Multiple%20myeloma Signs and Symptoms

• A bone marrow disease characterized by the presence of malignant plasma cells, and abnormal serum and/or urine immunoglobulin secondary to clonal plasma cell expansion

• Patients usually present with bone pain and fatigue due to anemia
• Nonspecific symptoms eg nausea, vomiting, malaise, weight loss, generalized body weakness, fatigue

• There are 2 processes being considered to be the root cause of multiple myeloma

Premalignant Stage: Appearance of Monoclonal Gammopathy of Undetermined Significance (MGUS)

• Brought about by the cytogenetic abnormalities and/or abnormal cellular response to an antigenic stimulus
• Malignant transformation of plasma cells leads to production of monoclonal paraprotein (M-protein) composed of single heavy and light chain immunoglobulins
  
  • Abnormal immunoglobulins include IgG, IgM, IgA, and rarely IgE and IgD
  • Light chain protein κ and λ are also seen
  • These immunoglobulins cause hyperviscosity and end-organ damage

• Chromosomal aberrations identified with multiple myeloma include del17p13, IgH gene rearrangement at 14q32, 14q32 translocations [t(11;14)(q13;q32), t(4;14)(p16;q32), t(14;16)(q32;q23), t(14;20)(q32;q12)], and chromosome 1 abnormalities
  
  • These aberrations lead to the development of plasma cell clones 

• An antigenic stimulus when interpreted by cells [eg toll-like receptors (TLRs) on myeloma cells, interleukin-6 (IL-6)] abnormally causes an increase in plasma cells, thereby causing chromosomal changes leading to plasma cell clones and abnormally produced immunoglobulins

Disease Progression from MGUS to Multiple Myeloma

• Triggering factors that contribute to the development of MGUS into multiple myeloma include secondary cytogenetic aberrations (secondary IgH translocation, Ras mutations, activation of the NF κ B pathway), abnormalities in the cell cycle pathway, interrupted apoptosis, and various factors affecting the bone marrow

• Age (increases risk)
• Immunosuppression
• Environmental exposures
• Gender (more common in men)
• Occupational exposure to toxic substances such as radiation, solvents, herbicides, insecticides

• Accounts for 1-2% of all cancers worldwide
  
  • 2nd most frequent hematologic malignancy in the US, with rapidly increasing incidence rate in Asia

• Median age of onset is 69 years old

• Always preceded by a premalignant stage, monoclonal gammopathy of undetermined significance (MGUS)
  
  • Only 10% of patients with newly diagnosed multiple myeloma have a documented history of pre-existing MGUS since patients with MGUS are asymptomatic
  • Rate of progression of MGUS to multiple myeloma is 1% per year
  • Non-IgM immunoglobulin MGUS (non-IgM MGUS) makes up 80% of premalignant multiple myeloma
  • Light-chain immunoglobulin MGUS makes up 20% of premalignant multiple myeloma
  • IgM immunoglobulin MGUS usually develops into Waldenström macroglobulinemia but may rarely evolve into multiple myeloma (IgM myeloma)