Evaluation of monoclonal gammopathies

Patients with M protein >1.5 g/dL and those with an IgA type paraprotein are at higher risk of progression to myeloma.[19]Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002 Feb 21;346(8):564-9. https://www.nejm.org/doi/full/10.1056/NEJMoa01133202#t=article http://www.ncbi.nlm.nih.gov/pubmed/11856795?tool=bestpractice.com [21]Kyle RA, Durie BG, Rajkumar SV, et al; International Myeloma Working Group. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010 Jun;24(6):1121-7. http://www.ncbi.nlm.nih.gov/pubmed/20410922?tool=bestpractice.com

Abnormal sFLC is associated with increased risk of progression from monoclonal gammopathy of undetermined significance (MGUS) to myeloma or related disorders.[71]Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005 Aug 1;106(3):812-7. http://www.bloodjournal.org/content/106/3/812.long http://www.ncbi.nlm.nih.gov/pubmed/15855274?tool=bestpractice.com

The type of light chain, kappa or lambda, does not have any prognostic value in this setting.

In older patients with anemia, additional studies should be performed to rule out other causes.

Presence of elevated creatinine is often the result of comorbid conditions such as diabetes mellitus or hypertension.

If elevated calcium is seen, other etiologies such as hyperparathyroidism should be ruled out.

Diagnosis is often made on abnormal blood counts on routine CBC.

Lymphocytes express B-cell-associated antigens, including CD19, CD20 (weak), CD21, CD23, CD24, CD5 (a T-cell-associated antigen), and low levels of surface membrane immunoglobulin.

Can be used to accurately estimate albuminuria. Renal involvement is typically characterized by nephrotic-range proteinuria.

Anemia is not a common feature, and may reflect renal disease or co-existent myeloma.

Patients with light chain deposition disease may progress to develop myeloma, or myeloma may be present at diagnosis.

Electron microscopy may be required to distinguish from amyloid deposits. In light chain deposition disease, amyloid fibrils are not formed.

Findings need to be distinguished from those of amyloidosis.

In older patients with anemia, additional studies should be performed to rule out other causes.

Presence of elevated creatinine can be seen and is often the result of comorbid conditions such as diabetes mellitus and hypertension.

If elevated calcium is seen, presence of other etiologies such as hyperparathyroidism should be ruled out.

The presence of abnormal sFLC is associated with poorer outcomes in patients with myeloma. High levels of sFLC in association with acute renal failure increases the likelihood of cast nephropathy.

Anemia is a common feature in patients with active myeloma. Thrombocytopenia is also a common finding and may have prognostic implications.

Leukopenia and leukocytosis are uncommon findings.

A large proportion of patients may have abnormal renal function at time of diagnosis. It is useful to determine if the abnormality is of recent onset.

Calcium should be corrected for the albumin level or ionized calcium should be obtained.

If elevated calcium is the only laboratory abnormality, presence of other etiologies such as hyperparathyroidism should be ruled out.

The presence of bone lesions denotes active, symptomatic myeloma, and generally the need for treatment. Long bone lesions that demonstrate cortical destruction typically are in danger of impending fracture and need to be treated urgently. Occasionally patients may have 1 to 3 lesions that are small and may remain unchanged over a long time (indolent myeloma). [Figure caption and citation for the preceding image starts]: Myeloma bone diseaseFrom the personal collection of Dr Kumar [Citation ends].

Nearly 3% of patients with myeloma have <10% plasma cells. The plasma cells may be in aggregates or in diffuse sheets. Scattered distribution of plasma cells can contribute to sampling errors. Bone marrow aspirate can be used to evaluate genetic abnormalities.

Along with albumin is part of the International Staging System (ISS): beta 2 microglobulin levels >3.5 mg/L are seen in patients with ISS stage 2, and >5.5 mg/L in ISS stage 3.

Beta 2 microglobulin is an indirect measure of tumor burden and can be significantly elevated in renal failure.

May show the presence of monoclonal proteins that may migrate to the beta regions on SPEP such as IgA. Suppression of uninvolved immunoglobulins is a common finding.

Hypogammaglobulinemia may be seen in the presence of light chain myeloma.

Anemia due to other causes should be ruled out.

The presence of cytogenetic abnormalities is linked to prognostic outcomes in patients with myeloma. Patients with hyperdiploidy have a better outcome than those with hypodiploidy or chromosome 13 deletion abnormalities.

FISH genetic testing is an important component of the evaluation and can be used for risk stratification in these patients. Patients with 17p-, t(4;14) or t(14;16) have a poor outcome with the available treatments.

Often elevated in myeloma. This is a prognostic factor in these patients.

Elevated levels typically denote aggressive disease with rapid proliferation, and are associated with a poor outcome.

The presence of abnormal sFLC is associated with poorer outcomes in patients with myeloma. High levels of sFLC in association with acute renal failure increases the likelihood of cast nephropathy.

May show the presence of monoclonal proteins that may migrate to the beta regions on SPEP such as IgA. Suppression of uninvolved immunoglobulins is a common finding.

An absolute plasma cell count >2000/microliter or 20% of the peripheral WBCs is required for diagnosis.

A large proportion of patients may have abnormal renal function at the time of diagnosis. It is useful to determine if the abnormality is of recent onset

Calcium should be corrected for the albumin level or ionized calcium should be obtained. If elevated calcium is the only laboratory abnormality, presence of other etiologies such as hyperparathyroidism should be ruled out.

The presence of bone lesions denotes active symptomatic disease and usually denotes the need for treatment. Long bone lesions that demonstrate cortical destruction typically are in danger of impending fracture and need to be treated urgently. Occasionally patients may have 1 to 3 lesions that are small and may remain unchanged over a long time (indolent course).

The plasma cells may be in aggregates or in diffuse sheets. Scattered distribution of plasma cells can contribute to sampling errors. Bone marrow aspirate can be used to evaluate genetic abnormalities.

Along with albumin is part of the International Staging System (ISS): beta 2 microglobulin levels >3.5 mg/L are seen in patients with ISS stage 2, and >5.5 mg/L in ISS stage 3.

Beta 2 microglobulin is an indirect measure of tumor burden and can be significantly elevated in renal failure.

Anemia due to other causes should be ruled out.

Conventional cytogenetics may not demonstrate any abnormality due to the low proliferative rate of plasma cells and the consequent difficulty in getting informative metaphases.

FISH genetic testing is an important component of the evaluation and can be used for risk stratification in these patients. Patients with 17p-, t(4;14) or t(14;16) have a poor outcome.

Elevated LDH levels typically denote aggressive disease with rapid proliferation, and are associated with a poor outcome.

It is important to rule out hyperviscosity, especially in the presence of symptoms or high levels of IgM. Increased serum viscosity when accompanied by symptoms may need urgent interventions such as plasmapheresis.

Renal dysfunction is not a common finding in Waldenstrom macroglobulinemia, unless complicated by cryoglobulinemia or other associated conditions.

Anemia is a common feature in patients with active disease.

Often used to follow up patients on therapy for response.

The MYD88 L265P gene mutation can be seen in tumor cells in over 90% of patients with Waldenstrom macroglobulinemia, and can be of help in differentiating Waldenstrom macroglobulinemia from other conditions.[72]Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström's macroglobulinemia. N Engl J Med. 2012 Aug 30;367(9):826-33. https://www.nejm.org/doi/full/10.1056/NEJMoa1200710 http://www.ncbi.nlm.nih.gov/pubmed/22931316?tool=bestpractice.com

Solitary bone plasmacytoma should be diagnosed by tissue biopsy: fine needle aspirate is not adequate.[73]Hughes M, Soutar R, Lucraft H, et al; UKMF Guidelines Working Group. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas: 2009 update [internet publication]. https://www.ukmf.org.uk/wp-content/uploads/2012/11/solitary_plamacytoma_bcsh_FINAL_190109.pdf

Used to determine the extent and size of the lesion. Helps rule out other lesions and confirm diagnosis of solitary plasmacytoma.[73]Hughes M, Soutar R, Lucraft H, et al; UKMF Guidelines Working Group. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas: 2009 update [internet publication]. https://www.ukmf.org.uk/wp-content/uploads/2012/11/solitary_plamacytoma_bcsh_FINAL_190109.pdf [Figure caption and citation for the preceding image starts]: PlasmacytomaFrom the personal collection of Dr Kumar [Citation ends].

Used to determine the extent and size of the lesion.[73]Hughes M, Soutar R, Lucraft H, et al; UKMF Guidelines Working Group. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas: 2009 update [internet publication]. https://www.ukmf.org.uk/wp-content/uploads/2012/11/solitary_plamacytoma_bcsh_FINAL_190109.pdf

Presence of additional lesions on the skeletal survey raises the possibility of myeloma rather than solitary plasmacytoma.[73]Hughes M, Soutar R, Lucraft H, et al; UKMF Guidelines Working Group. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas: 2009 update [internet publication]. https://www.ukmf.org.uk/wp-content/uploads/2012/11/solitary_plamacytoma_bcsh_FINAL_190109.pdf

Abnormal serum free light chain is associated with increased risk of myeloma.[73]Hughes M, Soutar R, Lucraft H, et al; UKMF Guidelines Working Group. British Committee for Standards in Haematology. Guidelines on the diagnosis and management of solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas: 2009 update [internet publication]. https://www.ukmf.org.uk/wp-content/uploads/2012/11/solitary_plamacytoma_bcsh_FINAL_190109.pdf

Anemia if present can be due to other conditions. Additional studies should be performed to rule out other causes.

Presence of elevated creatinine can be seen and is often the result of comorbid conditions such as diabetes mellitus or hypertension.

If elevated calcium is seen, other etiologies such as hyperparathyroidism should be ruled out.

Anemia is not a common feature in these patients, and when present typically is anemia of chronic disease.

Thrombocytosis and less often leukocytosis can be seen.

Over 90% of patients with POEMS syndrome have sclerotic lesions that can be recognized on CT scans. Radiation therapy to a single or a few lesions may constitute definitive therapy.

CT scan can also be used to assess organomegaly and lymphadenopathy given the association with Castleman disease.

These are typically elevated in patients with POEMS syndrome.

POEMS syndrome is typically associated with lambda light chain restriction.[74]Chee CE, Dispenzieri A, Gertz MA. Amyloidosis and POEMS syndrome. Expert Opin Pharmacother. 2010 Jun;11(9):1501-14. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2874109/pdf/nihms-187828.pdf http://www.ncbi.nlm.nih.gov/pubmed/20426710?tool=bestpractice.com

Diabetes mellitus may accompany this disorder.

Nearly 20% of patients may have bone marrow plasmacytosis.

Pleural effusions may be symptomatic and require thoracentesis.

Required in the presence of symptomatic neuropathy or autonomic nerve involvement.

Recombinant immunoblot assay (RIBA) is more specific than enzyme immunoassay (EIA) and helps rule out a false-positive antibody result.

However, in practice only an EIA or an RIBA test is performed, and positive results are confirmed by nucleic acid amplification.

Indicative of AIDS.

Opportunistic infections may be confirmed on bone marrow exam.

Renal involvement is typically characterized by nephrotic-range proteinuria.

sFLC may be the only method that detects presence of a monoclonal protein in these patients because the degree of elevation of free light chain may be minimal.[9]Kumar S, Dispenzieri A, Katzmann JA, et al. Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features. Blood. 2010 Dec 9;116(24):5126-9. http://bloodjournal.hematologylibrary.org/content/116/24/5126.long http://www.ncbi.nlm.nih.gov/pubmed/20798235?tool=bestpractice.com

This can be achieved by fat aspirate and/or marrow biopsy and examination with Congo red stain in the majority of patients. In the remaining patients biopsy directed towards the involved organ will help make the diagnosis.

The amyloid deposits should be confirmed as light chain-related using mass spectrometry.

Anemia is not a common feature in patients with amyloidosis and when present typically is anemia of chronic disease.

Thrombocytosis usually reflects splenic involvement.

When present indicates hyposplenism.

Renal involvement in amyloidosis typically presents as nephrotic-range proteinuria. A small proportion of patients may present with renal insufficiency.

Calcium should be corrected for the albumin level or ionized calcium should be obtained.

Elevated serum calcium may reflect diuretic use or concomitant myeloma.

Elevation of alk phos in isolation is the typical presentation of hepatic involvement in amyloidosis.

Elevation of bilirubin may reflect advanced involvement with amyloid.

Abnormalities of coagulation tests in amyloidosis may be related to factor X deficiency, or other acquired factor deficiencies.

Often a reflection of the nephrotic syndrome that accompanies the renal involvement.

May demonstrate lytic lesions when accompanied by symptomatic myeloma.

Nearly 20% of patients may have bone marrow plasmacytosis of >10%.

Abnormalities such as those with myeloma may be observed in patients with amyloidosis, but the prognostic relevance remains unknown.

Abnormalities such as those with myeloma may be observed in patients with amyloidosis, but the prognostic relevance remains unknown. Studies have suggested that presence of t(11;14) may be associated with a poorer outcome.

Common findings include conduction abnormalities with varying degrees of atrioventricular (AV) block as well as bundle branch blocks. Changes may mimic those resulting from ischemic heart disease.

Pleural effusions may be symptomatic and require thoracentesis.

The ejection fraction is typically preserved in these patients except in advanced disease. Diastolic dysfunction is the most common finding and reflects the stiffness of the myocardium due to amyloid infiltration.

Septal thickness is an indirect measure of the degree of involvement that lends itself to serial follow-up. Additional echocardiographic modalities such as myocardial strain patterns have been identified as useful adjuncts.

Required in the presence of symptomatic neuropathy or autonomic nerve involvement.

To detect cryoglobulins, blood should be drawn into tubes that have been prewarmed to 98.6°F (37°C) without anticoagulants. After clotting, the serum is separated and refrigerated to allow the precipitation of cryoglobulins.

Anemia is not a common feature in these patients and when present typically is anemia of chronic disease. Anemia may accompany renal disease.

May be associated with renal insufficiency.

To exclude other diagnoses.

Typically small amounts of a monoclonal protein are found in urine.