × 6 over 10 days); 4) 10% tumor kill per day with hemodialysis for 4 hours, 3 times a week; 5) 10% tumor kill per day with hemodialysis for 4 hours per day; 6) 10% tumor kill per day with hemodialysis for 12 hours per day; 7) No tumor kill with 8 hours hemodialysis on alternate days 8) No tumor kill with no direct removal. Simulations of aFLC removal by plasma exchange versus hemodialysis on the Gambro HCO 1100. Simulations: 1) 100% tumor kill on day one with only reniculoendothetial removal; 2) 10% tumor kill per day reniculoendothetial removal alone; 3) 10% tumor kill per day with plasma exchange (3.5 liters exchange in 1.5 hrs × 6 over 10 days); 4) 10% tumor kill per day with hemodialysis for 4 hours, 3 times a week; 5) 10% tumor kill per day with hemodialysis for 4 hours per day; 6) 10% tumor kill per day with hemodialysis for 12 hours per day; 7) No tumor kill with 8 hours hemodialysis on alternate days 8) No tumor kill with no direct removal.

Description: Cast nephropathy is the main cause of renal impairment in patients with multiple myeloma (MM). Serum free light chain (sFLC) removal by extended hemodialysis on a protein leaking membrane may aid renal recovery. A patient presenting with MM, high serum FLC concentrations and dialysis dependent acute renal failure was studied. A renal biopsy showed monoclonal kappa FLC cast nephropathy. He was dialysed for 2–8h on daily / alternate days using the Gambro HCO 1100 dialyser. sFLC were measured at frequent intervals in the serum and dialysate fluids. Albumin and urea concentrations were measure pre- and post-dialysis. Over 22 days the patient underwent 14 dialysis sessions with an average sFLC reduction of 38% (15.2–61.8%). A total of 16.5g of kappa was removed in the dialysate fluid with an average concentration of 18.3mg/L (3.3–27.3). Figure 1 demonstrates serum reductions in kappa concentrations pre- and post-dialysis and timing of chemotherapy. The average serum reductions were: albumin 2.1g/L, urea 56% and creatinine 44%. By day 22 the patient was independent of dialysis. Four months later renal function is stable with an eGFR of 35ml/min (Cockcroft-Gault). Further studies are needed to determine whether this method would benefit many patients with acute renal failure and light chain cast nephropathy. Figure Figure

Description: Multiple myeloma is the most frequent monoclonal gammopathy to involve the kidney; however, a growing number of kidney diseases associated with other monoclonal gammopathies are being recognized. Although many histopathologic patterns exist, they are all distinguished by the monoclonal immunoglobulin (or component) deposits. The hematologic disorder in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with multiple myeloma. Unfortunately, due to the limitations of the current diagnostic schema, they are frequently diagnosed as MGUS. Because treatment is not recommended for MGUS, appropriate therapy is commonly withheld. In addition to end-stage renal disease, the persistence of the monoclonal gammopathy is associated with high rates of recurrence after kidney transplantation. Preservation and restoration of kidney function are possible with successful treatment targeting the responsible clone. Achievement of hematologic complete response has been shown to prevent recurrence after kidney transplantation. There is a need for a term that properly conveys the pathologic nature of these diseases. We think the term monoclonal gammopathy of renal significance is most helpful to indicate a causal relationship between the monoclonal gammopathy and the renal damage and because the significance of the monoclonal gammopathy is no longer undetermined.

Description: Elevated serum free light chain (sFLC) concentrations are associated with glomerular and tubulointerstitial disease. We have analyzed a cohort of patients with chronic kidney disease (CKD) to determine the relationship between sFLC and clinical outcomes. 369 patients from the renal clinics at the Queen Elizabeth hospital in Birmingham were followed for a period of 8 years. We reviewed renal outcomes and all cause mortality over this period. sFLC levels were measured on baseline serum samples using a nephelometric immunoassay (The Binding Site Ltd.). The CKD patients had mean sFLC concentrations significantly higher than the normal population (kappa: 77 vs. 8.4mg/L p