Absence Of Monoclonal Gammopathy Research Articles

Natural Language Processing of Serum Protein Electrophoresis Reports in the Veterans Affairs Health Care System.

Serum protein electrophoresis (SPEP) is a clinical tool used to screen for monoclonal gammopathy, thus it is a critical tool in the evaluation of patients with multiple myeloma. However, SPEP laboratory results are usually returned as short text reports, which are not amenable to simple computerized processing for large-scale studies. We applied natural language processing (NLP) to detect monoclonal gammopathy in SPEP laboratory results and compared its performance at multiple hospitals using both a rules-based manual system and a machine-learning algorithm. We used the data from the VA Corporate Data Warehouse, which comprises data from 20 million unique individuals. SPEP reports were collected from July to December 2015 at 5 Veterans Affairs Medical Centers. Of these reports, we annotated the presence or absence of monoclonal gammopathy in 300 reports. We applied a machine learning-based NLP and a manual rules-based NLP to detect monoclonal gammopathy in SPEP reports at each of the hospitals, then applied the model from 1 hospital to each of the other hospitals. The learning system achieved an area under the receiver operating characteristic curve of 0.997, and the rules-based system achieved an accuracy of 0.99. When a model trained on 1 hospital's data was applied to a different hospital, however, accuracy varied greatly, and the learning-based models performed better than the rules-based model. Binary classification of short clinical texts such as SPEP reports may be a particularly attractive target on which to train highly accurate NLP systems.

Treatment of Non-Amyloid Monoclonal Gammopathies of Renal Significance (MGRS) with Clone Directed Therapies-Single Center Experience

Background: MGRS is a group of heterogeneous disorders characterized by renal dysfunction related to monoclonal immunoglobulin deposition where the underlying plasma cell or B cell clone does not cause tumor complications or meets current hematological criteria for specific therapy (1). The diagnosis of these disorders is established by renal biopsy demonstrating glomerular or tubulointerstitial monoclonal protein deposition. The glomerular disorders include proliferative glomerulonephritis with monoclonal Ig deposition (PGNMID), paraprotein associated C3 glomerulopathy, immunotactoid glomerulopathy, and paraprotein associated fibrillary glomerulonephritis and Type 1 cryoglobulinemic glomerulonephritis. The tubulointerstitial disorders include fanconi syndrome and proximal light chain tubulopathy (2). Given the pathogenesis of the disorders, therapies targeting the underlying plasma cell and/or B cell clone have been used in the past but standard therapy has not been established. Given the rarity of MGRS as defined above, we report our single center experience for therapy of such disorders. Methods: We retrospectively reviewed the charts of patients treated for MGRS at Columbia University Medical Center and collected information on the renal pathologic diagnosis, presence or absence of monoclonal gammopathy and therapy and response. The diagnosis of MGUS and MGRS was based on standard criteria (3). For the assessment of renal response, we used criteria for renal organ response for AL amyloidosis (4). Results: A total of 8 patients were treated at our center for MGRS between 3/2015 and 1/2019. The type of MGRS diagnosis was PGNMID in 5 patients, C3 glomerulopathy in 1 patient, immunotactoid GN in 1 patient and MGUS associated dense deposit disease (DDD) in 1 patient. Monoclonal Ig deposit was IgG kappa type in 3, IgG Lambda in 2, IgM lambda in 1 patient and only Complement deposits C3 glomerulopathy and DDD. All pts had proteinuria at diagnosis with median proteinuria 4g/24hr (range 2.8-11.7g/24hr). Impaired renal function was present 5/8 pts with median serum creatinine 1.4mg/dl (range 1-4.6). None of the patients with PGNMID (N=5) had a concurrent monoclonal gammopathy by standard testing but the rest 3 patients had MGUS with positive SPEP and bone marrow involvement by a clonal plasma cells. First line treatment regimens included use of Bortezomib based regimen (Bortezomib, cyclophosphamide, dexamethasone) in 3 patients, Rituximab based regimens (Rituximab, Prednisone and Rituximab, cyclophosphamide, prednisone) in 4 patients and Daratumumab in one patient. Second line Daratumumab based therapy was used in 2 patients who did not respond to the first line therapy and lead to response in one patient. Improvement in proteinuria was seen in 6/8 patients with >30% decrease in proteinuria (range 50-90% reduction). The median time to response was 2 months (range 1-4 months). Improvement in eGFR was seen in 1/8 patients but majority of patients continuing to have stable eGFR and 1/8 patient progressed to ESRD. The responses were durable and after a median follow-up of 11.8 months only one patient had recurrent disease. Conclusion: Currently there is no standard of care therapy for treatment of patients diagnosed with MGRS disorders. Clone directed therapies including Bortezomib, Daratumumab and Rituximab based regimens aimed at suppressing the production of the involved immunoglobulin are effective for treatment of these disorders both in the presence and absence of a concurrent MGUS. These therapies should be explored further in a larger prospective multi-center trial for MGRS disorders.

Serum Free Light Chain Assay and κ/λ Ratio Performance in Patients Without Monoclonal Gammopathies: High False-Positive Rate.

Serum free light chain assay is a recommended screening test for monoclonal gammopathies. Anecdotal observations indicated a high rate of false-positive abnormal κ/λ ratios. This study was undertaken to ascertain the magnitude of the false-positive rate and factors contributing to the error rate. Results of serum protein electrophoresis, serum free light chains, and related tests, usually done for investigation of suspected monoclonal gammopathy, were reviewed retrospectively for 270 patients and 297 observations. Using the conventional κ/λ ratio, 36.4% of the ratios were abnormal, in the absence of monoclonal gammopathy. When the renal κ/λ ratio was used, the rate of abnormal κ/λ ratios was 30.1%. In patients with a γ-globulin concentration of 1.6 g/dL or more, the usual κ/λ ratio was abnormal in 54.8% of the patients. Urine protein electrophoresis was used in 53 (19.6%) instances, whereas bone marrow examination was done in 65 (24.1%) cases. Usual κ/λ ratio was abnormal in 36.4% of the observations in patients without evidence of monoclonal gammopathy, and an abnormal κ/λ ratio should not be used as the sole indicator for diagnosis of neoplastic proliferation of the lympho-plasmacytic system. Hypergammaglobulinemia is associated with a higher rate of false-positive abnormal κ/λ ratios. Examination of urine for monoclonal immunoglobulins may be underused, and recommendations by some to use serum free light chain assay in place of, rather than as an adjunct to, urine electrophoresis are not warranted.

Monoclonal gammopathy related to Sjögren syndrome: A key marker of disease prognosis and outcomes

ObjectiveTo analyze the monoclonal expression of SS through the detection of serum monoclonal immunoglobulins (mIgs) in a large series of patients with Sjögren syndrome (SS), focusing on the etiology, characterization and evolution of the monoclonal band and the association with SS clinical expression and outcomes. MethodsSerum immunoelectrophoresis (IE) was performed to 408 consecutive patients who were evaluated by our unit between 1992 and 2011: 221 patients who fulfilled the 2002 American–European criteria for primary SS, 122 primary SS patients who fulfilled exclusively the 1993 European criteria and 65 patients with SS-associated hepatitis C virus infection. IE was performed at diagnosis and every year during the follow-up. ResultsOf the 221 patients with primary SS, 48 (22%) had monoclonal gammopathy. In the control groups, the prevalence was 16% in patients with SS who fulfilled the 1993 criteria (p > 0.05) and 52% in SS-HCV patients (p < 0.001). Monoclonal bands were characterized in 47/48 patients with primary SS: IgG (n = 21), IgM (n = 16), IgA (n = 5) and free light chains (n = 5); the light chain was κ in 28 patients and λ in 19 (κ:λ ratio 1.5). Primary SS patients with monoclonal gammopathy had a higher prevalence of parotidomegaly (38% vs 20%, p = 0.021), vasculitis (21% vs 6%, p = 0.003), neurological involvement (42% vs 23%, p = 0.016), higher mean values of circulating gammaglobulins (23.4 vs 20.6%, p = 0.026), ESR (56.6 vs 37.6 mm/h, p = 0.003), a higher prevalence of RF (69% vs 50%, p = 0.022), low C3 levels (24% vs 11%, p = 0.028), low C4 levels (24% vs 7%, p = 0.003), low CH50 activity (28% vs 11%, p = 0.008) and cryoglobulins (23% vs 8%, p = 0.012) compared with those without monoclonal gammopathy. Of the 48 patients with primary SS and monoclonal gammopathy, 8 developed hematologic neoplasia after a mean follow-up of 10 years, a higher prevalence than observed in patients without monoclonal gammopathy (17% vs 5%, p = 0.009). Survival rates according to the presence or absence of monoclonal gammopathy were 83% and 97%, respectively (log rank 0.004). ConclusionMonoclonal gammopathy was detected in 22% of patients with primary SS fulfilling the 2002 criteria, with mIgGκ being the most frequent type of band detected. In HCV-associated SS patients, the prevalence was higher (52%) with IgMκ being the most prevalent band detected. Monoclonal gammopathy was associated with a higher prevalence of parotid enlargement, extraglandular features, hypergammaglobulinemia, cryoglobulinemia and related markers (rheumatoid factor, hypocomplementemia), and with a poor prognosis (development of neoplasia and death).

High-Dose Melphalan and Autologous Stem Cell Transplantation In AL Amyloidosis and Monoclonal Immunoglobulin Deposition Disease Associated End-Stage Renal Disease Requiring Dialysis

AbstractAbstract 3553Treatment of AL amyloidosis (AL) and monoclonal immunoglobulin deposition disease (MIDD) with high dose melphalan and autologous stem cell transplant (HDM/SCT) offers a high rate of durable complete hematologic responses and leads to clinical responses and improvement in survival. The development of end-stage renal disease (ESRD) is common among patients with AL amyloidosis and MIDD-associated renal disease leading to requirement for renal replacement therapy. Because of toxicity associated with HDM/SCT, there has been concern about its safety in patients with ESRD Therefore the role of HDM/SCT for patients with renal insufficiency has been called into question. Here we report on standard operating procedure, toxicities, hematologic responses and survival of patients with ESRD treated with HDM/SCT for AL amyloidosis and MIDD. Between 7/1994 and 6/2010, 32 patients with AL amyloidosis and 4 patients with MIDD associated ESRD were treated with HDM/SCT. The median age was 53 (range, 28–68). There were 21 (58%) males and 18 (50%) with kappa clonal plasma cell dyscrasia. Organ involvement distribution was typical for this disease: 75% patients (n=27) had 2 or more organs involved; 25% (n=9) had only renal involvement and 28% (n=10) had symptomatic cardiac involvement. The median duration of dialysis-dependence prior to HDM/SCT was 3.4 months and the median time from diagnosis to HDM/SCT was 6.5 months. Peripheral blood stem cells were mobilized using G-CSF alone at 10–16 m/kg/day for 3–4 days. Melphalan was administered intravenously in divided doses on 2 consecutive days. Oral cryotherapy was administered during and 15 minutes before and after infusion of melphalan since 2/2002 to reduce the incidence and severity of mucositis. The total dose of melphalan ranged from 100–200 mg/m2, depending on age, severity of cardiac disease and performance status. Stem cells were infused 24–72 hours after completion of melphalan. Hemodialysis patients were dialyzed according to the patient's usual schedule but with an interval of at least 2 hours between the administration of melphalan or infusion of stem cells and the initiation of hemodialysis. An extra session of hemodialysis was performed either on the second day of melphalan infusion and/or the day of stem cell infusion. Peritoneal dialysis exchanges were performed according to the patient's usual schedule. Antimicrobial prophylaxis with an oral quinolone, acyclovir and fluconazole was started on D + 1. Five patients received peritoneal dialysis and the remainder received hemodialysis. Thirty-one % (n=11) received 200 mg/m2 HDM, 47% (n=17) 140 mg/m2 HDM and 22% (n=8) 100 mg/m2 HDM. Treatment-related mortality, defined as deaths within 100 days of SCT, occurred in 6% (n=2/36). There were no deaths during stem cell mobilization and collection or stem cell infusion. There were additional 7 deaths (19%) during the first year after HDM/SCT. Hematologic response was assessed at 1 year following HDM/SCT. Hematologic complete response (CR) was defined as absence of monoclonal gammopathy by serum and urine by IFE, absence of clonal plasma cells in the bone marrow, and normalization of serum free light chain concentration and ratio since 2003. CR occurred in 70% (n=19) of 27 surviving patients at 1 year following HDM/SCT. The median time to neutrophil and platelet engraftment was 10 and 14 days, respectively. The median number of red cell and platelet transfusion was 4 units and 6 packs, respectively. Thirteen (36%) patients developed grade 3 or 4 mucositis. Of note, 45% (n=10/22) developed grade 3 or 4 mucositis before institution of oral cryotherapy compared to 14% (n=2/14) after its initiation (p=0.07). The median survival for the entire group of 36 patients is 64 months (5.3 years) from the time of SCT. The median survival is 62 months from the time of initiation of dialysis. The median survival is 74 months (6.1 years) for the patients achieving a CR compared to 38 months (3.1 years) for those not achieving a CR (p=0.439). Nine patients with hematologic CR have either undergone or are awaiting renal transplantation. In conclusion, HDM/SCT is an effective treatment in selected patients with AL amyloidosis or MIDD associated ESRD with treatment-related morbidity and mortality and outcomes similar to those for non-dialysis patients. Disclosures:No relevant conflicts of interest to declare.

Early Serum Free Light Chain Responses Following High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis.

Abstract 4352AL amyloidosis is a clonal plasma cell dyscrasia which produces insoluble amyloid fibrils from Ig light chains, leading to multiorgan failure. High dose melphalan and autologous stem cell transplantation (HDM/SCT) can induce remission and extend survival, but response is assessed at 6 and 12 months. Serum free light chain (FLC) assays can improve detection of AL amyloidosis, have prognostic significance, and are routinely used to assess response to treatment. Serum half life of FLCs is only 2-6 hours, even with diminished glomerular filtration rates. In a small prospective series, we previously reported that FLC levels 1-3 weeks after HDM/SCT correlate with hematologic response at 1 year. This study was performed to confirm these results on a larger scale. A prospective analysis of patients with AL amyloidosis treated with HDM/SCT was performed to determine the extent to which early FLC responses predict hematologic complete response (CR). Exclusion criteria included initial normal FLC concentrations and ratios and chronic renal insufficiency (Cr>1.2 mg/dL) with a normal FLC ratio. Hematologic responses, as defined by standard traditional criteria, were determined at 6 and 12 months. Traditional criteria define hematologic CR as by normalization of bone marrow exam and absence of monoclonal gammopathy in urine and serum by immunofixation electrophoreses. Serum FLC concentrations were measured by a sensitive nephelometric analysis within 10 days and within 3 weeks of HDM/SCT. Complete response for serum FLC was defined as normalization of FLC concentration and ratio or normalization of the ratio in renal failure (Cr>1.2 mg/dL). Serum FLC levels or k/l FLC ratios were abnormal and informative in 124 patients (87%) prior to HDM/SCT, and these patients were included in subsequent analyses. One week after transplant, sensitivity of FLC to predict hematologic CR was 0.64, specificity was 0.67, positive predictive value (PPV) was 0.49, negative predictive value (NPV) was 0.79, positive likelihood ratio (LR) was 1.92, and negative LR was 0.54. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.36, specificity was 0.86, PPV was 0.54, NPV was 0.75, positive LR was 2.59, and negative LR was 0.74. Two to three weeks after transplant, sensitivity of FLC CR to predict hematologic CR was 0.72, specificity was 0.74, PPV was 0.57, NPV was 0.85, positive LR was 2.78, and negative LR was 0.38. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.34, specificity was 0.86, PPV was 0.52, NPV was 0.74, positive LR was 2.40, and negative LR was 0.77. Serum FLC concentrations within 3 weeks of HDM/SCT have poor predictive values and should not be used to predict hematologic CR. However, failure to reduce FLC concentrations by 90% has a somewhat higher negative predictive value and could be used to guide additional post-transplant management. Disclosures:No relevant conflicts of interest to declare.

Long Term Results of High-Dose Melphalan and Autologous Stem Cell Transplantation in Non-Amyloid Monoclonal Immunoglobulin Deposition Disorders.

Abstract 4356Monoclonal Immunoglobulin Deposition Disorder (MIDD) is a plasma cell dyscrasia in which whole immunoglobulins or heavy or light chain subunits form non-fibrillar deposits in various tissues, causing organ dysfunction. Several studies have previously reported that high dose melphalan and autologous stem cell transplantation (HDM/SCT) is safe and effective at achieving a complete hematologic response in this disease, but long term data is sparse. Hematological complete response is defined as normalization of serum free light chain ratio and concentration, bone marrow exam with less than 5% plasma cells, and absence of monoclonal gammopathy in serum and urine by immunofixation electrophoresis. Between 2003 and 2008, ten patients with MIDD were treated with HDM/SCT at a dose of 200mg/m2 (n=6) or 100-140 mg/m2 (n=4) depending upon age and clinical status and were assessed for hematologic responses and improvements in organ function at 3-6 and 12 months, and annually thereafter. The median age was 45 years (range, 34 to 70); all but one patient were male. Six patients had kappa clonal predominance and four patients had lambda clonal predominance. All ten patients had renal involvement, two were on dialysis and one had undergone a renal transplant. Two patients also had extrarenal manifestations with cardiac involvement. The median creatinine clearance was 26 mL/min (range 20 to 100) and the median 24 hour urine total protein excretion was 4,037 mg (range, 458 to 15,632). Peripheral blood stem cells were collected after GCSF mobilization and a median of 6.9 ×106 CD34cells/kg were collected. There was no treatment related mortality within 100 days of SCT. One patient developed end stage renal disease during the peri-transplant period. Of the seven patients who have had follow-up of at least a year, five (71%) achieved a complete hematological response (CR) and two (29%) had a partial hematological response. One patient died six months after HDM/SCT due to progressive disease. Clinical and organ responses were also evident after HDM/SCT in 5 out of 7 patients. The median creatinine clearance was 42 mL/min (range, 38-55) and the median 24 hour urine total protein excretion was 179 mg (range, 150 to 349) at 2 years after treatment. Of the five patients with hematologic CR, 3 (60%) have relapsed at a median of 3 years (range, 2-3). Two of the 5 patients continue to have hematologic CRs at four and six years after HDM/SCT. In summary, HDM/SCT in MIDD often results in hematological CRs, as well as an improvement in renal function. However, the 5-year relapse rate is high. This group of patients may benefit from maintenance anti-plasma cell therapy. Disclosures:No relevant conflicts of interest to declare.

Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies.

Approximately 10% of patients with peripheral neuropathy of otherwise unknown etiology have an associated monoclonal gammopathy. Both the neuropathies and the monoclonal gammopathies in these patients are heterogeneous, but several distinct clinical syndromes that may respond to specific therapies can be recognized. It is important to recognize these syndromes because monoclonal gammopathies also occur in 1% of the normal adult population, and in some cases, monoclonal gammopathies are coincidental and unrelated to the neuropathy. In patients with IgM monoclonal gammopathies, IgM M proteins frequently have autoantibody activity and are implicated in the pathogenesis of the neuropathy. IgM M proteins that bind to myelin-associated glycoprotein (MAG) have been shown to cause demyelinating peripheral neuropathy; anti-GM1 antibody activity is associated with predominantly motor neuropathy, and anti-sulfatide or chondroitin sulfate antibodies are associated with sensory neuropathy. The IgM monoclonal gammopathies may be malignant or nonmalignant, and polyclonal antibodies with the same specificities are associated with similar clinical presentations in the absence of monoclonal gammopathy. IgG or IgA monoclonal gammopathies are associated with neuropathy in patients with osteosclerotic myeloma or the POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy myeloma, and skin changes). Amyloidosis or cryoglobulinemic neuropathies can occur with either IgM or IgG and IgA monoclonal gammopathies. Therapeutic intervention depends on the specific clinical syndrome but is generally directed at removing the autoantibodies, reducing the number of monoclonal B cells, and interfering with the effector mechanisms.

Antibodies to sulfated glucuronic acid containing glycosphingolipids in neuropathy associated with anti-MAG antibodies and in normal subjects

Serum of patients with neuropathy and IgM monoclonal antibodies (M-proteins) that bind to the myelin-associated glycoprotein (MAG) were tested for binding to the major cross-reactive sulfated glucuronic acid containing glycosphingolipid, sulfated glucuronic acid paragloboside (SGPG). IgM binding to the glycolipid was detectable at serum dilutions of 1 : 10 000 and reactivity was greatest at 4°C. Low titers of IgM binding to the glycolipid were also detected in sera from normal subjects and from patients with neurologic or rheumatologic diseases without serum M-proteins. Binding activity was prosent in 25% of the sera tested, and titers ranged between 1 : 25 and 1 : 400. One patient with peripheral neuropathy, however, had a measurable titer of 1 : 12 800 in the absence of monoclonal gammopathy. The study indicates that cold reacting anti-SGPG IgM antibodies are frequent constituents of the normal human antibody repertoire, and that monoclonal or polyclonal expansion of B cells that secrete these antibodies, is associated with peripheral neuropathy.