Differential Diagnosis

Once the presence of an M protein is detected on protein electrophoresis or immunofixation, it is important to consider and rule out other plasma cell proliferative disorders, including MM, amyloidosis, and macroglob-ulinemia. The presence of anemia without another explanation, hypercalcemia, lytic bone lesions, renal insufficiency that cannot be attributed to another cause, M protein > 3 gm/dL, large amounts of paraprotein in the urine, bone marrow plasma cells of over 10%, or a high bone marrow PCLI should all raise the suspicion of MM, rather than MGUS. However, no one clinical feature distinguishes one from the other with certainty, and differentiation of myeloma from MGUS may be difficult (Table 89.2) There is a distinct group of patients with features consistent with MGUS except for an M-protein concentration of >3gm/dL and >10% plasma cells in the marrow, for whom the term smoldering (asymptomatic) multiple myeloma (SMM) has been coined.39 40 This group of patients has also been referred to as having monoclonal gammopathy of borderline significance (MGBS).26 These patients often have small amounts of M protein in the urine and a reduction of uninvolved immunoglobulins, as well as a low labeling index. At the time of diagnosis, it is often difficult to predict the course of these patients, and this condition is difficult to distinguish from symptomatic myeloma and needs to be closely followed. Patients with SMM are at a higher risk of progression to another plasma cell disorder compared to those with MGUS. In the group of patients reported by Baldini et al., the risk of malignant transformation for the MGBS group was 37% at a median follow-up of 53 months, compared to 6.8% for those with MGUS. Cesana et al. reported a higher risk of progression for patients with SMM (19.7%), compared to 5.8% among those with MGUS, at a median follow-up of 65-72

Diagnostic features of MGUS, SMM, and MM Disease stage Diagnostic Features

Monoclonal gammopathy of Undetermined significance (MGUS)

■ Serum monoclonal protein <3 g/dL

■ Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions

Smoldering multiple myeloma (SMM)

■ Serum monoclonal protein >3 g/dL or bone marrow plasma cells >10%

■ Absence of anemia, renal failure, hypercalcemia, and lytic bone lesions

Symptomatic multiple myeloma (MM)

■ Presence of a serum or urine monoclonal protein

■ Bone marrow plasmacytosis

■ Anemia, renal failure, hypercalcemia, or lytic bone lesions

months. This group of patients may need immediate treatment for their disease, though many have a relatively stable course for several years.

While high serum levels of M protein and large amounts of M protein in the urine increases the likelihood of myeloma, MGUS patients can occasionally have high levels of Bence Jones protein in their urine, and there is no cutoff value that can be reliably used for discrimination. As many as 17% of patients with MGUS can have urinary monoclonal proteins of more than 150 mg/24 h.13 While reduction of uninvolved immunoglobulin points toward myeloma, these findings can be seen in as many as 38% of the patients with MGUS.13 While >10% plasma cells in the bone marrow points toward myeloma, some of these patients can have a stable clinical course, as previously mentioned. Atypical plasma cells, especially those with a plasmablastic morphology, point toward myeloma, even though they may occasionally be seen in patients with MGUS or SMM. In a study of 566 patients enrolled in a multicenter trial (MGUS = 295; myeloma = 266), consistent differences were observed in the bone marrow histology between patients with MGUS and MM.41 Changes in bone marrow composition from MGUS to early MM and to advanced MM followed a precise pattern which, in addition to increasing plasma cell percentage, included a shift from plasmocytic to plasmablastic cytology, an increase in bone marrow cellularity and fibrosis, a change in bone marrow infiltration (becoming diffuse rather than interstitial), a decrease in residual hematopoiesis, and an increase in osteoclasts. Patients with MGUS generally have plasma cell labeling index values close to 0, which may be a valuable discriminator when other features are equivocal.42 A value of over 0.4% raises the likelihood of myeloma or impending transformation to one. However, nearly a third of patients with symptomatic myeloma can have normal labeling index values. The value of the labeling index in differentiating benign monoclonal gammopathy from myeloma has been reported by others.4344 The ratio of the plasma cell cytoplasmic light chains has been suggested as a useful differentiating feature, with a ratio of 8 or below pointing toward MGUS.45 Circulating clonal plasma cells can be detected using immunofluorescence microscopy, flow cytometry, or more sensitive techniques, such as allele specific oligonucleotide-polymerase chain reaction (ASO-PCR) in patients with monoclonal gam-mopathies, and are seen in higher numbers in patients with myeloma compared to those with MGUS.46 In patients with MGUS and SMM, the presence of these cells predicts for a higher risk of progression.

While the presence of lytic bone lesions in the setting of a monoclonal protein points to myeloma, this patient population is at risk for other malignancies, and the bone lesions may be related to metastatic disease. Occasional patients have one or more sclerotic bone lesions, M protein in the serum or urine (typically lambda), endocrine and skin abnormalities, and often debilitating neuropathy—a syndrome referred to as osteosclerotic myeloma or POEMS syndrome. More sensitive imaging of the bone using techniques such as MRI or whole body PET imaging may help distinguish patients with MGUS from those with other disorders. Bellaiche et al. performed MRIs of the thoracolumbar spine in 24 patients with MGUS comparing the results to those in 44 patients with myeloma.47 All findings on magnetic resonance examination were normal in those with MGUS, whereas findings on 38 patients (86%) with MM were abnormal. CT evaluations of the thora-columbar spine, iliac crests, and sacrum showing lacunae larger than 5 mm with trabecular disruption have been reported in myeloma—a finding not observed in any of the patients with MGUS.48 Durie et al. found that a normal whole-body 18F-FDG PET reliably identified patients with stable MGUS.37 Others have reported that markers of increased bone turnover, such as car-boxy-terminal telopeptide of type I collagen (ICTP) and deoxypyridinoline (Dpd), may help distinguish patients with MGUS.49 Bataille et al., using histomor-phometric parameters of bone resorption, demonstrated decreased levels of bone resorption in MGUS compared to active MM.36

Levels of cytokines either in the serum or those demonstrated in the plasma cells have been suggested as having diagnostic value. Interleukin (IL)-1p is produced by plasma cells from patients with MM, whereas those from patients with MGUS rarely do.50 IL-1p is thought to be an important player in the osteoclast-mediated bone destruction seen in myeloma. Serum levels of IL-6 have been reported to be higher in patients with myeloma compared to in those with MGUS. In one study, significant serum IL-6 levels were detected in only 3% of the MGUS/SMM group, compared to 35% of the overt MM group and 100% of those with plasma cell leukemia.51 Serum levels of IL-2 have been reported to be higher in MGUS patients compared to those with myeloma.52 Serum p2 microglobulin, while increased in myeloma compared to MGUS, does not have enough discriminatory power to be of clinical value in differentiating between MGUS and myeloma.53-55

Increased bone marrow angiogenesis is a prominent feature of MM and is a prognostic factor for overall survival. Patients with MGUS do not have any significant increase in the bone marrow microvessel density, though the clinical applicability of this test is low given that many patients with myeloma can have normal findings.56 Presence of cytoplasmic 5'nucleotidase (c5NT) in plasma cells has been reported to discriminate between MGUS and myeloma.57

An M-protein can be detected in the presence of many lymphoproliferative disorders, including non-Hodgkin's lymphoma and CLL, and should be kept in mind when evaluating these patients. Over a ten year period, Malacrida et al. performed protein electrophoresis on

102,000 samples, detecting 730 cases of M-protein, of whom 114 could be classified as B cell malignancies and 261 as monoclonal gammopathy of undefined significance.58

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