106 Myeloma Flashcards
(166 cards)
1
Q
Represents the second most common hematologic cancer
A
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.
2
Q
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
A
1% per year
3
Q
Lifestyle and occupational factors associated with myeloma
A
- 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)
4
Q
Mutations more frequent in myeloma
A
- Chromosome 13 deletions
- RAS mutations
- Non–Ig locus–associated MYC translocations
5
Q
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.
A
Intramedullary phase
6
Q
Most common genomic aberrations in MGUS
A
Cyclin D dysregulation (60%)
Hyperdiploidy (50%)
7
Q
Most common genomic aberrations in Myeloma
A
Cyclin D dysregulation (80%)
8
Q
Most common genomic aberrations in Plasma Cell leukemia
A
- Del(13q)/monosomy13 (60%)
- Chr 1g21 amplification (60-80%)
PTEN losses, methylations of p14 promoter, and RB1 inactivations
9
Q
Mutations that are present at similar rates in MGUS and myeloma.
A
- Hyperdiploidy
- IGH translocations (t(11;14), t(4;14) and MAF translocations)
These abnormalities are not considered driver events in myeloma.
10
Q
Postulated as driver myeloma events
A
- MYC secondary rearrangements
- deletion 13p
- Chromosome 1 abnormalities
- RAS mutations
11
Q
Traditionally, myeloma patients have been divided into 2 subgroups:
A
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
12
Q
Characteristics of hyperdiploid patients
A
- 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
13
Q
Employed to detect five major primary IGH translocations in myeloma, which occur more frequently in nonhyperdiploid patients (85% vs <30%).
A
Fluorescence in situ hybridization (FISH) analysis
14
Q
Most frequent translocation (20% of cases)
A
t(11;14)(q13;q32)
Leading to upregulation of cyclin D1
15
Q
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
A
CD-1 subgroup
16
Q
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)
A
CD-2 subgroup
17
Q
MAF translocations include:
A
- 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
18
Q
The prevalence of these three primary IGH rearrangements is similar in MGUS, indicating the need for additional transforming events to precipitate active myeloma.
A
- t(6;14)
- t(11;14)
- t(14;16)
19
Q
Copy Number Alterations in Myeloma
Genomic aberrations associated with poor prognosis in myeloma patients
A
- Deletion of chromosome 13
- Deletion of chromosome 17p13
- Amplification of chromosome 1q21
20
Q
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.
A
chromosome 13
21
Q
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).
A
chromosome 17p involving the TP53 locus
22
Q
Amplification of________ is detected by FISH in approximately 40% of newly diagnosed myeloma and in 70% of relapsed myeloma, and negatively affects OS
A
Amplification of 1q21
23
Q
Translocation described with the TP53 genomic locus, causing simultaneous gain of 1q21 and deletion of 17p.
A
Jumping translocation of 1q12 (JT1q12)
24
Q
5 of the 11 genes commonly mutated in myeloma
A
KRAS, NRAS, FAM46C, DIS3, and TP53
25
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
## Footnote
*Increased soluble CD138 levels correlate with tumor burden and poor outcomes.*
26
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
27
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)
28
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)
## Footnote
**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
29
# 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.
30
# 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**.
31
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
32
An inhibitor of osteoblast activity
Dickkopf-1 (DKK1)
33
“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
34
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)
35
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)
36
Most common symptom and laboratory feature
Symptom: Anemia (73%) Bone pain (58%)
Lab: Monoclonal Ig peak on immunofixation of serum or urine (97%)
37
Myelomatous involvement of the marrow typically causes **anemia**, which is present in more than ____________ of patients
Two-thirds
38
In contrast to other lymphoproliferative disorders, **thrombocytopenia is uncommon** at diagnosis, even with extensive marrow infiltration, possibly because _________ has thrombopoietic activity
IL-6
39
# 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.
## Footnote
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.
40
**Overt bleeding** is a relatively uncommon presenting symptom for myeloma patients; however, it occurs more commonly with ___________
IgA paraproteins
41
**Easy bruising** is more common in _______________ (15–41% of patients at diagnosis)
Systemic AL amyloidosis
42
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
43
The **VTE prophylaxis** of choice for patients who are at **low risk** for VTE
Aspirin
44
The M protein presents as a single narrow peak, migrating in the___________region of the densitometer tracing.
γ, or, less often, β
45
Test that identifies the unique and specific Ig idiotypes.
Immunofixation analysis
46
Most common M protein
**IgG 60%**
IgA 20%
Ig light chains alone 20%
IgD, IgM, and biclonal 5%
47
A **low M-spike** concentration is particularly suggestive of _____myeloma isotype
IgD myeloma isotype
48
**Light-chain myeloma** patients should be followed by _____________________
These patients present more often with **renal failure** or increased creatinine levels.
UPEP and urine immunofixation
49
**Light-chain proteinuria** is frequent, especially in _______ myeloma
IgD myeloma
50
# 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
51
The κ light chain isotype is twice as common as the λ isotype, except in _____ myeloma.
IgD myeloma
## Footnote
IgD was strongly associated with **elevated serum β2-microglobulin (β2M) and lactate dehydrogenase (LDH) levels,** reflecting high tumor burden.
52
A technique used to detect monoclonal **FLCs** and provides an FLC κ:λ ratio
FLC assay (FREELITE assay)
53
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)
54
Half-life of FLCs
2–4 hours
## Footnote
Ig : **17–21 days**
55
# 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**.
56
# 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).
## Footnote
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.
57
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
58
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)
## Footnote
These abnormal cells are characteristic of **plasmablastic myeloma**, a poor prognostic type of myeloma with a high number of mitotic figures
59
# 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.
## Footnote
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
60
Immunophenotype of myeloma cells
CD138+, CD45−, CD38+, and CD19−, and are CD56+
## Footnote
A few cases are **CD20+ or CD117+ (KIT),** but responses to treatment with rituximab or imatinib mesylate are uncommon.
61
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
62
**Microvessel density** can be assessed by staining for endothelial markers such as
CD131 and CD34
63
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
64
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%
## Footnote
**End-stage renal disease** requiring hemodialysis can occur in up to **10%** of patients.
65
Renal insufficiency is related to 2 major causes:
* Myeloma cast nephropathy (also called light-chain cast nephropathy or myeloma kidney)
* Hypercalcemia
66
# 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.
67
# TRUE OR FALSE
Lambda light chains tend to be more nephrotoxic than the κ type, and renal impairment can be present with modest λ light chain secretion.
TRUE
**Lambda** light chains tend to be **more nephrotoxic** than the κ type, and renal impairment can be present with modest λ light chain secretion.
68
Management of hypercalcemia
* Loop diuretic to promote calciuresis
* Calcitonin
* Slow infusion of a single dose of a bisphosphonate or denosumab
## Footnote
Cytoreductive chemotherapy should be started as soon as possible.
69
A complex syndrome related to **deposition in target organs**, such as heart or kidney, of amyloidogeneic **Ig light chains** organized in fibrillary structures.
AL amyloidosis
70
**AL amyloidosis with renal dysfunction** is more common in patients with λ light chains, especially those with the __________subgroup.
λ VI light-chain subgroup
## Footnote
Occasionally, tubular amyloid deposits can be found and result in **type 1 (distal) renal tubular acidosis** or **nephrogenic diabetes insipidus**
71
A safer alternative for **bone-protective therapy** in patients with **advanced renal disease**, as it is not renally excreted
Denosumab
72
# TRUE OR FALSE
Renal dysfunction is a negative prognostic factor, and it results in use of suboptimal therapies, longer hospitalization, and an increased risk of infection.
TRUE
Renal dysfunction is a **negative prognostic factor**, and it results in use of suboptimal therapies, longer hospitalization, and an increased risk of infection.
## Footnote
Hence, patients who recover normal kidney function have a better outcome compared to those who do not.
The consensus recommendation is to ***pursue a renal biopsy*** to perform direct microscopy, Congo red staining, immunofluorescence, and electron microscopy studies, in patients with a plasma cell disorder
73
Leading cause of morbidity and mortality in myeloma
Infections
74
Responsible for a myeloma patient’s susceptibility to encapsulated organisms, such as Streptococcus pneumoniae and Haemophilus influenza
Hypogammaglobulinemia
75
The invariant chain of the major histocompatibility class 1 molecule, which is shed by myeloma cells
Levels correlate with **tumor burden** and are important for patient **staging** using the International Staging System (ISS)
β2M
76
**Polyneuropathy**, typically **demyelinating**, is a mandatory diagnostic criteria together with presence of a plasma cell disorder, generally **λ-restricted**
POEMS syndrome or osteosclerotic myeloma
77
Incidence of hyperviscosity syndrome
Myeloma: less than 10%
Waldenstrom macroglobulinemia: 30%
78
Have the highest risk of developing hyperviscosity
IgM myeloma
## Footnote
Followed by IgA and IgG3 myeloma
79
**Plasma cell leukemia** is diagnosed when circulating plasma cells comprise more than _______% of white cells in the blood or exceed an absolute level of ______ x 109/L.
20% of white cells in the blood
Absolute level of 2x 109/L
## Footnote
Plasma cell leukemia is categorized as **primary** when occurring de novo as the initial manifestation of plasma cell disorder or **secondary** when complicating the terminal stages of advance myeloma, when tumor cells have become independent of the marrow microenvironment for their growth and EMD occurs.
80
The presence of a clonal plasmacytic infiltrate outside the marrow
Extramedullary Disease (EMD)
## Footnote
EMD only if the infiltrate is present at anatomic sites **distant from the bone or adjacent soft tissue**, hence excluding cases where soft-tissue masses arise in contiguity with the marrow.
81
Characteristics of EMD cells
* CD56− or CD56low
* Present t(4;14) and del(17p) more commonly
* TP53 mutations, TP53 nuclear localization, or high expression levels of focal adhesion kinase
## Footnote
It has been speculated that ***high-dose melphalan and possibly the monoclonal antibody daratumumab targeting CD38, may increase the incidence of EMD*** as a result of longer survival, selection of dormant, more immature myeloma cells, and poor penetration of the drugs to sanctuary sites like the central nervous system.
82
# TRUE OR FALSE: Spinal cord compression
The use of chemotherapy concomitantly with radiotherapy is discouraged, as it may result in profound cytopenia
TRUE
The use of chemotherapy concomitantly with radiotherapy is **discouraged**, as it may result in profound cytopenia
## Footnote
**Spinal cord compression** is a medical emergency, and patients should be empirically started on **steroids** while receiving evaluation with spinal **MRI**
83
Treatment options for spinal cord compression
Local radiotherapy and/or decompressive surgery
* **Local radiotherapy using less than 30 Gy over the course of 5–6 weeks** is potentially curative in the presence of a **solitary plasmacytoma**
* **Higher intensity radiotherapy protocol over the course of 5 fractions** together with **pulse steroids bortezomib** may be used in patients with **single site of EMD complicating myeloma**
84
Treatment of choice if a singular vertebral collapse is evident without a plasmacytoma
Decompressive laminectomy
85
Diagnostic procedure In patients with suspected signs/symptoms of **AL amyloidosis** such as heart failure, nephrotic syndrome, periorbital purpura or macroglossia
Fat pad aspirate or fat punch biopsy
## Footnote
If negative despite high clinical suspicion for AL amyloidosis, **biopsy of target organ** should be pursued.
86
Emerging as a powerful technique to investigate **posttransplantation modification** and **detect minimal levels of paraprotein that can be missed by FLC assays and SPEP**.
Mass spectrometry
87
*In patients with a negative skeletal survey*, _____________ should be pursued to exclude radiographically **occult bone disease**, particularly in patients with a provisional diagnosis of smoldering myeloma, and to assess **EMD in patients with overt myeloma**.
MRI and PET-CT
88
Old staging system that relates myeloma cell mass to the extent of bony disease, hemoglobin, and calcium levels, as well as the monoclonal Ig levels in serum and urine
Durie-Salmon staging system
## Footnote
However, measurement of bone disease by skeletal survey in myeloma is observer dependent and potentially subjective.
89
The ISS is based on two widely available parameters
serum β2M and albumin
90
Stages of Myeloma based on ISS
* Stage I: β2M <3.5 ALB ≥3.5
* Stage II: ALB <3.5 OR β2M 3.5–5.5
* Stage III:β2M >5.5
## Footnote
The **revised ISS (R-ISS)** includes the **cytogenetics** and other markers of tumor burden, such as **LDH**
91
Correlates with **tumor mass** and impairment in **renal function**
β2M
92
Reflects the **effect of IL-6** produced by the microenvironment of myeloma cells on the liver
Low albumin
93
A complete skeletal survey includes:
Posteroanterior view of the chest; anteroposterior and lateral views of the cervical spine, thoracic spine, lumbar spine, humeri, femora, and skull; as well as an anteroposterior view of the pelvis
## Footnote
* A limitation of plain radiographs is that they **cannot be used to assess response to therapy**, as lytic lesions seldom show evidence of healing.
* Skeletal survey can still be used for the initial evaluation of myeloma when whole-body CT and other novel imaging modalities are not available.
94
Roentgenographically detectable osteolytic lesions require at least ________% loss of bone mass and hence represent advanced bone destruction.
50% to 70%
95
Has been shown to provide statistically significant **superior sensitivity** compared with radiography for the detection of osteolytic lesions in patients with myeloma
Whole-body CT, either alone or in combination with PET
96
The first-choice imaging technique to identify and to assess the extent of osteolytic lesions.
Whole-body CT
97
Widely used in both newly diagnosed and relapsed myeloma and in the event of suspected **cord compression**
MRI
## Footnote
Has the ability to **discriminate myeloma from normal marrow**.
MRI allows **visualization of the medullary cavity** and thus direct assessment of the extent of myeloma cell infiltration of the bone
98
# TRUE OR FALSE
Every newly diagnosed myeloma patient should be assessed for fitness to undergo autologous HSCT (auto-HSCT).
TRUE
Every newly diagnosed myeloma patient should be assessed for fitness to undergo autologous HSCT (auto-HSCT).
99
Refers to a planned second course of high-dose chemotherapy followed by HSCT within 6 months of the first.
Tandem Stem Cell Transplantations
100
Effective combination therapy for newly diagnosed patients and is particularly useful in the setting of **renal dysfunction**.
CyBorD
101
A study that compared the addition of **daratumumab** (Darzalex), an anti-CD38 monoclonal antibody, to bortezomib, thalidomide, and dexamethasone (D-VTd) versus bortezomib, thalidomide, and dexamethasone (VTd) alone
CASSIOPEIA study
102
# TRUE OR FALSE
For newly diagnosed transplantation-eligible patients, combinations that include alkylating agents should be avoided as damage to normal hematopoietic stem cells can be incurred, which may render it impossible to collect stem cells for auto-HSCT.
TRUE
For newly diagnosed transplantation-eligible patients, combinations that include **alkylating agents should be avoided** as damage to normal hematopoietic stem cells can be incurred, which may render it impossible to collect stem cells for auto-HSCT.
## Footnote
* **Lenalidomide** may also hamper the collection of stem cells
* The number of cycles of treatment, especially with lenalidomide-containing regimens, is usually limited to **4 cycles** before stem cell collection, as additional cycles may compromise stem cell harvesting.
103
The traditional age limit for auto-HSCT has been ____ years,
65 years
104
# TRUE OR FALSE
Chronologic rather than physiologic age is more suitable for determining transplantation eligibility
FALSE
**Physiologic rather than chronologic age** is more suitable for determining transplantation eligibility
105
A significant concern with maintenance therapy with__________ is the risk of secondary malignancy
Lenalidomide
## Footnote
* Both hematologic malignancies, such as acute myelogenous leukemia, and solid tumors
* Risk is greatest when lenalidomide is given in combination with oral melphalan
106
Options for maintenance therapy
* Lenalidomide
* Bortezomib
* Ixazomib (Ninlaro)
107
Study that evaluated **ixazomib** (Ninlaro) as a maintenance therapy following auto-HSCT
TOURMALINE-MM3 study
108
Two phase II studies, that demonstrated activity of **bortezomib** in patients with relapsed or refractory myeloma.
SUMMIT and CREST
109
Study which compared **bortezomib** with dexamethasone alone, found a median OS of 30 months in the bortezomib group versus 24 months in the dexamethasone group.
APEX study
110
PI granted accelerated FDA approval as a single agent for the treatment of patients who have received at least two prior lines of therapy
Carfilzomib
111
If the relapse occurs more than ________ months after the discontinuation of the initial therapy, patients *may be treated with the same primary therapy.*
6 months
112
IMiDs that are FDA approved for the treatment of relapsed or refractory myeloma
Thalidomide, lenalidomide, and pomalidomide
113
Side effects of **Thalidomide**
Sedation, peripheral neuropathy, and severe constipation
114
The most common side effects with **Pomalidomide**
Myelosuppression and infections
115
A phase 3 study comparing **pomalidomide**, bortezomib, and dexamethasone with bortezomib and dexamethasone in patients with prior lenalidomide exposure.
OPTIMISMM trial
116
An IMID and a potent cereblon E3 ligase modulator with immunomodulating and proapoptotic activity
Iberdomide (CC-220)
117
# Histone Deacetylase Inhibitors
A phase III, randomized trial, showed that the combination of **vorinostat (Zolinza) and bortezomib** was active and well tolerated.
Vantage 088 trial
118
Common side effect of histone deacetylase inhibitors
Myelosuppression and diarrhea
119
A monoclonal **anti-CD38 antibody**, was granted Fast Track Designation and Breakthrough Therapy Designation by the FDA based on results of a phase I/II trial that demonstrated single-agent activity in relapsed, refractory myeloma.
Daratumumab
## Footnote
Another anti-CD38: **Isatuximab**
120
The **bortezomib, dexamethasone, with or without daratumumab trial**, favored the use of the triplet combination compared to bortezomib and dexamethasone alone.
Castor trial
121
A study that compared lenalidomide and dexamethasone alone with lenalidomide, dexamethasone, and **daratumumab**.
POLLUX study
122
A phase III randomized study, which compared **Isatuxumab** + Pd with pomalidomide and dexamethasone (Pd) for relapsed disease.
ICARUS
123
A humanized monoclonal IgG1 antibody directed against human **CS1** (also known as CD2 subset 1, SLAMF7, CRACC, and CD319), a cell-surface antigen glycoprotein that is highly expressed on myeloma cells and normal plasma cells, also has been approved by the FDA for the treatment of relapsed disease.
Elotuzumab (Empliciti)
124
A a selective inhibitor of nuclear export
Gained FDA approval in 2019 in combination with dexamethasone to treat patients with **relapsed or refractory myeloma who have received at least four prior therapies**, and whose disease is *refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody*
Selinexor (Xpovio)
125
# Antibody-Drug Conjugates
An afucosylated humanized IgG1 that binds specifically to BCMA and is conjugated to the microtubuledisrupting agent monomethyl auristatin-F (MMAF)
Belantamab mafodotin (GSK2857916)
126
The most notable toxicity of Belantamab mafodotin
Keratopathy
127
A selective oral inhibitor of B-cell lymphoma-2 (BCL-2)
Venetoclax
## Footnote
Approximately, 20% of myeloma patients will exhibit t(11;14) associated with high BCL-2 expression
128
Adverse prognostic factors for allogeneic transplantation:
* Transplantation more than 1 year after diagnosis
* Serum β2M higher than 2.5 mg/dL at time of transplantation
* Female patients transplanted from male donors
* Having received more than eight cycles of chemotherapy
* Salmon-Durie stage III disease at presentation
129
Bisphosphonates
Pamidronate (Aredia) and zoledronic acid
## Footnote
**Zoledronic acid**, which is **more potent** than pamidronate, is superior to pamidronate for the treatment of hypercalcemia.
**Bisphosphonates may have a direct antitumor effect.**
130
RANKL inhibitors
Denosumab
131
The IMWG and the National Comprehensive Cancer Network (NCCN) panels advocate the use of either a bisphosphonate or denosumab______________ for patients with myeloma and lytic bone disease
Monthly
132
Doses of:
Pamidronate:
Zoledronic acid:
Denosumab:
* Pamidronate: 90 mg delivered IV for at least 4 hours every 3–4 weeks
* Zoledronic acid: 4 mg IV for 15 minutes every 3–4 weeks
* Denosumab: 120 mg SQ every 4 weeks
133
A key concern with bisphosphonates, especially zoledronic acid, is the risk of ________________
Osteonecrosis of the jaw (ONJ)
134
**Percutaneous procedures** for treating **compression fracture**s and also have been used in the setting of myeloma
**Vertebroplasty** (injection of methyl methacrylate or bone cement)
**Kyphoplasty** (use of an inflatable balloon followed by instillation of bone cement)
135
The primary indication for the use of radiation therapy
Palliation of bone pain
## Footnote
Other indications include impending fracture, cord compression, or relief of symptoms associated with a mass (ie, cranial nerve palsies, cosmesis, or organ or joint dysfunction).
Doses of **20 Gy**, delivered in either 5 or 10 fractions, typically provide adequate symptom relief.
136
The incidence of VTE is highest during
First 4 months following diagnosis
## Footnote
Occurs in approximately **3-4%** of patients receiving either **dexamethasone alone or MP**, but is much higher when newer agents are combined with dexamethasone and melphalan.
137
# TRUE OR FALSE
Most VTEs occur within the first 60 days of therapy, coinciding with maximum cytoreduction.
TRUE
Most VTEs occur within the **first 60 days of therapy**, coinciding with maximum cytoreduction.
138
Three risk factors for **lenalidomide-associated VTE**
* Higher dexamethasone doses
* Administration of erythropoietin (Epogen, Procrit), and
* Concomitant administration of other agents
139
Prevention of VTE is based on the assessment for known risk factors for VTE:
* (a) **myeloma-related** (hyperviscosity, newly diagnosed status)
* (b) **therapy-related** (high-dose dexamethasone [≥480 mg/month], doxorubicin, multiagent chemotherapy)
* (c) **individual factors** (age, history of VTE, inherited thrombophilia, obesity, immobilization, central venous line, infections, surgery, administration of erythropoietin)
* (d) **factors related to comorbidities** (acute infection, diabetes mellitus, cardiac or renal dysfunction)
140
# TRUE OR FALSE
Therapy-related risk factors weigh heaviest in the determination of risk for VTE.
TRUE
**Therapy-related risk factors** weigh heaviest in the determination of risk for VTE.
141
The following thromboprophylaxis is recommended:
(a) **acetylsalicylic acid (aspirin)** in either a standard dose of 325 mg/day or in a low dose of 81 mg/day for patients with *one or no risk factor* or
(b) **low-molecular-weight heparin (LMWH) once a day**, or **full-dose warfarin** for patients if *two or more risk factors or therapy-related risks are present*
142
The recommended duration of **prophylaxis**
6–12 months
143
A ______% dose reduction should be made for bortezomib-induced grade 2 neuropathy while grade 3 or 4 requires _______________
50% dose reduction
drug discontinuation
144
Preferred route of administration of Bortezomib
SQ
145
Symptomatic treatment for thalidomide-induced and bortezomib-induced neuropathy
Gabapentin (Neurontin), pregabalin (Lyrica), or tricyclic antidepressants
146
A severe “bone” disease, associated with **bisphosphonate therapy** that affects the **jaws** and typically presents as infection with necrotic bone in the **mandible or maxilla**
Presence of exposed bone in the maxillofacial region that **does not heal within 8 weeks**.
Osteonecrosis of the Jaw
## Footnote
To prevent ONJ, **patients should be referred for dental evaluation** prior to commencing intravenous bisphosphonates and should be advised to maintain excellent oral hygiene and avoid dental procedures while receiving these agents.
147
Management of ONJ
Management is usually conservative:
* Discontinuation of bisphosphonates
* Limited debridement
* Antibiotic therapy
* Topical mouth rinses
## Footnote
Surgical resection of necrotic bone should be reserved for refractory cases.
148
# TRUE OR FALSE
Stable disease is no longer used as a measure of treatment efficacy, but rather time to progression, which is measured from the start of therapy and, importantly, includes all patients entered into clinical studies.
TRUE
**Stable disease is no longer used as a measure of treatment efficacy**, but rather **time to progression**, which is measured from the start of therapy and, importantly, includes all patients entered into clinical studies.
149
# TRUE OR FALSE
Dynamic changes in skeletal events readily identified by modern imaging techniques such as MRI and PET-CT are included in response assessments.
FALSE
**Dynamic changes in skeletal events** readily identified by modern imaging techniques such as MRI and PET-CT are **excluded** from response assessments.
150
At least _________ **myeloma protein evaluations** should be performed during **induction**.
Monthly
151
*After 2–4 induction cycles and prior to high-dose melphalan-based auto-HSCT*, the disease is **restaged** to include _________________________ of indicator lesions to assess whether intramedullary or EMD has been reduced.
Marrow examination with cytogenetics and MRI and/or PET-CT
152
Disease monitoring should be performed at least every _______ for the first year and at a minimum _______________ thereafter.
every month
every other month
## Footnote
* **Marrow biopsy, including cytogenetic**examinations, should be performed at the *time of progression or change in therapy.*
* **Imaging** should be performed *annually* or in the *presence of new symptoms*
153
The prognosis of myeloma is determined by 3 factors:
* (a) host
* (b) tumor biology and disease burden
* (c) type of therapy applied
154
Features of Immunoglobulin M Myeloma (compared to WM)
* Upon microscopic examination, plasma cells, rather than lymphoplasmacytic cells
* Resistant to purine analogues, which are effective in WM
155
Collections of monoclonal plasma cells originating either in bone or in soft tissue
Plasmacytoma:
* Bone (solitary osseous plasmacytoma [SOP])
* Soft tissue (extramedullary plasmacytoma [EMP])
156
Plasmacytomas comprise less than _____% of plasma cell neoplasms.
10%
## Footnote
The median age at time of diagnosis of either SOP or EMP is approximately **50 years**, nearly 10 years younger than that for myeloma
157
# TRUE OR FALSE
Although patients with SOP and EMP can both progress to myeloma, persons with SOP progress in the majority of cases, in contrast to EMP, where only up to 50% eventually develop myeloma.
TRUE
Although patients with SOP and EMP can both progress to myeloma, persons with **SOP progress in the majority of cases**, in contrast to **EMP, where only up to 50%** eventually develop myeloma.
158
Standard treatment for SOP and EMP
Local therapy
Primarily radiotherapy with surgery
## Footnote
* Patients with *soft-tissue solitary plasmacytomas* can often be cured with appropriate **local radiation (dose of at least 4.5 Gy)**.
* By contrast, this local treatment approach *fails in the majority of patients with SOP.*
159
Clinical features of congestive heart failure, nephrotic syndrome, malabsorption, coagulopathy, rash (oral mucosal rash, “raccoon’s eyes”), or neuropathy
Primary amyloidosis
160
The primary difference between AL amyloidosis and LCDD
The difference in structure of the deposited protein; in AL amyloidosis, it is fibrillar versus granular in LCDD.
LCDD is usually associated with the κ light chain subtype, whereas AL amyloidosis is associated with the λ light chain subtype of myeloma
161
The diagnosis of AL amyloid often can be made by
Fine-needle aspiration of SQ fat or by biopsy of the rectal mucosa
## Footnote
Although biopsy of accessible clinically involved tissue is preferable
162
Staining the tissue with ________may reveal **perivascular amyloid** with its classical **apple-green birefringence** when viewed under polarized light.
Congo red
## Footnote
**Thioflavin T** is also a useful stain, producing intense **yellow-green fluorescence** in AL amyloidosis.
163
LCDD diagnosis require
Immunofluorescence analysis of unfixed tissue
## Footnote
Formalin fixation should be avoided whenever it is suspected.
164
Patients with SM should be followed at close intervals of every _________months
3–6 months
165
Smoldering myeloma patients who may **benefit from therapy** based on IMWG
* Patients who have greater than 60% marrow plasma cells
* κ:λ FLC ratios greater than 100
* Two lesions on MRI or PET-CT imaging
166
The IMWG has proposed the ff **high-risk smoldering myeloma** features:
* Marrow plasmacytosis greater than 20%
* M protein greater than 2 g/L
* κ:λ ratio greater than 2
## Footnote
Study suggests that **lenalidomide** can **delay progression** in high risk smoldering myeloma defined using these criteria.
