106 Myeloma Flashcards
Represents the second most common hematologic cancer
Myeloma
- Most patients are diagnosed between 65 and 74 years of age, with a median age at onset of 69 years; only 4% of cases occur before age 45 years.
- Men are affected more frequently than women (ratio: 1.6:1), and individuals of African descent have twice the prevalence of myeloma as those of European descent, regardless of gender.
MGUS is an asymptomatic condition that typically develops years before the diagnosis of myeloma and evolves to a lymphocytic or plasma cell neoplasm at a rate of approximately ______ per year
1% per year
Lifestyle and occupational factors associated with myeloma
- High body mass index
- Exposure to pesticides, organic solvents (benzene, petroleum derivatives, styrene), or chronic radiation
- Thorium dioxide (thorotrast)
- Exposure to acute radiation
- Exposure to fresh wood, wood dust, or working in sawmill factories
- Autoimmune diseases (especially rheumatoid arthritis and pernicious anemia) and chronic viral infections (such as HIV and hepatitis C)
Mutations more frequent in myeloma
- Chromosome 13 deletions
- RAS mutations
- Non–Ig locus–associated MYC translocations
At early stages during the so-called _______________ phase, myeloma cells are totally dependent on marrow microenvironment to survive and on interleukin (IL)-6 and other cytokines.
Intramedullary phase
Most common genomic aberrations in MGUS
Cyclin D dysregulation (60%)
Hyperdiploidy (50%)
Most common genomic aberrations in Myeloma
Cyclin D dysregulation (80%)
Most common genomic aberrations in Plasma Cell leukemia
- Del(13q)/monosomy13 (60%)
- Chr 1g21 amplification (60-80%)
PTEN losses, methylations of p14 promoter, and RB1 inactivations
Mutations that are present at similar rates in MGUS and myeloma.
- Hyperdiploidy
- IGH translocations (t(11;14), t(4;14) and MAF translocations)
These abnormalities are not considered driver events in myeloma.
Postulated as driver myeloma events
- MYC secondary rearrangements
- deletion 13p
- Chromosome 1 abnormalities
- RAS mutations
Traditionally, myeloma patients have been divided into 2 subgroups:
Hyperdiploid: more than 46 but less than 76 chromosomes (34–60% of myeloma)
Nonhyperdiploid: up to 44-45 chromosomes
**Pseudodiploid: 44/45 or 46/47 chromosomes with gains or losses
**Near-tetraploid
Characteristics of hyperdiploid patients
- IgG kappa type with bone involvement
- Gains of odd-numbered chromosomes, including trisomies of chromosomes 15, 9, 5, 19, 3, 11, 7, and 21 (ordered by decreasing frequency)
- Favorable prognosis
Employed to detect five major primary IGH translocations in myeloma, which occur more frequently in nonhyperdiploid patients (85% vs <30%).
Fluorescence in situ hybridization (FISH) analysis
Most frequent translocation (20% of cases)
t(11;14)(q13;q32)
Leading to upregulation of cyclin D1
Subgroup of cyclins with high level expression of cyclin D1, typically responds well to treatment, has an increased frequency of early relapse, but enjoys excellent long-term survival
CD-1 subgroup
Subgroup of cyclins with igh levels of cyclin D3, typically exhibits lymphoplasmacytoid morphology, and has a worse progression-free survival (PFS) and overall survival (OS)
CD-2 subgroup
MAF translocations include:
- t(14;16) : c-MAF overexpression
- t(14;20): deregulates MAFB
- t(8;16): involving MAFA
Rare (5%, 2%, <1% of cases, respectively), but associated with poor prognosis
The prevalence of these three primary IGH rearrangements is similar in MGUS, indicating the need for additional transforming events to precipitate active myeloma.
- t(6;14)
- t(11;14)
- t(14;16)
Copy Number Alterations in Myeloma
Genomic aberrations associated with poor prognosis in myeloma patients
- Deletion of chromosome 13
- Deletion of chromosome 17p13
- Amplification of chromosome 1q21
Deletion of chromosome ______________ affects 50% to 60% of newly diagnosed myeloma, is more frequent in the nonhyperdiploid group (>70%) in comparison to the hyperdiploid group, and often cooccurs with t(4;14) or t(14;16) translocations.
chromosome 13
Deletions of chromosome _______________are rare in newly diagnosed myeloma (5–10%), more common in relapsed and refractory cases (20–40%), and inevitably associated with a negative prognosis, causing early relapse in patients treated with or without autologous stem cell transplantation (SCT).
chromosome 17p involving the TP53 locus
Amplification of________ is detected by FISH in approximately 40% of newly diagnosed myeloma and in 70% of relapsed myeloma, and negatively affects OS
Amplification of 1q21
Translocation described with the TP53 genomic locus, causing simultaneous gain of 1q21 and deletion of 17p.
Jumping translocation of 1q12 (JT1q12)
5 of the 11 genes commonly mutated in myeloma
KRAS, NRAS, FAM46C, DIS3, and TP53
A transmembrane heparan sulfate bearing proteoglycan expressed during the plasma cell stage of B-cell maturation and can bind to type I collagen, thereby inducing expression of metalloproteinases and promoting bone resorption and invasion
CD138
Increased soluble CD138 levels correlate with tumor burden and poor outcomes.
Regulates not only specific homing of myeloma cells to the marrow but also mobilization or marrow egress, being possibly accountable for the multifocal marrow localization and blood circulation of myeloma cells
CXCL12 (also called SDF-1α)/CXCR4 axis
Binds to the RANK (receptor activator of NF-κB) receptor to stimulate osteoclast differentiation, formation, and survival; myeloma cells produce RANKL and upregulate RANKL expression in BMSCs and osteoblasts via direct contact interaction, signaling induction or production of IL-7.
Ligand for receptor activator of NF-κB (RANKL)
A decoy receptor that normally prevents RANK–RANKL interaction via soluble factors, integrin α4β1- vascular cell-adhesion molecule (VCAM) 1 interaction, production of Dickkopf-1 (DKK1), or inactivation by syndecan-mediated internalization into myeloma cells.
Osteoprotegerin (OPG)
OPG levels are decreased in the serum of myeloma patients and correlate with lytic bone lesion development; a high RANKL-to-OPG ratio is associated with worse prognosis
TRUE OR FALSE
In a noninferiority, phase 3 double-blind study, denosumab was not inferior to zoledronic acid (Zometa), leading to its approval by the FDA in 2018.
TRUE
In a noninferiority, phase 3 double-blind study, denosumab was not inferior to zoledronic acid (Zometa), leading to its approval by the FDA in 2018.
TRUE OR FALSE
Bisphosphonates not only block osteoclasts and modulate osteoblasts but also have an effect on tumor burden.
TRUE
Bisphosphonates not only block osteoclasts and modulate osteoblasts but also have an effect on tumor burden.
Stimulate osteoclastogenesis and osteoclast activity
- Receptor activator of nuclear factor-κB (RANK) receptor/receptor activator of nuclear factor-κB ligand (RANKL)
- Macrophage inflammatory protein (MIP)-1α
An inhibitor of osteoblast activity
Dickkopf-1 (DKK1)
“CRAB” criteria
- Hypercalcemia: serum calcium ≥ 11.5 mg/100 mL
- Renal insufficiency: serum creatinine > 2 mmol/L
- Anemia: normochromic, normocytic with a hemoglobin value of >2 g/100 mL below the lower limit of normal or a hemoglobin value < 10 g/100 mL
- Bone lesions: lytic lesions, severe osteopenia, or pathologic fractures
Myeloma defining biomarkers:
- Clonal marrow plasma cell percentage equal to or greater than 60%
- Ratio of involved versus uninvolved FLCs equal to or exceeding 100
- Presence of more than 1 focal lesion on magnetic resonance imaging (MRI)
Criteria for Diagnosis of Myeloma
All 3 criteria must be met:
* Clonal marrow plasma cells ≥10% and/or presence of a biopsy-proven plasmocytoma
* Presence of serum and/or urinary monoclonal protein (except in patients with true nonsecretory myeloma)
* Evidence of end-organ damage (CRAB)
Most common symptom and laboratory feature
Symptom: Anemia (73%) Bone pain (58%)
Lab: Monoclonal Ig peak on immunofixation of serum or urine (97%)
Myelomatous involvement of the marrow typically causes anemia, which is present in more than ____________ of patients
Two-thirds
In contrast to other lymphoproliferative disorders, thrombocytopenia is uncommon at diagnosis, even with extensive marrow infiltration, possibly because _________ has thrombopoietic activity
IL-6
TRUE OR FALSE
Bortezomib causes a cyclic thrombocytopenia with different kinetics from cytotoxic drugs.
TRUE
Bortezomib causes a cyclic thrombocytopenia with different kinetics from cytotoxic drugs.
It appears during the first 10 days of each cycle, has a short recovery time, no cumulative or persistent effects, and there is an absence of marrow megakaryocyte toxic damage, as the thrombocytopenia primarily results from a functional alteration in platelet budding.
Overt bleeding is a relatively uncommon presenting symptom for myeloma patients; however, it occurs more commonly with ___________
IgA paraproteins
Easy bruising is more common in _______________ (15–41% of patients at diagnosis)
Systemic AL amyloidosis
Drugs that have antiangiogenic properties and are associated with an increased risk of venous thromboembolism (VTE), ranging from 5% to 18% of treated patients, when combined with other chemotherapeutic agents or erythropoietic agents
(IMiDs)
Such as thalidomide, lenalidomide, and pomalidomide
The VTE prophylaxis of choice for patients who are at low risk for VTE
Aspirin
The M protein presents as a single narrow peak, migrating in the___________region of the densitometer tracing.
γ, or, less often, β
Test that identifies the unique and specific Ig idiotypes.
Immunofixation analysis
Most common M protein
IgG 60%
IgA 20%
Ig light chains alone 20%
IgD, IgM, and biclonal 5%
A low M-spike concentration is particularly suggestive of _____myeloma isotype
IgD myeloma isotype
Light-chain myeloma patients should be followed by _____________________
These patients present more often with renal failure or increased creatinine levels.
UPEP and urine immunofixation
Light-chain proteinuria is frequent, especially in _______ myeloma
IgD myeloma
TRUE OR FALSE
The κ light chain isotype is twice as common as the λ isotype
TRUE
The κ light chain isotype is twice as common as the λ isotype
The κ light chain isotype is twice as common as the λ isotype, except in _____ myeloma.
IgD myeloma
IgD was strongly associated with elevated serum β2-microglobulin (β2M) and lactate dehydrogenase (LDH) levels, reflecting high tumor burden.
A technique used to detect monoclonal FLCs and provides an FLC κ:λ ratio
FLC assay (FREELITE assay)
The κ:λ ratio is considered abnormal if :
Less than 0.26 (λ-restricted Ig light chain)
OR
More than 1.65 (κ-restricted Ig light chain)
Half-life of FLCs
2–4 hours
Ig : 17–21 days
TRUE OR FALSE
SPEP can be used to detect early treatment responses and should be evaluated routinely in patients with AL amyloidosis and oligosecretory myeloma.
FALSE
FLC assay can be used to detect early treatment responses and should be evaluated routinely in patients with AL amyloidosis and oligosecretory myeloma.
TRUE OR FALSE
High baseline FLC correlates with shorter survival in newly diagnosed myeloma patients despite achievement of complete response (CR).
TRUE
High baseline FLC correlates with shorter survival in newly diagnosed myeloma patients despite achievement of complete response (CR).
A rapid reduction in FLCs after therapy is also linked to inferior OS and event-free survival (EFS), suggesting the presence of highly proliferative myeloma cells, particularly sensitive to combination chemotherapy.
Plasma cells description
Abundant basophilic cytoplasm and round, eccentrically located nuclei, with “clock-face” or “spoke-wheel” chromatin without nucleoli; paranuclear clear area (golgi zone), deeply blue cytoplasm
Inclusion bodies in plasma cells
- Russell bodies (cherry-red refractive round bodies)
- Multiple pale bluish-white, grape-like accumulations (Mott-cells or Morula cells)
- Crystalline rods
- Glycogen-rich IgA (flame cells)
These abnormal cells are characteristic of plasmablastic myeloma, a poor prognostic type of myeloma with a high number of mitotic figures
TRUE OR FALSE
Myeloma cells are clonal by definition and produce both κ or λ light chains, which are present in the membrane surface but not on the cytoplasm
FALSE
Myeloma cells are clonal by definition and produce either κ or λ light chains, which are present in the cytoplasm but not on the membrane surface.
A κ:λ ratio greater than 4:1 (2:1 is normal) or less than 1:2 is considered an index of κ or λ monoclonality, distinguishing this condition from reactive plasmacytosis
Immunophenotype of myeloma cells
CD138+, CD45−, CD38+, and CD19−, and are CD56+
A few cases are CD20+ or CD117+ (KIT), but responses to treatment with rituximab or imatinib mesylate are uncommon.
If amyloid deposition is suspected, ___________staining can be performed on the marrow biopsy, showing diffuse involvement or focal perivascular niche localization of amyloid protein.
Congo red
Microvessel density can be assessed by staining for endothelial markers such as
CD131 and CD34
Corresponds to the percentage of plasma cells in the S phase of the cell cycle and has traditionally been measured by assessing the uptake of DNA precursors (tritiated thymidine or 5-bromo-2′-deoxyuridine [broxuridine]) during short in vitro culture periods.
Plasma cell labeling index
Renal failure (creatine >2.0 mg/dL or an estimated glomerular filtration rate <40 mL/min) occurs in ___________ of myeloma patients at diagnosis
30% to 50%
End-stage renal disease requiring hemodialysis can occur in up to 10% of patients.
Renal insufficiency is related to 2 major causes:
- Myeloma cast nephropathy (also called light-chain cast nephropathy or myeloma kidney)
- Hypercalcemia
TRUE OR FALSE
The urine dipstick can detect Bence Jones proteinuria, and it is a technique that should be used to assess the presence of a urinary M spike.
FALSE
The urine dipstick does not detect Bence Jones proteinuria, and it is therefore not a technique that should be used to assess the presence of a urinary M spike.
