Medicine

Last updated on: August 14th, 2020

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Multiple myeloma

Clinicals - History

Introduction

Multiple myeloma (MM) consists of a neoplastic proliferation of plasma cells that accumulate in the bone marrow and produce a monoclonal immunoglobulin (IgG, IgM, IgA, or rarely, IgE or IgD) or light chain protein (kappa or lambda).


MM accounts for 1% of all cancers and ~10% of all hematologic malignancies. It is twice more common in blacks than whites, with a slight male predominance. Median survival is 5 to 7 years.

Advanced age

The median age of presentation is 70 years of age; 15% of patients are less than 65 years old. Persons of African descent tend to present at a younger age.

Asymptomatic

Multiple myeloma is asymptomatic initially. In such individuals, it is usually identified incidentally, e.g. via laboratory studies showing hypercalcemia, anemia, or proteinuria.

Bone pain

Bone disease is present in 80-90% of patients. Pain is due to bony infiltration and pathologic fractures.

Features of hyperviscosity syndrome

Features of hyperviscosity syndrome range from mild headache, dizziness or dyspnea, to severe manifestations such as altered mentation, transient ischemic attacks, retinal hemorrhages, and deep venous thrombosis.


Hyperviscosity syndrome occurs due to high concentrations of serum monoclonal proteins.

Features of hypercalcemia

Hypercalcemia can present with numerous symptoms, including:


○ Neurologic symptoms (e.g. fatigue and altered mental status);

○ Gastrointestinal symptoms (e.g. anorexia, nausea, vomiting, and constipation); and,

○ Renal symptoms (e.g. polyuria due to nephrogenic diabetes insipidus)

Clinicals - Examination

Normal physical examination

Most patients present with a normal physical examination.

Features of amyloidosis

Glossomegaly and periorbital ecchymosis may indicate amyloidosis.

Focal neurological signs

Spinal cord compression due to bone disease can present as limb weakness and sensory impairment.


Hyperviscosity syndrome can present with focal neurological deficits, due to stroke syndromes; neuropathy due to deposition of monoclonal proteins on the myelin sheath of peripheral nerves; or visual abnormalities due to retinal vein occlusion or hemorrhages.

Features of heart failure

Amyloidosis may give rise to edema, hypotension, and right-sided heart failure. Hyperviscosity syndrome can cause myocardial infarction, with subsequent heart failure.

Features of venous thromboembolism

These include calf swelling, tenderness, and erythema due to deep venous thrombosis.


Multiple myeloma by itself increases the risk of venous thromboembolism. This risk is further increased by reduced mobility secondary to neurological complications or bone pain; the use of chemotherapeutic and erythropoiesis-stimulating agents; and, by a personal or familial predisposition for venous thromboembolism.

Differential Diagnoses

Monoclonal gammopathy of unditermined significance (MGUS)

Similarly to multiple myeloma (MM), these patients will have increased serum monoclonal protein levels. However, serum monoclonal protein levels will be <3 g/dL and clonal bone marrow plasma cells will be <10%.


There will also be no evidence of other B-cell proliferative disorders, or myeloma-related organ or tissue impairment (e.g. hyperviscosity syndrome, amyloidosis, recurrent infections related to hypogammaglobulinemia, hypercalcemia, renal disease, anemia, or bone involvement).

Smoldering multiple myeloma

These patients will also have serum monoclonal protein ≥3 g/dL, or urinary monoclonal protein ≥500 mg/24 hours.


However, clonal bone marrow plasma cells will be between 10-60% and these patients will not have myeloma-defining events (e.g. anemia, hypercalcemia, renal disease, or bone disease) or amyloidosis.

Solitary plasmacytoma

These patients will have a biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells.


However, their bone marrow will be normal, with no evidence of clonal plasma cells. The skeletal survey will be normal except for the primary solitary lesion. There will be no organ or tissue impairment that can be attributed to a lymphoplasma cell proliferative disorder.

Plasma cell leukemia

These patients may demonstrate elevated serum monoclonal proteins, bone marrow infiltration, and myeloma-related organ or tissue impairment.


However, they will also have circulating clonal plasma cells in the peripheral blood that are >2,000/μL or >20% of leukocytes, therefore indicating that this is a plasma cell leukemia.

Waldenström macroglobulinemia

Similarly to multiple myeloma, these patients will have an IgM monoclonal gammopathy. They may also have anemia, hepatosplenomegaly, and systemic symptoms.


However, they will also have bone marrow lymphoplasmacytic infiltration ≥10%, indicating Waldenström macroglobulinemia.

Primary amyloidosis

These patients will show evidence of a monoclonal plasma cell proliferative disorder (e.g., the presence of a serum or urinary monoclonal protein, abnormal serum free light chain ratio, or clonal bone marrow plasma cells). However, the monoclonal protein will be composed of light chains.


The diagnosis can be confirmed by a positive amyloid tissue stain using Congo red, or by the presence of amyloid fibrils upon electron microscopy.

POEMS syndrome

The term POEMS stands for "polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes". These patients have a monoclonal plasma cell proliferative disorder and may also present with osteosclerotic or mixed sclerotic/lytic lesions.


However, they will also have other features not typically found in MM:


○ Polyneuropathy

○ Organomegaly (e.g. splenomegaly, hepatomegaly, or lymphadenopathy)

○ Endocrinopathies (excluding diabetes mellitus and hypothyroidism)

○ Skin changes (such as hyperpigmentation, hypertrichosis, acrocyanosis, plethora, hemangioma, telangiectasia)

○ Castleman disease (e.g. giant lymph node hyperplasia and angiofollicular lymph node hyperplasia)

○ Extravascular volume overload (e.g. peripheral edema, ascites, or pleural effusions),

○ Papilledema

○ Thrombocytosis and/or polycythemia.

○ Elevated serum vascular endothelial growth factor levels

Investigations - Diagnosis

Diagnostic criteria for multiple myeloma

Both of the following criteria must be met:


1) Clonal bone marrow plasma cells ≥10%, or biopsy-proven bony or extramedullary plasmacytoma, and



2) At least one of the following myeloma defining events:



a) Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder (i.e. hypercalcemia, renal insufficiency, anemia, bone lesions);

b) Clonal bone marrow plasma cells ≥60%;

c) Involved to uninvolved serum free light chain ratio ≥100;

d) More than 1 focal lesion on magnetic resonance imaging studies (≥5 mm in size).

Evaluation of the monoclonal component

The monoclonal component can be evaluated by serum and urine protein electrophoresis; quantification of IgG, IgA and IgM immunoglobulins; and, characterization of heavy and light chains by immunofixation and serum-free light chain measurement.

Evaluation of bone marrow plasma cell infiltration

Bone marrow aspiration and biopsy should be performed to ascertain the degree of plasma cell infiltration, identify their characteristics, and characterize any cytogenetic abnormalities.

Evaluation of lytic bone lesions

Whole-body low-dose computed tomography is the new standard for the diagnosis of lytic disease, although conventional radiography can still be used. Magnetic resonance imaging is recommended if spinal cord compression is also suspected.

Complete blood count

Anemia is almost always present. This is defined as a hemoglobin value 2 g/dL or more below the lower limit of normal, or a hemoglobin value <10 g/dL.

Serum calcium

Hypercalcemia indicates end-organ damage. This is defined as a total serum calcium >1 mg/dL (>0.25 mmol/L) higher than the upper limit of normal or >11 mg/dL (>2.75 mmol/L).

Renal function tests

In multiple myeloma, renal insufficiency is defined as a creatinine clearance <40 mL/min or serum creatinine >177 mmol/L (>2 mg/dL).


Renal injury is due to the combination of free light chain damage to proximal tubules, hypercalcemia, hyperuricemia, volume depletion, infections, and the use of nephrotoxic drugs and contrast media.

Investigations - Management

Staging the disease

There are multiple staging systems for multiple myeloma. The most frequently used are the International Staging System (ISS) and the Revised International Staging System (R-ISS).


Both of the above use serum levels of beta2-microglobulin and albumin as prognostic markers. The R-ISS also takes into account serum lactate dehydrogenase levels and the presence of high-risk cytogenetics.

Fluorescence in situ hybridization (FISH)

Fluorescence in situ hybridization (FISH) helps detect cytogenetic abnormalities. These are a major prognostic factor.


The abnormalities associated with a poorer outcome are t(4;14), deletion(17p), and the t(14;16) and chromosome 1 abnormalities.

Management - Supportive

Treatment of renal disease

Good hydration is important for all patients. Where used, treatment measures are aimed at controlling levels of light chains, which is the key cause of renal injury.


Dexamethasone can be used in conjunction with chemotherapy to reduce light chain load. Bortezomib-based therapies are preferred if frank renal failure is present. The use of high cutoff dialysis filters to remove free light chains is under evaluation.

Treatment of bone disease

Intravenous zoledronic acid or pamidronate are recommended in almost all cases, as bisphosphonates have been shown to reduce the number of skeletal lesions. Patients should also take calcium and vitamin D3 supplements (with caution in case of renal disease).


If vertebral compression fractures occur, vertebroplasty, balloon kyphoplasty and local radiation therapy improve pain and function. Patients with impending fractures may need prophylactic surgery.

Prevention of thromboembolic events

Patients being treated for multiple myeloma, especially if on immunomodulatory drugs, should receive thromboprophylaxis with low-molecular-weight heparin or warfarin. Aspirin alone can be considered for the lowest-risk patients.

Prophylaxis against infections

Acyclovir or valacyclovir is recommended for patients receiving proteasome inhibitor-based therapies, because of the risk of varicella-zoster virus reactivation. Vaccination against influenza and pneumococcus is also recommended.


Prophylaxis against bacterial infections is controversial but may be beneficial within the first 2–3 months of initiation of therapy, especially in patients receiving lenalidomide or pomalidomide, or if there is a high risk of infection (i.e. previous serious infections or neutropenia).

Treatment of anemia

Once other causes of anemia have been excluded, recombinant human erythropoietin and darbepoetin alfa can be prescribed; the aim is to maintain hemoglobin at around 12 g/dL.


Note that these agents can increase the risk of thromboembolic complications and death. Maintaining hemoglobin levels <14 g/dL reduces this risk.

Treatment of hyperviscosity syndrome

Hyperviscosity syndrome should be treated via urgent plasma exchange and antimyeloma chemotherapy.

Treatment of hypercalcemia

Hydration, corticosteroids, and bisphosphonates are the mainstay of therapy. In patients with refractory disease, salmon calcitonin can be used.

Management - Specific

Autologous stem cell transplantation

Autologous stem cell transplantation improves response rates and prolongs the median overall survival by approximately 12 months.


Eligibility is based on age, performance status, and comorbidities.

Management of transplant ineligible persons

Patients who are over 75 years of age, physically frail, or with multiple comorbidities may not be eligible for stem cell transplantation. They should be offered chemotherapy instead.


Commonly used chemotherapy regimens include the combination of lenalidomide (a thalidomide analog) and dexamethasone; and regimens based on bortezomib (a proteasome inhibitor).

Maintenance therapy

Currently, systemic maintenance therapy is only recommended in young patients who have undergone autologous stem cell transplantation.

Treatment of relapsed or refractory disease

The management of patients with previously treated MM is complex, with the choice of therapy heavily depending on the individual clinical context.


Autologous stem cell transplantation should be considered in patients who did not receive this earlier, and are eligible. In addition, persons who received stem cell transplantation earlier and demonstrated a durable response should be considered for a second round of transplantation.

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References

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