107 Multiple Myeloma Flashcards
1
Q
A 69M complains of bone pain and easy fatigability. Labs: creatinine 2.5 mg/dl, hemoglobin 8 mg/dl, serum calcium 12 mg/dl, serum M component and bone marrow plasmacytosis. What is the cause of the bone lesions of this patient?
A. Apoptosis of tumor cells
B. Activation of osteoclasts
C. Activation of osteoblast that form new bone
D. Hypercalcemia
A
B. Activation of osteoclasts
2
Q
Monoclonal neoplasm a related to each other by virtue of their development from common progenitors in the late B lymphocytes lineage
A
Plasma cell disorder
3
Q
What composes plasma cell disorders?
A
Multiple myeloma
Waldenstroms macroglobulinemia
Primary amyloidosis
Paraproteinemias/monoclonal gammopathies
4
Q
What are the heavy chain isotypes and light chain isotopes?
A
Heavy chain isotopes: M, G, A, D, E
Light chain isotopes: kappa, lambda
5
Q
What are the 3 structural variation of immuboglobulins?
A
Isotopeas
Allotypes
Idiotypes
6
Q
Distinguish between main classes of antibodies of a given species
A
Isotypes
7
Q
Reflect differences between individuals of the same species of otherwise similar immunoglobulins
A
Allotypes
8
Q
Formed by unique structure of the antigen binding protein portion of the molecule
A
Idiotypes
9
Q
Forms the antigen recognition site of the antibody molecule
A
Variable region
VDJ: heavy chain
VJ: light chain
10
Q
Which antibody molecule is produced in excess and excreted in the kidneys?
A
Light chains
11
Q
Sharp spike in this region during electrophoresis in association with plasma cell disorders and an excellent tumor maker to manage therapy
A
M component
12
Q
Two rare skin disorders associated with monoclonal gammopathy
A
Lichen myxedematosus
Necrobiotic xanthogranuloma
13
Q
Most common serum concentration in the heavy chain class
A
IgG are more common than IgA and IgD myelomas
14
Q
Malignant proliferation of plasma cells derived from a single clone
A
Multiple myeloma
15
Q
What is the error found in multiple myeloma?
A
Errors in switch recombination, genetic mechanism to change antibody heavy chain isotypes in the early transformation process
16
Q
Common mutations in multiple myeloma
A
N Ras
K Ras
B raf
17
Q
Interluekin that play a role in driving myeloma cell proliferation?
A
Interluekin 6 (IL6)
18
Q
Mean age of diagnosis of MM
A
Mean age of diagnosis is 69 years old and uncommon under age 40
19
Q
Most common symptom of myeloma
A
Bone pain
20
Q
What causes the pain in myeloma
A
- Proliferation of tumor cells
- Activation of osteoclasts that destroy bone
- Suppression of osteoblast that form new bone
21
Q
Second common clinical problem in patient with myeloma
A
Susceptibility to bacterial infection
22
Q
Common infections in multiple myeloma
A
Pneumonias
Pyelonephritis
23
Q
Most frequent pathogens in myeloma
A
Strep pneumoniae
Staph aureus
Kleb pneumoniae
24
Q
Most common cause of renal failure in multiple myeloma
A
Hypercalcemia
25
Earliest manifestation of tubular damage in multiple myeloma
Adult fanconi syndrome: type 2 proximal renal tubular acidosis; loss of Glucose and amino acids as well as defects in the ability to acidify and concentrate urine
26
True or false. In multiple myeloma, very little albumin is in the urine because glomerular function is usually normal
True
27
Multiple myeloma is result with what type of anion gap and why?
Patients with multiple myeloma have decreased an anion gap because M component is cationic, resulting in retention of Chloride
28
Why type of electrolyte imbalance accompany multiple myeloma?
Pseudo Hyponatremia because each volume of serum has less water as a result of increased protein
29
True or false. Light chain cast nephropathy and amyloidosis is partially reversible with effective therapy
True
30
True or false. Patients with multiple myeloma are susceptible to developing AKI when dehydrated
True
31
Type of anemia in multiple myeloma. What's is the cause of this anemia?
Normocytic normochromic anemia
| Due to replacement of normal marrow by expanding tumor cells
32
Pathophysiology of Clotting abnormalities in multiple myeloma
Failure of the antibody-coated platelets to function properly
33
What Clotting factors are affected in multiple myeloma?
```
Clotting factors I, II, V, VII, or VII
2,3
2+3=5
5+2=7
5+3=8
```
34
Normal relative serum viscosity
1.8
35
What is hyperviscosity?
Relative viscosity of serum as compared to water
36
When does symptoms of hyperviscosity occur?
4.0 centipoise (cP)
37
When is hyperviscosity reached in patients with multiple myeloma?
IgM: 40 g/dl or 4 g/L
IgG3: 50 g/dl
IgA: 70 g/dl
38
What type of neuropathy is associated with multiple myeloma?
More sensory than motor and is associated with IgM
| IgM targets myelin-associated Globulin
39
Defines the diagnosis of multiple myeloma
Marrow plasma cytosis of more than 10%
Serum/urine M protein
*least one of the myeloma defining events
40
What is the character of bone marrow plasma cell in multiple myeloma?
CD138+ and either
| Kappa and lambda light chain positive
41
Important differential diagnosis of patients with multiple myeloma
MGUS
| smoldering multiple myeloma (SMM)
42
True or false. All cases of MGUS transform to multiple myeloma
False. Only 1% transform to multiple myeloma
43
True or false. All multiple myeloma preceded by MGUS
True
44
Associated with higher incidence of progression of MGUS to multiple myeloma
Non IgG subtype
Abnormal kappa/lambda ratio
Serum M protein more than. 15 g/dl (1.5 g/L)
45
Associated with higher incidence of progression of MGUS to multiple myeloma
Non IgG subtype
Abnormal kappa/lambda ratio
Serum M protein more than. 15 g/dl (1.5 g/L)
46
Features responsible for higher incidence of progression from SMM to MM
Bone marrow plasmacytosis more than 10%
Abnormal kappa/lambda free light chain rario
Serum M protein more than 30 g/L (3.0 g/dl)
47
Two important variants of multiple myeloma
Solitary bone plasmacytoma
| Solitary extramedullary plasmacytoma
48
Single lytic bone lesion without marrow plasmacytosis
Solitary bone plasmacytoma
49
Variant of multiple myeloma that involve submucosal lymphoid tissue of the nasopharybx or Paranasal sinuses without marrow plasmacytosis
Extramedullary plasmacytoma
50
True or false. Both solitary bone plasmacytoma and extramedullary plasmacytoma are highly responsive to local radiation therapy
True
51
True or false. Extramedullary plasmacytoma recur often and progresses to multiple myeloma
False
Extramedullary plasmacytoma: rarely recurs and rarely progress to multiple myeloma
Solitary bone plasmacytoma: recurs often and may evolve to multiple myeloma
52
What is usual level of serum alkaline phosohatase and why?
Serum alkaline phosohatase is usually normal even with extensive bone involvement because of the absence of osteoblastic activity
53
```
Myeloma that may present with light chain disease
A. IgM
B. IgG
C. IgD
E. IgA
```
IgD
54
Why will some patients with multiple myeloma had negative Bence Jones protein
Renal cataboismbwikk make light chains undetectable in urine
55
What type of light chain is more likely to cause renal damage
Kappa light chain
56
Multiple myeloma paraprotein associated with hyperviscosity
IgM
57
Subclass of multiple myeloma that has the highest tendency to form both concentration and temperatures dependent aggregates leading to hyperviscosity and cold agglutination at lower serum concentrations
IgG3
58
Recommended to distinguish between smoldering and acrivibe MM and to confirm suspected diagnosis of solitary plasmacytoma
F Fluorodeoxyglucose PET/CT
59
Single most powerful predictor of survival and can substitute for staging
Serum B2 microglobulin
60
Forms the basis for the three-stage International Staging System (ISS) that predicts survival
Serum B2 microglobulib and albumin levels
61
ISS. B2M less than 3.5. Alb more than 3.5
Stage I. Survival 62 months
62
ISS. B2M less than 3.5. Albumin less than 3.5 or B2M =3.6-5.5
Stage II. 44 months
63
ISS. B2M more than 5.5
Stage III. 29 months
64
Other features suggesting high risk disease
De novo plasma cell leukemia
Extramedullary disease
Elevated LDH
High risk gene expression profile
65
Median number of mutations per transcribed genome in myeloma
Around 58
66
Most frequently mutated gene in multiple myeloma
```
KRAS and NRAS
TP53
DIS3
FAM46C
BRAF
```
67
How frequent is the follow up in patients with MGUS
Low risk: Once a year
| High risk: every 6 months
68
May prevent progression from high risk SMM to active MM.
Early intervention with lenalidomide and dexamethasone
69
Solitary bone plasmacytoma and extramedullary plasmacytomas may be expected to enjoy prolonged disease free survival after what therapy?
Local radiation therapy at a dose of around 40 Gy
70
Purpose of therapy in multiple myeloma
1. Systemic to control myeloma
| 2. Supportive to control symptoms
71
What are the phases of therapy in multiple myeloma
1. Induction
2. Consolidation/maintenance
3. Relapse
72
Therapy that achieves response in two-thirds of newly diagnosed MM patients
Thalidomide + dexamethasone
73
Combination which achieved high response rate of 80% in patient with multiple myeloma and a 30% complete remission
Lenalidomide + bortezumib + dexamethasone
74
Other 3 drug combination therapy for multiple myeloma
Bortezumib + thalidomide + dexamethasone
| Bortezumib+ cyclosphosphamide + dexamethasone
75
Indicated if bortezumub is used
Herpes zoster prophylaxis
76
Lenalidomide requires additional prophylaxis for what?
Lenalidomide required DVT prophylaxis with aspirin
| If at greatest risk for DVT, warfarin or LMWH
77
Therapy given to all stages of multiple myeloma
Steroid: dexamethasone or prednisone
78
Therapy for newly diagnosed MM
Immunomodulatory: thalidomide
Proteasime inhibitor: bortezomib
Alkylating agents: melphalan, cyclophosphamide
79
Standard therapeutic agents in myeloma
6
1. Immunomodulatory: thalidomide, lenalidomide
2. Proteasome inhibitors: bortezomib, carfilzomib, ixazomib
3. Antibodies: daratumumab, elotuzumab
4. Histone deacetylase inhibitor: panobinostat
5. Alkylating agents: melphalan, cyclosphosphamide, bendamustine
6. Steroids: dexamethasone, prednisone
80
Only histone deacetylase inhibitor for MM
Panobinostat
81
Standard therapeutic agents given only on relapse
Antibodies
| Histone deacetylase
82
Avoid in patients for autologous transplant
Alkylating agents such as melphalan as it decrease ability to collect stem cells for autologous transplant
83
Who are not transplant eligible?
Age more than 70 years old
| Significant cardiopulmonary problems or comorbid illness
84
Newly diagnosed MM. Transplant eligible.
Induction therapy:
RVD: lenalidomide, bortezumib, dexamethasone
VCD: bortezomib, cyclosphosphamide, dexamethasone
VD: bortezomib, dexamethasone
LD:
85
Newly diagnosed MM. Transplant eligible. Response to induction therapy.
HDT with ASCT
| High dose therapy + autologous stem cell transplant
86
Newly diagnosed MM. Transplant eligible. No response to induction therapy.
```
Alternative regimen:
Daratumumab
Elotuzumab
Panobinostat
Carfilzomib
Ixazomib
Pomalidomide
```
87
Newly diagnosed MM. Transplant ineligible.
Induction therapy
RVD lite: lenalidomide, bortezumib, dexamethasone weekly
VCD: bortezomib, cyclosphosphamide, dexamethasone
VD: bortezomib, dexamethasone
RD: lenalidomide, bortezumib
88
Drug for MM, antibodies that target CD3i
Daratumumab
89
Drug for MM that target SLAMF7
Elotuzumab
90
True or false. Improvement in serum M component lag being the symptomatic improvement due to long half life of about 3 weeks
True
91
May fall during the first week of treament due to short half life
Light chain excretion. Half life is 6 hours
92
Predicts longer survival in MM
Absence of minimal residual disease (MRD) on sequencing or multicolor flow cytometry
93
Mean overall survival of patients with multiple myeloma
8+ years
94
Major cause of death in multiple myeloma
Renal failure
Sespsis
Progressive multiple myeloma
Therapy related myelodysplasia
95
Treatment of hypercalcemia in multiple myeloma
Biphosphonates: reduces osteoclastic bone resoprtion
Glucocorticoids
Hydration
Natriuresis
96
Adverse effect of biphosphonates
Osteonecrosis of jaw and renal dysfunction
97
During acute renal failure in patients with MM, what therapy is 10x more effective in clearing light chains
Plasmapharesis is 10x more effective at clearing light chains than peritoneal dialysis
98
Treatment of choice for hyperviscosity syndromes
Plasmapharesis
99
More protective vaccine against pneumonia in patients with MM
Pneumococcal conjugate may be more protective as MM patients may not elicit antibody response is given pneumococcal polysaccharide
100
Malignancy of lymphoplasmacytoid cells that secrete IgM
Waldenstroms macroglobulinemia
101
Differentiate MM from Waldenstroms macroglobulinemia
Waldenstroms macroglobulinemia: Lymphadenopathy, hepatosplenomegaly and hyperviscosity syndrome, no lytic bone lesion, no hypercalcemia
102
Difference between Waldenstroms macroglobulinemia and IgM myeloma
IgG myeloma: patients with lytic bone lesions and predominant infiltration with CD138+ plasma cells in the bone marrow
103
Somatic mutation seen in Waldenstroms macroglobulinemia
MYD88 L265P
104
Presence of this mutation status used to discriminate WM from marginal zone lymphoma, IgM secreting myeloma and CLL with plasmacytic differentiation
MYD88 mutation
105
Significant mutation in WM. Why?
MYD88: lower bone marrow burden
CXCR4: higher bone marrow birder and higher incidence of hyperviscosity
106
First line treatment for WM
Rituximab: Anti CD20
Alkylators: bendamustine, cyclosphosphamide
Proteasome inhibitors: bortezomib
107
Used for patients with WM and target the BTK (Burton tyrosine kinase)
Irbrutinib
108
Syndrome presenting wiht polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes
POEMS
109
Condition linked to IL 6 overproduction
Castleman disease
110
Defect in heavy chain diseases
Intact Fc fragment and deletion in the Fd region
111
Franklin's disase is frequently associated with what autoimmune disease
Rheumatoid Arthritis
112
What are the heavy chain diseases
Gamma heavy chain disease: Franklins disease
Alpha heavy chain disease: Seligmann's disease
Mu heavy chain disease
113
Most distinctive symptom of Gamma heavy chain disease
Palatal edema due to involment of nodes in the Waldeyers ring
114
Most common of the heavy chain diseases and what is it closely related to
Alpha chain disease or Seligmann's disease
| Closely related to mediterranean lymphoma
115
How is alpha heavy chain disease characterized
Infiltration of lamina propria of the small intestines with lymphoplasmacytoid cells that secrete truncated alpha chains
116
Recognized as infectious pathogen assosciated human lymphoma and what is the pathogen
Immunoproliferative small intestinal disease (IPSID),
| Campyobacter jejuni
117
Characterize mu heavy chain disease
Vacuoles in the malignant lymphocytes and excretion of kappa light chains in the urine
118
What is the defect in Mu heavy chain disease
Defect in the assembly of light and heavy chain
