Immunoproliferative diseases (monoclonal gammopathies)

10 ASCP MLS practice questions on Immunoproliferative diseases (monoclonal gammopathies), part of Immunology. The first 10 are below; the first 5 with answers and explanations (tap Show answer after you have chosen), the rest in Learn with a free account.

1. Question 1 · Hard

   A 63-year-old woman has a monoclonal band found during a work-up for a raised total protein. Results: total protein 8.5 g/dL [85 g/L]; albumin 3.6 g/dL [36 g/L]; densitometry puts the gamma-region M-spike at 40% of the total protein; immunofixation IgG kappa; serum free kappa 96 mg/L and free lambda 12 mg/L (ratio 8.0); bone marrow 8% clonal plasma cells. Calcium is 9.4 mg/dL [2.35 mmol/L] (reference 8.6-10.2 mg/dL [2.15-2.55 mmol/L]), creatinine 0.9 mg/dL [80 µmol/L] and hemoglobin 13.4 g/dL [134 g/L], and whole-body low-dose CT shows no bone lesions. Under the IMWG criteria, this is classified as:

   1. AActive multiple myeloma
   2. BSolitary plasmacytoma
   3. CIgG MGUS
   4. DSmoldering multiple myeloma

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   Answer: D · Smoldering multiple myeloma

   The M-protein is 40% of the total protein: 0.40 x 8.5 g/dL = 3.4 g/dL [34 g/L]. A serum IgG or IgA M-protein of 3 g/dL or more meets the IMWG definition of smoldering myeloma, even when the marrow has fewer than 10% clonal plasma cells. There is no myeloma-defining event: calcium, creatinine, hemoglobin and imaging are normal, the marrow is far below 60%, and the involved/uninvolved free light chain ratio of 8 is far below 100. MGUS needs both an M-protein below 3 g/dL and fewer than 10% clonal plasma cells, so here the calculation, not the marrow count, decides; taking 40% of the albumin instead (1.4 g/dL) would wrongly suggest MGUS. A solitary plasmacytoma needs a single bone or soft tissue lesion.

   • A: There is no CRAB feature, the marrow is under 60% and the FLC ratio is well under 100.
   • B: A solitary plasmacytoma needs a single lesion, and imaging shows none.
   • C: MGUS needs an M-protein below 3 g/dL, and 40% of 8.5 g/dL is 3.4 g/dL.

2. Question 2 · Hard

   A 66-year-old has an IgG kappa M-protein of 2.4 g/dL [24 g/L] and 30% clonal marrow plasma cells, with normal calcium, creatinine, hemoglobin and skeletal imaging. Serum free kappa is 1,040 mg/L and free lambda is 8.0 mg/L. The correct interpretation is:

   1. ARatio 130; smoldering myeloma, as there is no CRAB
   2. BRatio 0.0077; points to a lambda-producing clone
   3. CRatio 130; meets criteria for multiple myeloma
   4. DRatio 1,032; meets criteria for multiple myeloma

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   Answer: C · Ratio 130; meets criteria for multiple myeloma

   The involved/uninvolved ratio is 1,040 / 8.0 = 130. Under IMWG criteria, a ratio of 100 or more, with the involved light chain at 100 mg/L or more, is a myeloma-defining biomarker. With 10% or more clonal plasma cells, this patient has multiple myeloma even without CRAB features, because the risk of organ damage within 2 years is very high. Dividing lambda by kappa, or subtracting one from the other, gives the wrong figures.

   • A: A ratio of 100 or more is itself a myeloma-defining event, so this is not smoldering myeloma.
   • B: This is the ratio inverted; kappa is the involved light chain here.
   • D: 1,032 is the difference between the light chains, not their ratio.

3. Question 3 · Medium

   Marrow plasma cells are clonal in each patient below, and none has hypercalcemia, renal failure, anemia or bone lesions unless stated. Which result set fits monoclonal gammopathy of undetermined significance (MGUS)?

   1. AM-protein 2.1 g/dL [21 g/L]; plasma cells 65%
   2. BM-protein 1.4 g/dL [14 g/L]; plasma cells 5%
   3. CM-protein 3.6 g/dL [36 g/L]; plasma cells 14%
   4. DM-protein 1.8 g/dL [18 g/L]; plasma cells 12%; lytic lesions

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   Answer: B · M-protein 1.4 g/dL [14 g/L]; plasma cells 5%

   Non-IgM MGUS needs a serum M-protein below 3 g/dL (30 g/L), fewer than 10% clonal marrow plasma cells, and no myeloma-defining event. Smoldering myeloma has an M-protein of 3 g/dL or more and/or 10% to 59% plasma cells, still without a myeloma-defining event. Myeloma needs 10% or more plasma cells plus CRAB features or a biomarker such as 60% or more plasma cells. MGUS progresses at about 1% a year, so patients are followed with SPEP and free light chains.

   • A: 60% or more clonal plasma cells is a myeloma-defining event, even without CRAB.
   • C: An M-protein of 3 g/dL or more with 10% to 59% plasma cells is smoldering myeloma.
   • D: Lytic bone lesions with 10% or more plasma cells meet the criteria for myeloma.

4. Question 4 · Medium

   In light chain myeloma, serum protein electrophoresis may show no M-spike while the urine is full of Bence Jones protein. The main reason is that free light chains:

   1. AAre broken down by serum proteases
   2. BAre filtered rapidly by the glomeruli
   3. CMigrate hidden under the albumin band
   4. DDo not bind the protein stain used

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   Answer: B · Are filtered rapidly by the glomeruli

   Free light chains are small (about 25 kDa as monomers and 50 kDa as dimers), so they pass through the glomerulus and are cleared from serum within hours. Once tubular reabsorption is overwhelmed they appear in the urine as Bence Jones protein. The serum level can stay below what SPEP detects, which is why screening combines SPEP, immunofixation and the serum free light chain assay. A normal SPEP does not exclude light chain disease.

   • A: Light chains are removed by the kidney, not digested in serum.
   • C: Light chains usually migrate in the beta or gamma region, not with albumin.
   • D: Light chains are proteins and stain like any other band.

5. Question 5 · Hard

   An untreated patient with kappa light chain myeloma has heavy Bence Jones proteinuria. Last month serum free kappa by nephelometry was 6,800 mg/L; today it is reported as 42 mg/L. What should the laboratory do?

   1. ARecalibrate the nephelometer with a new reagent lot
   2. BClear lipemia by ultracentrifugation and repeat
   3. CReport it, noting that FLC methods differ
   4. DRepeat on further dilution to exclude antigen excess

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   Answer: D · Repeat on further dilution to exclude antigen excess

   In nephelometry, a huge excess of antigen saturates the reagent antibody and forms small complexes that scatter little light, so the result falls on the descending side of the curve and reads falsely low. Monoclonal light chains can reach thousands of mg/L, so free light chain assays are prone to this hook effect, and instrument checks can miss it. A result that rises out of proportion when the sample is diluted further confirms antigen excess. A result that does not fit the clinical picture should never be reported unchecked.

   • A: A calibration fault would not explain a 160-fold drop that conflicts with the clinical picture.
   • B: Lipemia increases light scatter and gives falsely high, not low, results.
   • C: Differences between methods are modest, not 160-fold.

6. Question 6 · Easy

   With the most widely used polyclonal serum free light chain assay, the reference interval for the kappa/lambda ratio in people with normal kidney function is:

   1. A0.26 to 1.65
   2. B0.37 to 3.10
   3. C0.80 to 1.20
   4. D1.50 to 2.50

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7. Question 7 · Hard

   A patient with IgG kappa myeloma is treated with daratumumab, an IgG1 kappa anti-CD38 antibody. The original band has gone, but immunofixation now shows a faint IgG kappa band in the cathodal gamma region. What is the best next step?

   1. ARun an anti-daratumumab shift immunofixation
   2. BReport a relapse of the original IgG kappa clone
   3. CRepeat IFE with anti-IgD and anti-IgE antisera
   4. DTreat the serum with DTT and repeat the IFE

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8. Question 8 · Hard

   A patient with an IgG kappa M-protein has purpura and Raynaud phenomenon in cold weather. Today's M-spike is far smaller than last month's, with no change in treatment; the blood was refrigerated before the serum was separated. The most likely explanation is that:

   1. AClotting consumed the IgG along with fibrinogen
   2. BThe M-protein is a cryoglobulin lost with the clot
   3. CRefrigeration denatured the IgG molecules
   4. DAntigen excess has suppressed the SPEP band

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9. Question 9 · Medium

   An IgA monoclonal protein can be missed on serum protein electrophoresis because it often migrates in the:

   1. AAlbumin region, ahead of the alpha bands
   2. BBeta region, alongside transferrin or C3
   3. CAlpha-1 region, with alpha-1 antitrypsin
   4. DFar cathodal end of the gamma region

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10. Question 10 · Medium

    In chronic kidney disease without any plasma cell disorder, serum free light chain results usually show:

    1. ABoth kappa and lambda low; ratio normal
    2. BBoth kappa and lambda high; ratio mildly raised
    3. CKappa high and lambda low; ratio above 10
    4. DKappa normal, lambda high; ratio below 0.26

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