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  Disease summary:

  
  
  
  
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    Multiple myeloma (MM) is a plasma cell malignancy characterized by accumulation of clonal antibody-secreting plasma cells.

    
    
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    MM accounts for 1% of all cancers and 10% of all hematologic malignancies.

    
    
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    Almost all MM evolves from an asymptomatic premalignant stage termed as monoclonal gammopathy of undetermined significance (MGUS).

    
    
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    MM is now believed to be curable in only a small fraction of cases, and has a median overall survival of 5 years.

    
    
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    The major clinical manifestations are bone lesions, anemia, hypercalcemia, renal failure, and an increased risk of infections.

    
    
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    Genetic abnormalities are used for disease risk stratification and therapeutic decision making.

  
  

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  Differential diagnosis:

  
  
  
  
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    Other hematologic disorders associated with monoclonal gammopathies, such as amyloidosis, Waldenström macroglobulinemia (WM) and polyneuropathy, organomegaly, endocrinopathy, M protein, and skin lesions (POEMS). Both IgM MGUS and WM represent fundamentally different disorders that arise from clonal cells different from the plasma cells.

  
  

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  Monogenic forms:

  
  
  
  
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    No single gene cause of MM is known to exist.

  
  

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  Family history:

  
  
  
  
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    Reports have described families with affected members in two or more generations, with two or more affected members in a single generation. First-degree family members of an MGUS affected individual have elevated risks of MGUS and MM.

  
  

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  Twin studies:

  
  
  
  
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    Few studies report the occurrence of MM in monozygotic or dizygotic twins.

  
  

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  Environmental factors:

  
  
  
  
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    Several studies have pointed to links between MM and environmental exposure to certain kinds of chemicals and radiation, however, most have been limited and there is no major environmental agent identified. It is currently believed that most MM is sporadic and not driven by genetic susceptibility or environmental factors.

  
  

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  Genome-wide associations:

  
  
  
  
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    First genome-wide association studies (GWAS) have been recently published in MM. One study suggested that MM patients could be classified based on the germline single-nucleotide polymorphism (SNP) profiles into two distinct groups of good prognosis (>3 year progression-free survival [PFS]) and bad prognosis (<1 year PFS). Another study proposed the correlation of several SNPs with the clinical extent of the bone disease. Further validations are needed to confirm these findings.

  
  

Diagnostic Criteria for MM

The diagnosis of MM requires 10% or more clonal plasma cells (PCs) on bone marrow examination or a biopsy-proven plasmacytoma, plus evidence of end-organ damage related to the underlying disorder. Organ damage is usually identified by the acronym CRAB, which includes

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  C—calcium elevation (>11.5 mg/dL)

  
  
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  R—renal dysfunction (creatinine >2 mg/dL)

  
  
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  A—anemia (hemoglobin <10 g/dL)

  
  
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  B—bone disease (lytic lesions or osteoporosis)

When MM is suspected clinically, diagnostic evaluation should include

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  Blood and urine tests: Patients should be tested for the presence of monoclonal proteins in blood and urine by serum or urine protein electrophoresis, serum immunofixation, and serum-free light-chain (SFLC) assays.

  
  
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  If M proteins are present, additional blood tests are recommended to measure blood cell counts and levels of calcium, uric acid, creatinine, and beta-2 microglobulin.

  
  
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  Bone marrow biopsy and aspirate.

  
  
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  Imaging which may include plain x-rays (metastatic bone survey), computed tomography (CT) scan, and magnetic resonance imaging (MRI).

Clinical Characteristics

The disease is systemic and can cause renal insufficiency, bone lesions and fractures, fatigue due to anemia, and degraded function of the marrow and the immune system.

Symptoms

The disease is asymptomatic in early stages (MGUS and smoldering multiple myeloma [SMM]). Symptoms at the time of disease progression mainly include bone pain and fractures, fatigue due to anemia, and symptoms of hypercalcemia such as loss of appetite, nausea, thirst, constipation, and confusion. Other symptoms may include weakness or numbness in the legs, weight loss, and repeated infections.

Risk Factors

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  Age: The median age of people who develop multiple myeloma is 65 years.

  
  
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  Sex: It is slightly more common in men than in women.

  
  
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  Race: Individuals of African origin have twofold risk to develop MM when compared with Caucasians.

  
  
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  History of MGUS: Every year 1% of the people with MGUS develop MM.

  
  
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  Obesity: The risk of MM is increased in obese individuals.

Screening

There are no specific genes or loci that confer increased susceptibility to myeloma. Therefore no genetic counseling is recommended on a routine basis. However, for families with more than one affected individual, counseling may be appropriate.

Regarding the genetic changes observed in the tumor cells, no specific genetic markers are required to make a MM diagnosis, as this can be solely made on the basis of morphologic changes in the bone marrow. However, significant advances have been made to identify genetic abnormalities and molecular signatures that can predict clinical outcome in MM patients and include them in the routine clinical tests. Several genetic classifications are used in MM, generating between five and eight disease subgroups depending on the classification used. A two-group classification (standard and high-risk categories) based on the presence of specific genetic abnormalities has been recently proposed by the Mayo Stratification of Myeloma and Risk-Adapted Therapy guidelines (Table 37-1).