Note: I have posted on this podcast* previously but wanted to review it again.
*Linking To CoreIM’s “MGUS to Multiple Myeloma Diagnostics and Counseling: 5 Pearls Segment”
Posted on February 2, 2025 by Tom Wade MD
Today, I review, link to, and excerpt from COREIM‘s MGUS to Multiple Myeloma Diagnostics and Counseling: 5 Pearls Segment.
All that follows is from the above resource.
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. ReyesPodcast: Play in new window | Download
Time Stamps
- 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!
Show Notes
Pearl 1: What is a monoclonal gammopathy? What is our expected clinical presentation?
Pearl 1: What is a monoclonal gammopathy?
- 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.
- UPEP has been 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.
