Page 45 - Haematologica Vol. 107 - September 2022

REVIEW ARTICLE - IgM monoclonal gammopathies of clinical significance J. Khwaja et al.
rituximab and dexamethasone may provide rapid disease control. The only prospective trial of this strategy recruited ten patients over 1 year.46 A hematologic response was achieved by 78% with sustained responses at a median of 11 months, after only two cycles. However, there were no complete responses. Treatment had to be interrupted in 30% of patients because of toxicity. Patients with grade 3 sensory and/or grade 1 painful neuropathy were excluded and treatment-related neuropathy is a particular concern in these patients. Responses to frontline alkylating agents have been disappointing. In a series of 46 patients treated after 2003, the hematologic response rate was 37% and there were no complete responses.41 Immunomodulatory drugs alone result in variable response rates, but mostly less than 50%. BTK inhibitors, although promising in WM, have been associated with low response rates in IgM-as- sociated amyloidosis. Of eight patients treated with ibruti- nib, only two achieved a hematologic response and the median overall survival was 9 months.47 No studies have examined anti-CD38-bortezomib combinations, which is the standard of care in non-IgM AL amyloidosis.48
We consider upfront bendamustine-rituximab the treat- ment of choice in IgM-associated amyloidosis, consoli- dated with autologous stem cell transplantation when the patient’s performance status allows. There is no consen- sus regarding less fit patients; treatment choices need to be individualized depending on affected organs and toler- ance of treatments. Overall in this condition, deep re- sponses remain poor. Future studies are required to address whether regimens based on novel agents (includ- ing venetoclax, daratumumab and the newer BTK in- hibitors) may lead to improvements in the outcomes of patients with non-IgM AL amyloidosis.
IgM-related neuropathies
IgM-related peripheral neuropathies encompass an array of entities including immune-mediated neuronal damage, such as that caused by antibodies to myelin-associated glycoprotein (MAG), or direct neurotoxicity with infiltration by lymphoma (neurolymphomatosis), light chains (amyloi- dosis) or cryoglobulins. Peripheral neuropathy has been found to occur in 15-30% of MGUS and WM cases,49,50 but the prevalence is likely affected by selection bias and vari- able neurological evaluation in patients as part of a work- up of IgM M-protein. The UK registry documented 153 patients with IgM-related neuropathy, comprising anti- MAG neuropathy (55%), non-MAG IgM neuropathy (35%) and less frequently (<4% each) AL amyloidosis, cryoglo- bulinemia, anti-ganglioside neuropathy and CANOMAD syndrome (chronic ataxic neuropathy, ophthalmoplegia, IgM M-protein, cold agglutinins and disialosyl ganglioside antibodies).50
Clinical characteristics
Anti-MAG neuropathy is the most common and best-de- fined IgM-related neuropathy. Patients typically present with chronic-onset, distal, symmetric neuropathy, sen- sory ataxia and tremor. Patients may be misdiagnosed as having chronic inflammatory demyelinating polyneur- opathy. It is important to correctly classify the neuro- pathy (Table 3) as this has significant management implications. Atypical “red flag” symptoms not consistent with anti-MAG peripheral neuropathies include acute onset, rapid tempo of symptoms, pain, dysautonomia, weight loss, and cutaneous or central nervous system signs. These should alert the clinician to consider alter- nate diagnoses (Figure 4). CANOMAD syndrome is a very rare chronic progressive condition associated with anti- ganglioside antibodies. This syndrome should be con- sidered if there is sensory loss with ophthalmoplegia or ataxia. Bing-Neel syndrome is the term for central nerv- ous system infiltration by lymphoplasmacytic lymphoma; consensus guidelines on its diagnosis, treatment and re- sponse criteria have been published.51 Cryoglobulinemia and amyloidosis are discussed in their respective sec- tions.
Diagnostic workup
The majority of patients with IgM-related neuropathy (>90%) have symptoms of the underlying neurological dis- order at diagnosis.50 This supports the strong need for careful early evaluation of patients jointly with an expert neurologist. The presence of a peripheral neuropathy alongside a serum monoclonal IgM or anti-MAG antibody does not equal a causal relationship, since gammopathies as well as peripheral neuropathies are both increasingly prevalent with age. Patients should be tested for anti-MAG antibodies, but only high-titer antibodies are clinically rel- evant in the presence of a characteristic clinical picture in anti-MAG neuropathy.52 A reduction in anti-MAG titers and levels of IgM M-protein with therapy appeared to cor- relate with improvement in neuropathy in a retrospective analysis of 50 studies.53 Responders also had a younger age of onset.53
Nerve conduction tests and electromyography are war- ranted and characteristically show demyelination with re- duced conduction velocity, disproportionately prolonged distal motor latency and absent sural potentials. Partial motor conduction block is rare. Progressive demyelination may result in secondary axonal loss which affects the like- lihood of neural recovery.52 Magnetic resonance imaging of the neuraxis and evaluation of large volumes of cerebro- spinal fluid may be required if central nervous system in- volvement is suspected. A nerve biopsy may be needed if the diagnosis remains elusive despite systematic investi- gation. Comprehensive consensus guidelines provide further details.52
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