3 DIAGNOSIS


3.1 Presenting symptoms and signs

3.1.1 Multiple myeloma
The most common presenting symptoms are related to bone disease, with bone pain that can be associated with compression fractures of spine or with pathologic fractures of long bones. Signs of spinal cord compression must be recognized early and usually present initially as radicular pain accentuated by coughing or sneezing.
Anemia and weakness are frequent at diagnosis. Recurrent bacterial infections (usually due to pneumococcus or other gram positive bacteria) are most common in patients with advanced disease but can also be present initially.
Hypercalcemia should be suspected in patients with nausea, fatigue, confusion, polyuria or constipation. AL amyloidosis is a complication of multiple myeloma occurring in about 15% of patients. The tissues most subject to amyloid disposition in myeloma include the tongue, gastrointestinal tract, heart, skin, skeletal muscles and carpal ligaments. Most frequent physical findings include enlargement of tongue, liver, periorbital purpura, ankle edema and peripheral neuropathy. However, in many cases, biological abnormalities diagnosed by chance on laboratory screening tests are the only presenting signs (anemia, serum M-component, hypercalcemia, renal failure).

3.1.2 Indolent and smoldering multiple myeloma
Indolent and smoldering multiple myeloma are usually diagnosed by chance in the absence of symptoms.

3.1.3 Solitary myeloma of bone or extramedullary plasmacytoma
Solitary myeloma of bone or extramedullary plasmacytoma are usually revealed by symptoms and physical signs related to the tumor.

3.1.4 Waldenstr&oumlm's macroglobulinemia
In Waldenstr&oumlm's macroglobulinemia the most common presenting findings are anemia and bleeding. Other common findings are analogous to those seen in non Hodgkin's lymphomas, namely lymphadenopathy and hepatosplenomegaly (40-50% of patients). Patients can also be initially seen because of symptoms resulting from the serum monoclonal IgM. The hyperviscosity syndrome is related to the intrinsic viscosity of the large IgM molecule. Clinical symptoms include fatigue, dizziness, blurred vision and easy bleedings. The fundi of patients should be examined with an ophtalmoscope and characteristic ocular findings include dilatation of retinal veins, hemorrhage and papilledema. Cryoglobulinemia is the reversible precipitation at low temperature of the monoclonal IgM. Clinical symptoms include acryocyanosis, Raynaud's phenomenon and purpura, particularly after cold exposure. However, while cryoglobulinemia can be detected in up to 15% of patients in the course of the disease, in less than 5% are these symptoms seen at initial presentation. Cold agglutinin hemolytic anemia is observed in up to 10% of patients with Waldenstr&oumlm's macroglobulinemia and can be revealed with symptoms like Raynaud's phenomenon, acryocyanosis and livedo reticularis. Peripheral sensorimotor neuropathy develops in up to 15-20% of patients. Finally signs and symptoms related to renal complications or to amyloidosis are much less common than in multiple myeloma.


3.2 Diagnostic Criteria

Three areas of evaluation are necessary to establish diagnostic criteria (major and minor).

3.2.1 Evaluation of bone marrow plasma cell infiltration
Bone marrow aspiration (either sternal or iliac) is the standard procedure to detect quantitative and/or qualitative abnormalities of bone marrow plasma cells which are specific of multiple myeloma. However, in a minority of cases bone marrow involvement is nodular and bone marrow aspiration can be falsely negative. Therefore, iliac bone marrow biopsy is appropriate for clinical use in those patients with negative marrow aspirate on a type R basis.

3.2.2 Evaluation of the presence of an M-component in the serum and/or the urines
Electrophoresis or nephelometry of the serum and of concentrated urines is the standard procedure for M-component detection and for quantification of M-component.
Immunoelectrophoresis or immunofixation are recommended for determination of the monoclonal immunoglobulin subtype. Immunodiffusion methods are recommended for quantification of residual normal polyclonal immunoglobulins but not for quantification of M-component.

3.2.3 Evaluation of lytic bone lesions
X-ray skeletal survey is recommended in the evaluation of the number of lytic bone lesions and of pathologic fractures. Usually, CT scan and magnetic resonance imaging are optional, but indicated in case of spinal cord compression symptoms in order to have a better evaluation of anatomic lesions. Lytic bone lesion from multiple myeloma are usually not evidenced by bone scintigraphy.

3.2.4 Other recommended exams
Full blood cell count, serum calcium and serum creatinine are useful for prognosis evaluation and are recommended to distinguish symptomatic from asymptomatic multiple myeloma.

3.2.5 Diagnostic criteria of different plasma cell neoplasms
The commonly used diagnostic criteria of multiple myeloma, indolent myeloma and MGUS are shown below:

A. Multiple myeloma
Major criteria IPlasmacytoma on tissue biopsy
IIBone marrow plasmacytosis with > 30% plasma cells
IIIMonoclonal globulin spike on serum electrophoresis (> 3 g/dL for IgG, > 2 g/dL for IgA)
or on concentrated urine electrophoresis (> 1g/24h of k or l light chains)

Minor criteria aBone marrow plasmacytosis 10 to 30% plasma cells
bMonoclonal globulin spike less than the level defined above
cLytic bone lesions
dResidual normal IgM <0.05 g/gL, IgA < 0.1g/dL, IgG < 0.6g/dL
The diagnosis of multiple myeloma requires a minimum of two major criteria or one major criteria + one minor criteria, or three minor criteria always including a and b.



B. Indolent (or asymptomatic) multiple myeloma
Same as multiple myeloma except :
No bone lesions or one asymptomatic lytic lesion (X-ray survey)
M component level <3 g/dL for IgG, 2 g/dL for IgA urine light chain < 4 g/24h
No symptoms :
- hemoglobin > 10 g/dl
- serum calcium normal
- serum creatinine <2 mg/dL
- no infections

C. MGUS
M component present, but at levels IgG <3 g/dL
IgA <2 g/dL
BJ protein <1 g/24h

Furthermore:
Normal level of residual polyclonal immunoglobulins
Bone marrow plasma cells <10% (and without cytological abnormalities)
No bone lesions
No bone pain and normal physical examination
No symptoms or associated disease features
- hemoglobin > 10 g/L
- serum calcium normal
- serum creatinine <20 mg/L
- no infections


3.2.6 Waldenström's macroglobulinemia
Serum electrophoresis and immunoelectrophoresis (or immunofixation) are recommended for evaluation of the presence of a monoclonal IgM. Bone marrow biopsy is the standard procedure for detection of the bone marrow infiltration by lymphoplasmacytic cells. Bone marrow aspiration is also useful but can be negative in case of nodular infiltration.
Abdominal ultrasound or, better, CT scan are required to search for clinically undetectable hepatosplenomegaly and mesenteric or retroperitoneal enlarged lymph nodes.


3.3 Exams useful in some clinical circumstances

3.3.1 Solitary plasmacytoma of bone or soft tissues
To be sure that the plasmacytoma is unique, it is necessary to check the absence of occult disseminated disease. It has recently been demonstrated that in some patients with apparent solitary bone plasmacytoma on skeletal X-ray survey (only one area of bone destruction), magnetic resonance imaging of thoracic and lumbar spine may show additional foci of marrow replacement identical to those of the primary tumor. Therefore, magnetic resonance imaging is appropriate for individual clinical use in patients with apparent solitary bone plasmacytoma on a type 3 level of evidence (3.VI) in the staging of patients presenting with a solitary plasma cell tumor.

3.3.2 Spinal cord compression
Spinal cord compression is a serious complication of multiple myeloma occurring in 10% to 15% of patients, at any phase of the disease. It results from either growth of paraspinal mass through an intervertebral foramina or by direct extension from a heavily involved vertebra. In these circumstances, evaluation by a CT scan or by magnetic resonance imaging is strongly recommended to exclude invasion of the spinal canal.

3.3.3 Amyloidosis
Rectal biopsy has been the classic method of establishing the diagnosis of amyloidosis and it is positive in 60% of patients. Biopsies of the liver or kidney may be useful but are more hazardous. Congestive heart failure caused by amyloid deposits is associated with a very poor prognosis. Low voltage of EKG can be suggestive of cardiac involvement but two-dimensional echocardiography is recommended to detect cardiac amyloidosis.

3.3.4 Peripheral neuropathy
In Waldenstr&oumlm's macroglobulinemia, electromyographic studies are needed to determine if the neuropathy is demyelinating (as seen in the majority of patients) or axonal. Immunocytochemical studies on sural nerve biopsies can reveal a IgM deposit on the outer layer of the myelin sheath, suggesting an anti-myelin activity of the IgM.


3.4 New diagnostic approaches

3.4.1 Bone evaluation
Magnetic resonance imaging of bone (thoracic and lumbar spine) is useful for the diagnosis of occult bone lesions not evident on skeletal X-ray and are appropriate for individual clinical use on a type 3 level of evidence (3.VI, 3.II)Bone densitometry could be useful for treatment efficacy assessment but is still investigational (3.V).
Quantitative bone biopsy can assess an excessive osteoclastic-mediated bone resorption which is an early event in multiple myeloma and is considered as a sign of malignancy. Therefore it can be used in the differential diagnosis of MGUS and early multiple myeloma but at the moment should still be considered investigational (3.I).


References

3.I
Bataille R. The mechanisms of bone lesions in human plasmacytomas. Stem Cells 1995;13(suppl 2):40-7.

3.II
Dimopoulos MA, Moulopoulos A, Smith T, Delasalle KB, Alexanian R. Risk of progression in asymptomatic multiple myeloma. Am J Med 1993;94:57-61.

3.III
Fielder K, Durie BGM. Primary amyloidosis associated with multiple myeloma. Predictors of successful therapy. Am J Med 1986;80:413-9.

3.IV
Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history of 241 cases. Am J Med 1978;64:814-26.

3.V
Mariette X, Khalifa P, Ravaud P et al. Bone densitometry in patient with multiple myeloma. Am J Med 1992;93:595-8.

3.VI
Moulopoulos LA, Dimopoulos M, Weber D, Fuller L, Libshitz HI, Alexanian R. Magnetic resonance imaging in the staging of solitary plasmacytoma of bone. J Clin Oncol 1993;11:1311-5.

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