IgM Monoclonal Gammopathy Research Articles

Molecular characterization of heavy chain immunoglobulin gene rearrangements in Waldenstrom's macroglobulinemia and IgM monoclonal gammopathy of undetermined significance

Waldenström macroglobulinemia (WM) and monoclonal gammopathy of undetermined significance (MGUS) are IgM-related disorders in which monoclonal B cells harbor a unique clonotypic rearrangement of the immunoglobulin heavy chain gene (IgH). The aim of this study was to characterize IgH rearrangements in a larger series of IgM-related disorders than any previously described. Seventy-two patients with monoclonal IgM disorders (64 with WM and eight with IgM-MGUS) were studied to amplify and sequence both VDJH and DJH rearrangements. Twenty-nine of them were also tested for the existence of class switch recombination (CSR). VDJH and DJH rearrangements were detected in 91% and 42% of WM patients and in 100% and 13% of IgM-MGUS patients, respectively. In WM, the most frequently observed VH family and single segment were VH3 and VH3-23 (76% and 29%, respectively), with their frequencies differing markedly from those that would occur if the rearrangements were random. The VH3-23 segment was never selected in IgM-MGUS. The distribution of both DH and JH families in WM did not differ from that in normal B-lymphocytes. Somatic hypermutation with >2% deviation was seen in 90% of cases of WM and in 71% of IgM-MGUS. DJH rearrangements were more frequent in WM than in MGUS (42% and 13%, respectively). All DJH rearrangements were unmutated, which makes them an attractive target for minimal residual disease investigation. IgM clonotypic transcripts were observed in all cases and IgD in 83%. IgA and/or IgG monoclonal isotypes were seen in three WM cases (14%) but in none of the IgM-MGUS patients. WM and IgM-MGUS exhibit dissimilarities in VDJH and DJH rearrangements that could suggest different differentiation processes. There is evidence that WM cells are able to undergo CSR in vivo, a fact that was initially thought to be impossible in this disease.

Prompt response of refractory Schnitzler syndrome to treatment with anakinra

To the Editor: Schnitzler syndrome (SS), first reported by a French dermatologist in 1972,1 is an extremely rare and probably underrecognized disorder. It is defined as chronic urticarial rash with a monoclonal IgM gammopathy (seldom IgG type).2-4 After 10 to 20 years, 15% of patients with SS develop lymphoproliferative disorders.3,5 Further cardinal features are intermittent fever of unknown origin, disabling bone pain, hyperostosis, and increased erythrocyte sedimentation rate. Even though it is a rare disease, SS should be considered in case of dramatic bone pain, mainly located in the distal femur and proximal tibia, and a minimally itchy chronic urticaria.

Nephrotic syndrome in a patient with IgM myeloma with associated neutrophilia

An unusual case having IgM monoclonal gammopathy with clinical and pathologic features of multiple myeloma (MM) in association with neutrophilia and nephrotic syndrome is reported. The patient showed lytic bone lesions, decreased IgG and IgA levels, Bence-Jones proteinuria, nephrotic proteinuria with edema, and histological plasma cell infiltration typical of MM. Moreover, mature neutrophilic leukocytosis, hepatomegaly, high leukocyte alkaline phosphatase score (LAP), absence of Philadelphia (Ph) chromosome and bcr gene rearrangement were also evidenced, all these features representing findings typical of the recently described plasma cell dyscrasia-associated neutrophilia. After the diagnosis, the patient was treated with melphalan and prednisone, with an excellent response to the treatment. Different from the 30 cases so far reported, this is the first case of plasma-cell dyscrasia with associated neutrophilia due to IgM-producing monoclonal gammopathy. At the same time, this is the first reported case of nephrotic syndrome secondary to IgM myeloma.

The incidence and survival of Waldenström's Macroglobulinaemia in South East England

Waldenström's Macroglobulinaemia (WM) is an uncommon B-cell lymphoproliferative disorder defined as a predominately inter-trabecular bone marrow infiltration of small lymphocytes with an IgM monoclonal gammopathy. There are little reliable incidence and survival data for the disease in the UK since epidemiological studies have usually grouped it with other plasma cell dyscrasias. This study uses data from the South Thames Haematology Register and the Thames Cancer Registry for South East England to describe the incidence and survival of WM, and the influence of selected clinical factors on survival. Between 1999 and 2001, there were 152 new cases of WM recorded in the South Thames Haematology Register, giving an age standardised rate of 0.55 per 100,000 European standard population (0.73 for males and 0.42 for females). The incidence increased with age, and the median age at diagnosis was 75 years (range 45–93 years). The estimated 5 year survival was 57% (95% CI: 47–66%). Age over 70, haemoglobin less than 10g/L and the Eastern Cooperative Oncology Group (ECOG) Performance Status grade 3–4 at diagnosis were associated with worse survival. Between 1985 and 2002, the Thames Cancer Registry recorded 750 cases of WM occurring in the wider area of South East England. The relative 5 year survival for patients aged less than 70 years was 70% (95% CI: 60–81%) and for patients aged 70 and over it was 50% (95% CI: 41–60%).

Bilateral orbital tumor formation and isolated facial palsy in Waldenstrom’s macroglobulinemia

A 32-year-old lady presented with bilateral painful proptosis and left infranuclear facial palsy. She was mildly anemic. Ocular examination revealed a firm non-tender mass in the super lateral quadrant of both orbits. Fine-needle aspiration cytology from the orbital mass showed the presence of lymphoplasmacytoid cells. Bone marrow aspiration also showed the presence of similar cells. An IgM monoclonal gammopathy was seen on serum protein electrophoresis. A diagnosis of Waldenstrom's macroglobulinemia was made on the basis of these findings. Hyperviscosity retinopathy is the most commonly reported ocular abnormality in Waldenstrom's macroglobulinemia. Orbital tumor formation and cranial nerve palsies are rarely reported in this condition. We describe the first case of Waldenstrom's macroglobulinemia presenting as an isolated orbital mass and facial nerve palsy.

Serum Free Light Chain (SFLC) Elevation Is Associated with High β2-Microglobulin and with a Shorter Time to Treatment in Waldenström Macroglobulinemia (WM).

WM is a rare lymphoproliferative disorder caracterised by bone marrow lymphoplasmacytic infiltration with IgM monoclonal gammopathy. Assessing the tumor burden in WM is challenging and is not directly related to IgM level or bone marrow infiltration. Thus treatment criteria are based on clinical symptoms related to IgM or pancytopenia. SFLC quantification is a useful tool for the diagnosis and follow-up of gammopathies such as amyloidosis and light chain myeloma. So far its quantification has never been studied in WM. We investigated whether SFLC quantification was correlated with monoclonal component value and established prognostic factors, or was predictive of a shorter time to treatment.We analyzed 45 untreated WM patients (IgMκ: 37; IgMλ: 8) at the time of diagnosis (n=23) or during the follow-up (n=22). Patients were assessed for physical examination, body CT scan, serum protein electrophoresis with albumin (g/l) and monoclonal component (g/L) measurements, SFLC level (The Binding Site®, cut-off: SFLCκ 19.4 mg/L and SFLCλ 26.3 mg/L), peripheral blood count and β2-microglobulin (β2-m). Cut-off values of prognostic factors were those defined by the International Prognostic Index for WM (Morel ASH 2006) ie. β2-m > 3mg/L, Hb < 115 g/L, platelets < 100 G/L, albumin < 35 g/L. Treatment was initiated at diagnosis in 7 patients or during the follow-up in 23 patients. Median follow-up for the whole population was 15 months (1 – 74).Median SFLCκ value was 39 mg/L (1.73–399), median SFLCλ was 12.6 mg/L (1.93–19400). 75 % of patients had upper to normal SFLC value (34/45). Table 1 summarizes univariate analysis of (1) the relationship between high SFLC value (SFLC > N) and known biological prognostic factors, and (2) the impact of SFLC > N and other biological parameters on time to treatment. Our results showed that high SFLC correlated with β2-m but not with other biological prognostic factors or with monoclonal IgM value. (2) Patients with SFLC > N had a shorter time to treatment than patients with normal SFLC value. Furthermore, taking SFLC as a continuous variable in patients with SFLC > N, treatment time was strongly correlated to the SFLC quantification (κ: p=0.01; λ: p=0.01). SFLC could thus be used as a new marker of tumor burden in WM and its prognostic value must be tested in larger WM series. The correlation between SFLC variation and response to treatment is still under investigation.Table 1SFLC > N (1)time to treatment (2)SFLC > NNAp=0.03monoclonal IgM valuep=0.08p=0.001β2-m > 3 mg/Lp=0.03p=0.44Hb < 115 g/Lp=0.43p=0.009Platelets < 100 G/Lp=1p=0.36Albumin < 35 g/Lp=0.3p=0.011

Imatinib Mesylate (Gleevec®) Is Active in Relapsed/Refractory Waldenstrom's Macroglobulinemia: Planned Interim Results of WMCTG Clinical Trial 05-140.

Waldenstrom's macroglobulinemia is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells (LPC) in the bone marrow (BM), along with an IgM monoclonal gammopathy. Characteristic of WM is an increased number of mast cells (MC) which are found in association with LPC, and stimulate LPC growth through several TNF-family members including CD40L, APRIL and BLYS (Ann Oncol 17:1275; Blood 104:917A). As such, we have targeted MC in WM. One important growth and survival factor for MC is stem cell factor (SCF), which signals through CD117. Imatinib mesylate blocks SCF signaling through CD117, and induces apoptosis of WM BM MC and LPC, both of which highly express CD117 (Blood 2004; 104:314b). As such, we performed this Phase II study of imatinib mesylate in patients with relapsed and refractory WM. Intended therapy consisted of imatinib mesylate which was initiated at 400 mg po qD over the first month, and subsequently dose escalated to 600 mg po qD for up to 2 years. Dose de-escalation to 300 mg po qD was permitted for toxicity. Thirteen patients were enrolled and are eligible for evaluation at interim analysis. Median age was 64 (range 53–80 years), and median prior therapies was 2 (range 1–5). Nine and four patients had relapsed and refractory disease, respectively. Following a median of 3 months of therapy, median serum IgM levels for all evaluable patients declined from 3190 (range 763–8130 mg/dL) to 2095 (range 695–7340 mg/dL) at best response (p=0.009). On an intent to treat analysis, 6/13 (46.2%) of patients attained a ≥25% decrease in serum IgM. Responses were prompt, and occurred at a median of 2.5 months. Overall, therapy was well tolerated with ≥grade 2 toxicities as follows: anemia (n=4); edema (n=3); hyperglycemia (n=2); leukopenia (n=2); thrombocytopenia (n=1); neutropenia (n=1); and resulted for 4 patients in dose modification (n=4) or treatment cessation (n=3). The interim results of this study demonstrate that imatinib mesylate is an active and well-tolerated salvage therapy for WM.

Renal involvement in non-malignant IgM gammopathy

Renal involvement is observed frequently in association with malignant gammopathies, mainly those related to light chain deposition [1]. Nevertheless, light chain deposition renal disease has also been described in non-malignant monoclonal gammopathy, namely in IgG or IgA plasma cell dyscrasia [2,3]. Renal involvement in IgM monoclonal disorders is traditionally described in patients with malignant disease (Waldenstrom’s macroglobulinaemia) that includes the deposition of monoclonal IgM and light chains on mesangium and glomerular capillary wall [4–6]. IgM monoclonal gammopathy without malignant criteria can be found in asymptomatic patients or associated with polyneuropathic disease, but renal involvement has rarely been described in this clinical setting [7,8]. We report the case of a patient with non-malignant IgM/k gammopathy, who developed nephrotic proteinuria and progressive renal failure in association with renal deposition of IgM and k light chains.

Rituximab in the treatment of peripheral neuropathy associated with monoclonal gammopathy

Peripheral neuropathy associated with immunoglobulin (Ig)M gammopathy and anti-myelin-associated glycoprotein antibodies is frequently treatment-resistant and different treatment regimens carry substantial toxicity and side effects. More recently, the chimeric anti-CD20 monoclonal antibody rituximab has shown benefits in the treatment of peripheral neuropathy associated with IgM gammopathy with a favorable side-effect profile. There are no published reports of its use in the treatment of neuropathy associated with IgG and IgA gammopathies. Rituximab is usually given at 375 mg/m2 intravenously with four weekly doses that may be repeated after 6–12 months. Large controlled studies are still pending but rituximab is an exciting and promising treatment offering another option in the treatment of peripheral neuropathy associated with IgM monoclonal gammopathy.

6q deletion discriminates Waldenström macroglobulinemia from IgM monoclonal gammopathy of undetermined significance

IgM monoclonal gammopathy of undetermined significance (IgM MGUS) and Waldenström macroglobulinemia (WM) are sometimes clinically difficult to distinguish. In our previous study, deletion of the long arm of chromosome 6 (6q) was found in about half of WM patients. To further clarify the area of minimal deletion at 6q (6q−) and to address the issue of whether 6q− occurs in IgM MGUS, 12 IgM MGUS and 38 WM patients were studied by fluorescence in situ hybridization using probes targeting different chromosomal segments of 6q. No 6q deletions were found in IgM MGUS samples. Of 38 successfully studied WM patients, 21 (55%) showed a deletion of 6q. The area of minimal deletion was between 6q23 and 6q24.3, but the deletion usually encompassed a large fragment of the 6q arm. These results indicate that 6q− can distinguish WM from IgM MGUS and is likely to be a secondary event.

N.P.1 05 Cytogenetic aberrations in neuropathy associated with IgM monoclonal gammopathy

N.P.1 05 Cytogenetic aberrations in neuropathy associated with IgM monoclonal gammopathy

Schnitzler syndrome associated with systemic marginal zone B-cell lymphoma

Schnitzler syndrome is a rare condition defined by chronic urticaria and monoclonal IgM gammopathy. Malignant evolution to Waldenström disease (WD) has been reported in several cases. We report a 49-year-old man who developed a marginal zone B-cell lymphoma (MZL) 3 years after the beginning of Schnitzler syndrome. This is the first report of MZL in association with Schnitzler syndrome. IgM gammopathy is a clue for the diagnosis of Schnitzler syndrome. This condition needs to be closely monitored; it can precede the onset of an authentic lymphoproliferative disorder including WD and rarely MZL.

Therapeutic targeting of CD70 and CD27-CD70 interactions with the monoclonal antibody SGN-70 in Waldenstrom’s Macroglobulinemia (WM)

2509 Background: WM represents a lymphoplasmacytic lymphoma characterized by a monoclonal IgM gammopathy and possesses a mast cell component that may contribute to its pathogenesis. The tumor necrosis factor (TNF) receptor family member, CD27, is a transmembrane co-stimulatory molecule that is also secreted in a soluble form (sCD27). Recent evidence has suggested that interactions between CD27 and its TNF-like ligand, CD70, play a critical role in regulating B-cell activation and survival, and therefore, may provide a viable therapeutic target for the treatment of WM. Methods: Patients with the consensus panel diagnosis of WM who provided written consent were evaluated. ELISA assay kits were obtained from Bender MedSystems. Flow cytometric analysis, RT-PCR, and calcein ADCC assays were performed as previously described (Santos et al, in press). Results: By ELISA, WM patients displayed dramatically higher levels of sCD27 in their sera (median 7.45, range 0–19.42 U/ml) versus healthy donors (median 0, range 0–2.78 U/ml; p = 2.5 × 10−7). CD27 was expressed in 7/7 patients using RT-PCR analysis, and on the tumor cell surface of 5/12 patients. CD70, the target for CD27, was widely expressed on tumor cells (6/6) and mast cells (10/11) using flow cytometric analysis. To define the functional role of sCD27 in WM, we cultured BCWM.1 (CD27−CD70+) WM cells, LAD1 (CD27−CD70+) mast cells, and primary tumor and mast cells (CD70+) isolated from WM patients with sCD27 (0.1–50 ug/mL), and observed no effect on their proliferation or induction of apoptosis. However, culture of LAD1 and primary WM mast cells (10/10) with sCD27 resulted in marked upregulation of two TNF family ligands which support the growth and survival of WM cells: CD40L (CD154) and a proliferation induction ligand (APRIL). Importantly, the anti-CD70 mAb SGN-70 (1 ug/ml) inhibited this upregulation by sCD27, establishing the specificity of the CD27-CD70 interaction. In addition, SGN-70 demonstrated significant ADCC against BCWM.1 WM cells at dose levels up to 20 ug/ml. Conclusions: Taken together, these studies suggest a novel functional role for sCD27 in the pathogenesis of WM, and demonstrate the feasibility of targeting CD70 and sCD27-CD70 interactions with the SGN-70 monoclonal antibody. [Table: see text]

Macroglobulinemia de Waldenström

Waldenstrom macroglobulinemia is an uncommon B-cell lymphoproliferative disorder characterized by bone marrow infiltration of luymphoplasmatic lymphoma, although sometimes there is a extramedullary lymphoma (nodal), with demonstration of an IgM monoclonal gammopathy. It must be distinguished from monoclonal gammopathy of undetermined significance and IgM- related disorders. The median survival of patients with Waldenstrom's macroglobulinemia averages 5 years. Asymptomatic cases should not be treated. Symtomatic cases could be treated with alkylating agents, nucleoside analogues (fludarabine or cladribine), and the monoclonal antibody rituximab. For the managment of hyperviscosity and neuropathies plasmapheresis could be used successfully.

Update on treatment recommendations from the Third International Workshop on Waldenström's Macroglobulinemia

Waldenström macroglobulinemia (WM) is a B-cell disorder characterized by the infiltration of lymphoplasmacytic cells into bone marrow and the presence of an IgM monoclonal gammopathy. As part of the Third International Workshop on WM, held October 7 to 10, 2004 in Paris, France, a consensus panel charged with providing treatment recommendations for WM updated its recommendations on both frontline and salvage therapies. The panel considered encouraging results from recent studies that addressed the use of extended-dose rituximab as well as other treatment options: therapy with either nucleoside analogs and alkylator agents, rituximab in combination with nucleoside analogs, nucleoside analogs plus alkylator agents, or combination chemotherapies, such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or cyclophosphamide and dexamethasone. The panel determined that these were reasonable treatment options for WM patients and such therapeutic approaches were likely to yield results that are at least as good as if not better than the currently recommended use of single-agent alkylator, nucleoside analog, or standard-dose rituximab therapy. Such approaches were deemed to be reasonable treatment for WM patients in both the upfront and salvage settings, though randomized studies addressing the efficacy and toxicity of such novel approaches over previously established standard of care options are needed.

Impaired class switch recombination (CSR) in Waldenström macroglobulinemia (WM) despite apparently normal CSR machinery

AbstractAnalysis of clonotypic isotype class switching (CSR) in Waldenström macroglobulinemia (WM) and IgM monoclonal gammopathy of undetermined significance (MGUS) reveals a normal initial phase of B-cell activation as determined by constitutive and inducible expression of activation-induced cytidine deaminase (AID). Switch μ (Sμ) analysis shows that large deletions are not common in WM or IgM MGUS. In CD40L/IL-4-stimulated WM cultures from 2 patients, we observed clonotypic IgG exhibiting intraclonal homogeneity associated with multiple hybrid Sμ/Sγ junctions. This suggests CSR had occurred within WM cells. Nevertheless, the estimated IgG/IgM-cell frequency was relatively low (1/1600 cells). Thus, for the majority of WM B cells, CSR does not occur even when stimulated in vitro, suggesting that the WM cell is constitutively unable to or being prevented from carrying out CSR. In contrast to WM, the majority of IgM MGUS clones exhibit intraclonal heterogeneity of IgH VDJ. Furthermore, most IgM MGUS accumulate more mutations in the upstream Sμ region than do WM, making them unlikely WM progenitors. These observations suggest that switch sequence analysis may identify the subset of patients with IgM MGUS who are at risk of progression to WM.

Immunoglobulin gene analysis in polyneuropathy associated with IgM monoclonal gammopathy

Antineural antibody activity is the implicated pathogenic mechanism in polyneuropathy associated with monoclonal gammopathy. Recognition of antigen depends on immunoglobulin variable regions, encoded by V genes. We studied V HDJ H and V LJ L gene use in monoclonal B cells by clonal analysis in 20 patients with polyneuropathy and IgM monoclonal gammopathy. V genes associated with bacterial responses appear over-represented and V H3–23 was preferentially used, without association with specific D, J H or V LJ L. V genes revealed somatic mutation and intraclonal variation was found in 9 of 20 patients. Polyneuropathy associated with monoclonal gammopathy may be caused by an immune response to bacterial antigens, which recruit somatically mutated autoreactive B cells.

Length dependence in polyneuropathy associated with IgM gammopathy

In polyneuropathy associated with monoclonal IgM gammopathy, nerve conduction studies may show disproportionate distal slowing consistent with segmental demyelination. This was suggested to represent a length-dependent demyelinating process, starting in distal and proceeding to proximal segments. Because the evidence for this is incomplete, we assessed whether length dependence occurs in IgM neuropathy. In 22 patients with IgM neuropathy, 20 disease controls with chronic inflammatory demyelinating polyneuropathy (CIDP) and 36 normal controls, we investigated motor conduction, sensory conduction, and needle electromyography for nerves with short, intermediate-length, and long axons as well as conduction in short segments of the ulnar nerve from proximal to distal. To compare variables in nerves of different length, we normalized individual values with respect to the median in normal controls. In IgM neuropathy, distal slowing and features of axon loss increased with nerve length, and ulnar nerve conduction became gradually slower from proximal to distal when the elbow segment was excluded. In CIDP, no clear length dependence was found except for distal amplitude. The disproportionate distal slowing in IgM neuropathy may be part of a length-dependent process, assuming that this process is randomly distributed due to a generalized exposure to IgM.

IgM multiple myeloma: Report of four cases and review of the literature

The differential diagnosis between multiple myeloma (MM) and Waldenström's macroglobulinemia (WM) is generally well defined. Consistent with a diagnosis of MM is the presence of a non-IgM monoclonal gammopathy associated to multiple osteolytic lesions and plasma cell infiltration of the bone marrow. Characteristic of WM is the presence of an IgM monoclonal gammopathy associated to lymphoadenopathy, hepatosplenomegaly, anemia and hyperviscosity syndrome in the presence of a monoclonal lymphoplasmacytoid proliferation in the bone marrow. Nonetheless, few cases of IgM myeloma have been reported that display clinico-pathologic features intermediate between MM and WM. Here, this study describes four of 317 (1.2%) patients with an IgM monoclonal gammopathy in whom the morphologic and clinical features were consistent with a diagnosis of IgM myeloma.

Cold Hemolytic Syndrome

In most cases, immune-mediated hemolysis occurs extravascularly and is associated with IgG antibodies on the surface of red cells. Rare syndromes include IgG antibodies that cause direct intravascular hemolysis, such as paroxysmal cold hemoglobinuria. Also rare are extravascular hemolytic syndromes caused by IgM polyclonal or monoclonal antibodies that demonstrate red cell agglutination at 3 degrees C, so-called cold antibodies. Because cold agglutinin disease has a high association with several lymphoproliferative disorders and IgM monoclonal gammopathies, its management differs significantly from that associated with warm autoimmune hemolytic anemia. This case-based presentation is designed to guide the reader to the diagnosis and to the initiation of prompt, effective therapy.