Background: The detection of monoclonal free light chains (FLCs) is an important diagnostic aid for a variety of monoclonal gammopathies and is especially important in light-chain diseases, such as light-chain myeloma, primary systemic amyloidosis, and light-chain-deposition disease. These diseases are more prevalent in the elderly, and assays to detect and quantify abnormal amounts of FLCs require reference intervals that include elderly donors. Methods: We used an automated immunoassay for FLCs and sera from a population 21–90 years of age. We used the calculated reference and diagnostic intervals to compare FLC results with those obtained by immunofixation (IFE) to detect low concentrations of monoclonal κ and λ FLCs in the sera of patients with monoclonal gammopathies. Results: Serum κ and λ FLCs increased with population age, with an apparent change for those >80 years. This trend was lost when the FLC concentration was normalized to cystatin C concentration. The ratio of κ FLC to λ FLC (FLC K/L) did not exhibit an age-dependent trend. The diagnostic interval for FLC K/L was 0.26–1.65. The 95% reference interval for κ FLC was 3.3–19.4 mg/L, and that for λ FLC was 5.7–26.3 mg/L. Detection and quantification of monoclonal FLCs by nephelometry were more sensitive than IFE in serum samples from patients with primary systemic amyloidosis and light-chain-deposition disease. Conclusions: Reference and diagnostic intervals for serum FLCs have been developed for use with a new, automated immunoassay that makes the detection and quantification of monoclonal FLCs easier and more sensitive than with current methods. The serum FLC assay complements IFE and allows quantification of FLCs in light-chain-disease patients who have no detectable serum or urine M-spike.

Background: Bence Jones proteins or monoclonal immunoglobulin κ and λ free light chains (FLCs) are important markers for identifying and monitoring many patients with B-cell tumors. Automated immunoassays that measure FLCs in urine and serum have considerable clinical potential. Methods: Sheep antibodies, specific for FLCs, were prepared by immunization with pure κ and λ molecules and then adsorbed extensively against whole immunoglobulins. The antibodies were conjugated onto latex particles and used to assay κ and λ FLCs on the Beckman IMMAGETM protein analyzer. Results: The unconjugated antibodies showed minimal cross-reactivity with intact immunoglobulins or other proteins. With latex-conjugated antibodies, κ and λ FLCs could be measured in normal sera and most normal urine samples. Patients with multiple myeloma had increased concentrations of the relevant serum FLC, whereas both FLCs were increased in the sera of patients with systemic lupus erythematosus. Conclusions: We developed sensitive, automated immunoassays for κ and λ FLC measurements in serum and urine that should facilitate the assessment of patients with light chain abnormalities.

Background In multiple myeloma, severe acute kidney injury due to myeloma cast nephropathy is caused by pathogenic free light chain immunoglobulin in serum. High cutoff haemodialysis (HCO-HD) can remove large quantities of free light chain immunoglobulin from serum, but its effect on clinical outcomes is uncertain. We therefore aimed to assess whether HCO-HD could increase the frequency of renal recovery in patients with de novo multiple myeloma, severe acute kidney injury, and myeloma cast nephropathy relative to treatment with standard high-flux haemodialysis (HF-HD). MethodsIn this open-label, phase 2, multicentre, randomised controlled trial (EuLITE), we recruited patients with newly diagnosed multiple myeloma, biopsy-confirmed cast nephropathy, and acute kidney injury that required dialysis from renal services in 16 hospitals in the UK and Germany. Patients were randomly assigned (1:1) by random number generation to receive intensive HCO-HD (in sessions lasting 6-8 h) or standard high-flux haemodialysis (HF-HD) and they were stratified by age and centre. Patients and the medical staff treating them were not masked to treatment allocation. Patients received bortezomib, doxorubicin, and dexamethasone chemotherapy, and were then followed up for 2 years. The primary outcome was independence from dialysis at 90 days after random allocation to groups, which was assessed in an intention-to-treat population. The trial has completed follow-up, and is registered at the ISRCTN registry, number ISRCTN45967602.Findings Between June 7, 2008, and Sept 18, 2013, we recruited 90 patients, of whom 43 (48%) were randomly assigned to receive HCO-HD and 47 (52%) were randomly assigned to receive HF-HD. All 90 patients were included in the analysis of the primary outcome. One (2%) patient from the HF-HD group withdrew consent before receiving treatment. During treatment, nine (21%) patients from the HCO-HD group and two (4%) patients in the HF-HD group discontinued trial treatment. After 90 days, 24 (56%) patients in the HCO-HD group and 24 (51%) patients in the HF-HD group were independent from dialysis (relative risk 1.09, 95% CI 0.74-1.61; p=0.81). During the 2year follow-up, 98 serious adverse events were reported in the HCO-HD group and 82 serious adverse events were reported in the HF-HD group. The most common serious adverse events were infections and adverse events related to the cardiovascular and thrombotic and musculoskeletal systems. During the first 90 days, 26 infections were reported in the HCO-HD group and 13 infections were reported in the HF-HD group, including 14 lung infections in the HCO-HD group and three lung infections in the HF-HD group.Interpretation In this phase 2 study, HCO-HD did not improve clinical outcomes for patients with de novo multiple myeloma and myeloma cast nephropathy who required haemodialysis for acute kidney injury and who received a bortezomib-based chemotherapy regimen relative to those receiving HF-HD. These results do not support proceeding to a phase 3 study for HCO-HD in these pa...

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.