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Multiple Myeloma

  • Multiple Myeloma (MM) is the result of a neoplastic proliferation of immunoglobulin-secreting plasma cell. Myeloma cells infiltrate the bone marrow, producing cytokines and immunoglobulins which are responsible for the disease's clinical manifestations. Classically these include bone pain and fracture, hypercalcemia, anemia, renal failure, and infection susceptibility. Myeloma is a disease of the elderly and tends to occur more commonly in Blacks
  • A large variety of genetic alterations have been found in MM cells and more are being discovered thanks to whole-genome tumor sequencing approaches. However, a clear etiological story remains to be delineated.
  • In keeping with their origin from plasma cells, myelomas produce large amounts of antibody, usually of the IgG subtype, although other subtypes, light-chain only, or absent production are also possible. Because neoplastic myeloma cells are monoclonal, the immunoglobulin produced by the neoplastic clone are all of a single sequence and can be detected as an outlying spike when plasma proteins are separated by electrophoresis. The presence of this spike, termed the "Monoclonal-spike" or "M-spike", is one the major diagnostic criteria of MM, and the primary method by which disease progression is tracked.
Pathogenesis and Clinical Consequences
  • Overview
    • As mentioned above, the clinical consequences of MM are a direct result of myeloma cell production of cytokines and immunoglobulins. We discuss the pathogenesis of these clinical consequences individually below.
  • Bone Pain and Fractures
    • Like normal plasma cells, myeloma cells live in the bone marrow. There they inappropriately produce a large variety of cytokines, some of which activate local osteoclasts to resorb bone. This can produce lytic lesions that appear as "punched-out" areas on radiography and when large enough will yield pathologic bone fractures.
  • Hypercalcemia
    • The hypercalcemia of MM is a direct consequence of the inappropriate bone resorption precipitated by myeloma cells described above.
  • Chronic Renal Failure
    • Renal Failure caused by myeloma is likely multi-factorial some of which may be due to the effects of hypercalcemia. However, many myelomas also secrete free antibody light-chains which are small enough that a proportion filter through the glomerulus. Mechanisms exist to resorb filtered light chains; however, in many myeloma patients this resorptive capacity is exceeded, yielding toxic levels of tubular light chain accumulation and over time renal failure.
  • Normocytic Anemia
    • Patients with MM often display a normocytic anemia which likely draws from multiple factors including inflammatory cytokine production as well as marrow infiltration by neoplastic cells, also known as a myelophthisic process. Renal failure, as described above, may also contribute by causing reduced erythropoietin levels.
  • Infection Susceptibility
    • Myeloma patients display an increased susceptibility to bacterial infections which is likely the result of complex derangements in both innate and adaptive immunity. Ultimately, this increased susceptibiltiy to infection is the most common cause of death in myeloma patients.