Bone marrow neoplastic

Bone marrow - plasma cell and lymphoid neoplasms

Plasma cell neoplasms

Plasma cell myeloma (multiple myeloma)

Minor changes: 22 July 2021

Copyright: 2001-2021,, Inc.

PubMed Search: myeloma [title]

Genevieve M. Crane, M.D., Ph.D.
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Cite this page: Crane GM. Plasma cell myeloma (multiple myeloma). website. Accessed November 27th, 2021.
Definition / general
Essential features
  • Diagnosis requires synthesis of clinical, laboratory, radiologic and histologic findings
  • Serum or urine M protein, clonal plasma cells in bone marrow and presence of end organ damage critical for diagnosis (especially if < 10% plasma cells or M protein levels below threshold)
ICD coding
  • C90.0 multiple myeloma
  • C90.1 plasma cell leukemia
  • C90.2 extramedullary plasmacytoma
  • C90.3 solitary plasmacytoma
  • ~1.8% of malignant tumors, ~15% of hematopoietic neoplasms, 20% of deaths from hematopoietic malignancies, ~4 cases/100,000 persons/year in the US
  • M:F 1.4:1, twice as frequent in African Americans compared to Caucasians, not seen in children, rarely seen in adults under 30, median age of diagnosis is 68 years
  • 3.7 fold increased risk with affected first degree relative
  • Interactions between bone marrow stroma and plasma cells directly influences disease with a potential key role of IL6 to support survival and expansion of myeloma cells
  • IL6 with other cytokines promotes osteoclastic activity and lytic bone lesions
  • Chronic antigen stimulation, exposure to radiation or toxins results in increased risk but most patients do not have these associated factors
Clinical features
  • Often presents with bone pain, lytic bone lesions (thoracic vertebrae most common, also ribs, skull, pelvis, femur); spinal cord compression or peripheral neuropathy are less common presenting symptoms
  • Renal failure / elevated creatinine / hyperuricemia (renal tubular reabsorption of light chain results in damage); hypercalcemia; hypoalbuminemia; hyperviscosity in ~7% (usually IgA or IgG3)
  • Recurrent infections due to impaired humoral immunity (immunoglobulin production, often < 50% normal) including Streptococcus pneumoniae, Staphylococcus aureus, E. coli
  • Anemia (bone marrow infiltration often in areas of most active hematopoiesis and renal failure causing loss of erythropoietin)
  • Bone marrow or extramedullary involvement or lytic bone lesions generally associated with advanced disease
  • Fun fact: Bence-Jones proteins were the first tumor marker
  • References: Approaches to diagnosis, assessment of disease severity and treatment of AL amyloidosis (Clin J Am Soc Nephrol 2006;1:1331), Clinicopathologic data reviewed for 15 cases to delineate the pathology of immunoglobulin M producing multiple myeloma (Am J Clin Pathol 2013;140:519), Workshop focused on salient diagnostic, clinical and genetic features of plasma cell myeloma (Am J Clin Pathol 2011;136:168)
Clinical variants:
  • Asymptomatic (smoldering): more likely to progress to symptomatic myeloma than monoclonal gammopathy of uncertain significance (MGUS); both show gammopathy without symptoms
    • Risk of progression 10% per year for the first 5 years
    • Lower risk if no progression in the first 5 years after diagnosis (N Engl J Med 2007;356:2582)
  • Nonsecretory myeloma ( < 5% of cases): SPE / IFE negative, 85% with impaired secretion and have cytoplasmic Ig by IHC
    • 15% nonproducers, serum free light chain may still be detected
    • Lower incidence of renal insufficiency, hypercalcemia and depression of normal IgG
  • Plasma cell leukemia: aggressive with short survival
    • > 2 x 109/L or 20% of the leukocyte count on differential are monoclonal plasma cells
    • May be primary plasma cell leukemia ( < 5% of myeloma) or represent a late stage transformation (secondary)
    • Typically lack CD56, more frequent abnormal karyotype
    • Bone pain and osteolytic lesions less common
    • Myeloma cells have ability to survive and grow outside of the marrow
    • Typically associated with extramedullary lesions (e.g. skin, pleural effusions, lymphadenopathy and organomegaly)
  • Division into these categories will guide plan for therapy:
    • Symptomatic (active) myeloma (Swerdlow: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue, Fourth Edition, 2008):
      • M protein in serum or urine (usually > 30 g/L of IgG or > 25 g/L IgA or > 1 g/24 hr of urine light chain); no level included in criteria
      • Clonal plasma cells in bone marrow or plasmacytoma (usually > 10%, not required)
      • Related organ or tissue impairment (CRAB = hypercalcemia, renal failure / insufficiency, anemia, lytic bone lesions)
      • Revised NCCN guidelines (J Natl Compr Canc Netw 2016;14:389) diagnostic criteria differ slightly from the WHO 2008 monograph with diagnostic criteria continuing to evolve:
        • Clonal bone marrow plasma cells ≥ 10% or biopsy proven bony or extramedullary plasmacytoma
        • And at least one myeloma defining event:
          • Calcium > 1 mg/dL above upper limit of normal or > 11 mg/dL
          • Creatinine > 2 mg/dL or creatinine clearance < 40 ml/min
          • Hemoglobin < 10 g/dL or > 2 g/dL below lower limit of normal
          • One or more osteolytic bone lesions on skeletal radiograph, CT or PET / CT
          • Clonal bone marrow plasma cells ≥ 60%
          • Involved / uninvolved light chain ratio ≥ 100
          • > 1 focal lesions on MRI studies > 5 mm
    • Asymptomatic (smoldering) myeloma (J Natl Compr Canc Netw 2016;14:389):
      • M protein in serum at ≥ 3 g/dL when IgG or IgA
      • Or
        • Bence-Jones protein ≥ 500 mg/24h
        • 10 - 60% clonal plasma cells in bone marrow
      • And
        • No related tissue damage / myeloma defining event or amyloidosis; if bone survey negative, bone disease should be assessed with whole body MRI or PET / CT
  • 97% have an M protein in serum or urine, 3% are nonsecretory
  • IgG (50%), IgA (20%), light chain (20%), others < 10% (IgD, IgE, IgM and biclonal)
  • Serum protein electrophoresis (SPEP): serum proteins normally separate into 5 major fractions based on electric charge and size
    • Albumin
    • Alpha1 globulins
    • Alpha2 globulins
    • Beta1 and beta2 globulins
    • Gamma globulins
  • Gamma globulins include polyclonal antibodies and light chains, with a normal gamma zone appearing as a symmetrical smear, but there is a peak in myeloma
  • Urine protein electrophoresis (UPEP): monoclonal light chains in urine = Bence-Jones protein
  • Immunofixation electrophoresis (IFE): used to characterize the M spike, by reacting with specific antisera to heavy chains IgG, IgA, IgM, IgD, IgE and kappa and lambda light chains
  • Serum free light chain assay (SFLCA) (Freelite): more sensitive for monitoring light chain disease and nonsecretory myeloma
Laboratory Images

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Serum protein immunofixation shows IgD lambda myeloma

IgD lambda myeloma

Another IgD myeloma

Radiology description
  • MRI most sensitive
  • Evidence of one or more sites of osteolytic bone destruction (at least 5 mm in size) seen on CT or skeletal radiographs
  • Increased uptake on PET / CT alone is not adequate without evidence of underlying osteolytic bone destruction
Radiology images

AFIP images

Plasma cell myeloma

Solitary plasma cell myeloma

Contributed by Mark R. Wick, M.D.

Skull xray

Tibia xray

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Prominent skull defect

Prognostic factors
  • Usually incurable with median survival 3 - 4 years
  • Higher risk:
    • Elevated beta2 microglobulin, lactate dehydrogenase, C reactive protein, plasma cell proliferation or bone marrow infiltration
    • Low serum albumin
    • Plasmablastic morphology
    • Abnormalities by conventional cytogenetics
  • Active myeloma can be staged using the Durie-Salmon staging system (using clinical factors to predict myeloma burden and prognosis, Cancer 1975;36:842) but the International Staging System (ISS) or revised International Staging System (R-ISS) (J Natl Compr Canc Netw 2016;14:389, J Clin Oncol 2015;33:2863) is preferred
  • R-ISS:
    • Stage I: serum beta2 microglobulin < 3.5 mg/L, serum albumin ≥ 3.5 g/dL, standard risk chromosomal abnormalities by FISH (absence of del(17p), t(4:14) or t(14;16)) and serum LDH < upper limit of normal
    • Stage II: not R-ISS stage I or III
    • Stage III: serum beta2 microglobulin ≥ 5.5 mg/dL and either high risk chromosomal abnormalities (del(17p), t(4:14) or t(14;16)) or serum LDH > upper limit of normal
  • Additional prognostic chromosomal abnormalities:
    • Worse: t(4;14), MAF translocations t(14;16) and t(14;20), del(17p), del 13, aneuploidy, hypodiploidy
    • Better: hyperdiploid, t(11;14), t(6;14), cyclin D1 or D3 positive
  • References: Analysis of prognostic value of most frequent chromosomal changes in a large series of patients with newly diagnosed symptomatic myeloma (Blood: Genetic Abnormalities and Survival in Multiple Myeloma)
Case reports
  • Waiting for end organ damage alone to start therapy may increase morbidity and mortality
  • Updated diagnostic criteria (above and as detailed in J Natl Compr Canc Netw 2016;14:389) from the International Myeloma Working Group to initiate therapy, including sensitive imaging, may help identify patients who would benefit from treatment before CRAB features appear
  • Treatment regimens are discussed in the NCCN guidelines (J Natl Compr Canc Netw 2016;14:389)
Gross description
  • Bone defects are filled with a soft, gelatinous "fish flesh," hemorrhagic tissue
Gross images

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Vertebrae with myeloma lesions

Skull lesions

Microscopic (histologic) description
  • Core biopsy: interstitial clusters, nodules or sheets of plasma cells
    • Areas of bone marrow may be spared with preserved hematopoiesis, other cases may have diffuse involvement and markedly suppressed hematopoiesis
    • Prominent osteoclastic activity may be seen
    • IHC to quantify plasma cells (CD138), stains for kappa and lambda to establish clonality
Microscopic (histologic) images

Contributed by Genevieve M. Crane, M.D., Ph.D.

Trephine biopsy


In situ hybridization for kappa (left) and lambda (right)

Contributed by Tapan Bhavsar, M.D., Ph.D.

Myeloma involving bone marrow

Myeloma with plasmablastic transformation

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Hypercellular marrow with plasmacytoid cells

Bone marrow biopsy has blast-like cells

Lambda staining

Cytology description
  • Cytology can assess plasma cell morphology (e.g. mature, intermediate, immature, plasmablastic), but:
    • Number of plasma cells present may vary substantially from the core biopsy
    • Immature or pleomorphic features are rare in reactive plasma cell proliferations
  • Mature plasma cells: oval with abundant basophilic cytoplasm, perinuclear hof, round eccentric nuclei, "clock face" chromatin and indiscernible nucleoli
  • Immature plasma cells: higher nuclear / cytoplasmic ratio, more abundant cytoplasm and hof region compared to plasmablastic, more dispersed chromatin, often prominent nucleoli
  • Plasmablastic: less abundant cytoplasm with little or no hof region, fine reticular chromatin, large nucleus ( > 10 microns) or large nucleolus ( > 2 microns) (Blood 1998;91:2501)
  • Pleomorphic: multinucleated, polylobated
    • Rare cases may have small, lymphoid appearing plasma cells or plasma cells with marked nuclear lobation
  • Morphologic features:
    • Mott cells / morula cells: multiple grape-like cytoplasmic inclusions comprised of crystalized Ig
    • Russell bodies: hyaline intracytoplasmic and intranuclear inclusions
    • Flame cells: vermillion staining glycogen rich IgA in cytoplasmic projections
    • Gaucher-like cells / thesaurocytes: overstuffed fibrils
    • Cytoplasmic crystals: occasional in myeloma, common in adult Fanconi syndrome
    • Dutcher bodies: pale staining nuclear inclusions, single and usually large, more common in IgA myeloma
Cytology images

Contributed by Genevieve M. Crane, M.D., Ph.D.

Bone marrow touch preparation

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Bone marrow aspirate has plasmacytoid cells

Peripheral blood shows plasma cells (right: with blastic features)

Peripheral smear description
  • Rouleaux formation: erythrocytes resemble stacked coins; related to quantity and type of M protein
  • Leukoerythroblastic reaction can occur with extensive marrow involvement
  • Circulating plasma cells can be seen in ~15% of cases, usually small numbers not meeting criteria for plasma cell leukemia ( > 2 x 109/L or 20% of the leukocyte count)
Positive stains
  • Similar to normal plasma cells: CD138, CD79a, strong CD38, MUM1, EMA
  • May have aberrant expression of CD56 (70 - 80%) and less frequently CD117, CD20, CD52 or CD10, occasional myeloid or monocytic markers
  • Monoclonal light chain
  • Cyclin D1 positive in presence of t(11;14)(q13;q32)
Negative stains
  • Nearly always CD19 negative in contrast to normal plasma cells
  • Plasma cell leukemias usually negative for CD56 (80% of cases)
Flow cytometry description
  • Usually lack surface light chain with monotypic cytoplasmic Ig
  • Express bright CD38, often CD56+ or CD117+; may have partial CD45, usually negative for CD20, CD19 and CD10
Flow cytometry images

Contributed by Genevieve M. Crane, M.D., Ph.D.

Dim kappa

Strong cytoplasmic expression

Neoplastic plasma cells

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Prominent monotypic pattern
(lambda, with minimal kappa)

Electron microscopy description
  • Prominent rough endoplasmic reticulum, often with Russell bodies budding off of it
Molecular / cytogenetics description
  • Immunoglobulin heavy and light chain genes are clonally rearranged with a high load of IGHV gene somatic hypermutation; immunoglobulin gene deletion (chromosome 14) may be seen with light chain only disease
  • Cytogenetics: abnormalities by conventional cytogenetics seen in 1/3 of cases, but identified by FISH in > 90% including trisomies, deletions, translocations
  • IGH@ translocations in 55 - 70% of tumors with 5 recurrent oncogenes:
    • CYCLIN D1 (11q13)
    • c-Maf (16q23)
    • FGFR3 / MMSET (4p16.3)
    • CYCLIN D3 (6p21)
    • MAFB (20q11)
  • Tumors without one of the frequent IGH@ are more often hyperdiploid with gains of odd numbered chromosomes (3, 5, 7, 9, 11, 15, 19, 21)
  • Monosomy or partial deletion of chromosome 13 (13q14) found in nearly 50% by FISH
  • Activating mutations of NRAS or KRAS in 30 - 40% of tumors
  • Other: TP53 deletion or mutation, translocations involving MYC or N-Myc, gain of 1q, loss of 1p, NF kappa B pathway activation, inactivation of RB1, DNA methylation changes
Differential diagnosis
Board review style question #1
A 56 year old man was brought to emergency by his wife, who reported that he was playing catch with his son when he suddenly experienced acute pain in his right arm, accompanied almost immediately by swelling and loss of mobility. An Xray revealed a fracture of the right humerus with an associated lytic lesion. A needle biopsy of the lesion and a bone marrow biopsy were performed, with similar findings, shown below (bone marrow biopsy).

All of the following are true of this patient EXCEPT:

  1. An immunohistochemical stain for CD20 will most likely be negative.
  2. An immunohistochemical stain for CD38 will most likely be positive.
  3. An immunohistochemical stain for cyclin D1 will most likely be positive.
  4. Plasma cells typically make up at least 10% of the nucleated cells.
  5. t(4;14) is seen in 25% of cases.
Board review style answer #1
C. Immunostains for cyclin D1 are typically negative (except when t(11;14) is present, which occurs in up to 20% of cases)

Reference: Plasma cell myeloma (multiple myeloma)

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Source: BoardVitals, 2/5/2014
Board review style question #2
Which of the following cytogenetic findings is associated with a more favorable risk in plasma cell myeloma?

  1. Deletion 13
  2. Hypodiploidy
  3. t(4:14)
  4. t(11;14)
  5. t(14:16)
Board review style answer #2
Board review style question #3
Which of the following findings would most strongly favor the presence of a neoplastic plasma cell process rather than a reactive plasma cell proliferation?

  1. Interstitial plasma cells comprising 10% of cellularity
  2. Plasma cells with prominent "clock face" chromatin
  3. Russell bodies
  4. Scattered immature plasma cells
  5. Scattered Mott cells with grape-like inclusions
Board review style answer #3
D. Scattered immature plasma cells

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Reference: Plasma cell myeloma (multiple myeloma)
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