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Plasma cell disorders, cryoglobulins and tumor immunity

16 min

  • Tell MGUS from myeloma by M protein, marrow plasma cells, and myeloma-defining events
  • Reject a cryoglobulin specimen that was not kept warm until separation
  • Predict how tumor-antigen or HLA class I loss changes T-cell and NK-cell attack

Read the full reference

Try first

Try first

Two patients each have a serum IgG monoclonal protein of 2.0 g/dL. Neither has hypercalcemia, kidney injury, anemia or bone lesions. Which added finding moves one of them out of the MGUS category?

The next section explains it.

Right. The next section explains why.

The next section explains it.

The next section explains it.

The next section explains it.

Get the idea

Three categories from three findings

A monoclonal protein comes from one expanded plasma-cell or B-cell clone. Serum protein electrophoresis with serum free light chains detects it, and immunofixation types it.1 The International Myeloma Working Group then sorts the disorder by the M protein, the clonal marrow plasma cells and any myeloma-defining event.2

CategoryPattern
Non-IgM MGUSM protein below 3 g/dL, clonal marrow plasma cells below 10%, no defining event
Smoldering myelomaM protein at least 3 g/dL (or urine M protein at least 500 mg/24 h), or clonal plasma cells 10% to below 60%, and no defining event
Multiple myelomaClonal plasma cells at least 10% or a biopsy-proven plasmacytoma, plus at least one defining event

2

The defining events are the CRAB findings attributable to the clone: calcium above 11 mg/dL or more than 1 mg/dL above the upper reference limit, creatinine above 2 mg/dL or creatinine clearance below 40 mL/min, hemoglobin below 10 g/dL or more than 2 g/dL below the lower reference limit, and lytic bone lesions. Three biomarkers also count: clonal plasma cells at least 60%, an involved to uninvolved free-light-chain ratio at least 100 with the involved light chain at least 100 mg/L, and more than one focal MRI lesion of at least 5 mm.2

Cryoglobulins leave with a cold clot

Cryoglobulins precipitate in the cold and redissolve on warming. The specimen stays at 37 °C from collection through clotting and serum separation. A tube that cools early loses its precipitate into the clot, and warming the separated serum cannot bring it back. The laboratory rejects that specimen and asks for a new warm collection. A cryoglobulin can be monoclonal or mixed, so a positive result does not by itself show a plasma-cell neoplasm.3

What lets immunity see a tumor

Tumor cells can display neoantigens from mutations, viral proteins, and self proteins expressed out of place or in excess. CD8 T cells recognize these peptides on HLA class I. A tumor that loses HLA class I escapes much of the CD8 attack. The same loss removes an inhibitory signal for NK cells, which can then kill it. Antigen loss and checkpoint ligands such as PD-L1 are other escape routes.4,5

References
  1. Keren DF, Bocsi G, Billman BL, et al. Laboratory detection and initial diagnosis of monoclonal gammopathies. Arch Pathol Lab Med. 2022;146(5):575-590. doi:10.5858/arpa.2020-0794-CP
  2. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15(12):e538-e548. doi:10.1016/S1470-2045(14)70442-5
  3. Gulli F, Santini SA, Napodano C, et al. Cryoglobulin test and cryoglobulinemia hepatitis C-virus related. Mediterr J Hematol Infect Dis. 2017;9(1):e2017007. doi:10.4084/MJHID.2017.007
  4. Abbas AK, Lichtman AH, Pillai S, Henrickson S. Cellular and Molecular Immunology. 11th ed. Elsevier; 2025. Elsevier.
  5. Mittal D, Gubin MM, Schreiber RD, Smyth MJ. New insights into cancer immunoediting and its three component phases: elimination, equilibrium and escape. Curr Opin Immunol. 2014;27:16-25. doi:10.1016/j.coi.2014.01.004

Watch one

Rosalind Achebe, 71, a retired choir director, has back pain and fatigue. Her marrow biopsy report is back.

Which IMWG category do these results fit?

TestResultPreviousReference intervalFlag
M protein2.1 g/dLNot detectedHigh
ImmunofixationIgA lambdaNo monoclonal band
Clonal marrow plasma cells18 %High
Calcium11.8 mg/dL8.6–10.3 mg/dLHigh
Creatinine1.1 mg/dL0.5–1.1 mg/dL
Hemoglobin11.9 g/dL12.0–15.5 g/dLLow

Specimen: H 4, L 15, I 2. Serum, collected 07:50; marrow aspirate and biopsy the same week

  1. Confirm the clone. Immunofixation shows an IgA lambda M protein of 2.1 g/dL.

    Classification starts from a confirmed, typed monoclonal protein.

  2. Read the marrow next. Clonal plasma cells at 18% are at least 10%, so the pattern is beyond MGUS.

    The marrow percentage separates MGUS from the other two categories.

  3. Look for a CRAB finding. Calcium 11.8 mg/dL is above 11 mg/dL.

    A defining event separates myeloma from smoldering myeloma.

  4. Check the other CRAB findings. Creatinine 1.1 mg/dL is under 2 mg/dL, and hemoglobin 11.9 g/dL is above 10 g/dL and within 2 g/dL of the lower limit.

    Each CRAB criterion has its own cutoff, and a mild change does not qualify.

  5. Put the pattern together: at least 10% clonal plasma cells plus one defining event, attributable to the clone.

    The clinical team decides whether the hypercalcemia comes from the clone.

The results fit the IMWG pattern of multiple myeloma: 18% clonal marrow plasma cells plus hypercalcemia of 11.8 mg/dL as a defining event.

Your turn

Problem 1 of 3

A cryoglobulin specimen was cooled before clotting and serum separation, contrary to the receiving laboratory's instructions. Which action is appropriate?

Incorrect. Protein that precipitated with the clot was discarded at separation, and warming the serum afterward cannot recover it.

Incorrect. Acceptable assay controls show the method worked. They cannot establish recovery of protein lost from this patient's specimen.

Correct. Premature cooling leaves precipitated cryoglobulin with the clot and can produce a falsely negative serum result, so request a new specimen and keep it warm, commonly at 37 °C, through clotting and serum separation.

Hint
  1. Follow where the cryoglobulin went when the tube cooled.
  2. Ask whether anything done to the serum now can reach protein that left with the clot.

Review Cryoglobulin recovery

Problem 2 of 3

A melanoma loses HLA class I expression on its cells. How does this change the attack by cytotoxic cells?

Class I loss removes an inhibitory signal for NK cells. NK cells can then attack the tumor.

Assumed reduced HLA class I prevents all immune recognition

Loss of HLA class I lowers CD8 T-cell recognition and removes an inhibitory signal for NK cells, which can then attack. Assuming class I loss hides the tumor from all immunity misses the NK-cell response and the other escape routes, such as antigen loss and checkpoint ligands.

CD8 T cells need peptide on HLA class I. HLA class I sends NK cells an inhibitory signal, so its loss leaves them free to kill.

CD4 T cells recognize peptide on HLA class II. They do not read class I.

CD8 T cells recognize tumor peptides only when HLA class I presents them. Fewer class I molecules means less CD8 recognition.

Hint
  1. Name the cell that reads peptides on HLA class I.
  2. Now name the cell that HLA class I normally tells to stand down.

Review Tumor antigens

Problem 3 of 3

A 64-year-old man has a serum IgG kappa M protein of 3.4 g/dL. Clonal marrow plasma cells are 14%. Calcium, creatinine and hemoglobin are within their reference intervals, imaging shows no bone lesions, and the involved to uninvolved free-light-chain ratio is 12. Which category fits?

MGUS needs an M protein below 3 g/dL and clonal plasma cells below 10%. He exceeds both limits.

Myeloma needs a defining event. He has no CRAB finding, 14% is below 60%, and a ratio of 12 is below 100.

Called every monoclonal protein multiple myeloma

Non-IgM monoclonal gammopathy of undetermined significance (MGUS) has M protein below 3 g/dL, clonal plasma cells below 10%, and no myeloma-defining event. Myeloma needs at least 10% clonal plasma cells or a biopsy-proven plasmacytoma plus a defining event. Calling every M protein myeloma skips the marrow and organ criteria that separate the categories.

Waldenström macroglobulinemia needs an IgM protein with lymphoplasmacytic lymphoma in the marrow. His protein is IgG.

An M protein of at least 3 g/dL and 10% to below 60% clonal plasma cells, with no defining event, fits smoldering myeloma.

Review MGUS, smoldering myeloma, and multiple myeloma

Use it

  • Leopold Vance, 67, a retired jazz trumpeter, says his fingertips turn blue whenever he plays outdoors in winter.
  • His provider orders serum protein studies and a cryoglobulin.
  • The cryoglobulin tubes reach the laboratory in a courier cooler with ice packs, clotted and cold.
  • His marrow biopsy later shows 7% clonal plasma cells. Calcium, creatinine, hemoglobin and bone imaging are unremarkable.
TestResultPreviousReference intervalFlag
M protein1.6 g/dLNot detectedHigh
ImmunofixationIgG kappaNo monoclonal band
Kappa/lambda free-light-chain ratio3.10.26–1.65High

Specimen: H 3, L 11, I 1. Serum protein studies collected 10:20 and kept at room temperature

Decision 1 of 3

What does the laboratory do with the cold cryoglobulin tubes?

The cryoglobulin precipitated as the tubes cooled and stayed in the clot. Warming the serum now cannot recover it.

Rewarmed separated serum to recover protein lost in the clot

Cooling before separation lets cryoglobulin precipitate and leave with the clot. Warming the separated serum cannot bring it back, and passing controls cannot show what the specimen lost. Testing that serum can report a falsely negative cryoglobulin.

Only a specimen kept warm through clotting and separation holds all of its cryoglobulin. Record the cold transport as the reason.

A comment cannot tell the reader how much protein was lost. A negative result from this serum could be falsely negative.

Review Cryoglobulin recovery

Decision 2 of 3

Which category do his protein and marrow results fit?

He has fewer than 10% clonal plasma cells and no defining event. Myeloma needs both a larger clone and a defining event.

Called every monoclonal protein multiple myeloma

Non-IgM monoclonal gammopathy of undetermined significance (MGUS) has M protein below 3 g/dL, clonal plasma cells below 10%, and no myeloma-defining event. Myeloma needs at least 10% clonal plasma cells or a biopsy-proven plasmacytoma plus a defining event. Calling every M protein myeloma skips the marrow and organ criteria that separate the categories.

Smoldering myeloma needs an M protein of at least 3 g/dL or at least 10% clonal plasma cells. He has neither.

An IgG M protein of 1.6 g/dL, 7% clonal plasma cells and no defining event fit MGUS. A ratio of 3.1 is far below the biomarker cutoff of 100.

Review MGUS, smoldering myeloma, and multiple myeloma

Decision 3 of 3

The warm recollection shows a cryoprecipitate that redissolves at 37 °C. Does the category change?

Cryoglobulins can be monoclonal or mixed. The category still rests on the M protein, the marrow and the defining events.

Cryoglobulin is not one of the CRAB findings or biomarker events. It does not move the category.

Immunofixation typed his protein as IgG. A cryoglobulin can be IgG, IgM or mixed.

Review MGUS, smoldering myeloma, and multiple myeloma

The clue that settled this case is the cold courier cooler. It made the first cryoglobulin unusable, and only a warm recollection could answer the question. His protein and marrow results fit MGUS, and the cryoglobulin found later does not change that category.

Keep

Sources checked