Abstract
Anti-myelin-associated
glycoprotein (MAG) neuropathy is a rare, immune-mediated demyelinating
condition. It is characterised by an association with an IgM monoclonal
gammopathy and the presence of pathogenic anti-MAG antibodies. Research into
this field began in the 1980s. Initial therapeutic approaches aimed to reduce
the M protein concentration using treatments such as plasma exchange, steroids,
chlorambucil, azathioprine and cyclophosphamide. Some
patients experienced partial benefit, indicating that mechanisms beyond damage
solely caused by elevated M protein are involved. Consequently, immune-directed
therapies, such as IVIg and rituximab, have demonstrated some efficacy in this
patient group. Some case reports suggested the use of Lenalidomide as a potential
therapeutic option. This is the first case report showing the successful use of
pomalidomide in anti-MAG neuropathy.
Keywords: Anti-myelin-associated glycoprotein, MAG
antibodies, Rituximab
1. Introduction
Peripheral
neuropathy is a well-recognised manifestation of paraproteinemia, commonly
referred to as paraproteinemic neuropathy (PPN). Studies have shown that
paraproteins are present in 3% to 4% of individuals over the age of 50 years,
more than 5% of those over 70 years and in approximately 3% to 5% of patients
with chronic peripheral neuropathy1. Peripheral neuropathy
associated with an IgM monoclonal gammopathy is characterised by a distal,
acquired, demyelinating and symmetric pattern, often referred to as Distal
acquired demyelinating symmetric (DADS) neuropathy with M-protein (DADS-M).
This condition most frequently presents in elderly men as symmetric, distal
neuropathy that primarily targets large sensory nerve fibres, leading to
sensory ataxia. Although anti-MAG antibodies are found in about 50% of these
patients, their presence or absence does not appear to correlate with the
severity or specific type of neuropathy experienced2.
2. Case
Summary
A 65-year-old male with a known case of hypertension and
a history of occasional alcohol consumption presented with an insidious onset
and gradually progressive imbalance while walking for 6 years. He also
complained of tremors in both hands, symmetrical and progressive over the last
6 years. He had paraesthesia’s and numbness of both feet with slipping of
footwear. On examination, he was found to have wasting of the small muscles of
the hands with mild weakness. Power was normal (5/5) across all 4 limbs except
at the ankle, where it was 3/5. He had b/l foot-drop and coarse kinetic
symmetrical tremors involving both upper limbs at the distal joints. Romberg’s
test was positive, along with positive cerebellar signs and an ataxic
high-stepping gait.
His investigations showed near normal blood counts
(Hb-11.1gm%; TLC- 11,360; Plts: 271000), ESR -12 mm. Metabolic parameters were
normal except for mild hypoalbuminemia (3.3 g/dl) and elevated LDH (509). TSH
and Vit B12 were normal. MRI Brain and Lumbo-sacral spine showed generalised
brain atrophy, chronic ischemic changes and degenerative changes in the spine.
Cerebrospinal fluid examination demonstrated a mild increase in proteins. Nerve
conduction studies revealed bilateral symmetrical sensorimotor demyelinating
and axonal neuropathy. His serum protein electrophoresis was suggestive of an M
Band (0.33 gm%), which on immunofixation electrophoresis showed IgM Kappa
subtype. Bone Marrow Aspiration and Biopsy showed a Hypercellular marrow with
trilineage hematopoiesis. His anti- MAG antibody was found to be positive. He
was diagnosed with Anti-MAG positive Sensory Ataxic Neuropathy. He was treated
with pulse doses of methyl prednisolone (1gm for 5 days) followed by oral
prednisolone in tapering doses. He developed mild breathlessness and was found
to have ischemic changes on ECG. His Coronary angiography revealed stenosis of
the Left Anterior Descending
(LAD) and Left Circumflex (LCx) arteries. He underwent Percutaneous
Transluminal Coronary Angioplasty (PTCA). Following the interruption of his
neuropathy treatment due to the procedure, the patient was referred back to the
neurologist. He was then started on Injection Rituximab, receiving two 1 g
doses 15 days apart. The patient was followed up monthly for 4 months without
any evidence of improvement.
Exhausted both
financially and morally, the patient and his relatives declined any further
diagnostic evaluations. Given the lack of therapeutic alternatives, a trial of
low-dose immunomodulatory therapy was initiated. The patient was started on
pomalidomide 2 mg daily along with dexamethasone 20 mg once weekly. After 1
month of treatment, he demonstrated early symptomatic improvement, able to
stand and ambulate a few steps with support. Over the subsequent four months,
his neurological function continued to improve and he was able to walk
independently without support. Dexamethasone was discontinued after one year,
while pomalidomide 2 mg was continued as monotherapy. Two years into treatment,
the patient remains functionally independent. At the last follow-up, he was
able to independently climb stairs, walk without assistance and perform all
activities of daily living. His most recent immunofixation electrophoresis
results continue to show an IgM Kappa level of 0.27 g%.
3. Discussion
Anti-MAG antibody
neuropathy typically presents as a chronic, slowly progressive, large-fibre
sensory-motor polyneuropathy, most commonly starting in the lower extremities.
Clinical features often include sensory ataxia, leading to gait imbalance and
the development of action-induced tremor in the fingers and hands in some
patients. The condition predominantly affects elderly males. The initial
symptom is usually the neuropathy itself. Neurological signs develop gradually
over one to two decades, sparing the cranial nerves and progress slowly,
leading to cumulative disability over the years3.
The pathophysiology
of Anti-MAG neuropathy is largely attributed to IgM antibody-mediated damage to
the myelin glycoprotein, causing thinning of the myelin and widening of the
myelin lamellae. The link between this condition and IgM monoclonal gammopathy
is thought to arise from both B-cell clonal proliferation and accompanying
autoimmune processes4.
Therapeutic
strategies in anti-MAG neuropathy have traditionally focused on immune-directed
treatments like corticosteroids, IVIg and plasma exchange with variable and
often transient benefit. Cytotoxic agents such as chlorambucil,
cyclophosphamide and fludarabine can reduce IgM production but are associated
with significant toxicity, limiting their long-term use5.
Rituximab, a CD20-directed monoclonal antibody, has been the most widely
studied agent; however, observational studies suggest some benefit in approximately
30-50% of patients. In a double-blind, placebo-controlled study, an improvement
of at least 1 point in the INCAT lower limb disability scores was observed in 4
out of 13 patients after 8 months. However, this change, which was the study's
aim for detecting a change of 1 or more, did not achieve statistical
significance6.
Immunomodulatory
drugs (IMiDs) have a biologically plausible role in paraproteinemic
neuropathies due to their antiplasma cell activity, inhibition of
pro-inflammatory cytokines and suppression of monoclonal immunoglobulin
production. Lenalidomide has previously been explored in anti-MAG neuropathy,
with early case reports suggesting benefit7,8. It
also showed a response in combination with rituximab9.
However, a recent phase 1 study demonstrated limited clinical efficacy and a
higher-than-expected incidence of venous thromboembolism, raising concerns
regarding its long-term safety in this population. These findings underscore
the need for alternative agents with improved tolerability10.
Pomalidomide, a
third-generation IMiD, has enhanced immunomodulatory potency with a more
favourable toxicity profile compared to earlier agents. Although data on
pomalidomide in anti-MAG neuropathy are lacking, its efficacy in other
monoclonal gammopathy–associated conditions and its ability to suppress
IgM-producing clones provide a strong mechanistic rationale for its use.
Pomalidomide exerts its effects through multiple mechanisms, including directly
inhibiting tumour cell proliferation and inducing apoptosis and enhancing the
immune system’s ability. Additionally, pomalidomide interferes with the tumour
supportive microenvironment, including stromal cells that shield myeloma cells
from immune responses. These multifaceted actions make pomalidomide an
effective therapeutic option in treating resistant or relapsed myeloma.
Evidence supports the effectiveness and tolerability of
pomalidomide-dexamethasone combination in patients who have already been
treated with lenalidomide and bortezomib11. Expert
guidelines recommend the standard starting dose for this therapy is 4 mg of
pomalidomide, taken on days 1-21 of each 28-day cycle, along with a weekly dose
of 40 mg of dexamethasone. However, a phase 2 trial with 35 patients per cohort
demonstrated an overall response rate (ORR) of 49% in the 2-mg group and 43% in
the 4-mg group, with no clear advantage of the higher dose. The 6-month overall
survival rate was 78% for the 2-mg group and 67% for the 4-mg group12.
In this context, the
present case is notable for the magnitude and durability of neurological
improvement achieved with low-dose pomalidomide and dexamethasone. The patient
demonstrated early symptomatic improvement within one month, followed by
sustained functional recovery over several months, eventually regaining full
independence in ambulation and activities of daily living. In conclusion, this
case provides preliminary evidence that pomalidomide, in combination with
dexamethasone, may represent a promising and well-tolerated therapeutic option
in selected patients with refractory anti-MAG neuropathy.
References