IgM Paraproteinemia Research Articles

Prognostic Significance of Monoclonal Paraproteinemia in Marginal Zone Lymphoma

Introduction and aim:Marginal zone lymphoma (MZL) is an indolent lymphoma which can progress with frequent relapses and transform to aggressive lymphoma. Therefore, the factors that affect prognosis are important fields of interest. This study was aimed to investigate the effect of immunoglobulin (Ig) paraproteinemia on MZL prognosis and survival. Material and method: Between January 2000 and June 2022, 73 patients who applied to Dokuz Eylül University Faculty of Medicine Hospital Department of Hematology, diagnosed with MZL, and continued their follow-up in our center were assessed. Patients whose paraproteinemia was investigated by immunofixation (SIFE), serum protein electrophoresis (SPEP), or free kappa and lambda free light chain (FLC) assays were included in the study. Demographic characteristics and laboratory data were retrospectively analyzed. Results: Ig paraproteinemia was ascertained in 20 patients which 11 of 20 was IgM type. The median follow-up was 58 (3-200) months. Median overall survival (OS) and progression free survival (PFS) were not reached. Mean OS and PFS were 169±8.5 and 146±10.6 months, respectively. Serum Ig paraproteinemia was detected in 20 of 73 patients (27.3%). Most were IgM- κ (9, 45%), followed by IgG-κ (7, %35), IgM-λ (2, %10), IgA-λ (1, %5), and IgA-κ (1, %5). The presence of Ig paraproteinaemia was significantly associated with advanced age (p<0.001), advanced disease stage (III-IV) (p=0.023), elevated ß2 microglobulin (ß2MG) level (p=0.001), decreased hemoglobin level (p=0.002), decreased albumin level (p<0.001), and bone marrow involvement (p=.026). Gender, elevated lactate dehydrogenase (LDH) level, and elevated Ki-67 were not significantly associated with the presence of Ig paraproteinaemia. In our cohort Ig paraproteinemia was shown in 35%, 10% and 55% of extranodal MZL, splenic MZL and nodal MZL respectively (p=0,009) which favors nodal MZL dominance. The prognostic value of Ig paraproteinaemia and other clinical outcomes are summarized in Table 1. The OS rate at 5 and 10 years was %87.2 and %81.9, respectively. The PFS rate at 5 and 10 years was %71.5 and %68.3 respectively. Patients with Ig paraproteinaemia has shorter OS compared to patients without any paraproteinemia (73,8 mo. vs 178,8 mo. p<0,05). This survival disadvantage was more pronounced in patients with IgM paraproteinemias. Kaplan-Meier survival curve analysis of PFS according to the occurrence of Ig paraproteinaemia are shown in Figure 1. Conclusion: Although MZL is an indolent lymphoma type and there are many prognostic factors affecting its prognosis, it may show relapsed or refractory disease course or histological transformation. 55% of our nodal MZL cohort had Ig paraproteinemia which is higher than all reported cohorts in the literature so far. Several studies have previously shown that Ig paraproteinemia may be a potential prognostic factor for NHL and MALT lymphoma 1-3. Ren et al. showed that Ig paraproteinemia was an independent prognostic predictor for MALT lymphoma 4. Epperla et al. showed that patients diagnosed with MZL with Ig paraproteinemia had inferior survival in comparation with no-M protein group 5. In conclusion, this study provides evidence that Ig paraproteinaemia and especially of IgM type shortens PFS and OS in patients with MZL. Thus, our study is the first in literature to show survival disadvantage for MZL patients specifically with IgM paraproteinemia and deserves confirmation with further studies.

Diagnosis and management of AL amyloidosis due to B-cell non-Hodgkin lymphoma.

Immunoglobulin light chain (AL) amyloidosis may be caused by a B-cell non-Hodgkin lymphoma (NHL) rather than a plasma cell neoplasm in rare cases, which presents unique diagnostic and management considerations. NHL associated with AL will often have an IgM paraprotein; thus, this disease is termed IgM-related AL amyloidosis (IgM AL). The clinical presentation of IgM AL is more likely to involve the lungs, peripheral nerves, and soft tissue; cardiac involvement is less common. Patients with IgM AL amyloidosis should undergo a lymphoma-directed work-up including evaluation for nodal and extranodal disease. Additionally, patients with an IgM paraproteinemia should be screened for AL amyloidosis through history and physical examination. Treatment regimens active against underlying lymphoma, rather than plasma cell-directed regimens, are recommended. Historical response rates in IgM AL have been poor; prospective studies of novel antineoplastic regimens may improve treatment outcomes.

Serum neurofilament light chain, contactin-1 and complement activation in anti-MAG IgM paraprotein-related peripheral neuropathy

IntroductionIn anti-myelin-associated glycoprotein IgM paraprotein-related peripheral neuropathy (anti-MAG PN), there is a lack of reliable biomarkers to select patients eligible for therapy and for evaluating treatment effects, both in routine practice and in clinical trials. Neurofilament light chain (NfL) and contactin-1 (CNTN1) can serve as markers of axonal and paranodal damage. Complement activation is involved in the pathogenesis in anti-MAG PN. We, therefore, hypothesized that serum NfL, CNTN1, C3b/c and C4b/c may function as biomarkers of disease activity in anti-MAG PN.MethodsIn this prospective cohort study, we included 24 treatment-naïve patients with anti-MAG PN (mean age 69 years, 57% male) that had IgM paraproteinemia, a high IgM MAG-antibody, and clinical diagnosis of anti-MAG PN by a neurologist specialized in peripheral nerve disorders. We measured serum NfL, CNTN1, C3b/c and C4b/c, reference values were based on healthy controls. As controls, 10 treatment-naïve patients with IgM Monoclonal gammopathy of undetermined significance (MGUS) or Waldenström’s Macroglobulinemia (mean age 69 years, 60% male) without signs of neuropathy were included (non-PN).ResultsNfL, CNTN1 levels in serum were mostly normal in anti-MAG PN patients and comparable to non-PN patients. C3b/c and C4b/c levels were normal in anti-MAG PN patients.ConclusionOur results do not support serum NfL, CNTN1, and C3b/c and C4b/c as potential biomarkers in anti-MAG PN, although we cannot exclude that subgroups or subtle abnormalities could be found in a much larger cohort with longitudinal follow-up.

Ethnic Disparities in Waldenström's Macroglobulinaemia in the United Kingdom - Analysis from the Wmuk Rory Morrison Registry

Introduction: Waldenström's Macroglobulinaemia (WM) is a rare indolent B-cell lymphoma characterised by lymphoplasmacytic infiltrate with an IgM paraproteinaemia. Approximately 400 patients (pts) are diagnosed annually in the United Kingdom (UK). National and regional registries provide important insights on the epidemiology and clinical features of this distinct uncommon disorder. Previous authors from the United States have reported significant differences in age at diagnosis and overall survival (OS) in WM between ethnic groups from Surveillance, Epidemiology and End Results data [1]. We aimed to determine baseline demographics, symptoms and survival outcomes across different ethnic groups in the UK.Methods: We retrospectively reviewed data from the WMUK Rory Morrison Registry, collating descriptive data of WM as well as non-IgM Lymphoplasmacytic lymphoma (LPL) cases from 20 centres across the UK, diagnosed between June 1978 and May 2021. Research ethics approval was obtained.Results: 732 pts with documented ethnicity were included here. Ethnicity was categorised in accordance with the UK National Census. Those other than the White cohort (662/732; 90%) were collectively termed ‘Ethnic Minorities’ (EM) (70/732; 9%): 39/70 (56%) Asian (13 Indian, 6 Chinese, 4 Pakistani, 16 other); 19/70 (27%) Mixed (1 White & Black African, 1 White & Asian, 1 Arab, 16 other); 12/70 (17%) Black (6 Caribbean, 3 African, 3 other).Baseline characteristics are displayed in table 1. EM presented at a significantly younger age compared to White cohort (60 vs 64 years, p=0.01) and had a significantly lower paraprotein at diagnosis (11 vs 18g/L, p=0.05). MYD88 L265P mutation tested in 250 pts (34%): positive in the majority 218/250 (87%) and notably less common in EM (p=0.09), most significantly in the Asian cohort compared to White (67% v 88%, p=0.01). The EM cohort had a smaller proportion of WM diagnoses compared to White cohort (77% vs 93%, p=0.02) with the Asian cohort accounting for the highest proportion of non-IgM LPL (15% vs 4%, p=0.002). Bone marrow trephine infiltration at diagnosis was lower in the EM cohort compared to the White cohort, although not statistically significant (25% vs 37%, respectively; p=0.10). IPSSWM scores were similar throughout.Approximately half of both the White & EM cohorts were asymptomatic at diagnosis. The most common presenting symptoms in EM were anaemia-related (10/34; 29%), B symptoms (6/34; 18%) and fatigue (4/34; 12%). 6/18 (33%) of Asians presented with cryoglobulinaemia, amyloid, nephropathy or acquired von Willebrand's Disease.Of EM, 51/70 (73%) had treatment, 35/51 (69%) within the first year from diagnosis with time to treatment 2 months (range 0-364). Time to next therapy was 14 months. Median lines of therapy were 2 (range 1-8). The most common indication for first line therapy was lymphoma-related (16/39; 41%) followed by paraprotein-related (peripheral neuropathy, hyperviscosity and autoimmune) (13/39; 33%). First line therapies included Bendamustine-Rituximab (BR; 8/49; 16%), Dexamethasone Rituximab Cyclophosphamide (DRC; 7/49; 14%) and R-CHOP (5/49; 10%) with smaller proportions receiving Rituximab monotherapy, Cladribine + Rituximab or Fludarabine + Cyclophosphamide + Rituximab (FCR) (3/49 (6.1% each). Two of 41 (5%) of EM had first treatment as a part of a clinical trial, compared to 16/156 (10%) of the White cohort (p=0.28). Response to first line therapy was similar between the White & EM cohorts (Table 1).For EM, at a median follow up of 7 years, 17 died (1/17; 6% disease related). Median OS was not reached (Figure 1). Estimated 5-year and 10- year OS was 91% (95% CI 96-80%) and 75% (95% CI 85-60%), respectively.Conclusions: This first report on ethnic disparities in WM and non-IgM LPL in the UK identified key differences in presentation of disease. Ethnic minorities present at a younger age, with a lower paraprotein. The Asian cohort had a greater proportion of non-IgM LPL cases and fewer MYD88 mutated cases. A small proportion of Ethnic Minorities have treatment on a clinical trial which may warrant further attention. Further analysis including associations with socioeconomic status, deprivation indices and comorbidities are ongoing.•Ailawadhi, Sikander et al. “Outcome disparities among ethnic subgroups of Waldenström's macroglobulinemia: a population-based study.” Oncology vol. 86,5-6 (2014): 253-62. doi:10.1159/000360992 DisclosuresMcCarthy: Janssen: Honoraria; Astra zenica pharmaceuticals: Honoraria; Amgen: Honoraria. Pratt: Amgen: Consultancy; Binding Site: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Takeda: Consultancy. El-Sharkawi: AbbVie: Honoraria, Other: Travel Support, Ad boards; AstraZeneca: Honoraria, Other: Ad boards; Janssen: Honoraria, Other: Ad boards; Roche: Honoraria; Takeda: Honoraria; Novartis: Other: Travel Support; ASTEX: Other: Ad boards; Beigene: Other: Ad boards; Kyowa Kirin: Other: Ad boards. Linton: Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aptitude Health: Honoraria; Hartley Taylor: Honoraria; Celgene: Research Funding; BeiGene: Research Funding; University of Manchester: Current Employment. Gatto: Roche: Consultancy. D'Sa: Janssen Cilag: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Sanofi: Honoraria.

Serum Immunoglobulin Paraprotein Associated with Inferior Progression Free Survival in Patients with Mucosa-Associated Lymphoid Tissue Lymphoma

IntroductionIn order to investigate the clinical and certain laboratory features of mucosa-associated lymphoid tissue (MALT) lymphoma patients with immunoglobulin (Ig) paraproteinemia and identify the potential prognostic value of Ig paraproteinemia in MALT lymphoma.Methodswe reviewed the medical records of all patients diagnosed with MALT lymphoma and performed Ig paraprotein test at the First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital from April 2010 to December 2016. A total of 115 patients were diagnosed with MALT lymphoma, of which 78 patients had been tested for serum Ig paraprotein. The correlations between serum Ig paraprotein and other prognostic factors were analyzed. Univariate and cox regression analyses were used to assess associations between survival time and potential risk factors.ResultsAmong 78 MALT lymphoma cases, 16 (20.5%) had Ig paraproteinemia, mostly IgM-K (5, 31.3%), followed by IgM-L, IgG-L, IgM-K/IgA-K, IgA-L, IgM-L/IgA-L. According to the correlation analysis, male (P=0.022), advanced Ann Arbor stage (P <0.001), lymph nodes involvement (P <0.001), high level of serum β2-microglobulin (P <0.001) and low level of serum albumin (P= 0.001) were significantly related to the presence of Ig paraproteinemia. Survival analysis illustrated that patients with IgM paraproteinemia had significantly shorter progression-free survival (PFS) (P=0.005) than those without IgM paraproteinemia (Figure 1). Cox regression analysis showed that IgM paraproteinemia was an independent prognostic factor for PFS of MALT lymphoma patients (P=0.037). Risk stratification based on IPI together with IgM paraproteinemia could divide patients with MALT lymphoma into four groups and better identify high or low risk of PFS (P <0.0001) and OS (P <0.0001) in MALT lymphoma patients (Figure 2).ConclusionMALT lymphoma patients with Ig paraproteinemia represent a subgroup with inferior PFS. Serum Ig paraprotein might be applied for the assessment of prognosis in patients with MALT lymphoma. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Application and Outcomes of Bendamustine- or Bortezomib-Based Therapy for Waldenstrom's Macroglobulinemia

Background: Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) is a rare lymphoproliferative disorder typically affecting older patients and characterized by unique complications of IgM paraproteinemia. Treatment of this disease largely relies on phase 2 clinical trials or extrapolation of data from pooled studies in indolent B-cell lymphomas. We have previously shown a rapid uptake of novel, expensive therapies (bendamustine and bortezomib) for WM/LPL in the US, despite uncertain advantage over classical cyclophosphamide-based chemoimmunotherapy (Olszewski et al., Oncologist, 2016). We now examined patterns of use of these novel agents, associated survival, and cost outcomes, in population-based data. Methods: Using Medicare claims linked to the Surveillance, Epidemiology, and End Results registry, we identified WM/LPL patients aged ≥65 years who initiated first-line rituximab-based therapy in 2008-2014, and had complete Medicare claims available. We classified regimens into: rituximab alone, rituximab in combination with classical cytotoxic agents (cyclophosphamide, fludarabine, etc.) or with novel agents: bendamustine or bortezomib. We evaluated patient characteristics associated with the use of classical immunochemotherapy, bendamustine, or bortezomib, in a multinomial logistic model, reporting relative risk ratio (RRR) with 95% confidence intervals (CI). We then compared overall survival (OS) after therapy in a proportional hazard model adjusting for age, sex, race, comorbidity index, presence of kidney disease, poor performance status, and indicators of WM severity: anemia, neuropathy, need for plasmapheresis, transfusions, or hospitalization prior to therapy. Mean total Medicare spending within 1 year from starting therapy was compared in a log-gamma model, inflation-adjusted to 2013 dollar value. Results: Among 681 patients, 58% received upfront rituximab alone (N=392), 22% rituximab in combination with classical chemotherapy (N=151), 11% with bortezomib (N=76), and 9% with bendamustine (N=62). The proportion receiving bendamustine or bortezomib significantly increased between 2008 and 2014, displacing classical immunochemotherapy, but not rituximab monotherapy (Fig. A). In the multivariable model, patients treated with bortezomib were significantly more likely to be black than white (RRR, 7.49; 95%CI, 1.62-34.7; P=.010), more likely to be diagnosed as WM rather than LPL (RRR 2.38; 95%CI, 1.25-4.53; P=.008), and more likely to have chronic kidney disease (RRR, 3.18; 95%CI, 1.12-9.02; P=.029) or plasmapheresis before treatment (RRR, 2.99; 95%CI, 1.01-8.85; P=.048). Conversely, no black patients received bendamustine, which was also significantly less often administered to women (RRR, 0.46; 95%CI, 0.23-0.92; P=.027), patients with a prior hospitalization (RRR, 0.37; 95%CI, 0.17-0.78; P=.009), or with WM diagnosis code (RRR, 0.55; 95%CI, 0.29-1.04; P=.07). After adjustment for baseline patients characteristics we observed no significant difference in OS between immunochemotherapy combinations with classical agents and with bendamustine (hazard ratio, HR, 0.84; 95%CI, 0.46-1.53; P=.57) or bortezomib (HR, 1.07; 95CI, 0.68-1.69; P=.77; Fig. B). Mean total Medicare spending during the first year of therapy was over $20,000 higher for patients treated with bortezomib (P=.015) or bendamustine (P=.011) compared with the classical immunochemotherapy (Fig. C). Conclusions: Although about half of older patients with WM/LPL in the US continue to be treated with rituximab alone, bendamustine and bortezomib have largely replaced classical cytotoxic agents for those who receive combination immunochemotherapy. Clinicians favor bortezomib for patients with paraprotein-associated complications, and bendamustine for LPL-like presentations, even though differential benefits of these drugs are not supported by prospective evidence. Treatment decisions may thus result from extrapolation of data on myeloma or other lymphomas. Considering no apparent survival difference and higher costs of treatment with the novel agents, their value compared with classical regimens (like dexamethasone-cyclophosphamide-rituximab [Kastritis et al., Blood, 2015]) should be reconsidered in the US practice, and more precisely defined with further clinical research. Download : Download high-res image (145KB) Download : Download full-size image Disclosures Treon: Pharmacyclics: Consultancy, Research Funding. Castillo: Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Research Funding.

Reactive Versus Neoplastic Bone Marrow Lymphoid Nodules—Diagnostic Challenge in a Case with Anemia and IgM Para-proteinemia

Reactive Versus Neoplastic Bone Marrow Lymphoid Nodules—Diagnostic Challenge in a Case with Anemia and IgM Para-proteinemia

Anti-myelin-associated glycoprotein antibody positive IgM monoclonal gammopathy related peripheral neuropathy: 11 cases and literature review

目的提高对罕见的抗髓鞘相关糖蛋白（MAG）抗体阳性的IgM相关性周围神经病（IgM-PN）的认识。方法总结2014年1月至2019年4月北京协和医院诊断的11例抗MAG抗体阳性的IgM-PN患者的临床特点、实验室检查、治疗方案和预后。结果11例患者中，男8例，女3例，中位发病年龄63（52~77）岁。其中9例患者以远端肢体麻木起病，6例伴肌力减退。神经传导速度检查示，均为周围神经脱髓鞘损害，以下肢感觉神经损害为主，6例伴慢性轴索损害。11例患者均存在血清IgM型单克隆免疫球蛋白，6例为IgM κ型，3例为IgM λ型，2例为IgM κ/IgG κ双克隆型。3例患者继发于巨球蛋白血症。11例患者的血清抗MAG抗体均为阳性。9例患者接受利妥昔单抗单药或联合化疗，治疗后7例患者的神经症状稳定或改善。结论抗MAG抗体阳性的IgM-PN是一种罕见的M蛋白相关性疾病。对于伴IgM型M蛋白的周围神经病患者，应常规筛查抗MAG抗体。基于利妥昔单抗的治疗可作为其一线治疗方案。

What is new in the treatment of Waldenstrom macroglobulinemia?

Waldenstrom macroglobulinemia (WM) is a rare type of non-Hodgkin lymphoma. The diagnosis of WM is established by the presence of lymphoplasmacytic lymphoma in the bone marrow or other organs, a monoclonal IgM paraproteinemia and the recurrent MYD88 L265P somatic mutation. Some patients with WM can be asymptomatic, in which case treatment is not indicated. However, most patients with WM will become symptomatic during the course of the disease, due to anemia, hyperviscosity, neuropathy, or other processes, necessitating therapy. Current treatment options for symptomatic WM patients include alkylating agents, proteasome inhibitors and anti-CD20 monoclonal antibodies. The approval of the oral Bruton tyrosine kinase (BTK) inhibitoribrutinib alone and in combination with rituximab has expanded the treatment options for WM patients. The present Perspective would focus on exciting treatment strategies under development for WM patients, such as proteasome inhibitors (e.g., ixazomib), BTK inhibitors (e.g., acalabrutinib, zanubrutinib, vecabrutinib), BCL2 inhibitors (e.g., venetoclax), and anti-CXCR4 antibodies (e.g., ulocuplumab), among others. It is certainly an exciting time for WM therapy development with novel and promising treatment options in the horizon.

Validation and method comparison of the use of densitometry to quantify monoclonal proteins in canine sera

Densitometric quantitation using serum protein electrophoresis (SPE) is used to monitor monoclonal proteins (M-proteins) in human patients but has not been validated in the dog. Serum globulin concentrations, species-specific radial immunodiffusion (RID), and ELISAs are currently used in veterinary medicine. We aimed to compare four methods that quantify M-proteins using densitometry and biuret protein (dM-protein) measurements. We also validated the best performing method and compared it with the RID and ELISA methods for measuring canine serum M-protein. Serum from six normal dogs and 83 serum samples from 46 dogs with confirmed monoclonal gammopathies were used. A spike and recovery experiment with purified monoclonal IgG and IgM, inter-run and intra-run variability, linearity under dilution, and lower limit of detection were performed. Results of commercial canine RID and ELISA kits for total class-specific immunoglobulin were compared with dM-proteins. The corrected perpendicular drop gating method had <20% error for IgG/γ-globulin and IgM/β-globulin M-protein quantifications. Linearity (r>.99), intra-run CV (1.1%-2.3%), and inter-run CVs (2.0%-3.5%) were acceptable. Correlation between the RID and densitometry results ranged from r=.25 to r=.88, depending on the class. The RID result was greater than that of the biuret total protein in 26/63 (41%) IgA cases. A panel of IgG, IgA, and IgM RIDs failed to correctly identify an IgM paraproteinemia in 6/6 (100%) cases. Densitometry was not comparable with any other tested method. Densitometric quantitation is a valid technique for measuring M-proteins in the β- and γ-globulin regions. Immunotyping via RID using the tested kit does not appear to detect IgM. Densitometry is recommended for measuring M-proteins in canine patients.

Non-IgM Secreting Lymphoplasmacytic Lymphoma - Experience of a Reference Center for Waldenstrom Macroglobulinemia

Background: Lymphoplasmacytic lymphoma (LPL) secreting immunoglobulins other than IgM is rare. Therefore, there are very few case series on non-IgM LPL and little is known about the clinical features and outcomes of patients with this disease.Aim: To describe disease characteristics and clinical outcomes of patients with non-IgM LPL.Methods: We identified cases of non-IgM LPL in the records of the Waldenström Macroglobulinemia (WM) clinic at our institute, between the years of 2000-2018. All patients were part of the clinic's registry. We extracted data from their electronic records and included only cases with centrally-confirmed diagnosis. Response assessment was based on 6th IWWM criteria. Time to events was estimated using the Kaplan-Meier method.Results: We found 31 patients with non-IgM LPL. Median age at diagnosis was 63 years (range, 37-83 years), 45% were over the age of 65, and 65% were women. The paraprotein secreted by these tumors was IgG in 20 cases (65%); IgA in 5 (16%), light-chain (LC) in 2 (6%) and was non-secretory (NS) in 4 (13%). Median level of IgG and IgA at diagnosis was 3,967 mg/dl (range, 804-8,006 mh/dl) and 1,980 mg/dl (range, 1,020-6,210 mg/dl), respectively. We included 5 cases with concurrent IgM paraproteinemia, when it was clearly secreted to a lesser extent than dominant immunoglobulin and had similar LC restriction.Five patients had MGUS preceding diagnosis of LPL. Presenting symptoms were anemia-related (n=13), asymptomatic (n=7), neuropathy, autoimmune phenomena, elevated creatinine, bleeding diathesis and recurrent infections (n=3, each). Only 1 patient had B-symptoms. One patient with IgA LPL and serum IgA level of 4,000 mg/dl presented with retinal vein occlusion due to hyperviscosity. Non-bulky (<5 cm) lymphadenopathy was found in 11 patients (35%), and mild splenomegaly in 5 (16%). Anemia was prevalent (53%) with hemoglobin <10 g/dl in 23%. No patient had neutropenia (ANC <1 K/uL) or thrombocytopenia (platelets <100 K/uL) at presentation. Five patients (16%) presented with mild lymphocytosis (median, 7.1 K/uL; range, 3.3-20.6 K/uL). Βeta-2-microglobulin level was >3 mg/L in 48% of available patients (n=12/24).All bone marrow biopsies showed that malignant cells were positive for CD20 and CD19 by flow cytometry; 14% were CD5 positive (subset/dim); 29% CD23 partially-positive; and all were CD10 negative. Five of 19 cases (26%) had cytogenetic abnormalities, but apart from del6q (n=1), none were of commonly known aberrations in hematological malignancies. Only 1 patient with kidney disease underwent renal biopsy that revealed light-chain deposition disease. Amyloidosis was detected in 2 patients, one with neuropathy and the other patient was asymptomatic. The MYD88 L265P mutation was detected in 10 of 14 patients (71%) tested, and CXCR4 mutations in 2 of 8 patients (25%) tested. Both patients with a CXCR4 mutation needed treatment immediately at diagnosis and subsequently had 4 or more lines of therapy.With a median follow up of 4.6 years (95% CI 2.5-7.6 years), 68% of the patients had been treated (n=21), 90% of whom within the first year from diagnosis. As such, the median time to first treatment was 2.3 months. However, time to next therapy was significantly longer, with a median of 4.7 years. Patients had a median of 3 lines of therapy (range, 1-8), including purine analogues in 33% of patients, alkylating agents in 48%, bendamustine in 38%, anti-CD20 monoclonal antibodies in 90%, proteasome inhibitor in 24%, and immunomodulating drugs in 14%. Two patients received ibrutinib: one achieved VGPR with over 3 years remission duration, after prior 7 lines of therapy; and the other, who had only a brief response, was found to carry the CXCR4 mutation. There were 4 (13%) deaths: 1 patient developed Bing-Neel syndrome at first relapse that ultimately lead to his demise; 1 died from treatment complications; and 2 of unknown cause. The 5-year and 10- year OS are 90% (95% CI 64-98%) and 81% (95% CI 49-94%), respectively (Figure 1).Conclusion: To our knowledge, this is the largest reported series of non-IgM LPL and the first to demonstrate excellent long-term outcomes in these patients. [Display omitted] DisclosuresHunter:Pharmacyclics: Consultancy. Treon:Janssen: Consultancy, Other: Travel, Accommodations, Expenses; BMS: Research Funding; Johnson & Johnson: Consultancy; Pharmacyclics: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding. Castillo:Beigene: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; Millennium: Research Funding.

An Undetectable Serum Prealbumin (Transthyretin) Measurement led to the Discovery of a Monoclonal Gammopathy: The Role of an Astute Scientist

Case: A 93-year-old male presented to hospital with lower limb weakness. A ‘nutritional screen’ was performed and serum prealbumin measurement (turbidimetric assay) was undetectable (<30 mg/L) on the Beckman Coulter AU 5800. Compared to random controls, the assay reaction curve showed an abnormally high blank absorbance reading and a final ‘decreased’ (negative) absorbance. Two previous cases of undetectable serum prealbumin measurement were observed at our institution. Both females had IgM paraproteinaemia: one had persistently undetectable serum prealbumin despite optimal nutritional therapy; both also had undetectable serum vancomycin measurements. Reaction curves showed a high blank absorbance reading. Various dilutions did not eliminate the interference. Polyethylene glycol (PEG) precipitation procedure demonstrated post-PEG prealbumin results similar to measurements on an alternative instrument (interference-free). Precipitation with ethanol worked better for vancomycin.1 Serum protein electrophoresis showed a newly found IgM paraprotein (11 g/L) in our 93-year-old patient.

Advances in the Treatment of Paraproteinemic Neuropathy

Purpose of review Several advances have been made on the pathogenesis and therapy of neuropathies associated with paraproteinemia (monoclonal gammopathy). It is important for the neurologist to understand the pathogenetic relevance of this association especially when the hematological disease does not require per se any therapy. Recent findings Treatment of the neuropathy in patients with malignant paraproteinemia is mainly addressed by the hematologist while the neurologist is mainly involved in the initial diagnosis and in deciding whether the neuropathy is caused by the disease or by the chemotherapy used for the disease. There is little evidence that the neuropathy is caused by the hematological condition in patients with IgG or IgA monoclonal gammopathy of undetermined significance (MGUS) unless there is an evidence of a reactivity of the paraprotein with nerve or evidence of its presence in the nerve. Patients with a chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)-like presentation should be treated as CIDP while there is no evidence that immune or chemotherapy may be effective in the other patients. In most patients with IgM paraproteinemia, that is usually a MGUS or an indolent Waldenström's macroglobulinemia, the neuropathy is induced by an immune reactivity of the paraprotein with nerve and particularly with the myelin-associated glycoprotein. There are now consistent data also from controlled studies that the anti-CD20 monoclonal antibody rituximab may improve the neuropathy in these patients. POEMS syndrome is a severe condition characterized by a disabling neuropathy whose prognosis has improved in the last few years with therapies against the proliferating plasma cell clone or vascular endothelial growth factor including local radiotherapy and chemotherapy followed by autologous stem cell transplantation. Other therapies are also available for patients not eligible or resistant to transplantation, including lenalidomide and possibly thalidomide or bortezomib. Summary Several new therapies are now available for patients with paraproteinemic neuropathy consistently improving the prognosis of these neuropathies. In most instances, however, their efficacy needs to be confirmed in controlled trials.

R‐CP CHEMOIMMUNOTHERAPY IN PATIENTS WITH IGM PARAPROTEINAEMIC NEUROPATHY PRODUCES IMPROVEMENTS IN FUNCTIONAL, ELECTROPHYSIOLOGICAL AND SEROLOGICAL OUTCOMES

Introduction: Peripheral neuropathy is a well-recognized complication of IgM paraproteinaemia associated with both underlying NHL (usually LPL) and IgM MGUS. In 60% of cases, the M protein shows reactivity to myelin-associated glycoprotein (MAG). Anti-MAG antibodies have been shown to be neuropathic, and the natural history of the neuropathy is of persistent functional decline with poor response to immunomodulatory agents. We postulated that the neuropathic component may respond better to combination therapy than to chemo or immunotherapy alone as seen in LPL. Methods: A total of 25 patients (16 IgM MGUS, 8 LPL, 1 CLL) were treated with 6 cycles every 21 days of rituximab 375 mg/m2 and cyclophosphamide 750 mg/m2 i/v on day 1 and 5 days of oral prednisolone 50 mg/m2. Assessments carried out at baseline and then at 3 months, 1 and 2 years post-treatment were serum paraprotein and Anti-MAG titres, standardised neurological functional scores—Overall Neuropathy Limitation Score (ONLS), MRC Sum Score for muscle power, Sensory Sum Score and standard nerve conduction studies (NCS) as well as patient reported outcome measures (PROMS). BM biopsy and CT scans were performed at baseline and at 3 months post treatment to assess remission status. Results: The treatment was well tolerated. Post treatment, the ONLS was significantly improved at 1 year, p = 0.006 and MRC motor score at 2 years, p = 0.031. In NCS, mean sensory action potential sum score improved and mean distal motor latency sum score reduced. In PROMS at 1 year, 44% reported improvement in symptoms, 28% reported a stabilisation of symptoms previously deteriorating before treatment and only 24% reported continuing slow deterioration. All patients with underlying NHL achieved at least a partial remission at 3 months post-treatment. IgM paraprotein levels fell in all 25 patients from a baseline median level of 4.7 g/l to 2.25 g/l at 3 months, p = 0.000 and to 1.95 g/l at 2 years, p = 0.000. In patients with Anti-MAG antibody, levels fell from a baseline median of 38,956 to 14,783 units by 2-year post-treatment, p = 0.002. Keywords: immunochemotherapy; lymphoplasmacytic lymphoma/Waldenstroem (LPL/WM); monoclonal gammopathy of undetermined significance (MGUS).

Technical assessment of membrane plasmapheresis in treatment of a patient with IgM paraproteinemia

Technical assessment of membrane plasmapheresis in treatment of a patient with IgM paraproteinemia

MYD88 (L265P) somatic mutation in marginal zone B-cell lymphoma.

MYD88 L265P is a somatic mutation that has been identified in about 90% of Waldenström macroglobulinemia/lymphoplasmacytic lymphomas (LPLs). It has also been detected in a subset of marginal zone lymphoma (MZL) cases, but the frequency and clinical and histologic features of these mutated MZL cases has only been partially characterized. We have developed a customized TaqMan allele-specific polymerase chain reaction for sensitive detection of this mutation in paraffin-embedded tissue. We analyzed samples from 19 patients with LPL, 88 patients with splenic marginal zone lymphoma (SMZL), 8 patients with nodal marginal zone lymphoma (NMZL), 21 patients with extranodal mucosa-associated lymphoid tissue (MALT), and 2 patients with B-cell lymphoma not otherwise specified. By integrating mutational, histologic, and clinical data, 5 cases were reclassified as LPL. After reclassification, MYD88 L265P was detected in 13/86 (15%) SMZL and in 19/24 LPL (79%) cases. The mutation was absent from NMZL and MALT cases. A strong correlation was found between the presence of an IgM monoclonal paraproteinemia and the MYD88 L265P mutation (P<0.0001). SMZL cases positive for MYD88 L265P were also associated with monoclonal IgM paraproteinemia (4/13 cases; P<0.0283), although with less serum paraproteinemia. They also had a higher frequency of plasmacytic differentiation (9/13) but with no correlation between the presence of mutation and of light chain-restricted plasma cells in tissue. Demonstration of the MYD88 L265 mutation is a valuable tool for the diagnosis of LPL, although some SMZL cases carrying the mutation do not fulfill the diagnostic criteria for LPL.

IgM multiple myeloma: diagnostic difficulties and results of bortezomib treatment – case report

The IgM paraprotein secretion is most frequently associated with Waldenstrom’s macroglobulinemia. In very rare cases it may also occur in multiple myeloma. The diagnostic and therapeutic process of a 84 year old male suffering from IgM multiple myeloma is described, including difficulties in establishing this diagnosis. Due to infectious complications, after the first cycle of melphalan– prednisone–bortezomib treatment, melphalan was stopped, subsequently, bortezomib and prednisone doses were also reduced. Two treatment interruptions have occurred. Despite reduced treatment intensity, the patient was in very good partial remission, while the toxicity profile was acceptable. IgM multiple myeloma should be included in the differential diagnosis of IgM paraproteinemia, also when osteolytic lesions and translocation 11:14 are not detected. Bortezomib-based therapy can be effective in elderly patients (also in those suffering from cardiac insufficiency), even when dose reduction is required.

93. CANOMAD: Clinical and neurophysiological findings in two cases

The acronym CANOMAD (Chronic Ataxic Neuropathy, Ophthalmoplegia, IgM paraproteinemia, cold Agglutinin and Disialosyl antibodies) refers a rare immune-mediated peripheral neuropathy, whose clinical spectrum has still to be fully delineated. Herein we report the clinical and neurophysiological features of two CANOMAD patients. A 52-year-old man suffering from distal sensory symptoms and ataxia had received a first diagnosis of chronic inflammatory prominent-sensory polyneuropathy 11 years ago. High-dose i.v. steroid treatment resulted in paradoxical severe worsening with ophthalmoplegia and ambulation loss. Based on immunological and clinical–neurophysiological revaluation a diagnosis of CANOMAD was made. Since then IVIg periodic infusions had allowed good clinical remission up to-day, although minor degree of motor impairment and ataxia relapsed during last years. This 62-year-old man had a 5-year history of mild lower limb ataxia. More recently, a fluctuating bilateral ptosis was seen. Serum was positive for anti-disialosyl IgM antibodies and cold agglutinins. NCS/EMG showed a mild chronic sensory-motor neuropathy. Cortical somatosensory evoked potentials by tibial nerve stimulation at the ankle were deranged, whereas responses at the popliteal fossa and sural NCS were largely preserved. This suggests a proximal alteration of peripheral sensory conduction. These data further confirm the heterogeneous presentation of CANOMAD.

Clinical Presentation and Treatment Responses in IgM AL Amyloidosis, a Series of 106 Patients

Objective: AL amyloidosis is a multiorgan disease due to deposition of misfolded monoclonal immunoglobulin light chains. AL amyloidosis with IgM paraproteinemia is a rare variant of this disease; accounting for approximately 6% of AL amyloidosis cases. The clonal cell of origin may be a plasma cell or lymphoplasmacytic cell, and treatments targeting each have been employed. This study describes clinical and laboratory features of IgM AL amyloidosis patients and their response to different therapeutic regimens.Methods: 106 patients with IgM-related AL amyloidosis were evaluated at the BUMC Amyloidosis Center during 1996-2012. Treatment and response information was available on 46 treated after 2003, during the era of new agents for plasma cell diseases. In this cohort, there were 5 treatment groups: high-dose melphalan/stem cell transplant (HDM/SCT); bortezomib-based regimens; standard doses of the alkylating agents melphalan or cyclophosphamide; immunomodulatory agents (IMiDs); and rituximab-based regimens. Treatment regimens were assigned by bone marrow pathology and patient-specific factors.Results: For the 106 patients, the median age at diagnosis was 67 years (range: 38-89 years) with 52 (56%) males. The kidney was the most commonly involved organ (51%) followed by heart (41%) and GI tract (23%). Median IgM was 590 g/dL (range: 29-9130). The clonal population had lambda light chain restriction in 69% of patients. For the 46 patients treated after 2003, overall response rates and rates of very good partial or complete responses were were 100% and 80% respectively, with HDM/SCT; 82% and 30% with bortezomib-containing regimens; 80% and 25% with regimens that included rituximab; 75% and 0% with regimens in which an IMiD was included; and 63% and 20% with other alkylator regimens. There was no association between treatment response and organ involvement, sex, or age. DisclosuresSloan:Millenium: Consultancy.

Low-grade B-cell lymphoma presenting primarily in the bone marrow.

Cases of low-grade B-cell lymphoma presenting primarily in the bone marrow are rare, and its clinicopathology remains unclear. We retrospectively examined patients with low-grade B-cell lymphoma presenting primarily in the bone marrow. Fourteen patients met the inclusion criteria, including 5 with lymphoplasmacytic lymphoma (LPL), 3 with chronic lymphocytic leukemia/small lymphocytic lymphoma, 2 with follicular lymphoma (FL), and 4 with low-grade B-cell lymphoma not otherwise specified (LGBCL-NOS). The median age was 69.5 years (range, 42-89 years), and a slight male predominance was noted (9 men and 5 women, 1.8: 1). Immunohistochemically, all cases were positive for CD20. One case was positive for CD138. Both cases of FL were positive for CD10 and B-cell lymphoma 2 (BCL-2), and immunoglobulin heavy locus (IgH)/B-cell lymphoma 2 rearrangement was observed by fluorescence in situ hybridization. The myeloid differentiation primary response gene (88) leucine to proline mutation was observed in 3 of 5 LPL, 1 of 2 FL, and 2 of 4 LGBCL-NOS patients. Paraproteinemia was observed in 10 patients; IgM and IgG paraproteinemia were observed in 6 and 3 patients, respectively. In this patient series, 3 patients had died at a median follow-up of 36.5 months; the cause of death of 1 LPL patient was malignant lymphoma itself. Thus, low-grade B-cell lymphoma presenting primarily in the bone marrow has various subtypes, and approximately one-third of the patients had LGBCL-NOS. The immunophenotypic features and myeloid differentiation primary response gene (88) leucine to proline mutation data of LGBCL-NOS suggested that some cases present with characteristics similar to those of LPL or marginal zone lymphoma.