HAEM5:Plasma cell myeloma / multiple myeloma

Haematolymphoid Tumours (WHO Classification, 5th ed.)

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Primary Author(s)*

• Huan Mo, MD, MS
• Zhenya Tang, MD, PhD

The University Of Texas MD Anderson Cancer Center, Department of Hematopathology, Houston, Texas

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	B-cell lymphoid proliferations and lymphomas
Family	Plasma cell neoplasms and other diseases with paraproteins
Type	Plasma cell neoplasms
Subtype(s)	Plasma cell myeloma / multiple myeloma

Definition / Description of Disease

• A type of hematologic malignancy of monoclonal plasma cell
• Originated from bone marrow but affecting multiple tissues and organs
• Hallmarks: presence of M protein, neoplastic plasma (myeloma) cells and sign(s) of end-organ damages (CRAB:  hypercalcemia, renal insufficiency, anemia and bone lesions)

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Synonyms / Terminology

• Multiple myeloma
• Medullary plasmacytoma
• Myelomatosis
• Myeloma, NOS
• Kahler disease (no longer used)

Epidemiology / Prevalence

• Plasma cell myeloma accounts for approximately 1% of all types of malignant tumors, 10-15% of all hematologic malignancies
• It is the third most common hematologic malignancies, next to lymphoma and leukemia
• Incidence: 4 per 100,000 individuals per year
• It’s estimated that 34,920 adults (19,320 men and 15,600 women) will be newly diagnosed with plasma cell myeloma and 12,410 patients (6,840 men and 5,570 women) will die from this disease in the United States in 2021.
• It affects mostly adults with an age > 50 years (median age at diagnosis: 70 years). Young adults (<30 years) are infrequently and children (<16 years) are almost never affected by this disease.
• Male : Female ratio: 1.1 : 1
• Black : white ratio: 2 : 1
• Current 5-year relative survival rate:  54%

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Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

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• A wide spectrum of clinical presentations: from asymptomatic (e.g., smoldering plasma cell myeloma) to highly aggressive with end-organ damages (e.g., one of more of CRAB presentations)
• Bone pain can be the initial presentation in many cases
• Pale appearance due to anemia and sometimes bleeding
• Spinal cord compression due to vertebrae damages
• Peripheral neuropathy
• Infections due to compromised immunity can occur
• Organomegaly
• Skin lesions

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Sites of Involvement

• Bone marrow, multifocal or generalized
• Involvement of other organs and / or circulating plasma cells may be secondarily but usually an indication of advanced disease (Is it ok? ~HM)
• Extramedullary sites: bones, kidney, upper airway, skin and so on. (Extramedullary plasmacytoma is a different disease and it is closer to marginal zone lymphoma ~ HM)

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Morphologic Features

Radiology findings:

• Osteolytic lesions are detected in approximately 70% of plasma cell myeloma cases on radiology skeletal survey, MRI and PET/CT. Other presentation such as osteoporosis, pathological bone fracture, and vertebral compression fracture can be observed as well. Vertebrae, ribs, skull, shoulders, pelvis and long bones are the sites frequently affected with bone lesion(s).

Macroscopy findings:

• During gross examination of severely affected bones, apparent defects filled with flesh-like hemorrhagic tissues can be observed.

Microscopy findings:

• Plasma cells in plasma cell myeloma can show mature and immature (or plasmablastic) forms.
• The mature plasma cells usually have eccentric nuclei, dense "clock face" chromatin, and abundant, deep basophilic (on Wright Giemsa stained marrow or cytological preparations) or amphophilic (on hematoxylin and eosin-stained histological sections) cytoplasm with a paranuclear hof.
• Histologically, the monotypic plasma cells may present as interstitial, scattered distribution, in a form of small clusters and/or focal nodules. In advanced disease stages, the neoplastic plasma cells proliferate as diffuse sheets and replace normal bone marrow.

Here I kept more detailed morphology descriptions ~HM

Differential diagnosis considerations may include:

• Lymphoplasmacytic lymphoma (LPL, related to Waldenstrom macroglobulinemia, WM) and splenic/nodal marginal zone lymphoma can have extensive monotypic plasmacytic differentiation.
• Mantle cell lymphoma (MCL) and a subset of plasma cell myeloma can share expressions of Cyclin D1 (CCND1) due to t(11;14)(q13;q32)(IGH/CCND1) translocation.
• In the setting of plasmablastic morphology, differential diagnosis includes: anaplastic plasma cell myeloma, plasmablastic lymphoma, primary effusion lymphoma (PEL), ALK-positive large B-cell lymphoma, immunoblastic diffuse large B-cell lymphoma, and HHV8-positive diffuse large B-cell lymphoma NOS.
• Non-hematopoietic neoplasms with plasmacytoid morphology can also mimic plasma cell myeloma, such as plasmacytoid myoepithelioma of minor salivary glands , medullary thyroid carcinoma (or other neuroendocrine tumors) , and melanoma. It is important to keep in mind that CD138 is positive in many normal and neoplastic epithelial cells.

Immunophenotype

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Finding	Marker
Positive (universal)	EXAMPLE: CD1
Positive (subset)	EXAMPLE: CD2
Negative (universal)	EXAMPLE: CD3
Negative (subset)	EXAMPLE: CD4

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• Plasma cell identification: For flow cytometry immunophenotyping, benign and neoplastic plasma cells can be identified with combined use of CD38 and CD138. However, since anti-CD38 monoclonal antibodies (such as daratumumab) are used in myeloma therapy regimens, the expression of CD38 on the residual myeloma cells can be decreased or negative on the marrow cells. It should be noted that plasma cells lose surface CD138 overtime after specimen procurement (such as from bone marrow aspirates); therefore, delayed specimen processing will cause underestimated plasma cell percentage in flow cytometry immunophenotyping and lower yield in CD138 enrichment of plasma cell for cytogenetic studies. For immunohistochemical studies on Formalin-Fixed Paraffin-Embedded (FFPE) tissue sections, CD138 and MUM-1/IRF4 can be used to identify plasma cells.
• Myeloma plasma cells: Unlike non-neoplastic plasma cells or plasma cells differentiated from lymphomas (especially marginal zone lymphoma and lymphoplasmacytic lymphoma), myeloma plasma cells often show aberrant loss of CD19 and CD45; they may also aberrantly express CD56, CD117, and/or Cyclin D1, which is associated with IGH/CCND1 translocation. For common aberrant immunophenotype patterns for myeloma cells, please see Flores-Montero et al. The aberrancy of immunophenotypes of myeloma plasma cells can be used for minimal/measurable residual disease (MRD) detection in myeloma.
• Monoclonality: confirmed by immunoglobulin (Ig) light chain analysis, presenting as monotypic cytoplasmic immunoglobulin (cIg) expression but lack surface immunoglobulin (sIg). On FFPE tissue sections, immunoglobulin light chain analysis on plasma cells can be assessed either by immunohistochemical stains or by chromogenic in situ hybridization (CISH).

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

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• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

Risk stratification of cytogenetic aberrations in plasma cell myeloma.

Table 4: Cytogenetic abnormalities on clinical course and prognosis in multiple myeloma (adapted from Rajan and Rajkumar 2015)

Cytogenetic abnormality	Smoldering plasma cell myeloma	Plasma cell myeloma ***
Trisomies	Intermediate risk of progression Median TTP of 3 years	Standard-risk, median OS 7-10 years Most have myeloma bone disease at diagnosis Excellent response to lenalidomide-based therapy
t(11;14)(q13;q32)	Standard risk of progression Median TTP of 5 years	Standard-risk, median OS 7-10 years. See below.
t(6;14)(p21;q32)	Standard risk of progression Median TTP of 5 years	Standard-risk, median OS 7-10 years
t(4;14)(p16;q32)	High risk of progression Median TTP of 2 years	Intermediate-risk (mSMART) or high-risk (IMWG), median OS 5 years Needs bortezomib-based initial therapy, early ASCT (if eligible), followed by bortezomib-based consolidation/maintenance
t(14;16)(q32;q23)	Standard risk of progression Median TTP of 5 years	High-risk, median OS 3 years Associated with high levels of FLC and 25% present with acute renal failure as initial MDE
t(14;20)(q32;q11)	Standard risk of progression Median TTP of 5 years	High-risk, median OS 3 years
Gain(1q21) **	High risk of progression Median TTP of 2 years	Intermediate-risk (mSMART) or high-risk (IMWG), median OS 5 years
Del(17p) *	High risk of progression Median TTP of 2 years	High-risk, median OS 3 years
Del(1p)	N/A	High-risk (mSMART)
Trisomies plus any one of the IgH translocations	Standard risk of progression Median TTP of 5 years	May ameliorate adverse prognosis conferred by high risk IgH translocations, and del 17p
Isolated monosomy 13, or isolated monosomy 14	Standard risk of progression Median TTP of 5 years	Effect on prognosis is not clear
Normal	Low risk of progression Median TTP of 7-10 years	Good prognosis, probably reflecting low tumor burden, median OS >7-10 years

* Presence of del(17p) indicates high risk MM regardless of other abnormalities.

** Gain(1q21) (without other high risk abnormalities) is considered intermediate-risk.

*** Risk stratifications are according to IMWG and mSMART systems unless otherwise specified.

ASCT, autologous stem cell transplantation; IMWG, International Myeloma Working Group  ; mSMART, Mayo stratification for myeloma and risk-adapted therapy classification  ; MDE, myeloma-defining event; OS, overall survival; TTP, time to progression.

The case of t(11;14) - IGH/CCND1:

• Currently classified as a standard-risk abnormality.
• However, with the advent of novel agents (including proteasome inhibitors, immunomodulatory agents, and, more recently, monoclonal antibodies), findings from more recent retrospective reviews have shown that t(11;14) may be associated with intermediate outcomes in patients treated with novel agents as compared with patients who have standard- or high-risk cytogenetic aberrations .
• Myeloma cells with t(11;14) have a unique biology, with relatively higher expression of the antiapoptotic protein BCL2 and lower expression of MCL1, in contrast to MM cells without this translocation.
• Venetoclax (BCL-2 inhibitor) mono-therapy has demonstrated anti-myeloma activity in patients with relapsed/refractory multiple myeloma positive for t(11;14).

Role of cytogenetic aberrations in Staging of multiple myeloma. (Revised International Staging System)

Table 6: Staging systems for multiple myeloma

Stage	International Staging System	Revised-ISS (R-ISS)
I	Serum beta-2 microglobulin <3.5 mg/L, Serum albumin ≥3.5 g/dL	ISS stage I and standard-risk chromosomal abnormalities by FISH and Serum LDH ≤ the upper limit of normal
II	Not ISS stage I or III	Not R-ISS stage I or III
III	Serum beta-2 microglobulin ≥5.5 mg/L	ISS stage III and either high-risk chromosomal abnormalities by FISH or Serum LDH > the upper limit of normal
Notes		Standard-risk: No high-risk chromosomal abnormality. High-risk: Presence of del(17p) and/or translocation t(4;14) and/or translocation t(14;16).

Survival data of plasma cell myeloma in clinical trial cohorts of selected cytogenetic aberrations are reviewed by Pieter Sonneveld et al.

Gene expression signatures through high-throughput methods such as gene expression profiling (GEP) have been reported as being capable of discerning risk/prognosis in plasma cell myeloma. There are several GEP platforms available, such as 15-gene, 70-gene and 92-gene models, but they are not commonly used in clinical practice yet (NCCN guidelines 1.2021 for multiple myeloma).

Gene mutations are also helpful for risk stratification in plasma cell myeloma, e.g., mutations of IRF4 or PRDM1 genes involving plasma cell differentiation are usually indicative for a favorable prognosis, while mutation of TP53, ATM or ATR genes involving DNA repair pathway mostly imply for a poor prognosis.

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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Numerical karyotype aberrations:

• Hyperdiploid/Trisomies plasma cell myeloma (≥47 and <75 chromosomes): It has been defined by multiple chromosomal gains, preferentially of the odd chromosomes 3, 5, 7, 9, 11, 15, 19 and 21.
• Non-hyperdiploid plasma cell myeloma: It has a high frequency of IgH translocations (14q32), which are thought to be early events in the disease.
  • Hypodiploid (≤44 chromosomes),
  • Pseudodiploid (45–46 chromosomes)
  • Near tetraploid (>75 chromosomes), where the last is regarded to originate from doubling of the hypodiploid and pseudodiploid karyotypes.

Primary cytogenetic aberrations: These aberrations may be present both prior to and in plasma cell myeloma, indicating that these primary events can be identified in patients with non-IgM MGUS or smoldering multiple myeloma, the precursor states of plasma cell myeloma.

• Trisomies (commonly involving odd- numbered chromosomes) and hyperdiploidy
• Immunoglobulin heavy chain (IgH) translocations and dysregulated oncogenes in the partner chromosome
  • t(4;14)/IGH/FGFR3 and MMSET
  • t(6;14)/IGH/CCND3
  • t(11;14)/IGH/CCND1
  • t(14;16)/IGH/MAF
  • t(14;20)/IGH/MAFB
  • IgH translocations with uncommon chromosome partners
• Trisomies plus any IgH translocation

Common secondary cytogenetic aberrations: *

• del13q or - 13 **
• del17p (TP53 deletion) or -17
• del1p (loss of CDKN2C and TP73)
• duplication or amplification of 1q (gain/amplification of CKS1B)

* Each secondary cytogenetic abnormality alone or in combination can occur in any primary molecular MM subtype.

** Del13q and -13 are considered as secondary events by the International Myeloma Working Group (IMWG), but they are listed as primary events in other publications.

Copy number alterations: According to genome-wide studies by array-based comparative genomic hybridization (aCGH), single nucleotide polymophism (SNP)–based CGH (SNP array) as well as massively parallel next generation sequencing NGS) of paired tumor/normal specimen from patients with diagnosed plasma cell myeloma, CNVs with a fluctuating frequency of <5 to >90% can involve both p and q arms of almost all chromosomes. Although their correlations with chromosomal abnormalities and their clinical significance are not well defined yet, the majority of these CNVs usually may indicate presence of additional aberrations that either routine chromosomal analysis have failed to detect or the concurrent FISH tests haven’t covered.

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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THIS SECTION NEEDS REFERENCES.

Up to date, there is no known gene mutation which is considered as plasma cell myeloma-specific. However, a median mutation rate of approximately 1.6 mutations/Mb is observed in plasma cell myeloma cases, lower than that of approximately 10 mutations/Mb in melanoma and lung cancer cases. Table 3 adapted from report by Kumar and Rajkumar in 2018 summarizes the most common somatic mutations, their frequencies and major function (Table 2). Some of them are actionable mutations, e.g., KRAS and NRAS mutations.

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Table 2. List of genes frequently mutated in plasma cell myeloma and their frequencies and main function

Gene	Mutation Effect	Frequency	Function
KRAS	Activation	20-25%	MAPK signaling pathway (cell survival and growth)
NRAS	Activation	23-25%	MAPK signaling pathway (cell survival and growth); mutation may be associated with reduced sensitivity to bortezomib
TP53	Complex	8-15%	Tumor suppressor involved in response to DNA damage and apoptosis
DIS3	Unclear	11%	Exosome endoribonuclease (RNA metabolism)
TENT5C (FAM46C)	Unclear	~11%	Nucleotidyltransferase that act as a non-canonical poly(A) RNA polymerase which enhances mRNA stability and gene expression.
BRAF	Activation	6-15%	MAPK signaling pathway (cell survival and growth)
TRAF3	Loss of function	3-6%	NF-κB signaling pathway (cell survival and proliferation)
ROBO1	Unclear	2-5%	Transmembrane receptor for SLIT2; may involved in myeloma-marrow niche interaction
CYLD	Loss of function	2-3%	NF-κB signaling pathway (cell survival and proliferation) and Wnt/β-catenin signaling
EGR1	Unclear	4-6%	Transcription factor; EGR1 interacts with JUN in modulating myeloma cell apoptosis ; the EGR1 mutation is associated with hyperdiploid cases and a better overall survival
SP140	Unclear	5-7%	Antigen-response mechanisms in mature B cells; only significantly mutated in the hyperdiploid samples
FAT3	Unclear	4-7%	Cadherin superfamily member (cell adhesion)
CCND1	Unclear	3%	Cell cycle progression; CCND1 mutation occurs in t(11;14) cases and is associated with a poor prognosis when compared with non-mutated t(11;14) patients.

Epigenomic Alterations

It has been reported that the translocation of t(4;14)(p16;q32) occurring in approximately 6 to 15% of all plasma cell myeloma cases causes a juxtaposition of two important genes, of FGFR3 and MMSET (also called as NSD2) adjacently located at 4p16 with the IGH enhancer located at 14q32, resulting in deregulation of FGFR3 and MMSET expressions. MMSET is functionally a methyl-transferase which plays an important role in the methylation of histone H3K36 and histone H4K20. The histone H3K36 modulates the expression of several genes, while the methylated histone H4K20 is involved in the recruitment of p53 binding protein 1 (53BP1) at the site of DNA damages.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

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Due to the wide spectrum of chromosomal abnormalities and somatic mutations identified in plasma cell myeloma, it’s believed that the oncogenesis and development of plasma cell myeloma may also involve many pathways. Please refer to review articles for more detailed information.

NF-κB pathway: Dysregulation of NF-kB pathway is found in approximately 20% of patients, including the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2, and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the non-canonical NF-kB pathway. The anti-myeloma activity of proteasome inhibitor bortezomib (PS-341) may partly involve NF-kB pathway.

RAS/MAPK pathway: This is the most frequently observed pathway mutations in plasma cell myeloma (~40%), including KRAS, NRAS, and BRAF. In addition, FGFR3, one of the affected gene in t(4;14) rearrangement, is a tyrosine-kinase receptor that is on the upstream of RAS/MAPK pathway.

Cell-cycle pathway: This pathway include cyclin D (such as CCND1 and CCND3) and cyclin-dependent kinases (such as CDK4 and CDK6), as well as the inhibitors (such as CDKN2C and RB1). Many of these genes are commonly involved in cytogenetic aberrations. An early stage clinical trial suggests biologic activity of CDK4/6 inhibitor palbociclib in myeloma patients.

DNA damage pathway: TP53 mutation and deletion (17p deletion) suggest a high risk disease.

MYC activation: MYC rearrangement is found in 8% of the newly diagnosed myeloma patient in a Mayo Clinic study. It is associated with high disease burden and is an independent adverse prognostic factor.

Genetic Diagnostic Testing Methods

Chromosomal analysis can detects abnormalities in only 30% of plasma cell myeloma cases at diagnosis, which are most likely due to the low proliferation of malignant plasma cells or myeloma cells and limit of availability of analyzable metaphase cells harvested from bone marrow culture. According to the updated American College of Medical Genetics and Genomics (ACMGG) technical standards and guidelines for chromosome studies in plasma cell dyscrasia, metaphase cells harvested from unstimulated 24- and 72-hour cultures as well as 120-hour IL-4-stimulated culture should be analyzed in each case. However, longer bone marrow culture may potentially increase the risk of contamination, the occurrence of possible culture artifacts and/or the turnaround time (TAT). Conventional karyotyping is useful to detect hypodiploidy and deletion 13, but if FISH studies are done, additional value in initial risk‐stratification may be limited.

CD138 enrichment: As recommended by ACMGG and the Cancer Genomics Consortium (CGC), bone marrow samples are subjected to be enriched for the CD138+ plasma cell fraction before applying for FISH and/CMA analyses, especially those with plasma cells percentage below a certain cutoff value for successful FISH and/or CMA analyses established by each laboratory. The enriched CD138+ plasma cells are usually not suitable for subsequently in vitro culture and chromosomal analysis.

Fluorescence in situ hybridization (FISH) testing is performed mainly targeting clinically relevant abnormalities with well-known implication for risk stratification in plasma cell myeloma cases. The National Comprehensive Cancer Network (NCCN) recommends that a panel of FISH tests including t(4;14), t(11;14), t(14;16), t(14;20), del 1p, gain or amplification of 1q21, del 13, and del 17p13 should be performed for all active plasma cell myeloma cases at their initial workup (NCCN guideline Version 4.2021 for Multiple Myeloma). Identification of cytogenetic aberrations of a low frequency (e.g., del6q and del16q) by FISH is feasible not not routinely performed in the majority of clinical cytogenetic laboratories, mainly due to additional expenses and limit of clinical specimen.

For the follow-up specimens, the previously abnormal FISH tests may be repeated. Additional FISH tests for secondary aberration and disease progression can be performed (such as TP73/1q22, TP53/D17Z1 and MYC probes).

In general, all these markers discussed above are not specifically for diagnosis of plasma cell myeloma and/or its precursors, MGUS and SMM. Instead, they are clinically applied for risk stratification and some of them, the actionable mutations, are also specifically utilized for choice of targeted and/or more efficient therapies.

Dr. Tang, Can you please verify the sensitivity numbers with our validation data? Also, can you add a comparison between marrow aspirate specimen and FFPE specimen in terms of assay specs?

A FISH test is considered very specific for the targeted aberration, but its sensitivity technically varies from 0.5% to 10% or higher (???). Depending on multiple factors such as type of FISH probes (fusion probe vs. break-apart probe), coverage of each probe, quality of test samples and so on.

Due to the extremely low levels of chromosomal abnormalities that are beyond the limit of detection by chromosomal analysis or FISH, high sensitive assays have been adopted for the evaluation of bone marrow aspirates for minimal residual disease (MRD), including multiparametric flow cytometry (MFC), allele-specific oligonucleotide (ASO)-qPCR and next-generation sequencing (NGS) of VDJ sequences to assess the status of MRD in plasma cell myeloma.  

Chromosomal microarray (CMA) is more and more frequently applied in the clinical studies of plasma cell myeloma cases. This assay theoretically has a full coverage of the whole genome, mainly for copy number variations (CNVs) and possible copy number-neutral loss of heterozygosity (CN-LOH)     analyses of the whole genome. It is not able to detect balanced structural chromosomal abnormalities, such as translocation (e.g., IGH rearrangement–related), insertion and/or inversion. In general, CMA analysis is not sensitive enough to identify any CNVs and/or CN-LOH at a low level, e.g., <25%).

Table 3: Common FISH assays detecting chromosomal abnormalities in plasma cell neoplasms

Chr. Abnormalitites	Target(s)	Type of Probe
14q32.33 rearrangement	IGH	Break apart
t(11;14)(q13;q32)	IGH/CCND1	Dual fusion
t(4;14)(p16;q32)	IGH/FGFR3 or IGH/MMSET *	Dual fusion
t(14;20)(q32;q11)	IGH/MAFB	Dual fusion
t(6;14)(p21;q32)	IGH/CCND3	Dual fusion
t(14;16)(q32;q23)	IGH/MAF	Dual fusion
8q24.1 rearrangement	MYC	Break apart
17p-	TP53	Deletion probes
1q21 amplification and 1p deletion	CKS1B and CDKN2C (P18)	Amplification/deletion probes
-13/13q-	RB1 and LAMP1	Deletion probes
+9/+15	Whole chromosomes	Centromere Enumeration Probe
+3/+7	Whole chromosomes	Centromere Enumeration Probe

* The FGFR3 probe poses a coverage of approximately 1 MB, including the whole FGFR3 and MMSET (NSD2) genes and their flanking region (https://www.molecular.abbott/int/en/chromosome/4).

Familial Forms

Family members and relatives of plasma cell myeloma patients have a high possibility (approximately 2-4 fold elevated risk) of developing the disease, implying for inherited predisposition. According to genome-wide association studies (GWAS), more than 10 genetic susceptibility loci associated with plasma cell myeloma have been identified, such as rs603965A (current id: rs9344) located at 11q13.3 within the CCND1 gene and rs4407910 located at 8q24.12. Please refer to review article by Manier et al for detailed information.

Additional Information

• None

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

Acknowledgements:

We are grateful to Dr. Manisha Sutariya from Loma Linda University Health for providing additional information and guidance.

*Citation of this Page: “Plasma cell myeloma / multiple myeloma”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Plasma_cell_myeloma_/_multiple_myeloma.