Serum protein electrophoresis and immunofixation should be performed when looking for a monoclonal gammopathy. Immunofixation is more sensitive for detection of monoclonal proteins when compared to electrophoresis [5]. Serum-free light chain (FLC) ratio can also be done to further increase the sensitivity [6]. When detected, the amount of the monoclonal protein (M protein) needs to be quantified in both serum and urine (via 24-h urine collection). A complete blood count (CBC), serum electrolytes including calcium, renal function assessment, and skeletal survey should be done to assess for end-organ damage. Bone marrow aspirate and biopsy may be performed for individuals with high-risk features [7].

Given the risk of progression detailed above, routine follow-up testing should be performed. There is no consensus on the frequency of testing; nonetheless, it should be tailored to the size of the monoclonal protein and risk factor profile [7]. Usually, we monitor with SPEP and serum FLC ratio at 6 months then yearly thereafter. Urine protein electrophoresis is performed if an M spike was initially found in urine.

In the general population, the prevalence of length-dependent peripheral neuropathy is about 1.66% [8]. MGUS is found in up to 10% of patients with peripheral neuropathy seen at a tertiary referral center [9]. Due to the common occurrence of both peripheral neuropathy and MGUS, which increases with age, it is important to determine whether their presence is purely a chance association or whether the neuropathy is secondary to the process causing the monoclonal gammopathy. In the general population, IgG is the most common monoclonal gammopathy, while IgM is the most frequent monoclonal gammopathy found in patients with peripheral neuropathy (Fig. 32.1) [10, 11]. Laboratory work up, electrodiagnostic testing, and the neuropathy phenotype may help resolving this dilemma.

The classic phenotype of MGUS neuropathy is called DADS -M or distal acquired demyelinating symmetric neuropathy with M protein [12]. It affects men more than women usually between the fourth and ninth decade. Initially, the symptoms are predominantly sensory; however, mild distal lower limb weakness is not uncommon and patients might present with, or evolve into a disabling polyradiculoneuropathy with proximal and distal weakness. MGUS neuropathy is most commonly associated with IgM kappa monoclonal gammopathy. On electrodiagnostic testing, patients typically have demyelinating features with slowing of motor conduction velocities and marked prolongation of distal latencies implying terminal nerve involvement. Sensory potentials are typically reduced or absent.

Antibodies against myelin-associated glycoprotein (MAG) are found in nearly half of DADS-M patients. In patients with MAG positivity, the IgM binds to the peripheral nerve MAG causing widening of the myelin lamellae that can be seen on electron microscopy [13–16]. However, the clinical presentation and course of DADS-M is the same in the presence or absence of MAG antibodies [11, 17] and MAG positivity may be seen in amyloid neuropathy patients and in IgM MGUS without neuropathy [18]. Therefore, subdividing patients with MGUS neuropathy into two categories, based on the presence of anti-MAG antibodies, is of uncertain clinical significance.

DADS-M is often considered a subtype of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) [12, 19]. DADS-M was distinguished from CIDP as patients with CIDP and IgM MGUS were found to respond poorly to conventional CIDP treatment [11, 12, 20]. On the other hand, there was no difference in response between CIDP patients with and without IgA or IgG MGUS. Therefore, the presence of IgA and IgG in CIDP patients might be just an incidental finding. Furthermore, the evidence of an association of IgA or IgG MGUS with peripheral neuropathy in general remains unclear.

In summary, there is no definitive way to determine with confidence whether a MGUS and peripheral neuropathy have a causal relationship in a specific patient. Therefore, the clinician should gather as much evidence as possible before assuming the patient has a paraproteinemic neuropathy guided by the clinical phenotype, electrodiagnostic findings, the type of the monoclonal protein (IgM vs. non-IgM) and the presence of anti-MAG antibodies.

Multiple case reports and case series using different immunomodulating agents have been published with varying results. Some clinical trials only included patients with IgM anti-MAG neuropathies, while others treated all patients with IgM neuropathy regardless of anti-MAG status. A 2012 Cochrane Review did not find enough evidence to support the use of intravenous immunoglobulin, interferon alfa-2a, cyclophosphamide and steroids, and plasma exchange in IgM anti-MAG neuropathies [21]. Earlier small studies suggested possible benefit with rituximab [22, 23]. Subsequently, a double-blinded, placebo-controlled trial of rituximab in IgM anti-MAG neuropathy was performed [24]. The study did not meet the primary outcome of an absolute improvement on the inflammatory neuropathy cause and treatment (INCAT) sensory score at 12 months. However, there was evidence of some improvement in secondary outcomes including the INCAT disability scale in 20% of patients and self-evaluation scale.

Currently, there is no reliable evidence to support the use of immunotherapy in IgM neuropathy. Thus, treatment decision has to be made on a case by case basis. Treatment is usually offered for very young patients or older patients with significant disability. Patients with proximal weakness resembling a polyradiculoneuropathy tend to respond better to treatment [25].

Hyperviscosity syndrome is characterized by skin and mucosal bleeding, retinopathy with retinal hemorrhages mimicking central vein occlusion, and central nervous system (CNS) involvement (intracerebral hemorrhage, seizures, vertigo and altered level of consciousness including coma) [30]. In addition to hyperviscosity syndrome, CNS involvement can result from direct infiltration by lymphoplasmacytic cells known as Bing-Neel syndrome. MRI of the brain and cerebrospinal fluid (CSF) studies help establish the diagnosis. Furthermore, patients may also develop Bing-Neel syndrome without evidence of CNS infiltration. The underlying mechanism remains unclear but could be related to intraparenchymal IgM deposition [31]. When the CNS is involved, large cell transformation needs to be ruled out.

The peripheral neuropathy associated with WM is clinically indistinguishable from IgM-MGUS neuropathy. It is a predominantly sensory neuropathy with the most common symptom being foot numbness resulting in sensory ataxia.

Nerve conduction studies and EMG demonstrate that WM neuropathy is more commonly axonal with only 27% of patients having demyelinating features compared to 62% of patients with IgM-MGUS neuropathy [32]. The degree of axonal loss on nerve conduction studies/EMG and on teased nerve fibers is similar to that seen in IgM-MGUS, which likely accounts for the similar type and severity of impairments. Patients with WM have much higher IgM levels (median 3100 mg/dL) and much greater presence of anemia (median hemoglobin of 11.8 g/dL) when compared to patients with IgM MGUS (median IgM level of 650 mg/dL and median hemoglobin of 14.4 g/dL) [32]. While none of these findings in isolation can rule in or rule out WM, they should nonetheless serve as helpful clues to prompt further evaluation and hematology consultation.

CT scan of the chest, abdomen, and pelvis identifying hepatosplenomegaly or lymphadenopathy and bone marrow biopsy with lymphoplasmacytic infiltrate can establish the diagnosis of WM.

Given the relatively good long-term survival of patients with WM, potential toxicity of therapy should be taken in consideration and treatment should be tailored depending on disease severity [27]. Observation is recommended for asymptomatic patients. Patients with hemoglobin < 11 g/dL or platelet < 120,000/µL and patients with early disease including patients with WM neuropathy, hemolytic anemia or glomerulonephritis may be treated with one cycle of rituximab as a single agent. Patients with advanced disease including patients with bulky disease, profound cytopenias (hemoglobin ≤ 10 g/dL or platelets < 100,000/µL), or hyperviscosity symptoms should be treated with rituximab, cyclophosphamide, and dexamethasone [33]. Ibrutinib, an inhibitor of the Bruton’s tyrosine kinase, has been recently reported to be effective in WM-pretreated patients [34]. Plasmapheresis should be offered for patients with hyperviscosity symptoms. Autologous stem cell transplantation may be considered in relapsing/refractory cases [33].

AL amyloidosis results from the deposit of monoclonal light chains, kappa or lambda, in various tissues including the heart, kidneys, gastrointestinal tract, and peripheral nerves. Changes in the secondary and tertiary structure of the light chains result in the formation of insoluble beta-pleated sheets that disrupt organ function. Rarely, primary amyloidosis can be associated with a heavy-chain fragment [37].

AL amyloid has an incidence of 8 per 1 million people per year and median age of onset of 62 years [38]. It is uncommon in patients under the age of 40 [39]. It affects men more than women (ratio of 2:1) [40]. The most common symptoms are fatigue and weight loss in nearly half of the patients [40]. Cardinal clinical findings, including macroglossia, facial purpura, hepatosplenomegaly, and submandibular salivary gland enlargement, are present in a minority of cases. At time of diagnosis, nephrotic syndrome, with or without renal failure, is found in 28% of patients, carpal tunnel syndrome in 21%, peripheral neuropathy in 17%, congestive heart failure in 17%, and orthostatic hypotension in 11% [39]. Survival depends on the extent of cardiac involvement. Typically, patients develop a cardiomyopathy that results in congestive heart failure and/or cardiac arrhythmias that can result in sudden death [41]. With the use of high-dose chemotherapy, the availability of new chemotherapeutic agents, the decrease in post-stem cell transplant (SCT) mortality, and the better selection of SCT eligible patients, there is evidence of improvement in overall survival rate [42]. Currently, the median survival is about 2–4 years [43]. Nonetheless, the survival rate can vary from less than 6 months for patients with overt cardiac failure, to a 10-year survival of 43% after autologous stem cell transplantation (SCT) [44].

Peripheral neuropathy affects 15–20% of patients with AL amyloidosis [39]. The most common pattern of amyloidosis neuropathy (including both AL and familial forms) is seen in about two-thirds of patients and consists of generalized autonomic failure with a painful, length-dependent, sensorimotor peripheral neuropathy [45]. In some patients, the generalized autonomic failure may be associated with a painless, length-dependent, sensorimotor peripheral neuropathy or can happen in isolation. Less likely, patients can have a length-dependent, sensorimotor peripheral neuropathy without generalized autonomic failure or can have generalized autonomic failure associated with a small-fiber neuropathy [45].

The length-dependent peripheral neuropathy starts distally in the feet and spreads more proximally with time. It usually affects the hands when it reaches the knee level. Patients often report numbness, tingling, burning, stabbing pains, and weakness. On physical examination, patients commonly have pan-modality sensory loss including both large-fiber (light touch, vibration and proprioception) and small-fiber (pain, temperature) modalities. However, as mentioned above, patients may only have a small-fiber neuropathy with selective loss of pain and temperature sensation.

Autonomic involvement can affect the cardiovascular, gastrointestinal, and genitourinary systems. The most frequent symptom is orthostatic intolerance, followed by gastrointestinal symptoms including postprandial diarrhea or vomiting, severe constipation, and gastroparesis [46]. Genitourinary involvement manifests with erectile dysfunction early on and dysuria and urinary retention later with disease progression [36]. Patients also commonly have sweating abnormalities. Light-near dissociation of pupillary reactions (Argyll-Robertson pupil) may be observed.

Localized deposit of amyloid, termed amyloidoma, can cause a focal neuropathy by compression or amyloid deposition within the nerve [47, 48]. Rarely, the whole IgM molecule forms deposits within the nerve without amyloid-associated proteins [49, 50]. Morphologically, the deposition of the whole IgM molecule mimics amyloid, but does not stain with Congo red.

Nerve conduction studies/EMG typically shows a length-dependent axonal, sensorimotor peripheral neuropathy. However, in a pure small-fiber neuropathy, NCS/EMG will be normal. If clinically indicated, quantitative sudomotor axon reflex testing, thermoregulatory sweat test, and/or skin biopsy to determine epidermal nerve fiber density may be used to evaluate for small-fiber involvement. Autonomic reflex screening usually shows generalized adrenergic, cardiovagal, and sudomotor dysfunction. Screening for suspected AL amyloidosis should include serum and urine immunofixation as well as an immunoglobulin free light-chain assay [51]. When amyloidosis is suspected, tissue confirmation is required. Biopsy of the iliac crest bone marrow combined with abdominal subcutaneous fat aspiration will identify amyloid deposits in 85% of patients with amyloidosis [51]. If these are unrevealing, a biopsy of an affected tissue should be considered. Thereafter, amyloid protein composition should be determined by mass spectrometry [52, 53]. Screening for other organ involvement should include an echocardiography, 24-h urine total protein measurement, measurement of complete blood count, creatinine level, alkaline phosphatase level, troponin and N-terminal pro-brain natriuretic peptide levels [51].

It is crucial to make the diagnosis of AL amyloidosis early on as it has major treatment implications, and delay in diagnosis may affect eligibility for stem cell transplant. SCT is the treatment of choice for AL amyloidosis with survival rates of 53% for patients with a complete response and 43% for all treated patients [44, 54]. Unfortunately, only 20–25% of patients are eligible for SCT at diagnosis. Eligibility requirements include NT-proBNP <5000 ng/mL, troponin T < 0.06 ng/mL, age < 70 years, <3 organs involved, and serum creatinine ≤1.7 mg/dL [51]. SCT-ineligible patients should be given a chemotherapeutic regimen such as melphalan–dexamethasone or cyclophosphamide–bortezomib–dexamethasone. In patients with a peripheral neuropathy, some therapies, including bortezomib and thalidomide, should be used with caution due to the high risk of a length-dependent, sensory-predominant, axonal neuropathy as will be detailed in multiple myeloma section [55].

Laboratory evaluation should include serum and urine monoclonal protein screen as detailed in the monoclonal gammopathy section. Investigation should also evaluate for end-organ damage and bone involvement via skeletal survey or low-dose CT scan without contrast. The diagnosis of MM requires the presence of a monoclonal protein (except in non-secretory MM), plasma cell count greater than or equal to 10% on bone marrow evaluation by bone marrow aspirate or biopsy, and presence of end-organ damage [59]. In the absence of end-organ damage, MM can be diagnosed if bone marrow plasma cell count is ≥60% [60].