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Plasma cell disorders, cryoglobulins and tumor immunity

16 min

Skills you'll build3 skills
  • 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

At the bench: Check specimen identity and suitability before analysis

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?

Keep going to see the reasoning.

Right. Keep going to follow the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Keep going to see the reasoning.

Get the idea

Use the explanation to check your first decision.

IMWG categories

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 classifies 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

Cryoglobulin specimens

Cryoglobulins precipitate in the cold and redissolve on warming. The specimen stays at 37 °C from collection through clotting and serum separation. If the tube cools early, the cryoglobulin precipitates and is lost with the clot. Warming the separated serum cannot recover it. 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 establish a plasma-cell neoplasm.3

Tumor recognition and escape

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 mechanisms.4,5

Follow the bench demonstration

Sources for this step
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

Read each decision and its explanation.

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

Which IMWG category do these results fit?

TestResultReference intervalFlag
M protein2.1 g/dL HighNot detectedNot detectedHigh
ImmunofixationIgA lambdaNo monoclonal bandNo monoclonal band
Clonal marrow plasma cells18 % HighHigh
Calcium11.8 mg/dL High8.6–10.3 mg/dL8.6–10.3High
Creatinine1.1 mg/dL0.5–1.1 mg/dL0.5–1.1
Hemoglobin11.9 g/dL Low12.0–15.5 g/dL12.0–15.5Low

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 exceeds the MGUS criteria.

    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.

Practice this skill

Your turn

Problem 1 of 3 · Hints available

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 recover protein lost with the clot.

Review Cryoglobulin recovery

Problem 2 of 3 · Hints available

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 allows them to kill.

CD4 T cells recognize peptide on HLA class II. They do not recognize 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 recognizes peptides on HLA class I.
  2. Now name the cell that HLA class I normally inhibits.

Review Tumor antigens

Problem 3 of 3 · On your own

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 requires 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 requires 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

Read the case evidence, then make each decision. The step is complete without it.

  • Leopold Capper, 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.
TestResultReference intervalFlag
M protein1.6 g/dL HighNot detectedNot detectedHigh
ImmunofixationIgG kappaNo monoclonal bandNo monoclonal band
Kappa/lambda free-light-chain ratio3.1 High0.26–1.650.26–1.65High

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. Rewarming the separated serum does not recover it, and acceptable QC cannot detect this preanalytical loss. Testing that serum can give a falsely negative cryoglobulin result.

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

A comment cannot show 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 requires 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 requires 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 is still based on the M protein, the marrow and the defining events.

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

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

Review MGUS, smoldering myeloma, and multiple myeloma

The cold courier cooler made the first cryoglobulin specimen unacceptable, so only a warm recollection could be tested. His protein and marrow results fit MGUS, and the cryoglobulin found later does not change that category.

For reference

Sources checked