Monoclonal Protein Secretion Research Articles

Nonsecretory and Light Chain Escape in Patients With Multiple Myeloma

BackgroundMultiple myeloma (MM) is characterized by the secretion of monoclonal protein by malignant plasma cells in the vast majority of cases. We identified and analyzed patterns of disease relapse and progression associated with disappearance of the paraprotein (“nonsecretory [NS] escape”), or conversion from production of intact Ig molecule to its associated light chain (“LC escape”). Patients and MethodsWe retrospectively reviewed medical records and a database of 791 consecutive patients with symptomatic MM. ResultsTwenty-eight (3.5%) patients had disease evolution associated with either NS (n = 13) or LC (n = 15) escape. The event occurred at a median of 37 months (range, 3-156 months) after the diagnosis of MM, and after a median of 3 chemotherapy regimens (range, 1-8 regimens). Presence of extramedullary disease at progression was detected in 8 (29%) patients. Sensitivity to chemotherapy before and after escape was present in 21 (75%) and 14 (50%) patients, respectively. After a median follow-up of 55 months, 19 (68%) patients died, and progressive MM was the cause of death in 18 patients. The median overall survival after escape was 20 months (95% confidence interval, 9-25 months), and no significant difference was found between the NS and LC groups (P = .44). The median overall survival after diagnosis of MM was worse in patients with NS/LC escape than in those without escape (52 vs. 94 months; P = .018). ConclusionsOur study describes the largest series of NS and LC escape in MM to date. The development of this phenomenon is associated with more aggressive clinical features, frequent resistance to chemotherapy, and worse clinical outcome.

Mechanisms for autophagy modulation by isoprenoid biosynthetic pathway inhibitors in multiple myeloma cells.

Multiple myeloma (MM) is characterized by the production of monoclonal protein (MP). We have shown previously that disruption of the isoprenoid biosynthetic pathway (IBP) causes a block in MP secretion through a disruption of Rab GTPase activity, leading to an enhanced unfolded protein response and subsequent apoptosis in MM cells. Autophagy is induced by cellular stressors including nutrient deprivation and ER stress. IBP inhibitors have been shown to have disparate effects on autophagy. Here we define the mechanisms underlying the differential effects of IBP inhibitors on autophagic flux in MM cells utilizing specific pharmacological inhibitors. We demonstrate that IBP inhibition induces a net increase in autophagy as a consequence of disruption of isoprenoid biosynthesis which is not recapitulated by direct geranylgeranyl transferase inhibition. IBP inhibitor-induced autophagy is a cellular defense mechanism as treatment with the autophagy inhibitor bafilomycin A1 enhances the cytotoxic effects of GGPP depletion, but not geranylgeranyl transferase inhibition. Immunofluorescence microscopy studies revealed that IBP inhibitors disrupt ER to Golgi trafficking of monoclonal light chain protein and that this protein is not a substrate for alternative degradative pathways such as aggresomes and autophagosomes. These studies support further development of specific GGTase II inhibitors as anti-myeloma agents.

A Novel Class of Geranylgeranyl Diphosphate Synthase Inhibitors: Structure-Activity Relationships of Homoisoprenoid Triazoles in Myeloma Cells

The secretion of monoclonal protein and the dependence on the surrounding bone marrow microenvironment are key features of malignant plasma cells. We have previously demonstrated that targeting the Rab family of small GTPases via disruption of the post-translational modification geranylgeranylation not only impairs intracellular monoclonal protein trafficking, thus leading to endoplasmic reticulum stress and apoptosis, but also disrupts the interaction of the malignant plasma cells with key components of the bone marrow microenvironment. While developing agents that directly target the enzyme that geranylgeranylates the Rabs, we discovered several compounds that specifically and potently inhibit the enzyme geranylgeranyl diphosphate synthase (GGDPS). This enzyme is responsible for synthesis of the isoprenoid substrate which is used in geranylgeranylation reactions, thus inhibition of this enzyme is an alternative approach by which to target Rabs. Families of compounds were therefore designed which incorporated a hydrophobic chain, a triazole ring, and a bisphosphonic acid head group. The central triazole provides a potential zinc-binding element, and allows for divergent assembly of potential inhibitors through click chemistry. Through this strategy, prenyl, homoprenyl, geranyl, homogeranyl, farnesyl, homofarnesyl, geranylgeranyl, and homogeranylgeranyl triazole bisphosphonates have been prepared. All of these agents were subjected to in vitro enzyme assays for GGDPS as well as for the related enzyme farnesyl diphosphate synthase (FDPS), and IC50’s were determined. Cellular activity in human myeloma cell lines (RPMI-8226, U266, MM.1S) was assessed via immunoblot analysis of representative prenylated proteins. These studies revealed that in all cases, the homologated-version of the allylic triazole is more potent than the corresponding isoprenoid against GGDPS, ranging from 1.1-fold improvement in the homogeranylgeranyl:geranylgeranyl pairing to almost 300-fold in the homogeranyl:geranyl pairing. Chain length was found to be an important factor which determines the inhibitory activity within the homoisoprenoid series: the order of increasing potency against GGDPS was homogeranylgeranyl < homofarnesyl < homoprenyl << homogeranyl. The latter compound was determined to be the lead compound in this series with an IC50 of 58 nM against GGDPS and 480-fold selectivity for GGDPS compared with FDPS. Disruption of protein geranylgeranylation in myeloma cells with accompanying accumulation of intracellular monoclonal protein levels was observed at concentrations as low as 100 nM. This activity could be further potentiated with co-incubation with submicromolar concentrations of lovastatin, an HMG-CoA reductase inhibitor. Co-incubation studies with the isoprenoid intermediates mevalonate, farnesyl diphosphate and geranylgeranyl diphosphate (GGPP) revealed that the cellular activity of the homogeranyl triazole bisphosphonate is due to depletion of GGPP, consistent with the activity seen in the enzyme assays. Further studies demonstrated that this agent, in a concentration-dependent manner, induces elements of the unfolded protein response pathway and disrupts autophagy, as determined by immunoblot analysis of calnexin cleavage, levels of phosphorylated eIF2a, and LC3 cleavage. Treatment of human bone marrow stromal cells (HS-5 cell line) with the lead compound induced a concentration-dependent decrease in secreted IL-6 levels as measured via ELISA. In addition, myeloma cells pre-treated with the homogeranyl triazole compound displayed a decreased ability to adhere to HS-5 cells. In conclusion, these studies establish homogeranyl triazole bisphosphonate as the lead compound in a novel series of inhibitors against GGDPS and support the further development of GGDPS inhibitors as potential therapeutic agents for multiple myeloma. DisclosuresNo relevant conflicts of interest to declare.

Biclonal Gammopathy of IgA Kappa variants - A Case Report

Multiple myeloma is a clonal malignant neoplasm of plasma cells and is characterized by the secretion of monoclonal protein in plasma. Here, we report a case of biclonal multiple myeloma having two spikes on serum protein electrophoresis, one being in Beta-2 region and the other in gamma region. Further on immunofixation, both peaks were found to be of IgA-kappa variant. Biclonal gammopathy is a rare case, which accounts for only 1% of all myelomas but biclonal gammopathy of IgA kappa variant has not been described in the literature so far.

Abnormal Free Light Chain Ratios are Significantly Associated with Clinical Progression in Chronic Lymphocytic Leukemia

Serum Free Light Chains (FLC) have prognostic significance in diverse plasma cell dyscrasias. Although monoclonal protein secretion is a typical feature of these diseases, it can also be detected in other B cell malignancies including chronic lymphocytic leukemia. Recent data suggests a significant correlation between abnormal ratio of FLC and outcome. Therefore, we investigated the role of FLC in a large cohort of 135 patients and the correlation to immunofixation (IF) and flow cytometry. Abnormal FLC ratios were found in 78 patients (58%) whereas the IF was positive in only 32 cases (24%). In 55 cases the FLC ratio was positive while IF was negative and in only 9 cases IF was positive while the FLC ratio was normal. In 52 of 98 patients (53%) light chain restriction determined by flow cytometry was concordant with the monoclonal FLC whereas in 5 patients they did not agree. In 41 of 98 patients (42%) a normal ratio of FLC was observed while the immunophenotype was positive for lambda or kappa. Patients with an abnormal FLC ratio for lambda had a significantly shorter time to first therapy (TFT) than patients with an abnormal ratio for kappa FLC or with a normal FLC ratio (median TFT: 34 versus 76 versus 88 months, p for trend=0.039). Additionally, monoclonal FLC had a significantly shorter time to first treatment compared to polyclonal normal and abnormal FLC ratios (p for trend=0.0489). As expected, polyclonal sFLC correlated significantly with normal and abnormal serum-creatinine (p<0.0001). Future studies are warranted to elucidate the role of FLC as biomarkers of disease and as a prognostic factor for response.

Synthesis and Structure-Function Relationship Of Novel Triazole Phosphonates As Inhibitors Of Rab Geranylgeranyl Transferase

Multiple myeloma is characterized by the proliferation of malignant plasma cells which secrete large quantities of monoclonal protein (MP). As yet, no therapeutic strategies have been developed which directly target MP secretion. The Rab family of small GTPases plays key roles in intracellular vesicle trafficking. We have demonstrated that agents which impair the geranylgeranylation of Rab proteins induce apoptosis of myeloma cells by disrupting MP secretion, resulting in accumulation of MP within the cells and activation of the unfolded protein response pathway (UPR). Previously identified inhibitors of Rab geranylgeranyl transferase (Rab GGTase), the enzyme responsible for post-translational modification of Rab proteins, lack potency and have limited therapeutic potential. We hypothesized that potent and selective inhibitors of Rab GGTase could be designed based on available crystallographic data which reveals how the isoprenoid substrate interacts with the enzyme's active site. Families of compounds were therefore designed incorporating three motifs to allow for interaction with key components of the enzyme's active site: a non-hydrolyzable polar head group, a zinc-binding motif, and an isoprenoid or isoprenoid-like chain. The isoprenoid-based compounds were prepared using a divergent synthetic strategy based on azide-acetylene cycloadditions or “click” chemistry. We have previously demonstrated that direct use of an isoprenoid azide in a click reaction results in a triazole product that is a mixture of olefin isomers, due to an unavoidable [3,3] sigmatropic rearrangement that scrambles the stereochemistry of the first olefin prior to cycloaddition. This problem now has been circumvented by the development of a new synthetic strategy which is based on a regiospecific epoxidation of the C-2 olefin in the isoprenoid alcohol, followed by introduction of the azide and formation of the triazole. After completion of a click reaction the product can be reduced back to the parent olefin with good stereocontrol, to afford isoprenylated triazoles of the same chain length as those prepared directly from isoprenoid azides. Series of compounds were thus prepared in which chain length (including isoprenoid and isoprenoid-like), olefin stereochemistry, and polar head group (including bisphosphonic acids and carboxyphosphonic acids) were varied. All novel agents were subjected to in vitro enzyme assays for Rab GGTase as well as the related enzymes farnesyl transferase (FTase) and geranylgeranyl transferase I (GGTase I) and IC50 values were obtained. The cytotoxic activities of these agents were determined via MTT assays in human myeloma cell lines. Disruption of protein prenylation in myeloma cells was assessed via immunoblot analysis of farnesylated (Ras) and geranylgeranylated (Rap1a and Rab6) proteins. The results from these enzymatic and cell-based assays enabled the determination of a detailed structure-function relationship. These studies reveal that both chain length and olefin stereochemistry have a significant impact on both inhibitor potency and selectivity with respect to the target enzyme and the related prenyltransferases. For example, when the chain length was increased by just one methylene unit (farnesyl to homofarnesyl), the potency against Rab GGTase was enhanced by approximately 4-fold while changing the stereochemistry at the second olefin site from trans to cis diminished the potency by approximately 5-fold. These studies are guiding the design and synthesis of future generations of inhibitors with the ultimate goal of developing a potent and selective Rab GGTase inhibitor which can be utilized as a therapeutic agent for myeloma. Disclosures:No relevant conflicts of interest to declare.

Targeting Rab Geranylgeranylation Disrupts Myeloma-Stromal Cell Interactions

AbstractAbstract 1354Multiple myeloma is highly dependent on the interaction of the malignant plasma cells with the bone marrow environment. In particular, adhesion to bone marrow stromal cells stimulates myeloma cell proliferation and contributes to drug resistance. New therapeutic strategies which target the microenvironment that harbors myeloma are needed. We have previously demonstrated that isoprenoid biosynthetic pathway (IBP) and prenyltransferase inhibitors cause inhibitory effects in myeloma cells, particularly those agents which disrupt Rab geranylgeranylation. Our prior studies focused on the effects of these agents in disrupting monoclonal protein secretion and inducing the unfolded protein response. Whether disruption of Rab geranylgeranylation affects other key cellular processes in myeloma cells or the bone marrow microenvironment remains to be determined. In this study, we examined the effects of IBP and prenyltransferase inhibitors on several key aspects of myeloma-stromal cell interactions, including adhesion, proliferation, and cytokine secretion. The specific inhibitors utilized included lovastatin (HMG-CoA reductase inhibitor), zoledronic acid (farnesyl pyrophosphate (FPP) synthase inhibitor), digeranyl bisphosphonate (DGBP) (geranylgeranyl pyrophosphate (GGPP) synthase inhibitor), FTI-277 (farnesyl transferase (FTase) inhibitor), GGTI-2133 (geranylgeranyl transferase (GGTase) I inhibitor) and 3-PEHPC (GGTase II inhibitor). Studies were performed with the HS-5 human bone marrow stromal cell line as well as the RPMI-8226 and U266 human myeloma cell lines. MTT cytotoxicity assays demonstrated that the stromal cells are more sensitive to agents which deplete cells of isoprenoids than to direct prenyltransferase inhibitors. Co-incubation studies utilizing the isoprenoid intermediates mevalonate, FPP, and GGGP, revealed that depletion of GGPP, but not FPP, is responsible for IBP inhibitor-induced cytotoxicity in HS-5 stromal cells. Disruption of protein prenylation at the relevant drug concentrations was confirmed via immunoblot analysis of cytosolic and membranous fractions obtained from Triton X-114 lysis of HS-5 cells. Pre-treatment of U266 cells with lovastatin or 3-PEHPC for 24 hours significantly decreased the adhesion of those cells to either the HS-5 stromal cell layer or to fibronectin. To determine whether IBP or prenyltransferase inhibitors disrupt secretion of cytokines from the HS-5 cells, IL-6 ELISA studies were performed. Treatment of HS-5 cells for 24 hours with concentrations of IBP inhibitors that induce less than a 20% decrease in cell viability resulted in a decrease in IL-6 secretion by 20–40%. Of note, 3-PEHPC, but not the FTase or GGTase I inhibitors, significantly decreased IL-6 secretion. The sensitivity of RPMI-8226 and U266 cells to lovastatin or 3-PEHPC was not significantly altered when co-cultured with HS-5 cells as determined by a BrdU incorporation assay. In conclusion, these studies are the first to provide evidence for the role of Rab proteins in regulating myeloma cell adhesion and to demonstrate that disruption of Rab geranylgeranylation results in diminished stromal cell cytokine secretion. Further studies are required to determine the identity of the specific Rabs mediating these effects and the underlying mechanisms. This work supports the further investigation into agents which inhibit Rab geranylgeranylation as a novel strategy with which to target myeloma cells and the bone marrow microenvironment. Disclosures:No relevant conflicts of interest to declare.

Evaluation of Autophagy Modulators and Isoprenoid Biosynthetic Pathway Inhibitors in Multiple Myeloma Cells

Abstract 2488The production of monoclonal protein (MP) by malignant plasma cells is a hallmark of multiple myeloma (MM). We have previously demonstrated that select inhibitors of the isoprenoid biosynthetic pathway (IBP) which diminish Rab geranylgeranylation, disrupt MP trafficking in MM cells. The resulting intracellular accumulation of MP leads to induction of the unfolded protein response (UPR) pathway and apoptosis. The proteasome-mediated ER-associated degradation pathway has been shown to play an important role in intracellular degradation of monoclonal protein. Autophagy, another cellular process by which proteins are degraded, has been shown to play a role in clearing toxic aggregrated proteins in other systems. The extent to which autophagy is involved in clearing accumulated intracellular MP is unknown. We hypothesized that disruption of autophagy may enhance the cytotoxic effects of agents which impair MP trafficking. We therefore evaluated the effects of combining IBP and autophagy inhibitors in MM cells. Studies were performed in the lambda-light chain secreting RPMI-8226 (RPMI) MM line and the amyloidogenic lambda light chain-secreting ALMC-2 line. IBP inhibitors (IBPIs) included lovastatin (Lov) (HMG-CoA reductase inhibitor), digeranyl bisphosphonate (DGBP) (geranylgeranyl diphosphate synthase inhibitor), and 3-PEHPC (3P) (geranylgeranyl transferase II inhibitor). Autophagy modulators included bafilomycin A (Baf), 3-methyladenine (3-MA), and chloroquine (Chl). MTT cytotoxicity assays demonstrated differential effects when IBP and autophagy inhibitors were combined. Isobologram analysis revealed a synergistic interaction between Lov and Baf while predominantly additive or antagonistic interactions were observed with the combination of Lov and 3MA. A primarily additive interaction was observed between DGBP and Baf in the RPMI cells, while a synergistic effect was observed in the ALMC-2 cells. While concurrent incubation between 3P and Baf resulted in an additive interaction, pre-treatment with 3P for 24 h, followed by co-treatment with Baf for an additional 24 h, yielded a synergistic interaction. ELISA studies were performed to determine the effects of the autophagy modulators on MP trafficking. Treatment with Baf resulted in a concentration-dependent increase in intracellular MP level. Furthermore, addition of Baf potentiated the Lov-, DGBP-, or 3P-induced accumulation of intracellular MP. Neither 3-MA nor chloroquine increased intracellular MP levels by more than 20% and significant potentiation was not seen when these agents were combined with an IBPI. Finally, addition of the proteasome inhibitor bortezomib to the combination of Lov and Baf further increased intracellular MP levels. To evaluate the effects of combining IBPIs with autophagy inhibitors on autophagolysosome formation, studies were performed utilizing acridine orange staining and flow cytometric analysis. The shift from green to red fluorescence, a marker for acidic vesicular organelle (AVO) formation, was determined. These studies demonstrated that the select IBP inhibitors (DGBP and 3P to a greater extent than Lov) enhanced the Baf- and 3-MA-induced decrease in mean red:green fluorescence ratio. To determine whether Baf altered the ability of Lov to induce markers of the UPR, quantitative real time PCR studies were performed. These studies revealed that both Lov and Baf induce the upregulation of components of the UPR including PERK, IRE1, and GADD153. The combination of Lov and Baf further upregulated these UPR components compared with either agent alone. In conclusion, these studies demonstrate that the combination of the autophagy inhibitor Baf and select IBPIs results in enhancement of cytotoxic effects, disruption of MP trafficking, induction of components of the UPR, and inhibition of AVO formation. Further studies will be required to determine the extent to which autophagy regulates MP homeostasis, the mechanism underlying the differential effects of the autophagy inhibitors, and the effect of Rab inhibitors on autophagic processes in MM cells. This work forms the basis for future pre-clinical and clinical studies investigating the combination of inhibitors of MP secretion and autophagy in MM and related disorders. Disclosures:No relevant conflicts of interest to declare.

Isoprenoid biosynthetic pathway inhibition disrupts monoclonal protein secretion and induces the unfolded protein response pathway in multiple myeloma cells

Myeloma is characterized by the overproduction and secretion of monoclonal protein. Inhibitors of the isoprenoid biosynthetic pathway (IBP) have pleiotropic effects in myeloma cells. To investigate whether IBP inhibition interferes with monoclonal protein secretion, human myeloma cells were treated with specific inhibitors of the IBP or prenyltransferases. These studies demonstrate that agents that inhibit Rab geranylgeranylation disrupt light chain trafficking, lead to accumulation of light chain in the endoplasmic reticulum, activate the unfolded protein response pathway and induce apoptosis. These studies provide a novel mechanism of action for IBP inhibitors and suggest that further exploration of Rab-targeted agents in myeloma is warranted.

Abnormal Free Light Chain Ratios in Chronic Lymphocytic Leukemia: A New Prognostic Factor?.

Abstract 1237Poster Board I-259 IntroductionFree light chains (FLC) have prognostic significance in monoclonal gammopathy of undetermined significance, solitary plasmocytoma of bone, smouldering myeloma, multiple myeloma, Waldenstroms macroglobulinaemia and AL amyloidosis. Although monoclonal protein secretion is a typical feature of plasma cell dyscrasias, it can also be detected in other B cell malignancies including chronic lymphocytic leukemia (CLL). Recent data suggest a significant correlation between abnormal ratio of FLC and outcome. Therefore, we investigated FLC in a large cohort of 120 patients in order to assess the role of FLC in CLL. Methods and ResultsPlasma samples which had been previously cryopreserved and collected at the time before the initiation of therapy or six months after finishing therapy were used. The levels of FLC were assessed using nephelometric immunoassays (The Binding Site) and quantified nephelometrically with the BNII analyser. A normal FLC range (κlγ) was defined as 0.26-1.65. Moreover, in all cases we evaluated the M band on immunofixation (IF).Abnormal FLC ratios were found in 71 patients (59%) whereas the IF was positive in only 32 cases (27%). In 48 cases the FLC ratio was positive while IF was negative and in only 9 cases the IF was positive while the FLC ratio was normal. In total, 23 patients had both a positive IF and an abnormal FLC ratio.Patients with an abnormal FLC ratio for γ had a significantly shorter treatment-free survival (TFS) than patients with an abnormal ratio for κ or with a normal FLC ratio (median TFS: 34 versus 78 versus 109 months, p=0.042). Evaluation of several disease characteristics in association with FLC of the patients' B-CLL cells showed no significant differences for FLC in the different risk groups (ZAP-70 status, CD38 status, cytogenetics and Binet stage) suggesting no correlation of the FLC with these already established adverse prognostic factors. ConclusionFLC can be detected in a substantial fraction of patients with CLL and the FLC technique improves detection of M-proteins. Moreover, an abnormal FLC ratio is associated with worse outcome, particularly those with a low abnormal FLC ratio. Evaluation of the prognostic significance of abnormal FLC in a larger cohort is currently under way. This data will be presented at the meeting. Future studies are warranted to elucidate the role of FLC as biomarkers of disease and as a prognostic factor for response. DisclosuresNo relevant conflicts of interest to declare.

Comparison of Serum Free Light Chain Levels and 24 Hour Urinary Monoclonal Protein Secretion in Patients with Myeloma: Concordant Changes with Response to Therapy.

Background: The measurement of monoclonal (M) protein in the serum and urine is critical for response assessment and disease evaluation in patients with multiple myeloma (MM). The serum free light chain (FLC) assay offers a new and sensitive method of assessing response to therapy. An important question that has not been adequately addressed is the correlation between 24 hour urine M protein levels and serum FLC measurements, and the extent to which response to therapy estimated using the FLC assay correlates with that assessed using the 24 hour urine M protein level.Methods: A total of 2194 sets of data, with simultaneous UPEP and serum FLC measurement, were studied. These included 752 unique patients, with individual patients having 1–23 paired assessments over time. FLC estimation was carried out using the serum FLC assay (Freelite; The Binding Site Limited, UK) performed on a Dade-Behring Nephelometer. Based on the established reference range, kappa/lambda FLC ratio <0.26 or >1.65 were defined as abnormal indicating the presence of monoclonal lambda and kappa FLC, respectively. The monoclonal light chain isotype was considered the involved FLC isotype, and the opposite light chain type as the uninvolved FLC type. The Urine M protein by UPEP was compared to the serum levels of the involved light chain using Spearman Rank Correlation. For comparisons in individual patients over time, those with at least 10 measurements each were studied.Results: The median involved FLC level in patients with an undetectable urine M protein was 2.3 mg/dl compared to 32.2 mg/dL among those with a detectable urine M protein (P<0.001). Among the 1676 points with an abnormal FLC ratio, only 75% had an M protein detected in the urine, P < 0.001. Conversely, among patients with a positive urine M-protein, 91% had an abnormal FLC ratio. When all the 2194 data points were considered together, there was a significant correlation between the urine M protein level and the FLC levels (FLC level calculated as the difference between involved and uninvolved levels), rho=0.763, P < 0.001. The correlation did not change when patients with a serum creatinine of over 2.5 were excluded. The correlation between FLC levels and urinary M protein can be affected by several factors such as renal function that will differ across patients. Therefore, we examined whether the correlation between the two variables is stronger when the variations introduced by inter-patient differences in the relationship between the two variables are eliminated. In order to do this, we studied individual patients on whom multiple data points over time were available. One patient who had the maximum number of paired assessments (23 pairs) of serum FLC level and urinary M protein; the correlation between the two variables over time was highly significant, rho 0.981, p<0.001. Similarly 26 other patients who had measurable urine M protein levels in whom 10 nor more paired observations over time were available, also showed significant correlations, rho, range 0.726–0.981, p<0.01.Conclusion: There is a significant correlation between urine M-protein and serum free light chain across patients and the correlation is stronger in individual patients in whom the effect of inter-patient variation in other confounding factors can be eliminated. These data if confirmed in a clinical trial setting would support the use of serum FLC levels instead of urinary M protein measurements to assess response to therapy.

A case report: isolated α heavy chain monoclonal gammopathy in a patient with polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin change syndrome

A 45-year-old South-Korean man presented with abdominal distension, progressive paresthesia and motor weakness of both lower extremities. Our case was identified as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin change (POEMS) syndrome based on diagnostic criteria. Circulating M components of POEMS syndrome consist mainly of IgG or IgA-lambda and rarely IgM-lambda, IgG-kappa or isolated light chains. In this case, the M-band on serum protein electrophoresis and isolated IgA heavy chain on serum immunofixation electrophoresis were demonstrated, but there was no abnormal light chain. We suggest that this case may be associated with a pattern of abnormal secretion of monoclonal protein or a coincidence of a heavy chain disease in POEMS syndrome, even though the latter possibility may be very rare.