Linking To CoreIM’s “MGUS to Multiple Myeloma Diagnostics and Counseling: 5 Pearls Segment”

Today, I review, link to, and excerpt from CoreIM‘s MGUS to Multiple Myeloma Diagnostics and Counseling: 5 Pearls Segment.*

*MGUS to Multiple Myeloma Diagnostics and Counseling: 5 Pearls Segment
Posted: January 22, 2025
By: Dr. Nathaniel Long, Dr. Vincent Rajkumar, Dr. Aaron Goodman and Dr. Shreya P. Trivedi
Graphic: Dr. Jesse Powell
Audio: Jerome C. Reyes

All that follows is from the above resource.

Play Podcast 

Time Stamps Show Notes  Transcript References

Time Stamps

• 01:29 What is a monoclonal gammopathy? What is our expected clinical presentation?
• 10:25 What is our initial workup? Understanding SPEP, Immunofixation, and Free Light Chains
• 24:54 Do we need urine testing? When urine testing is necessary and when it is not
• 27:06 How should we differentiate monoclonal gammopathies? The continuum of MGUS, SMM, and MM
• 41:53 Demystifying Monoclonal gammopathy of clinical significance
• 49:10 BONUS Pearl!

Sponsor: Freed is an AI scribe that listens and writes your note in < 30 seconds. Freed learns your style over time and is HIPAA compliant!
Use the code CORE50 to get 50% off your first month with Freed

Show Notes

Pearl 1: What is a monoclonal gammopathy? What is our expected clinical presentation?

 

•  A monoclonal gammopathy is a clonal population of one type of plasma cell, which secretes one type of antibody.
  •  A monoclonal protein
    • The antibodies made by a single clone of cells, which are all the same type!
• Spectrum of severity:
  • • Monoclonal gammopathy of undetermined significance (MGUS)
      • Waldenstrom’s macroglobulinemia (WM) aka IGM MGUS
    • Smoldering multiple myeloma (SMM)
    • Multiple myeloma (MM)
    • Plasma cell leukemia/myeloma
    • Monoclonal gammopathy of clinical significance
• Epidemiology
  • About 5% of the general population > 50
  • years-old have a monoclonal protein so 1 in 20!

Clinical Presentation

• • By definition, MGUS and SMM have no symptoms attributable to their monoclonal protein.
  • Classic presentation of multiple myeloma (CRAB)
    • HyperCalcemia
      • Usually hypercalemia 2/2 lytic bone lesions
    •  Renal insufficiency
      • Especially if calcium HIGH, concerning myeloma
      • Since Ca is usually LOW in renal disease
    • Anemia
    • Lytic Bone lesions
  • Additional features:
    • Amyloidosis (“Big tongue” macroglossia, restrictive cardiomyopathy)
    • Hyperviscosity  (e.g., WM)
      • Gum bleeding, Epistaxis and Bruising without other explanation
    • Polyneuropathies

Pearl 2: What is our initial workup? Understanding SPEP, Immunofixation, and Free Light Chains

• (1) Serum protein electrophoresis (SPEP)
  • Electrophoresis gel that separates the proteins (e.g., immunoglobulins) in serum according to their electrical charge.
    • A clonal population of proteins all have the same charge, so will end at the same location, leading to a monoclonal (M) spike.
  • SPEP QUANTIFIES this M spike (usually in g/dL).
    • SPEP will NOT tell you what type of immunoglobulin (i.e igG, IgA, IgE, IgD, IgM) the monoclonal protein is.
• Immunofixation (IFE)
  • Test to identify WHAT TYPE of immunoglobulins you have
    • (i.e., IgG, IgM, IgA, kappa, and lambda).
  • More sensitive than SPEP (e.g., an SPEP could be negative, however the immunofixation could show a monoclonal protein)
• Serum Free Light Chains (FLC)
  • Measure serum free light chains (kappa or lambda) that are unbound to immunoglobulins (aka antibodies).
  • Normal ratio of serum kappa to lambda: 0.26 – 1.65
    • Ratio roughly ~1 from pure chance that different plasma cells will either have a kappa or lambda
  • BUT, if there is a clone, the clones will have either kappa OR lambda (NOT BOTH) and will skew ratio
  • Most sensitive test
    • If light chain only disease (~15 of the time)
      • Free light chains can easily be filtered through kidneys
      • It will NOT build up in the blood
      • Will not be detected in SPEP/immunofixation
• CAVETS in interpretation:
  • If GFR declines,
    • Cannot secrete Kappa light chains as fast, which will also skew the ratio to kappa
  • Chronic inflammation (TB, Hep B, etc)
    • Will led to polyclonal elevation of immunoglobulins (ex. IgG and IgA)
• Sensitive of tests:
  • SPEP with ~80% sensitivity
  • IFE increases sensitivity to ~93%
  • All 3 tests (SPEP, IFE and FLC) increases sensitivity to ~98%.

Pearl 3: Do we need urine testing? When urine testing is necessary and when it is not.

• Types of urine testing
  • UPEP (urine protein electrophoresis) and urine immunofixation
    • Similar to SPEP, leading to higher sensitivity to pick up
      • Smaller monoclonal proteins
      • A kappa or lambda process filtered through
  • In the past, urine testing helped detect light chain only monoclonal gammopathies and to add additional sensitivity.
    • Serum free light chains have largely replaced by serum free light chains test
  • 24-Urine protein versus spot protein:creatinine ratio
    • Measures total urine output over 24 hours, ideal form of testing urine as it can more clearly show the quantity of proteinuria versus a spot protein to creatinine ratio.
  • Urine testing is NOT needed for initial workup.
    • When to Use: If a monoclonal protein is detected, urine studies can quantify proteinuria and assess kidney damage.

Pearl 4: How should we differentiate monoclonal gammopathies? The continuum of MGUS, SMM, and MM.

• MGUS (Monoclonal gammopathy of undetermined significance)
  • Definition
    • Asymptomatic
    • SPEP with a total M protein < 3 g/dL.
    • Bone marrow with less than 10% plasma cells.
  • Risk of progression
    • < 1% per year of progressing to myeloma or other plasma cell dyscrasia.
    • What are risk factors MGUS to progress to myeloma? and Referral to hematology?
      • SPEP quantity >1.5 g/dL
        • >3.0 g/dL, no longer MGUS
      • non-IgG (IgM, A, D, or E)
        • Ex. IgM MGUS <3.0 g/dL
      • Kappa/lambda ratio > 5-8:1 (or vice versa)
        • **Normal range for free light chain ratio depend on age and renal function
  • Low-Risk MGUS (ex. igG Kappa MGUS):
    • Omit bone marrow biopsy and hematology referral
      • Repeat serum test in 6 months to ensure process is not evolving
      • If stable, check labs again only as symptoms occurs
    • Myelomarisk.com
  •  Light chain only MGUS
    • Serum SPEP and immunofixation are negative with no IgG, A, or M
      • BUT light chain ratio is abnormal.
    • Ratio < 5-8:1 is deemed low risk, you can omit the bone marrow biopsy.
• Smoldering Multiple Myeloma
  • Definition
    • No evidence of end-organ dysfunction.
    • SPEP with total M protein > 3 g/dL.
    • AND/OR Bone marrow with between 10-60% plasma cells.
  •  Risk of Progression
    • 10% per year for the first five years (following this the risk is lower if you have not yet progressed).
  • Diagnostic Workup
    • Bone marrow biopsy required if M protein > 3 g/dL.
• Multiple Myeloma
  • Definition (Plasma cell burden > 10% or biopsy-proven plasmacytoma) AND
    • Evidence of end-organ damage from the monoclonal gammopathy.
      • Features of end-organ damage aka CRAB criteria.
        • Hypercalcemia (> 1 mg/dL above ULN OR > 11 mg/dL).
        • Renal insufficiency (CrCl < 40 mL/min OR Cr > 2 mg/dL).
        • Anemia (> 2 g/dL below ULN OR < 10 g/dL).
        • One or more lytic bone lesions on imaging (X-Ray, CT, or PET/CT).
          • Note: MRI not included as so sensitive you need 2 lesions
    • AND/OR Myeloma-defining diagnostic features (SLiM features)
      • Bone marrow with > Sixty percent (60%) plasma cells.
      • Light chain ratio > 100:1.
      • MRI with 2 or more  focal lesions deemed from monoclonal gammopathy.
• Note: additional entities (Waldenstrom’s, plasma cell leukemia) were not covered in depth in this episode.

Pearl 5: Demystifying Monoclonal gammopathy of clinical significance (MGCS).

• Definition
  • Clonal gammopathies (not cancer, similar to MGUS aka precancer) in which the clone of plasma cells secrete immunoglobulins that have paraneoplastic properties
    • AKA secreting a functional antibody.
  • This secreted immunoglobulin can target different areas in the body, which typically include: *Non-exhaustive list. 
    • Kidney (most common)
      • Typically nephrotic syndromes (amyloid, light chain deposition disease).
    • Skin (many different syndromes)
    • Nerves
      • Often axonal or demyelinating; can be very painful.
      • e.g., POEMS, DADSM (Distal acquired demyelinating syndrome with M Protein)

Bonus Pearl: Be Judicious: Overdiagnosis and excessive testing can cause unnecessary anxiety for patients. Focus on clinically significant findings and appropriate monitoring.