Home > Bone marrow neoplastic > Plasma cell myeloma (multiple myeloma)

Bone marrow neoplastic

Bone marrow - plasma cell and lymphoid neoplasms

Plasma cell neoplasms

Plasma cell myeloma (multiple myeloma)


Editorial Board Member: Julie Feldstein, M.D.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Meryem Terzioglu, M.D.
Genevieve M. Crane, M.D., Ph.D.

Last author update: 16 June 2022
Last staff update: 27 September 2023

Copyright: 2001-2024, PathologyOutlines.com, Inc.

PubMed Search: Plasma cell myeloma (multiple myeloma)

Meryem Terzioglu, M.D.
Genevieve M. Crane, M.D., Ph.D.
Page views in 2023: 66,870
Page views in 2024 to date: 23,004
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Pathophysiology | Etiology | Clinical features | Clinical variants | Diagnosis | Laboratory | Laboratory images | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Minimal residual disease (MRD) testing | Gross description | Gross images | Frozen section description | Frozen section images | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Cytology description | Cytology images | Peripheral smear description | Peripheral smear images | Positive stains | Negative stains | Flow cytometry description | Flow cytometry images | Electron microscopy description | Molecular / cytogenetics description | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2 | Board review style question #3 | Board review style answer #3
Cite this page: Terzioglu M, Crane GM. Plasma cell myeloma (multiple myeloma). PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/lymphomamyeloma.html. Accessed April 25th, 2024.
Definition / general
  • Bone marrow based, multifocal plasma cell neoplasm usually associated with a monoclonal immunoglobulin (M protein) in serum or urine and evidence of organ damage related to the plasma cell neoplasm (J Natl Compr Canc Netw 2019;17:1154)
Essential features
  • Diagnosis requires synthesis of clinical, laboratory, radiologic and histologic findings
  • Assessment of serum or urine M protein, clonal plasma cells in bone marrow and presence of end organ damage related to the plasma cell neoplasm critical for diagnosis
Terminology
  • Multiple myeloma
  • Plasma cell myeloma
  • Myeloma
  • Medullary plasmacytoma
  • Myelomatosis
  • Kahler disease (no longer used) (Recent Results Cancer Res 2011;183:3)
  • Smoldering (asymptomatic) plasma cell myeloma
  • Nonsecretory myeloma
  • Plasma cell leukemia
ICD coding
  • ICD-O:
  • ICD-10:
    • C90.0 - multiple myeloma
    • C90.1 - plasma cell leukemia
    • C90.2 - extramedullary plasmacytoma
    • C90.3 - solitary plasmacytoma
Epidemiology
Pathophysiology
  • Bone marrow site of origin for nearly all cases
  • Interactions between bone marrow stroma and neoplastic plasma cells directly influences disease with a potential key role of IL6 to support survival and expansion of myeloma cells (Leukemia 2014;28:1647, Cancer 2003;97:2440, Cancers (Basel) 2021;13:216)
  • Role of IL6 and other cytokines in promoting osteoclastic activity and lytic bone lesions
  • Multiple myeloma cells suppress the differentiation and proliferation of osteoblasts while inducing osteoclast differentiation and hyperfunction (Cancers (Basel) 2021;13:216)
Etiology
Clinical features
  • Bone disease is the most frequent disease defining clinical feature (Am Soc Clin Oncol Educ Book 2018;38:638)
  • Often presents with bone pain due to lytic bone lesions (thoracic vertebrae most common, also ribs, skull, shoulders, pelvis and long bones); spinal cord compression or peripheral neuropathy are less common presenting symptoms
  • Renal failure / elevated creatinine / hyperuricemia (monoclonal light chain proteinuria results in renal tubular damage); hypercalcemia; hypoalbuminemia
  • Recurrent infections due to impaired humoral immunity (immunoglobulin production, often < 50% normal)
  • Anemia (bone marrow infiltration often in areas of most active hematopoiesis and renal failure causing loss of erythropoietin)
  • Extramedullary involvement generally associated with advanced disease
  • Historical fact: Bence Jones proteins were the first tumor marker (Clin Kidney J 2012;5:478)
Clinical variants
  • Smoldering (asymptomatic):
    • More likely to progress to symptomatic myeloma than monoclonal gammopathy of uncertain significance (MGUS)
    • Both show gammopathy without myeloma defining events (hypercalcemia, anemia, bone lesions and renal insufficiency)
    • 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 (~1% of cases):
    • Serum protein electrophoresis (SPE) / immunofixation electrophoresis (IFE) negative, 85% with impaired secretion and have cytoplasmic immunoglobulin (Ig) by IHC (Am J Clin Pathol 2011;136:168)
    • 15% nonproducers, serum free light chain may still be detected
    • Lower incidence of renal insufficiency, hypercalcemia and depression of normal IgG
    • Must be distinguished from the rare IgD and IgE myelomas
  • Plasma cell leukemia:
    • Typically aggressive with short survival < 1 year
    • > 2 x 109/L or 20% of the leukocyte count on differential are monoclonal plasma cells
    • Primary plasma cell leukemia (0.6% of myeloma) or develop as a late stage transformation (secondary) (Curr Oncol Rep 2019;21:8)
    • Usually lack CD56 (80% of PCLs), more frequent high risk genetic findings
    • Bone pain and osteolytic lesions less common
    • Typically associated with extramedullary lesions (e.g., body cavity effusions, lymphadenopathy and organomegaly)
Diagnosis
  • Division into these categories will guide plan for therapy (Am Soc Clin Oncol Educ Book 2016;35:e418):
    • Multiple (symptomatic) myeloma (J Natl Compr Canc Netw 2019;17:1154):
      • Clonal bone marrow plasma cells ≥ 10% or biopsy proven bony or extramedullary plasmacytoma
      • And ≥ 1 of the following myeloma defining events:
        • Calcium > 1 mg/dL above upper limit of normal or > 11 mg/dL
        • Renal insufficiency*; creatinine > 2 mg/dL or creatinine clearance < 40 mL/min (preferred)
        • Hemoglobin < 10 g/dL or > 2 g/dL below the lower limit of normal
        • 1 or more osteolytic bone lesions on skeletal radiography, CT or FDG PET / CT
        • Clonal bone marrow plasma cells ≥ 60% of bone marrow cellularity
        • Involved / uninvolved serum free light chain (FLC) ratio ≥ 100 and involved free light chain concentration 10 mg/dL or higher
        • > 1 focal lesion on MRI studies ≥ 5 mm
    • These include traditional CRAB features associated with end organ damage (hypercalcemia, renal failure, anemia and osteolytic bone lesions) and biomarkers associated with ~80% risk of progression to end organ damage (≥ 60% clonal plasma cells in bone marrow, serum FLC ≥ 100 with FLC level ≥ 10 mg/dL or > 1 focal lesion by MRI) (Am Soc Clin Oncol Educ Book 2016;35:e418)
    • *Only suspected or proven light chain cast nephropathy is considered a multiple myeloma defining event, consider renal biopsy to clarify if FLC < 500 mg/L (Am Soc Clin Oncol Educ Book 2016;35:e418)
    • Smoldering (asymptomatic) myeloma (J Natl Compr Canc Netw 2019;17:1154):
      • M protein in serum (IgG or IgA) at ≥ 3 g/dL
      • Or Bence Jones protein ≥ 500 mg/24 h urine
      • Or 10 - 59% 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, FDG PET / CT or low dose CT scan
Laboratory
  • 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)
  • SPEP: serum proteins normally separate into 5 major fractions based on electric charge and size (Am Fam Physician 2005;71:105):
    • Albumin
    • Alpha 1 globulins
    • Alpha 2 globulins
    • Beta 1 and beta 2 globulins
    • Gamma globulins
  • Gamma globulins include polyclonal antibodies and light chains, with a normal gamma zone appearing as a symmetrical smear; myeloma may appear as a spike in this region
  • Urine protein electrophoresis (UPEP): monoclonal light chains in urine = Bence Jones protein
  • 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 (Blood Cancer J 2020;10:2)
  • Mass spectrometry may have equivalent performance to IFE and better differentiate M protein from therapeutic antibodies (Blood Cancer J 2021;11:24)
Laboratory images

Images hosted on other servers:

Serum protein immunofixation shows IgD lambda myeloma

 

IgD lambda myeloma

Another IgD myeloma

Radiology description
  • Evidence of 1 or more sites of osteolytic bone destruction (at least 5 mm in size)
  • Advanced methods include low dose whole body CT, MRI and (18F) fluorodeoxyglucose PET (FDG PET), and FDG PET with PET / CT (Am Soc Clin Oncol Educ Book 2016;35:e418)
  • Increased uptake on PET / CT alone is not adequate without evidence of underlying osteolytic bone destruction; bone biopsy recommended if any doubt
Radiology images

Contributed by Mark R. Wick, M.D. and AFIP images
 

Skull Xray

Tibia Xray

Solitary plasma cell myeloma


   

Plasma cell myeloma



Images hosted on other servers:

Prominent skull defect

Prognostic factors
  • Usually incurable with median survival of ~5.5 years with a 5 year survival rate of 54% (ASCO: Multiple Myeloma - Statistics [Accessed 26 May 2022])
  • Higher risk:
    • Elevated beta 2 microglobulin, lactate dehydrogenase, C reactive protein, serum soluble receptor for IL6 and plasma cell proliferation or bone marrow infiltration
    • Reduced polyclonal (uninvolved) serum immunoglobulins
    • Plasmablastic morphology
    • Abnormalities by conventional cytogenetics
  • Active myeloma can be staged using the International Staging System (ISS) or revised International Staging System (R-ISS) (J Natl Compr Canc Netw 2019;17:1154)
  • Revised International Staging System:
    • Stage I: serum beta 2 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 normal serum LDH
    • Stage II: not R-ISS stage I or III
    • Stage III: serum beta 2 microglobulin ≥ 5.5 mg/L or either high risk chromosomal abnormalities [del(17p), t(4:14) or t(14;16)] and 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: hyperdiploidy, 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 2007;109:3489)
  • Model for identifying patients with increased risk of progression of smoldering myeloma (Mayo 2018 criteria or 20/2/20 criteria) with 3 independent risk factors:
    • Serum monoclonal protein > 2 g/dL
    • Involved to uninvolved serum free light chain ratio > 20
    • Bone marrow plasma cells > 20%
    • Low (0 factor), intermediate (1 factor) and high risk (2 - 3 factors) shown to have 2 year rates of progression to multiple myeloma of 5%, 17% and 46%, respectively (Am Soc Clin Oncol Educ Book 2020;40:1)
Case reports
Treatment
Minimal residual disease (MRD) testing
  • Sensitive measure of response to therapy to guide treatment decisions
  • Flow cytometry (Blood 2013;122:1088)
  • Molecular methods monitoring immunoglobulin rearrangement by NGS (Blood Adv 2020;4:4573)
  • Clonotypic peptides by mass spectrometry by liquid chromatography with tandem mass spectrometry (LC-MS / MS) (Clin Chem 2016;62:243)
  • MRD negativity associated with better progression free survival (Blood Adv 2020;4:4573)
Gross description
  • Bone defects are filled with a soft, gelatinous "fish flesh" hemorrhagic tissue
Gross images

Images hosted on other servers:

Vertebrae with myeloma lesions

Skull lesions

Frozen section description
  • Osseous or extraosseous plasmacytomas, particularly if the patient is not known to have a history of plasma cell myeloma, may be sent for frozen section evaluation (Borczuk: Frozen Section Pathology, 1st Edition, 2021)
  • Sites can include: mucosa of the upper respiratory tract, lymph nodes, thyroid, testes, breast, salivary gland and CNS (Int J Otolaryngol 2010;2010:302656)
  • Morphology may range from monotonous plasma cells to more irregular, multinucleated or pleomorphic forms in more advanced myeloma
Frozen section images

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

Touch preparation plasmacytoma

Frozen section plasmacytoma

Microscopic (histologic) description
  • Core biopsy (Am J Clin Path 1987;87:342):
    • 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 Ig kappa and lambda to establish clonality
Microscopic (histologic) images

Contributed by Genevieve M. Crane, M.D., Ph.D. and Tapan Bhavsar, M.D., Ph.D.

Amyloid deposition (Congo red stain)

Amyloid deposition
(Congo red stain
with birefringence)

Focal sheets of plasma cells

Extensive amyloid, bone marrow

 

Extensive bone marrow involvement by myeloma


 

Trephine biopsy

Trephine biopsy

Myeloma with plasmablastic transformation

 

CD138


In situ hybridization for kappa

In situ hybridization for lambda

 

Myeloma involving bone marrow


   

Bone marrow touch preparation



Images hosted on other servers:
   

Bone marrow aspirate has plasmacytoid cells

Virtual slides

Images hosted on other servers:

Plasmacytoma involving thyroid

 

Myeloma with pleomorphic features involving lymph node

Plasmacytoma

Myeloma with
pleomorphic features
diffusely involving
bone marrow

Cytology description
  • Cytology can assess plasma cell morphology (e.g., mature, immature, plasmablastic) but number of plasma cells present may vary substantially from the core biopsy
  • Mature plasma cells: oval with abundant basophilic cytoplasm, perinuclear hof, round eccentric nuclei, clock face chromatin and indiscernible nucleoli
    • Immature plasma cells: higher nuclear to 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
  • Immature or pleomorphic features are rare in reactive plasma cell proliferations
  • Morphologic features:
    • Mott cells / morula cells: multiple grape-like cytoplasmic inclusions comprised of crystalized immunoglobulin
    • Russell bodies: hyaline intracytoplasmic inclusions
    • Flame cells: vermillion staining glycogen rich IgA in cytoplasmic projections (American Society of Hematology: Flame Cells in Multiple Myeloma [Accessed 26 May 2022])
    • Pseudo-Gaucher cells / thesaurocytes: overstuffed fibrils (J Clin Pathol 1976;29:916)
    • Cytoplasmic crystals: occasional in myeloma, common in adult Fanconi syndrome (Am J Clin Pathol 1983;80:224)
    • Dutcher body: pale staining immunoglobulin filled cytoplasm invaginating into the nucleus and appearing as an intranuclear inclusion, single and usually large, more common in IgA myeloma
Cytology images

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

Extensive amyloid, aspirate

Peripheral smear description
  • Rouleaux formation: erythrocytes resemble stacked coins; related to quantity and type of M protein, not specific and may be caused by alterations in other plasma proteins (Biophys J 2000;78:2470, American Society of Hematology: Rouleaux Formation [Accessed 26 May 2022])
  • 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)
Peripheral smear images

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

Peripheral blood rouleaux

Rouleaux formation



Images hosted on other servers:
 

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

Positive stains
Negative stains
Flow cytometry description
Flow cytometry images

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

Dim kappa

Strong cytoplasmic expression

Neoplastic plasma cells

Myeloma with t(11;14) and partial CD19



Images hosted on other servers:

Prominent monotypic
pattern (lambda,
with minimal kappa)

Electron microscopy description
Molecular / cytogenetics description
  • Immunoglobulin heavy and light chain genes are clonally rearranged with a high load of IGHV gene somatic hypermutation; abnormalities in IGH rearrangement may be seen with light chain only disease (Blood 2004;103:3869)
  • Cytogenetics: abnormalities by conventional cytogenetics seen in 33% of cases but identified by FISH in > 90%, including trisomies, deletions and translocations (Blood Cancer J 2015;5:e365)
  • FISH studies often performed by enriching the plasma cell fraction using magnetic cell sorting (MACS) and fluorescence activated cell sorting (FACS) to increase detection of cytogenetic abnormalities in interphase cells (Am J Clin Pathol 2011;136:712)
  • IGH (14q32) translocations in 40% of tumors, recurrent oncogenes:
    • t(4;14) FGFR3 / MMSET (NSD2) (4p16.3); 15%
    • t(6;14) cyclin D3 (6p21); 4%
    • t(11;14) cyclin D1 (11q13); 20%
    • t(14;16) MAF (16q23); 4%
    • t(14;20) MAFB (20q11); 1%
    • MAFA (8q24)
    • Cyclin D2 (12p13)
  • Tumors without 1 of the frequent IGH are more often hyperdiploid with gains of odd numbered chromosomes (3, 5, 7, 9, 11, 15, 19, 21); 50%
  • Monosomy or partial deletion of chromosome 13 (13q14) found in nearly 50% by FISH
  • MYC rearrangements in nearly half of tumors
  • Activating mutations of KRAS, NRAS or BRAF in 40% of tumors
  • Other: TP53 deletion or mutation, gain of 1q, loss of 1p, NF kappa B pathway activation, inactivation of CDKN2C, RB1, FAM46C, DIS3 and DNA methylation changes
Videos

Video on myeloma MRD

Plasma cell neoplasms

Podcast on SPEP

Introduction to bone marrow interpretation

Sample pathology report
  • Bone marrow aspirate smears, touch imprints, core biopsy and clot section with peripheral smear:
    • Plasma cell myeloma (see comment)
    • Normocytic anemia, rouleaux formation
    • Comment: The patient is a 65 year old man who recently presented with back pain, anemia and hypercalcemia. Xrays demonstrated evidence of lytic bone lesions and serum protein analysis demonstrated an IgG kappa M protein. The bone marrow shows sheets of atypical plasma cells in a hypercellular bone marrow overall comprising 80% of the intertrabecular space. Flow cytometry as reported separately, demonstrates a CD56+, CD19- kappa restricted plasma cell population. Please correlate with forthcoming cytogenetics and myeloma FISH panel, which will be reported as an addendum.
Differential diagnosis
Board review style question #1


Which of the following findings would be compatible with a diagnosis of smoldering myeloma?

  1. 70% plasma cells in bone marrow
  2. Free light chain ratio is 0.01
  3. IgG lambda M protein in serum of 3.5 g/dL
  4. 1 osteolytic lesion on skeletal radiography
  5. Serum calcium of 11.2 mg/dL
Board review style answer #1
C. IgG lambda M protein in serum of 3.5 g/dL. In smoldering myeloma, end stage organ damage should be absent (no CRAB features), so the elevated serum calcium excludes answer E and the osteolytic lesion excludes option D. Plasma cells in excess of 60% or light chain ratio (involved to uninvolved) of ≥ 100 would qualify as active plasma cell myeloma excluding answers A and B. In the diagnosis of smoldering myeloma the patient may have M protein in serum (IgG or IgA) at ≥ 3 g/dL or Bence Jones protein ≥ 500 mg/24 h urine or 10 - 59% clonal plasma cells in bone marrow.

Comment Here

Reference: Plasma cell myeloma (multiple myeloma)
Board review style question #2


Clonal plasma cells in the setting of multiple myeloma are typically negative for CD19. What cytogenetic abnormality is typically associated with CD19 or CD20 positive plasma cells in the setting of a plasma cell neoplasm?

  1. Deletion 13
  2. Hypodiploidy
  3. t(4:14)
  4. t(11;14)
  5. t(14:16)
Board review style answer #2
D. t(11:14). The presence of CD19 positive clonal plasma cells may favor the presence of a small B cell lymphoma with plasmacytic differentiation as opposed to a plasma cell neoplasm in many cases. These entities are important to differentiate as the treatments are generally distinct. However, in the setting of a t(11;14) translocation, the plasma cells are cyclin D1+, typically retain CD19 expression and may express additional B cell markers including CD20. This can create potential diagnostic pitfalls (Leuk Res 2013;37:1251).

Comment Here

Reference: Plasma cell myeloma (multiple myeloma)
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 are more specific to a neoplastic process compared to binucleation, Russell bodies or mild plasmacytosis.

Comment Here

Reference: Plasma cell myeloma (multiple myeloma)
Back to top
Home > Bone marrow neoplastic > Plasma cell myeloma (multiple myeloma)
Image 01 Image 02