Novel approaches for reducing free light chains in patients with myeloma kidney

Myeloma kidney is a tubulointerstitial pathology that accounts for approximately 80-90% of severe acute kidney injury in patients with multiple myeloma. Unless there is rapid intervention, progressive irreversible damage from interstitial fibrosis and tubular atrophy occurs. Work over the past decade has demonstrated that an early sustained reduction in serum concentrations of pathogenic monoclonal free light chains (FLCs) leads to improved renal recovery rates. In turn, an early improvement in renal function is associated with improved patient survival. An early reduction in FLC levels should therefore become standard of care, although the optimum mechanisms to achieve this depletion of FLCs remain to be determined. To provide a coordinated, cross-disciplinary approach to research in this disease, the International Kidney and Monoclonal Gammopathy Research Group was formed. In this Review, we address the current state of knowledge in the management of myeloma kidney.     

Monitoring serum free light chains in patients with multiple myeloma who achieved negative immunofixation after allogeneic stem cell transplantation

Monitoring of serum free immunoglobulin light chains (FLC) in 26 myeloma patients who achieved immunofixation negativity after allografting showed a decrease of FLC at a median of 128 days before immunofixation negativity. In patients who subsequently relapsed, a 25% increase of FLC was observed at a median of 98 days before immunofixation positivity.     

An upsurge of the serum free light chains as a possible missing link in tumour lysis syndrome in multiple myeloma

Multiple myeloma (MM) is a slow-growing malignancy characterized by a low proliferation rate of plasma cells and a relatively rare incidence of tumour lysis syndrome (TLS). Three myeloma patients developed TLS following cytotoxic therapy (two after radiation treatment) that was associated with an abrupt increase of serum free light chains (FLC). All three patients demonstrated extramedullary plasmacytomas that exhibited aggressive features compared to the original myeloma. The findings suggested that an abrupt liberation (rather than slow secretion) of FLC from myeloma cells may trigger a fulminant cast nephropathy and present an unrecognized risk factor and potentially aggravating component of TLS.     

Uncommon combination of multiple myeloma in three patients

The authors describe uncommon combinations of multiple myeloma in three men aged 83, 63 and 55 years. In patient no. 1 both diseases--pernicious anaemia and multiple myeloma IgG-kappa were detected simultaneously. In patient no. 2 Crohn's disease preceded multiple myeloma IgA-lambda by more than 30 years. In patient no. 3 Gaucher's disease preceded multiple myeloma with paraproteinaemia IgA-lambda and IgG-kappa by more than 10 years. The diagnosis was facilitated by examination of the bone marrow, immunochemical examination of serum and urine and X-ray examination of the skeleton. In all patients the development of the myeloma had an adverse effect on the general course of the disease and despite treatment it soon proved fatal. In the discussion views on the possible causal associations between these diseases are discussed.     

Clinical usefulness of free light chain concentration as a tumor marker in multiple myeloma

Monoclonal immunoglobulin, as a marker for monoclonal gammopathy, is evaluated by protein electrophoresis (PEP) and immunofixation electrophoresis (IFE). However, PEP and IFE are not satisfactory in sensitivity, objectivity, and facility. Recently, a highly sensitive, automated immunoassay for measurement of free light chain (FLC) concentrations in serum and urine has been developed for the identification and monitoring of patients with monoclonal gammopathy. To explore the clinical usefulness of measurement of FLC concentrations, we measured the and FLC concentrations and calculated the / FLC ratios for three groups [multiple myeloma (MM), other diseases, and control] and compared the results of the FLC assay with the results of PEP or IFE. The concentrations of serum and FLCs and the / FLC ratios for the MM group and non-MM groups were distinct. In the MM group, some sera and urine samples had no evidence of M protein on PEP and IFE, but FLC assay showed abnormal concentrations of FLCs and abnormal / FLC ratios in most cases. As compared with the PEP, the / FLC ratio revealed higher sensitivity in all diagnostic ranges with different cutoff values. Particularly, when the cutoff value 2.0 for / FLC ratio was used, specificity and positive predictive value were largely improved than when the cutoff values 1.2 and 1.5 were used. These findings indicated that FLC assay enables to detect myeloma patients with very low M protein due to early stage or after therapy and to distinguish patients with monoclonal increase of FLC from patients with polyclonal increase of FLC due to other conditions, particularly using / FLC ratio 0.3–2.0 as a diagnostic range. Despite some technical limitations of the assay, the incorporation of / FLC ratios with FLC concentrations is useful in the detection of M protein, particularly with negative serum or urine IFE results, and differentiation of monoclonal gammopathies from patients with polyclonal increase in FLC due to other conditions.     

Serial measurement of free light chain detects poor response to therapy early in three patients with multiple myeloma who have measurable M-proteins

Free light chain (FLC) assays are important in the diagnosis and monitoring of patients with multiple myeloma (MM). Serum FLC concentrations also correlate with disease course in the majority of MM patients and have been incorporated into the new response criteria. Although baseline values of FLC are prognostic in newly diagnosed MM, serial measurement of serum FLC does not appear to be of greater value in patients who have measurable M-proteins by electrophoresis. We examined the kinetics of serum FLC in six patients with newly diagnosed MM during treatment with high-dose dexamethasone (HD-DEX) and bortezomib and dexamethasone. In some cases, the involved serum FLC increased in the latter part of each chemotherapy cycle before the start of the next cycle, especially in HD-DEX, suggesting that the response to these agents may be insufficient for induction therapy for MM. Earlier disease assessment by serum FLC assays may be of value in detecting poorly responding patients who require alternative forms of therapy.     

多发性骨髓瘤细胞遗传学三种检测方法的比较

SH检测18例MM患者检出12例异常(66.7%),其中1q21阳性4例(22.2%),RB1阳性5例(27.8%),IGH阳性8例(44.4%).结论 FISH技术能显著提高MM的染色体和基因组异常检出率.     

Staging systems for multiple myeloma: a comparison

In 152 patients with multiple myeloma who had been treated with cytostatic agents the prognostic value of seven staging systems was evaluated: Carbone et al (1967); Acute Leukemia Group B (ALGB) and Eastern Cooperative Oncology Group (ECOG) (Costa et al, 1973); Southeastern Cancer Study Group (SECSG) (1975); Durie & Salmon (1975); Alexanian et al (1975); Merlini et al (1980); British Medical Research Council (1980). The staging systems of the ALGB (Costa et al, 1973) and SECSG (1975), both dividing patients into 'good risk' and 'poor risk' groups, showed significantly different survival curves. Nevertheless, despite statistical significance the observed differences were rather small. In the systems of Carbone et al (1967), Merlini et al (1980), Alexanian et al (1975) and Durie & Salmon (1975) some of the differences in the survival curves were statistically significant while others were not. Our data best fitted into the British Medical Research Council (1980) staging system, the survival curves of all three stages showing significant differences, with median survival time dropping from 83 months in stage A to 52 months in stage B and 26 months in stage C. Nevertheless, none of those systems was clearly superior to single risk factors, especially creatinine and haemoglobin.     

Extramedullary relapse of multiple myeloma associated with a shift in secretion from intact immunoglobulin to light chains

Biological therapies in multiple myeloma have heralded a new and exciting era for treatment to combat this disease. However the evolutionary pressures that these drugs place on the microenvironment has resulted in a change in the biological behaviour of this malignancy and novel manifestations of relapsed disease. This is illustrated in our series of three patients showing fulminant relapse of disease with plasmablastic features, an extramedullary predilection and a shift in secretion from intact immunoglobulin to free light chains only.     

Prognostic value of serum free light chain ratio at diagnosis in multiple myeloma

The prognostic value of baseline serum free light chain ratio (sFLCR) was investigated in 94 multiple myeloma (MM) patients. sFLCR was calculated as kappa/lambda or lambda/kappa, depending on the patients' dominating monoclonal light chain. Median baseline sFLCR was 3.57 in kappa-MM patients, 45.09 in lambda-MM. 'High' sFLCR (> or = the observed median value for kappa- and lambda-MM respectively) correlated with elevated serum creatinine and lactate dehydrogenase, extensive marrow infiltration and light chain type MM. The 5-year disease-specific survival was 82% and 30% in patients with sFLCR lower than and equal or greater than the median, respectively (P = 0.0001). sFLCR was an independent prognostic factor.     

Measurement of free kappa and lambda chains in serum and the significance of their ratio in patients with multiple myeloma

An inhibition enzyme-linked immunoassay technique using commercially available antibodies has been developed for the quantitation of both kappa and lambda light chains in the serum of patients with B-cell malignancies. Assay conditions were selected to enable measurement of free light chains in the concentration range between 0.1 and 20 mg/l. The normal range for free lambda chains in serum was found to be 0.4-4.2 mg/l and for free kappa chains it was 1.6-15.2 mg/l. At diagnosis the serum of most patients with multiple myeloma contained increased levels of the malignant free light chain and in some cases there was also elevation of the non-malignant light chain. The absolute level of the malignant light chain at diagnosis did not correlate with survival nor with laboratory parameters such as IgM or creatinine. A correlation with beta 2 M and serum paraprotein levels was evident only in cases of IgA myeloma. Although the absolute level of free serum light chain had no value as a prognostic indicator, the ratio of kappa:lambda chains closely followed the clinical assessment of disease status, being near the normal range (1.2-9.1) in plateau phase or stable disease. During periods of progressive disease this ratio ranged from 19 to 460 (n = 14) in patients with kappa myeloma, and 0.0013-0.14 (n = 9) in patients with lambda myeloma. Determination of the ratio of free light chains in the serum may allow effective monitoring and earlier warning of disease progression in patients with multiple myeloma.     

不同年龄组多发性骨髓瘤患者的骨损表现

目的：观察不同年龄组多发性骨髓瘤患者的骨损临床表现以及预后.方法：将本院70例多发性骨髓瘤患者按年龄分成＜65岁和≥65岁2组，观察骨损表现形式（溶骨性损害、广泛的骨质疏松）、发生部位（颅骨、颈椎、胸肋骨、腰骶椎、骨盆、四肢长骨）、高钙血症和骨损的关系以及相关预后、骨损和血β2-微球蛋白（β2-MG）的关系.结果：≥65岁组溶骨性损害发生率要高于＜65岁组.前者溶骨性损害常见部位是颅骨和胸肋骨;后者常见部位是腰椎和胸肋骨.并发高钙血症的老年患者预后可能较差.＜65岁组β2-MG异常患者中，非骨痛起病者预后好于骨痛起病者.结论：骨损表现及其相关预后指标在不同年龄组多发性骨髓瘤患者中意义不同。     

Medium cut‐off dialyzers in a large population of hemodialysis patients in Colombia: COREXH registry

Expanded hemodialysis (HDx) provides increased clearance of conventional and large middle molecules through innovative medium cutoff (MCO) membranes. However, there is a paucity of real‐world data regarding the benefits and safety of HDx. This large observational study evaluated outcomes among patients in Colombia undergoing HDx at a extended dialysis clinical services provider. This was a prospective single cohort study of prevalent patients who were treated with HDx; baseline information was collected from the most recent data before patients were started on HDx. Patients were followed prospectively for 1 year for changes in serum albumin and other laboratory parameters compared with the baseline. Survival, hospitalization and safety were assessed from the start of HDx. A total of 1000 patients were invited to enroll; 992 patients met the inclusion criteria for data analysis and 638 patients completed the year of follow‐up. Seventy‐four (8%) patients died during 866 patient‐years (PY) of follow‐up; the mortality rate was 8.54 deaths/100 PY (95% confidence interval [CI], 6.8‐10.7). There were 673 hospitalization events with a rate of 0.79 events/PY (95% CI, 0.73‐0.85) with 6.91 hospital days/PY (95% CI, 6.74‐7.09). The observed variability from baseline and maximum average change in mean serum albumin levels were ?1.8% and ?3.5%, respectively. No adverse events were related to the MCO membrane. HDx using an MCO membrane maintains stable serum albumin levels and is safe in terms of nonoccurrence of dialyzer related adverse events.     

Differences in the distribution of cytogenetic subtypes between multiple myeloma patients with and without a family history of monoclonal gammopathy and multiple myeloma

We previously reported an increased risk of monoclonal gammopathy of undetermined significance (MGUS) in first‐degree relatives of MGUS and multiple myeloma patients. Here, we examine whether primary cytogenetic categories of myeloma differ between patients with and without a family history of MGUS or myeloma. We studied 201 myeloma patients with available data on family history and molecular cytogenetic classification. Myeloma with trisomies was more common in probands who had an affected first‐degree relative with MGUS or myeloma compared with those without a family history (46.9% vs. 33.5%, P = 0.125); however, the difference was not statistically significant. Additional studies on the cytogenetic types of myeloma associated with familial tendency are needed.     

Effects of paraprotein heavy and light chain types and free light chain load on survival in myeloma: an analysis of patients receiving conventional-dose chemotherapy in Medical Research Council UK multiple myeloma trials

While investigating 2592 patients enrolled in multicenter myeloma trials, we found light chain-only (LCO) patients had worse median survival times (1.9 years) than patients with IgA and IgG paraproteins (2.3 and 2.5 years, respectively) (P < .001). However, IgA and IgG patients with levels of LC excretion similar to those of LCO patients also had poor survival times because of renal failure, resulting in worse survival during induction therapy and at relapse with no difference in progression-free survival between LCO and IgG patients. LC excretion was higher for lambda than for kappa types, but there was no difference in survival between the 2 LC types when stratified for level of LC excretion, indicating that care of renal function is vital to improving the survival of any patient with LC excretion. LCO patients were younger (P = .001), had worse performance status (P = .001), and had more lytic lesions (P < .001), perhaps reflecting late and missed diagnoses in younger and older LCO patients, respectively. No differences were observed between IgA and IgG patients in presentation characteristics, response, or survival from disease progression. The worse survival of IgA patients was attributed to shorter progression-free survival (median, 1.2 vs 1.6 years; P < .001), which is important for maintenance therapy.