Episode 040: Myeloma Series, Pt.1 - Intro to Testing and MGUS

In the first episode in our highly-anticipated multiple myeloma series, we begin our discussion about introduction to testing/workup for plasma cell dyscrasias and having our initial discussion about monoclonal gammopathy of undetermined significance (MGUS).


This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.

  • What is the function of a plasma cell?

    • Plays role in humoral immunity in producing antibodies 

    • Normally, your body will have an elevation of many different immunoglobulins/antibodies

    • Remember that an antibody has heavy chains (defined by IgG, IgA, and IgM) and light chains (defined by kappa or lambda)

      • The light chains are the extra elements hanging off the Y shaped antibody 

      • When a B cell develops, it chooses either kappa or lambda for its light chain and your body has a good mix of kappa plasma cells and lambda plasma cells

      • We can quantify the heavy immunoglobulins in the serum and/or the light chains in the serum

Structure of antibody/immunoglobulin (Image from www.antibodies-online.com; no copyright infringement intended)

  • What is a plasma cell dyscrasia?

    • Abnormal production of a plasma cells that have undergone a mutation that preferentially choose to secrete a specific type of heavy and/or light chains in abundance (monoclonal protein)

  • Why are excess monoclonal immunoglobulin production bad?

      • Disruption of osteoclast/osteoblast homeostasis causing lytic lesions 

      • Disruption of erythropoiesis in the bone marrow resulting in anemia  

      • Excess immunoglobulin deposition or light chain cast neuphropathy resulting in renal failure

      • Development of immune mediated neuropathy (Waldenstrom’s Macroglobulinemia)

  • What is an “SPEP”?

    • Serum protein electropheresis

    • The test separates proteins based on size and charge

    • Normal peaks:

      • Albumin peak - usually largest peak 

      • Alpha1 

      • Alpha2

      • Beta

        • These alpha, beta beaks encompass proteins like the acute phase reactants

      • Gamma - Gamma is where most of your immunoglobulins will be found. Normally, you want a nice even curve since IGs should be heterogeneous

        • In a patient with clonal plasma cells, they will start making one particular type of Immunoglobulin over another, therefore you will see a spike in the gamma region 

    • This SPEP curve is interpreted by a pathologist to identify if a “monoclonal spike” or “M-spike” exists in the gamma region

    • The M-spike can then be quantified (i.e., this is a QUANTITATIVE test; it does not tell us what that protein is)

Comparing normal SPEP vs. patient with a monoclonal gammopathy: Note difference in gamma region (Image from https://cdn.lecturio.com; no copyright infringement intended)

  • What is “immunofixation”?

  • This test is often run in concert with the SPEP (but always check with your lab!), but this is a QUALITATIVE test

  • Immunofixation helps to identify what the monoclonal protein seen on the SPEP is

  • What are “serum free light chains”?

    • TFOC Pro-Tip: If you are ordering an SPEP/IFE, always order serum free light chains!

    • Important note: Kappa light chains are preferentially cleared by the renal system, therefore in patients with renal dysfunction, you can have abnormal values with a normal kappa/lambda ratio up to 3.1 (see episode 2 in this series)

    • The light chain values and the ratio have important prognostic information for our patients

  • For patients with a monoclonal gammopathy, also check urine protein electropheresis (UPEP)!

    • ALWAYS do 24 hour urine collection (spot is not useful)

    • This will help us determine if a mild elevation in Cr is more likely related to immunoglobulin deposition if a patient has a large detectable urine M protein for example 

    • This also gives us an idea of the extent of kidney damage as we should not be seeing larger heavy chains in the urine for a normal functioning kidney

  • Once you have your data, how do you decide if someone has multiple myeloma?

    • We will discuss this a lot more in our future episodes, but mutliple myeloma is diagnosed when there is a bone marrow biopsy showing >10% clonal plasma cells or biopsy proven plasmacytoma AND myeloma defining events

      • OR in a patient with a bone marrow biopsy showing >60% plasma cells

  • Wait, so does everyone with an abnormal SPEP need a bone marrow biopsy?!

    • NO, see below

  • What is a monoclonal gammopathy of undetermined significance?

    • First it is important to know that MGUS is incredibly common in the older adult population and does not mean that a patient has cancer or will develop myeloma

    • Population based studies have shown a prevalence of MGUS ~3% in adults over the age of 50 and in 6% of the African American population (Kyle et al. NEJM 2006)

    • Older studied suggested that rate of progression to myeloma is 1% per year for patients with MGUS (Kyle et al. NEJM 2002); we later learned that it is not that simple

    • Risk of progression to myeloma varies depending on baseline patient characteristics (i.e. how big was the M spike, what was the heavy chain classification, and what was the light chain discordance)

    • This is why we always need the serum free light chains - so that we can risk stratify the MGUS to see if we need to do a bone marrow biopsy and lytic lesion imaging study

      • Factors that influence risk of progression to MM (and therefore warrant a bone marrow biopsy):

        • Type of heavy chain involved (IgG vs. non IgG with non IgG as higher risk)

        • Quantity of M-spike (>1.5 is higher risk)

        • Abnormal free light chain ratio

        • For light chain only MGUS (FLC must be > 8 to be considered higher risk)

    • If one or more of the criteria above are met, then you do a bone marrow biopsy and either whole body PET/CT or MRI to evaluate for lytic lesions

      • This is done so that we can identify patients who may already have myeloma or have a very high risk of developing myeloma 

      • Affects surveillance strategies 

  • Calculator: https://qxmd.com/calculate/calculator_148/mgus-prognosis


References:

https://www.nejm.org/doi/full/10.1056/NEJMoa054494: 2006 article from Kyle et al. discussing MGUS prevalence in general population

https://www.nejm.org/doi/full/10.1056/nejmoa01133202: 2002 article from Kyle et al. discussing MGUS progression estimated 1% per year

https://ashpublications.org/blood/article/131/2/163/37011/How-I-manage-monoclonal-gammopathy-of-undetermined: Great review article on MGUS


The crew behind the magic:

  • Show outline: Vivek Patel

  • Production and hosts: Ronak Mistry, Vivek Patel, Dan Hausrath

  • Editing: Vivek Patel

  • Shownotes, graphics, social media management: Ronak Mistry

This episode has been sponsored by Primum. To sign up for a free account, check out: tfoc.primum.co.

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Episode 041: Myeloma Series, Pt.2 - Intro to MGUS and Smoldering Myeloma

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Episode 039: Hemophilia 101, Pt 4