M. Eurelings

Prognosis of polyneuropathy due to IgM monoclonal gammopathy: a prospective cohort study.

Background: The disease course of polyneuropathy associated with immunoglobulin M monoclonal gammopathy (IgM MGUSP) can be highly variable. In order to identify factors that influence long-term disease outcome, a prospective cohort study was performed of 140 patients with IgM MGUSP over a period of 23 years. Methods: All patients with IgM MGUSP who were diagnosed in our tertiary referral center for polyneuropathy were eligible. All patients underwent nerve conduction studies and were tested for anti-MAG antibodies. The modified Rankin Scale, graded muscle strength, quantified sensory function, and laboratory testing were performed at 0, 1, 2, and 5 years and at last visit. The primary outcome measure was the risk of developing a modified Rankin Scale score of ≥3 points. Results: A total of 140 patients with IgM MGUSP fulfilled inclusion criteria (101 [72%] demyelinating, 39 [28%] axonal, 63 [44%] MAG positive). The median age at onset was 59 years (interquartile range 52–67), median disease duration at baseline was 3.2 years (interquartile range 1.9–6). Anti-MAG antibodies were associated with a lower risk of Rankin Scale score ≥3. Demyelination and a higher age at onset were associated with a higher risk for Rankin Scale score ≥3. Based on these 3 factors, a Web-based prognostic model was developed that directly allows clinicians to estimate the probability of developing disability (http://www.umcutrecht.nl/subsite/Prognosis-MGUS-Neuropathy). Conclusion: Higher age at onset and demyelination increase the risk, whereas anti-MAG antibodies decrease the risk, of developing Rankin Scale score ≥3 in polyneuropathy associated with immunoglobulin M monoclonal gammopathy (IgM MGUSP). Our Web-based prognostic model allows determination of prognosis in IgM MGUSP.

Detection of anti-MAG antibodies in polyneuropathy associated with IgM monoclonal gammopathy

Background: Detection of serum antibodies to myelin-associated glycoprotein (MAG) by Western blot (WB) is a valuable assay to diagnose a distinct type of demyelinating polyneuropathy with immunoglobulin M (IgM) monoclonal gammopathy. In this study, the diagnostic accuracy of a new and more practical ELISA to detect these antibodies was validated. Methods: Routine WBs from 2 independent laboratories and ELISA were used to detect anti-MAG IgM in serum from 207 patients with neuropathy and controls. The sensitivity and specificity of these assays were compared and related to the patient clinical and electrophysiologic characteristics. Results: In ELISA, anti-MAG antibodies were found in serum from 49 (72%) of 68 patients with demyelinating polyneuropathy and IgM monoclonal gammopathy. However, in this subgroup of patients, only 30 (44%) and 37 (54%) were positive in the 2 WBs. All of the patients positive in the 2 WBs were also positive in ELISA. A high correlation was found for IgM activity in ELISA to MAG and sulfate-3-glucuronyl paragloboside (SGPG) (Spearman ρ = 0.72, p < 0.0001), supporting the notion that the shared sulfated glucuronic acid moiety of MAG and SGPG is preserved. Most patients positive in anti-MAG ELISA had a slowly progressive sensory–motor demyelinating polyneuropathy, even if the WB was negative. In control groups, however, 4 WB-negative patients with a nondemyelinating monoclonal gammopathy–related polyneuropathy were positive in anti-MAG ELISA. The remaining samples were negative in ELISA. Conclusion: ELISA is more sensitive than Western blot to diagnose anti–myelin-associated glycoprotein related polyneuropathy, although a positive serology may be found in other forms of polyneuropathy as well.

Antiganglioside antibodies in polyneuropathy associated with monoclonal gammopathy

Antibody reactivity to GA1, GM1, GM2, GD1a, GD1b, and GQ1b gangliosides was measured in 87 patients with polyneuropathy associated with monoclonal gammopathy (60 IgM, 25 IgG, 2 IgA) and 42 control patients with monoclonal gammopathy without polyneuropathy (21 IgM, 21 IgG). Of these 87 patients, 30% had anti-myelin-associated glycoprotein antibodies and 15% had antiganglioside antibodies. Antiganglioside antibodies were significantly associated with demyelinating neuropathy and with IgM monoclonal gammopathy. Anti-GD1b and anti-GQ1b antibodies were significantly associated with predominantly sensory ataxic neuropathy.

G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma

Expression of Bcl-2 in multiple myeloma is associated with resistance to chemotherapeutic drugs. Conversely, suppression of Bcl-2 enhanced the chemosensitivity of myeloma cells in vitro. G3139 is an antisense oligodeoxynucleotide targeted to the first six codons of the Bcl-2 mRNA open reading frame. In this study, G3139 was delivered as a continuous intravenous infusion for 7 days at a fixed dose of 7 mg/kg/day in combination with VAD (vincristine, adriamycin, and dexamethasone) chemotherapy. In total, 10 heavily pretreated patients with refractory myeloma participated in this trial, including eight patients with VAD refractory disease. The combination of G3139 and VAD was feasible and well tolerated. Seven patients (70%) responded including four patients (40%) with a partial response and three patients (30%) with a minor response. Median progression-free survival was 6 months (range, 2–7+ months) and median overall survival has not been reached. G3139 downregulated Bcl-2 protein levels in peripheral blood circulating myeloma cells, B cells, T cells, and monocytes. These results indicate that G3139 may overcome classical resistance and restore sensitivity of myeloma tumor cells to VAD chemotherapy.

Neuropathy and IgM M-proteins: prognostic value of antibodies to MAG, SGPG, and sulfatide.

Background: In polyneuropathy associated with immunoglobulin M (IgM) monoclonal gammopathy, antibodies to myelin-associated glycoprotein (MAG), sulfoglucuronyl paragloboside (SGPG), and sulfatide have been associated with specific clinical and electrophysiologic features. However, it is not known whether the results of antibody tests provide additional information for the individual patient (and the neurologist) in terms of future neurologic deficit or outcome. Objective: To study the independent contribution of potential prognostic factors to the prediction of outcome of neuropathy associated with IgM monoclonal gammopathy. Methods: In accordance with the chronology in which prognostic factors are available in clinical practice, the association between prognostic factors and outcome was evaluated by univariate and multivariate logistic regression analysis in 65 patients with polyneuropathy and IgM monoclonal gammopathy. Results: In univariate analysis, the initial symptoms, the IgM light chain type, electrophysiologic and pathologic studies, the presence of sural nerve IgM deposition, and anti-MAG or anti-SGPG antibodies were significantly associated with outcome. However, multivariate analysis showed that only initial symptoms and electrophysiologic studies are independent prognostic factors: initial sensory symptoms of the feet are prognostic for a slowly progressive disease course and less disability at 4 years, and evidence for demyelination on electrophysiologic examination is prognostic for development of weakness and symptoms of the upper extremities at 4 years. Addition of anti-MAG or anti-SGPG antibody tests did not yield any additional prediction of outcome. Conclusion: These results indicate that in clinical practice, antibody tests in polyneuropathy associated with IgM monoclonal gammopathy do not have a prognostic value in terms of future neurologic deficit or outcome.

Intermittent cyclophosphamide with prednisone versus placebo for polyneuropathy with IgM monoclonal gammopathy

Background: The best treatment for polyneuropathy associated with IgM monoclonal gammopathy (MGUS) is unknown. Oral cyclophosphamide combined with prednisone showed limited efficacy in a previous open label pilot study. We therefore performed a double-blind, randomized, placebo-controlled study of combined oral cyclophosphamide and prednisone in IgM MGUS polyneuropathy. Methods: Thirty-five patients with progressive IgM MGUS polyneuropathy were included. After stratification for anti-MAG antibodies patients were randomized to oral cyclophosphamide 500 mg once daily for 4 days combined with oral prednisone 60 mg once daily for 5 days (treatment) (n = 16), or placebo (n = 19), repeated every 28 days for six times. Primary outcome was improvement of the Rivermead Mobility Index (RMI). Secondary outcomes were improvement of the modified Rankin scale, Medical Research Council and sensory sum scores, levels of M protein, EMG, and Short Form–36 scale after treatment. Patients were examined at 0, 6, 12, 18, and 24 months. Results: After 6 months of treatment and at later follow-up, no difference in change of the RMI between the two groups was observed. Change of the Rankin scale was similar in both groups. Other outcome parameters showed more improvement in the treatment group: the MRC sum score improved more from 6 to 24 months after treatment; the sensory sum score improved more at 6 months; the SF 36 mean health change score and physical role score improved more; and the median nerve distal conduction (abductor pollicis brevis muscle) improved more in the treatment group. The most common adverse event was nausea. Conclusions: Compared with placebo treatment, this first double-blind randomized trial with cyclophosphamide and prednisone in IgM MGUS polyneuropathy showed no beneficial effect on the functional scales, but a beneficial effect on muscle strength and sensation was observed.

MRI of the brachial plexus in polyneuropathy associated with monoclonal gammopathy

On magnetic resonance (MR) imaging of the brachial plexus increased signal intensity and swelling of the brachial plexus has been found in chronic inflammatory demyelinating polyneuropathy (CIDP). Whether these proximal abnormalities are also present in the distal polyneuropathy associated with monoclonal gammopathy is unknown. Therefore, we performed MR imaging of the brachial plexus in 21 patients with polyneuropathy associated with IgM monoclonal gammopathy (11 IgM with anti‐MAG antibodies, 10 IgM without anti‐MAG antibodies). For comparison we studied 9 patients with polyneuropathy associated with IgG monoclonal gammopathy and 8 patients with CIDP. Among the 30 patients with monoclonal gammopathy, 24 patients had demyelinating polyneuropathy. Among these 24 patients, there was increased signal intensity of the brachial plexus on the T2‐weighted images regardless of whether clinical deficits were generalized or purely distal in location. No association was found with the isotype of the monoclonal gammopathy. Of the 8 patients with CIDP, 5 had brachial plexus abnormalities. None of the 6 patients with axonal polyneuropathy associated with monoclonal gammopathy had such abnormalities. Thus, MR imaging of the brachial plexus shows that the distal demyelinating polyneuropathy associated with monoclonal gammopathy is more generalized than presumed.

Malignant transformation in polyneuropathy associated with monoclonal gammopathy

Objective: To assess the frequency of hematologic malignancies at diagnosis and to determine the incidence and predictors of malignant transformation during follow-up in patients with polyneuropathy associated with monoclonal gammopathy. Methods: Potential predictors of malignant transformation from medical history, hematologic, neurologic, and laboratory examination performed each 6 months were evaluated by univariable and multivariable Cox proportional hazard analysis. Results: Of 193 patients with polyneuropathy associated with monoclonal gammopathy, 17 patients had a hematologic malignancy at diagnosis. The incidence rate of malignant transformation in 176 patients without a malignancy at diagnosis was 2.7/100 patient years. Weight loss, progression of the polyneuropathy, unexplained fever or night sweats, and M-protein level were independent predictors. Conclusions: Since hematologic malignancies occur frequently in polyneuropathy associated with monoclonal gammopathy, the authors suggest that all patients should be screened at diagnosis and subsequently during follow-up if malignant transformation is suspected.

Neurologic and hematologic response to fludarabine treatment in IgM MGUS polyneuropathy

We studied the efficacy of fludarabine in 16 patients with immunoglobulin M monoclonal gammopathy of unknown significance polyneuropathy in a prospective uncontrolled trial. The modified Rankin scale improved in 5/16 patients, all of whom had a demyelinating polyneuropathy. The motor conduction velocity improved by more than 10% in two or more nerves for four of five of these patients. Hematologic response in bone marrow occurred in three of five of these patients, whereas two of five already had small polyclonal B cell populations. There were no serious side effects.

Malignant Transformation of Monoclonal Gammopathy of Undetermined Significance: Cumulative Incidence and Prognostic Factors

The cumulative incidence of malignant transformation was studied in 88 patients with monoclonal gammopathy of undetermined significance (MGUS) that had a complete prospective follow-up. At a median follow-up of 6.75 years, 10 patients developed multiple myeloma (MM) (11.4 %) and 2 developed immunocytoma (2.3 %). The cumulative incidence of malignant transformation was 9.1, 21.3, 38 and 48.3 % at 5, 10, 15 and 20 years, respectively. In univariate analysis on 102 MGUS patients, M-component level, bone marrow plasma cell percentage and kappa light chain correlated significantly with the development of a malignancy (p=0.0289, 0.0265 and 0.0013, respectively). In multivariate analysis, light chain type of M-component and plasma cell percentage had independent prognostic significance. A high-risk (M-component level > 10 g/l and/or plasma cell percentage < 2 %) and a low-risk group (M-component level < 10 g/l and/or plasma cell percentage < 2 %) of MGUS patients was identified, which differed significantly in the cumulative incidence of developing a malignancy (p<0.001 for M-component level and p=0.007 for plasma cell percentage). These results imply that high-risk patients should receive a more frequent follow-up, in comparison to low-risk patients.