104 Plasma Cell Neoplasms: General Considerations Flashcards
Characterized by the same primary genetic mutations as in myeloma but do not cause end-organ damage and represent a precursor condition with an average 1%/year risk of progression into myeloma, AL amyloidosis or, more rarely, other lymphoproliferative disorders.
MGUS
The prevalence of FLC-only MGUS is 0.8% in the general population.
It progresses to myeloma in a minority of patients at the rate of 0.3% per year
Nonmodifiable, major risk factors for MGUS
Advanced age, male gender (twofold higher incidence), and African descent
OTHER RISK FACTORS:
Immunocompromised state and occupational exposures to wood and leather manufacturing, asbestos, fertilizers, and pesticides
A family history of MGUS or myeloma in a first-degree relative doubles the risk of developing MGUS.
Nearly 50% of patients with MGUS have PCs with translocations involving the IGH locus on chromosome __________ and most commonly one of these five partner loci: 11q13 (cyclin D1 gene), 4q16 (FGFR-2 and MMSET), 6q21 (CCND3), 16q23 (c-maf), and 20q11 (maf-B).
Chromosome 14q32
The biological events underlying the progression of MGUS to myeloma are undetermined, and there is no single gene mutation or molecular signature predictive of neoplastic transformation.
Compared with MGUS, SM carries a ________ times higher risk of progression to myeloma in the first 5 years after diagnosis.
10
(10% per year)
TRUE OR FALSE
No molecular or chromosomal abnormalities can distinguish between monoclonal gammopathy, SM, or myeloma at the time of diagnosis.
TRUE
No molecular or chromosomal abnormalities can distinguish between monoclonal gammopathy, SM, or myeloma at the time of diagnosis.
Secondary genetic events occur in much higher frequencies in myeloma, such as:
p53 deletions, especially in refractory and extramedullary presentations
N-RAS and K-RAS mutations,
Chromosome 1p deletion
Gain of 1q21
Translocations involving MYC (8q24).
TRUE OR FALSE
There is an increased relative risk of monoclonal gammopathy and myeloma in overweight and obese patients as determined by their body mass index (BMI).
TRUE
There is an increased relative risk of monoclonal gammopathy and myeloma in overweight and obese patients as determined by their body mass index (BMI).
Adiponectin serum concentrations were lower in patients with monoclonal gammopathy who subsequently developed myeloma.
Obese individuals have been shown to have shorter telomeres than nonobese individuals.
Fat tissue is a principal source of _____________, one of the principal growth and antiapoptotic cytokines acting on myeloma cells.
Interleukin (IL)-6
TRUE OR FALSE
Aspirin promotes proliferation and induces apoptosis of myeloma cell lines in vitro through regulation of BCL-2 and BAX and suppression of vascular endothelial growth factor (VEGF).
FALSE
Aspirin inhibits proliferation and induces apoptosis of myeloma cell lines in vitro through regulation of BCL-2 and BAX and suppression of vascular endothelial growth factor (VEGF).
The most important alterations during myeloma development
Decreases of the B-cell receptor (BCR) and the chemokine receptors CXCR5, and CCR7
In contrast, PCs upregulate CXCR4, CD138, and CD38.
PCs also undergo changes to transcription factors highlighted by a decrease in PAX5, CIITA, and EBF.
Represents the most commonly inactivated tumor-suppressor gene in MM
p53
p53 mutations are negatively correlated with survival
30% of patients with PC leukemia present with p53 mutations
The HIV protease inhibitor and ER stressor that has shown activity in overcoming bortezomib resistance in bortezomib-refractory patients in phase I and II clinical studies
Nelfinavir
OTHER PREDICTORS OF DRUG RESISTANCE
Expression of CRBN is therefore necessary for IMiDs to exert their antimyeloma activity, and CRBN downregulation has been reported as an escape mechanism in myeloma patients treated with IMiDs.
CD55 and CD59 levels were significantly higher at the time of progression, suggesting their role in mediating daratumumab resistance
The gold standard for the detection and classification of myeloma.
Fluorescence in situ hybridization (FISH)
Cytogenetic abnormalities, using FISH, are observed in more than 90% of patients with myeloma.
However, FISH cannot provide information about chromosomal abnormalities without the use of large-scale panels of probes.
Hyperdiploid cytogenetic :
Primary genetic mutations are mutually exclusive, and patients with myeloma can be broadly divided into those with hyperdiploidy and those with IgH translocations.
Trisomies of many odd-numbered chromosomes, namely, 3, 5, 7, 9, 15, 19, and 21
Associated with a favorable outcome and considered standard risk cytogenetics.
IgH translocations
Translocations at the IGH loci (14q32), t(4;14), t(14;16), and t(14;20)
Considered high-risk cytogenetics
________drives the overexpression of cyclin D1, is no longer considered a high-risk cytogenetic feature, and is predictive of response to a BCL2 inhibitor.
t(11;14)
Secondary cytogenetic abnormalities and are associated with unfavorable prognosis
Chromosome 17p/17 and 1q
Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART)
Standard-risk group
t(6;14) or the t(11;14) translocation
hyperdiploid group
Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART)
Intermediate-risk group
t(4;14) translocation and deletions of chromosome 13 or hypodiploidy
deletion of chromosome 13 by metaphase cytogenetics (not by FISH)
Noncytogenetic factor considered intermediate risk: PC labeling index equal or higher than 3%
Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART)
High-risk group
t(14;16) or the t(14;20) translocation or deletion 17p13
Noncytogenetic factor considered high risk: high-risk GEP signature
mSMART does not include deletion of chromosome 1p or gain of chromosome 1q in the current stratification.
Both are considered adverse prognostic factors in myeloma, and their occurrence appears in later stages of the disease.
TRUE OR FALSE
Chromosomal aberrations in AL need to be assessed by FISH analysis and conventional metaphase cytogenetics.
FALSE
Chromosomal aberrations in AL need to be assessed by FISH analysis and not by conventional metaphase cytogenetics.
The clonal PC burden in AL is usually small and similar to that seen in patients with MGUS.
Proliferation rate of PCs is very low
Approximately 80% of patients with AL have FISH abnormalities, the most common being
t(11;14)
Detected in 45% to 60% of patients with AL amyloidosis
Other chromosomal abnormalities seen in patients with AL include other IgH translocations, deletion 13/13q–, deletion 17, and gain(1q)
Deletion 17p13 is not seen in this form of amyloidosis.
TRUE OR FALSE
In particular, t(11;14) is associated with same prognosis in amyloidosis and in myeloma, in which it is associated with a good prognosis and is a predictive factor of poor response to bortezomib-based regimens.
FALSE
In particular, t(11;14) is associated with an inferior prognosis in amyloidosis in contrast to myeloma, in which it is associated with a good prognosis and is a predictive factor of poor response to bortezomib-based regimens.
The main cytokines involved in increased bone resorption and suppressed bone formation lead to OLs in patients with myeloma
IL-6, receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG), BAFF, chemokine (C-C motif) ligand 3 (CCL3)–macrophage inflammatory protein (MIP)-1α, and VEGF
Increased bone resorption and suppressed bone formation lead to OLs in patients with myeloma.
An inhibitor of the WNT signaling pathway
Inhibits osteoblast (OB) differentiation and promotes osteoclast (OC) maturation
DKK1
A DKK1-blocking antibody, proved to be an effective therapeutic agent to halt myeloma-related bone disease in preclinical and early-phase clinical studies; however, its clinical development was halted
BH880
One of the most important regulatory systems for homeostatic bone remodeling
RANK–RANKL-OPG pathway
A membrane-anchored signaling receptor of the TNF receptor family, is expressed on OC precursors
Induces osteoclastogenesis and activation of mature OCs
RANK
A soluble member of the TNF receptor family, is also produced by OBs and BMSCs
It blocks RANK-dependent OC maturation and activation.
OPG
The marrow plasma of myeloma patients contains elevated levels of RANKL and reduced levels of OPG, consistent with an osteoclast-enriched TME.
Also, low serum levels of OPG correlate with advanced MBD in patients with myeloma.
A myeloma cell–promoting member of the TNF superfamily of proteins that is expressed by OCs and BMSCs.
B-CELL ACTIVATION FACTOR (BAFF)
Significantly increased in the serum of patients with myeloma
A member of the TGF-β superfamily of proteins, activates a signaling pathway that results in phosphorylation of SMADs
A stimulator of osteoclastogenesis and is overexpressed in patients with myeloma
Activin A
IL-3, another stimulator of OCs, can induce the secretion of activin A by resident macrophages in the myeloma marrow microenvironment, providing a mechanism for the upregulation of activin A in patients with myeloma.
The root cause of relapse/refractory disease in myeloma
Presence of a less differentiated, myeloma stem cell that is not adequately eradicated by current treatment approaches
There is no agreement on the specific phenotype of the myeloma stem cell, but side-population (SP) cells, which constitute a minor fraction of the myeloma cells, have the features of stem cells.
Have greater clonogenic potential and drug resistance
Myeloma stem cells are drug-resistant subpopulation of memory B-cell–like cells with the ff pheonytype
CD138–/CD19+/CD27+ phenotype
TRUE OR FALSE
The CD138– cell population derived from myeloma cell lines contains significantly higher levels of aldehyde dehydrogenase, a marker for stem cells.
TRUE
The CD138– cell population derived from myeloma cell lines contains significantly higher levels of aldehyde dehydrogenase, a marker for stem cells.
The CD138– cells were not affected by the drugs typically used in myeloma, such as lenalidomide, bortezomib, dexamethasone, and cyclophosphamide.
Pathognomonic features of PC disorders
Capacity for secreting large amount of monoclonal proteins in the serum and urine
The monoclonal protein is either an intact Ig or its FLC.
The most common M-protein isotype in myeloma
IgG
Followed by IgA and rarely IgM
The most common screening test to identify a serum M protein
Serum protein electrophoresis (SPEP) with immunofixation electrophoresis (IFE)
TRUE OR FALSE
The quantity of M protein produced per cell reflect the Ig synthetic load of myeloma
FALSE
The quantity of M protein produced per cell does not entirely reflect the Ig synthetic load of myeloma
Cells tend to be less efficient in folding than normal PC and secrete a relatively decreased amount of M protein per cell.
In addition, the more immature and more proliferative myeloma cells are, the less Ig per cell per day they secrete
What is the light chain escape phenomenon
The decreased quality control, and the increased proteotoxicity burden of synthesis and folding of the heavy chain—> Myeloma cells only secrete FLCs in the absence of a heavy chain.
TRUE OR FALSE
Under physiologic conditions, κ-producing PCs are twice as abundant as λ-producing PCs.
TRUE
Under physiologic conditions, κ-producing PCs are twice as abundant as λ-producing PCs.
κ FLCs typically circulate as monomers and are renally cleared twice as efficiently as dimeric λ FLC, resulting in a physiologic κ/λ ratio around 1.147
TRUE OR FALSE
The half-life of serum FLCs is much shorter than that of the intact Ig (3–6 hours vs 21 days), serial serum FLCs allow early assessment of successful disease cytoreduction compared with SPEP.
TRUE
The half-life of serum FLCs is much shorter than that of the intact Ig (3–6 hours vs 21 days), serial serum FLCs allow early assessment of successful disease cytoreduction compared with SPEP.
TRUE OR FALSE
Patients with high levels of FLC and rapid reduction upon cytoreductive therapy have been identified as a high-risk group with a poor outcome.
TRUE
Patients with high levels of FLC and rapid reduction upon cytoreductive therapy have been identified as a high-risk group with a poor outcome.
An independent prognostic factor for progression of myeloma in monoclonal gammopathy and SM.
Serum FLC ratio
FLCs have also been incorporated into the updated Mayo 2012 staging for AL amyloidosis.
Use to to identify the nature of the M protein and to quantify Ig levels
Immunofixation electrophoresis (IFE)
Many of the IgA and some of the IgG myelomas have their M spike in the
β-globulin region
TRUE OR FALSE
If an M protein is identified on SPEP and IFE does not identify the heavy chain, quantitative analysis of IgD and IgE should be performed.
TRUE
If an M protein is identified on SPEP and IFE does not identify the heavy chain, quantitative analysis of IgD and IgE should be performed.
Most IgD myelomas are associated with _____ light chains.
λ light chains
Used to to assess the extent of proteinuria and discriminate between albuminuria and Bence Jones (BJ) proteinuria
24-hour urine collection for urine protein electrophoresis (UPEP) and IFE
In contrast to the serum FLCs, monitoring of urine FLCs is less reliable and difficult to interpret and is therefore not routinely used.
In a normal marrow with normal cellularity, there may be up to _______% nonclonal PCs present
2% to 5%
However, the percentage of PCs can be much higher in reactive marrows and hypoplastic or aplastic marrows in the absence of a PCN.
In normal marrow, there can be some clustering of PCs around the blood vessels. However, the presence of larger clusters of PCs away from the blood vessels should alert one to the possibility of PCN, especially myeloma.
A monoclonal antibody and a specific immune marker for PCs
CD138
In situ hybridization for cytoplasmic κ and λ should be used to assess clonality.
The best gating strategy in flow cytometry uses
CD38, CD138, CD45, and light-scatter
When used for MRD, at least 100 neoplastic PC events should be acquired.
The percentage of PCs detected by flow cytometry is typically an underestimate of real marrow plasmacytosis.
_____ is negative on normal PCs but is often positive on myeloma cells
CD56
The opposite is true for CD19
CD117 and CD20, which are negative on normal PCs and can be aberrantly expressed on myeloma cells
CD28 and CD200 are negative or only weakly expressed on normal PCs but can be strongly positive on myeloma cells
CD27 and CD81 are strongly expressed on normal PCs but weak or negative on myeloma cells.
In a skeletal x-ray survey, at least ___________% of trabecular bone must be lost to see a lytic lesion.
50% to 75%
TRUE OR FALSE
A skeletal survey is not an adequate technique to assess response to treatment or to diagnose early recurrence of myeloma before new lesions occur
TRUE
A skeletal survey is not an adequate technique to assess response to treatment or to diagnose early recurrence of myeloma before new lesions occur
The sensitivity and specificity of a skeletal survey is low
Skeletal survey is not an adequate technique to assess response to treatment or to diagnose early recurrence of myeloma before new lesions occur.
More sensitive imaging techniques for diagnosis and monitoring of myeloma
18F-fluorodeoxyglucose (FDG) positron emission tomography–computed tomography (PET/CT) and MRI
MRI should include the axial bones containing active hematopoiesis in adults (skull, spine, sternum, shoulders and upper humeri, pelvis, and upper femora)
It allows assessment of myeloma-related disease, including bone structures and extramedullary sites.
18F-Fluorodeoxyglucose Positron Emission Tomography–Computed Tomography
A small protein that associates with human leukocyte antigen class I and is almost exclusively catabolized in the kidneys
One of the most important prognostic factors in myeloma
β2-Microglobulin
The main source of β2m in the serum is membrane turnover.
Its level reflects tumor load and renal function
Typically reflects de-differentiated myeloma with plasmablastic features and is predictive of a poor prognosis.
Serum Lactic Dehydrogenase
High LDH levels were associated with hypercalcemia, elevated serum β2m levels, extramedullary manifestations, plasmablastic morphology, and short OS duration
Only test approved by the FDA for clinical use in myeloma to assess MRD
NGS
IMWG has defined MRD negativity as:
Absence of marrow PCs at the level of 10–5
Imaging negativity as PET/CT negative
Sustained MRD negativity as MRD negative status lasting for at least 1 year
