mGODS - Monoclonal Gammopathies Of Dermatological Significance

Pearls for working up monclonal gammopathies in setting of dermatological disease

TABLE OF CONTENTS

Overview & Learning Objectives
Pre-Lecture Questions 

Case 1
Additional Pre-Lecture Questions

Plasma Cell Dyscrasias
Detection and Identification of Monoclonal Proteins
References

Overview & Learning Objectives

• In this lecture we review mGODS: Monoclonal Gammopathies of Dermatological Significance¹, an umbrella term that captures diseases such as Cutaneous Amyloidoses, Scleromyxedema, Acquired Cutis Laxa, Mixed Cryoglobulinemia, Nodular Amyloidoses, PEOMS syndrome, Necrobiotic Xanthogranuloma, Schnitzler’s Syndrome etc.
  
• Specifically we will:
  • Provide an overview of plasma cell dyscrasias
    
  • Introduce the concept of mGODS
    
  • Review techniques to detect and identify monoclonal proteins
    
  • Review how to work up paraproteins
    
  • Provide an overview of MGUS

Here, we provide a primer for that lecture. We start with a clinical case and some discrete questions so that you can think through them ahead of the lecture. We will go through these as a group on Thursday.

Pre-Lecture Questions

CASE 1

Synopsis

• Ms. S is a 82-year-old who presents for follow up for “Pruritus Without Rash”. She has been seen by two of your colleagues before, but this is the first time you are seeing her. The initial “Pruritus Without Rash” work up was notable for a normal CBC with Diff, CMP, TSH and CXR. Given that this initial work up was non-diagnostic, a second round of investigation was performed and was notable for the following: Serum iron WNL; ferritin WNL; skin biopsy not diagnostic, DIF negative; SPEP demonstrated abnormal band in gamma region, identified by IFE as IgG Kappa, and represents by densitometry 10% (730 mg/dL) of total protein.

Case 1 Clinical Questions:

• What does this part of the work up mean?
  • SPEP demonstrated abnormal band in gamma region
    • Identified by IFE as IgG Kappa
      
    • Represents by densitometry 10% (730 mg/dL) of total protein
• What are you next steps in management?
  
• While referral to hematology is never the wrong answer, if you wanted to pursue additional work up, what would be your next steps?

Additional Pre-Lecture Questions

• True or False: An SPEP will both quantitate the M protein and identify the heavy and light chain associated with it?
  
• True or False: A Bone Marrow Biopsy is recommended in all patients with an MGUS?
  
• Myeloma is typically associated with: osteoblastic lesions or osteolytic lesions?
  
• Which of the following is the most appropriate screening test(s) for the vast majority of plasma cell dyscrasias?
  • SPEP
    
  • SPEP + sFLC
    
  • SPEP + sIFE
    
  • SPEP + sFLC + sIFE
    
  • SPEP + sIFE + uPEP/IFE
  • SPEP, sFLC, sIFE, uPEP/IFE

Plasma Cell Dyscrasias

Overview

• Plasma cell dyscrasia (PCD) is a term used to describe a constellation of pathology of plasma cells
  
• Subsets of PCDs range from Monoclonal Gammopathy of Undetermined Significance (MGUS) to Multiple Myeloma
• To understand PCDs, it is important to have a basic understanding of plasma cell development. In the figure below we outline some of those major developmental steps

Plasma Cell Development

Monoclonal Gammapathies

• Monoclonal gammopathies are the most common form of plasma cell dyscrasia²
  
• Monoclonal gammopathies were first described as a clinical entity in 1960 by Jan Gosta Waldenstrom³
  
• Monoclonal Gammopathy of Undetermined Significance (MGUS) was introduced in 1978 by Kyle et al.⁴

Detection and Identification of Monoclonal Proteins

Overview

• MGUS is a clonal plasma cell or lymphoplasmacytic proliferative disorder which presents without symptoms and is considered a premalignant process
• Diagnosis is made by the presence of the following features:
  • Detection of a low-level M-protein (<3 g/dL)
    • An M-protein is a serum Monclonal protein
      
  • Less than 10% monoclonal plasma cells on bone marrow biopsy
    
  • No end organ damage resulting from the monoclonal process
    • For example the absence of lytic bone lesions, anemia, hypercalcemia, renal insufficiency or hyperviscosity
• MGUS is fairly common and occurs in over 3 percent of the general Caucasian population over the age of 50
  • More specifically, the prevalence is 1% over age 50 & 3% over age 70
    
• Assuming you are starting with just an M-spike, the following steps is a very reasonable work up:
  • Step 1 – Interrogate the Monoclonal Protein
    
  • Step 2 – Assess for End Organ Dysfunction
    
  • Step 3 – Decide if the patient needs a BMBx
    
  • Step 4 – Decide Follow Up Interval
• In the lecture we will go into the details of each of these four steps, but below we list the take home points for Step 1

Take Home Points on Interrogating the Monoclonal Protein

• The most common diagnostic tools to work up monocloncal proteins involves the use of serum protein electropheresis (SPEP), free light chain (FLC) assays and immunofixation (IFE)
  
• For the vast majority of patients, SPEP and FLC is probably sufficient for screening for most plasma cell dyscrasias
  • 94% sensitivity for all plasma cell dyscrasias⁵
    
  • SPEP + FLC + IFE
    • 97% sensitivity
      • The disease where IFE may provide the most additive sensitivity is LCDD and POEMS
        
  • SPEP + FLC + IFE + UIFE
    • 98.6% sensitive (thus adding urine adds about 1.6% sensitivity)
      
  • SPEP
    • Allows for quantification of the M-protein (i.e. serum concentration)
      
    • Does not identify class of Ig or light chain component
      
    • About 79% sensitive for detecting all comers
      
  • IFE
    • More sensitive than SPEP in detection M proteins
      
    • Does not allow for serum concentration of M-protein
      
    • Thus always done in conjunction with SPEP
      
    • Is usually reflexed when M-protein detected; however, not always done, so if don’t order it and all you
      
    • About 87% sensitive for detecting all comers

References

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Footnotes

1. Shalhout et al. Generalized Acquired Cutis Laxa Associated with Monoclonal Gammopathy of Dermatological Significance. Case Reports in Dermatological Medicine. 2020

2. Katzmann JA. Screening panels for monoclonal gammopathies: time to change. Clin Biochem Rev. 2009;30(3):105-111.

3. Waldenstrom J. Studies on conditions associated with disturbed gamma globulin formation (gammopathies). Harvey Lect. 1960;56:211-231.

4. Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med. 1978;64(5):814-826.

5. Katzmann JA. Screening panels for monoclonal gammopathies: time to change. Clin Biochem Rev. 2009;30(3):105-111.