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Distinguishing Daratumumab from Monoclonal Proteins

Protein electrophoresis and immunofixation (IFE) are widely used to monitor monoclonal proteins (M-proteins) in patients with multiple myeloma. The approval of daratumumab (Darzalex) by the FDA in November 2015 for treatment of refractory or relapsed multiple myeloma has increased the difficulty of distinguishing residual disease from circulating therapeutic monoclonal antibody.

Daratumumab is a human monoclonal IgG kappa antibody that kills myeloma cells by binding with high affinity to CD38. Daratumumab is administered at high enough doses to be detected by serum protein electrophoresis and immunofixation. The mean peak concentration at the completion of dosing is 915 ug/mL (0.09 g/dL) and the mean trough concentration is 573 ug/mL (0.06 g/dL). The limit of detection of M-proteins is 0.1 g/dL by protein electrophoresis and 0.02 g/dL by IFE. In patients with treatment- associated hypogammaglobulinemia, IFE can detect M-proteins concentrations below 0.01 g/dL. Therefore, during treatment and several months after infusion of the last dose, there is a strong likelihood that daratumumab will be detected by IFE.

The International Myeloma Working Group definition of a complete clinical response requires that patients have no detectable M-protein by either protein electrophoresis or IFE. The presence of detectable daratumumab could cause patients to be misclassified due to an inability to differentiate residual disease from therapeutic monoclonal antibody.

Daratumumab is a human IgG kappa antibody. Detection of another isotype excludes it as the cause of a monoclonal spike. Because IgG kappa is the most common isotype produce by patients with multiple myeloma, other methods are needed. One possibility is measuring the migration distance of daratumumab on capillary electrophoresis and comparing it to the position of each patient’s IgG kappa M-protein. Other methods such as daratumumab specific immunofixation electrophoresis reflex assay (DIRA) and mass spectrometry have been described but are not available in most hospital laboratories.

Until more robust methods become available, a few other precautions can be taken:

  • Ask physicians to order a trough specimen for protein electrophoresis and IFE, just before the next dose, to minimize the possibility of detecting daratumumab.
  • Educate phlebotomists and nurses not to draw samples from patients being infused with daratumumab.
  • Recommend that pathologists check the electronic medical record on patients with small, suspicious IgG kappa M-proteins.


Keren DF. Therapeutic complications: A caveat for M-protein detection. J Appl Lab Med. 2017;01:342-45.

Mills JR & Murray DL. Identification of Friend or Foe: The laboratory challenge of differentiating M-proteins from monoclonal antibody therapies. J Appl Lab Med. 2017;01:421-31.

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