Management and long-term hematologic and neurologic outcomes of IgM-related neuropathy: A single center experience

Abstract Background: IgM-related neuropathy is associated with the presence of IgM monoclonal paraprotein [IgM monoclonal gammopathy of undetermined significance (MGUS) and/or Waldenström macroglobulinemia (WM)]. It is predominantly a demyelinating neuropathy, often linked to anti-myelin-associated glycoprotein (MAG) antibodies. Data on therapeutic options and patient outcomes are limited. Methods: All consecutive patients with IgM-related neuropathy diagnosed and treated at the Department of Clinical Therapeutics, Athens, Greece, from January 1st, 2000 to July 31st, 2025 were analyzed. Those with measurable disease (IgM≥500 mg/dL) were assessed for response to treatment based on the IWWM-11 criteria. Neuropathy assessment was performed prospectively based on the RODS and INCAT questionnaires at diagnosis, at 1, 6, 12 and 24 months post treatment initiation. RODS score ranges from 0 to 48 (higher is better), while INCAT score ranges from 0 to 10 (0-5 for upper and 0-5 for lower limbs, lower is better). Clinically relevant improvement was defined as an increase of at least 4 points in RODS and a decrease of at least 1 point in INCAT. Changes in scores from baseline at each timepoint were analyzed using the non-parametric and paired Wilcoxon Signed-Rank test. The study was approved by the Institutional Review Board (IRB). Results: 28 consecutive patients [16 (57.1%) with WM and 12 (42.9%) with IgM MGUS] were analyzed; median age was 65.5 years, 17 (60.7%) were males. 17 patients (60.7%) had anti-MAG neuropathy and the remaining (n=11, 39.3%) were categorized as non-anti-MAG demyelinating neuropathy. Among those with anti-MAG neuropathy, 12 were tested positive for anti-SGPG antibodies. Twenty-one patients (75%) presented with lower limb neuropathy, six (21.4%) had neuropathy in both upper and lower limbs, and only one patient (3.6%) presented with neuropathy affecting only the upper limbs. Treatment was initiated in all patients solely due to neuropathy symptoms; 19 (67.9%) were treated with dexamethasone-rituximab-cyclophosphamide (DRC), 6 (21.4%) with rituximab monotherapy and 3 (10.7%) with ibrutinib. In patients with measurable disease (n=17), best response was: 3 (17.6%) VGPR, 9 (53.0%) PR, 3 (17.6%) MR and 2 (11.8%) SD. After a median follow-up of 5.54 years, there were 2 (12.5%) deaths recorded; both were among WM patients, 1 due to disease transformation to high-grade lymphoma and 1 not related to WM. Moreover, there were 3 (18.8%) patients who experienced progressive disease among WM patients. At baseline, the median RODS score was 38.0 (range: 7.0–47.0). At 6 months post treatment initiation, the median score increased to 41.5 (range: 10.0–48.0) (p<0.001). Similarly, the median RODS score was 43.0 (range: 27.0–48.0) (p<0.001) at 1 year and 43.5 (range: 26.0–48.0) (p<0.001) at 2 years. These statistically significant differences from baseline indicate a gradual functional improvement over time. A clinically relevant improvement was evident in 5 (17.9%), 7 (25%), and 9 (32.1%) patients at 6, 12 and 24 months, respectively. Among evaluable patients, IgM reduction was not associated with RODS scores at any timepoint. At baseline, the median INCAT score was 2.0 (range: 0.0–7.0). At 6 months, the median score improved to 1.0 (range: 0.0–7.0) (p=0.001). At 1 year and 2 years post-treatment, the median INCAT score remained 1.0 (range: 0.0–6.0), and within-patient improvements compared to baseline remained significant (p<0.005). A clinically relevant improvement was evident in 13 (46.4%), 18 (64.3%), and 17 (60.7%) patients at 6, 12 and 24 months, respectively. In evaluable patients, IgM reduction was associated with improvement in INCAT scores at 6 months (p=0.041) and 1 year (p=0.030). RODS and INCAT scores were strongly correlated at all timepoints (baseline rho=-0.77, p<0.001; 1-month rho=-0.80, p<0.001; 6-months rho=-0.79, p<0.001; 1-year rho=-0.78, p<0.001; 2-years rho=-0.85, p<0.001). No flare events were observed at the 1-month assessment in terms of neuropathy symptoms, based on either of the two tools. Finally, there was one event of neurological deterioration 2-years post initial treatment with rituximab, which was managed effectively with DRC. Conclusion: In patients with IgM-related neuropathy, treated mainly with rituximab-based regimens, a significant and sustained improvement was demonstrated in both functional ability (RODS) and neurological disability (INCAT) over a 2-year period of follow-up.