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For orals By Princess > Multiple myeloma > Flashcards

Multiple myeloma Flashcards

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1
Q

Malignant proliferation of plasma cells

A

Multiple myeloma

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2
Q

Organs dysfunction and symptoms seen in MM

A

Bone pain or fracture
Renal failure
Susceptibility to infection
Anemia
Hypercalcemia
Clotting abnormalities
Neurologic symptoms
Manifestations of hyperviscosity

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3
Q

Participate in early transformation process in MM

A

Genetic mechanism to change antibody heavy chain isotype

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4
Q

What interleukin play a role in driving myeloma cell proliferation

A

Interleukin-6

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5
Q

Characteristic morphologic feature of plasma cells in MM

A

Round or oval cells
Eccentric nucleus composed of coarsely clumped chromatic
Densly basophilic cytoplasm
Perinuclear clear zone containing the Golgi apparatus

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6
Q

Most common symptom in myeloma

A

Bone pain (seen in 70% of patients)
Caused by: proliferation of tumor cells, activation of osteoclasts that destroy bone and suppression of osteoblasts the form new bone

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7
Q
A
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8
Q

Effect of localized bone lesions

A

Collapse of vertebrae–> spinal cord compression

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9
Q

Most common clinical problem in patients with myeloma

A

Susceptibility to bacterial infections

25% will have recurrent infections
>75% will have serious infection at some time in their course

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10
Q

Most common infections seen in MM

A

Pneumonia (Streptococcus pneumonia, S. auereus, K. pneumoniae)

Pyelonephritis (E. coli and other gram negative organisms)

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11
Q

Susceptibility to infection in MM is due to:

A

1 Diffuse hypogammaglobulinemia (if M component is excluded_
2 Greater population of regulatory cells in response to myeloma that can suppress normal antibody synthesis
3 Low Granulocyte lysozyme content and slow granulocyte migration

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12
Q

Pathogenesis of MM

A

MM cells interact with bone marrow stromal cells and extracellular matrix via adhesion molecules–>adhesion medated signaling and cytokine production –> cytokine-mediated signaling–>inhibition of osteoblast and increase in osteoclastic activity–> bone related issues in MM

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13
Q

Bone lesions in MM

A

Typical punched out lesions (skull)
Punched out lesion represent purely osteolytic lesion with little or no osteoblastic activity

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14
Q

Drugs in MM and related side effects

A

Dexamethasone
supress imune system
increase susceptibility to bacterial infection

B cell maturation antigen (BCMA) targetic chimeric antigen receptor cells (CAR-T)induces hypogammaglobulinemia

Bortezomib predisposes to herpresvirus reactivation

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15
Q

Most common cause of renal failure in MM

A

Hypercalcemia

Renal failure occurs in 25% of myeloma patients

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16
Q

What Renal pathology in MM is noted in >50% patinets

A

tubular damage associated with excretion of light chains

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17
Q

Earliest manifestation of tubular damage in MM

A

Fanconi’s syndrome
A type 2 proximal renal tubular acidosis
Noted loss of glucose and amino acd
Defect in the kidney to acidify and concentrate urine
Proteinuria is not accompanied by hypertension
Protein is all light chain with very little albumin
With normal glomerular function

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18
Q

Aside from hypercalcemia what other electrolyte imbalance is seen

A

Pseudohyponatremia
Because each volume of serum has less water as a result of the increased protein

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19
Q

Causes of renal dysfunction in MM

A

Light chain deposition disease
Light chain cast nephropathy
Amyloidosis

Renal dysfunction is partially reversible
Susceptible to acute renal failure if patients are dehydrated

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20
Q

What type of anion gap is seen in MM

A

M component is cationic–> retention of chloride –>
Decreased anion gap

Formula for Anion gap
Na-Cl+Hco3

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21
Q

Type of anemia seen in patients wth MM

A

Normocytic normochromic anemia (80%) due to
Replacement of normal marrow with tumor
Inhibition of hematopoeisis
Reduced production of erythropoietin

Megaloblastic anemia
due to folate or vitamin b12 deficiency

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22
Q

Clotting abnormalities

What clotting factors interact with the M component

A

Factor I, II, V, VII, VIII

Result in failute of antibody coated platelets to function properly

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23
Q

Deep venous thrombosis in MM is associated with the use of

A

Thalidomide
Lenalidomide
Pomalidomide
Combination with dexamethasone

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24
Q

Reynaud’s phenomenon and impared circulation is due to

A

M component forming cryoglobulin

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25
Hyperviscosity syndromes in MM
Depend on the physical properties of the M component (most common with IgM, IgG3 and IgA paraproteins) MM occur when relative serum viscosity is >4 Normal relative serum viscosity 1.8
26
Causes of neurologic symptoms in MM
Hypercalcemia --> lethargy , depression, confusion Hyperviscosity--> headache, somnolensce Bone collapse--> cord compression Infiltration of peripherl nerves by amyloid--> carpal tunnel syndrome
27
Neuropathy associated with monoclonal gammopathy of undertermined significance and myeloma is it motor or sensory
More frequently SENSORY neuropathy (associated with IgM)
28
Sensory neurpathy is a side effect of what therapy
Thalidomide Bortezomib
29
Tumor expansion of MM
Within the bone However there is widespread distribution of plasma cells
30
Diagnosis of MM requires the following
Marrow plasmacytosis >10% Serum and or urine M component At least one of the myeloma defining events
31
Bone marrow plasma cells are Positive for
CD 138+ Monoclonal kappa ligh chain Lambda light chain
32
Most important differential diagnosis of MM
Monoclonal gammopathy of undertemined significance (MGUS) Smoldering multiple myeloma (SMM)
33
True or false All cases of myeloma are preceded by MGUS but only 1% of patients per year with MGUS go on develop myeloma
True
34
Presence of the following are associated with higher incidence of progression of MGUS to myeloma
Non-IgG subtype Abnormal kappa/lambda free light chain ration Serum M protein >15 g/L Absence of 3 features: only 5% chance progression of MGUS to myeloma Presence of all 3 features: 60% chance of progression of MGUS to myeloma
35
Presence of the folowwing are predictive of higher progression from SMM to MM
Bone marrow plasmacytosis >10% Abnormal kappa/lambda free light chain ratio Serum M protein >30 g/L One of 3 features: 25% chance of progression to MM in 5 years 3 of 3 features: 76% chance of progression to MM
36
Two important variants of myeloma Solitary bone plasmacytoma Solitary extramedullary plasmacytoma
Solitary bone plasmacytoma (single lytic bone lession without marrow plasmacytosis; recurs to other sites, evolve into myeloma) Solitary extramedullary plasmacytoma (involve the submucosal nasopharynx or paranasal sinus without marrow plasmacytosis; rarely recur or progress) these lesions are associated with M component in <30% of cases (disappears after treatment) Affect younger individuals Mean survival of >= 10 years responsive to local radiation
37
Diagnostic criteria of Monoclonal Gammopathy of Undetermined Significance (MGUS)
Serum monoclonal protein (non-IgM type )<30 g/L Cloncal bone marrow plasma cells <10% Absence of myelma defining events or amyloidosis
38
Diagnostic criteria for smoldering multiple myeloma (Asymptomatic Myeloma)
Both criteria must be met 1 Serum monoclonal protein (IgG or IgA) >=30 gL or urinary monoclonal protein >=500 mg per 24 h and or clonal bone marrow plasma cells 10-60% 2 Absence of myeloma-defining events or amyloidosis
39
Diagnostic criteria for symptomatic multiple myeloma Clonal bone marrow plasma cells OR biopsy proven bony or extramedullary plasmacytoma AND any one or more following myeloma defining-events
Evidence of end-organ damage attributed to plasma cell proliferative disorder 1 Hypercalcemia >11 mg/dl or >1 mg/l higher than the ULN 2 Crea > 2mg/dl or crea clearance <40 ml/min 3 Hgb<100 g/L 4 Bone lesions: one or more osteolytic lesions on skeletal radiography, CT or petCt Any one or more following biomarkers of malignancy Clonal bone marrow plasma cell percentage >=60%, serum free light chain ratio >=100, >1 focal lesion on MRI
40
Diagnostic criteria for Nonsecretory myeloma
No M protein in serum and or urine with immunofixation Bone marrow clonal plasmacytosis >10% or plasmacytoma Myeloma-related organ tissue impairement
41
Diagnostic criertia for solitary plasmacytoma
Biopsy proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells Normal bone marrow with no evidence of clonal plasma cells Normal skeletal survery Absence of end organ damage attributed to a lymphoplasma cell proliferative disorder
42
Diagnostic criteria for POEMS syndrome
all of the following 4 criteria must be met 1 polyneuropathy 2 Monoclonal plasma cell proliferative disorder 3 any one of the ff a. sclerotic bone lesion, castleman diseas, elevated levels of vascular endothelial growth factor 4 any one of the ff organomegally, extravascular volume overload, endicrubioathy , skin changes
43
44
Serum M component with be:
IgG: 53% patients IgA: 25% IgD: 1% <1% of patients have no identifiable M component IgD myeloma: present with light chain disease IgM paraproteins: develop hyperviscosity IgG3 sublass: highest tendency to form both concentration and temperature dependent aggregates->leading to hyperviscosity and cold agglutination at lower serum concentration
45
what tests are useful for detecting and chracterizing M spikes
Serum protein electrophoresis Masurement of serum immunoglobulins and free light chains Serum immunoelectrophoresis (identifying low concentration of M component)
46
Identifying bence jonce proteins
24 h urine specimen : quantitates Bence Jones proten (immunoglobulin light chain) Heat test: may yield to false negative results
47
Laboratory parameters to be requested in patients with MM
CBC - anemia ESR -elevated elevated serum ca, urea nitrogen creatinine and uric acid Alkaline phosphatase: normal (absence of osteoblastic activity) Chest and bone radiography: lytic lesions or diffuse osteopenia MRI: extent of bone marrow infiltration and root compresions PEt/CT asses bone damage and extramedullary sites of disease F-FDG PET/CT: distinguish smoldering and active MM
48
single most powerful predictor of survival and can substitute for staging
serum beta 2 microglobulin -is the light chain of the class HLA
49
Factors associated for poor prognosis in MM
high labeling index circulating plasma cells Performance status High levels of lactate dehydrogenase Other factors that may influenxe prognosis Hypodiploidy by karyotype, FISH identified chromosome 17p deletion and translocation t(4;14), (14,16) and (t 14;20) and 1q34 amplification
50
Most frequently mutated genes
KRAS NRAS
51
Follow up for MM
follow up once a year except in high risk MGUS High risk MGUS: repeat every 6 months serum protein electrophoresis, CBC, creatinine, Ca
52
TREATMENT for SMM - early intervention with lenalidomide and dexamethasone (prevent progression)
Solitary bone plasmacytomas and extramedullary plasmacytomas -local radiation therapy of 40 Gy
53
Treatment of Symptomatic MM Purpose: 1. Systemic therapy to control myeloma 2. Supportive care to control symptoms of the disease, complications and adverse effects of theraphy
Includes: Initial induction regime ->consolidation AND OR maintenance therapy -> progression, management of relapsed disease
54
Treatment of Symptomatic MM
**Preferred for induction therapy Three important classes of agents appoved 1. immunomodulatory agents (thalidomide, lenalidomide) 2. Proteosome inhibitors (Bortezomib, Carfilozomib) 3. Targeted antibodies (daratumumab (anti-CD38 antibody)
55
Preferred induction regimen in transplant -eligible patients with MM
Combination of Lenalidomide +Bortezomib/ Carfilzomib+Dexamethasone attains 100% response rate, >30% complete response (CR) rate *Usually between 4 and 6 cycles of combination regimens to achieve iitial deep cytoreduction before consideration of high-dose therapy with autologous stem cell transplantation
56
Not transplant candidates Age>70 years Significant cardiopulmonary problems Other comorbid illness
Lenalidomide+ Dexamethasone +Darutumumab Standard of care regimen for older adults with myeloma
57
Standard therapy in majority of eligible patients for autologous stem cell
High dose therapy and consolidation/maintenance Melphalan (alkylating agents): avoided since they damage stem cells and compromise the ability to collect stem cells Lenalidomide (stem cells should be collected within 6 months sinxw continued use of lenalidomide compromises the ability to collect stem cells)
58
Treatment of Relapsed Myeloma 1 Lenalidomide and or bortezoib (if not used previously) 2. Carfilzomib (proteosome inhibitor) and Pomalidomide (immunomodulator) 3. Ixazomib (oral proteosome inhibitor) +lennalidomide+dexamethasone = all oral regiemn for relapsed MM 4. Daratumumab (antibody targeting CD38): improved progression free survival as a single agent 5. Isatuximab (antibody targeting CD38): improved progression free survival in combination with pomalidomide and dexamethasone
6. Elotuzumab (targets SLAMF7): significant activity in combination with lenalidomide and dexamethasone 7. Panobinostat (histone deacetylase inhibitor ): incombination with bortezomib and dexamethasone: treatment of relapsed refractory myeloma 8. Belantamab( anti=BCMA antibody drug conjugate): delivers auristatin to tumar cells ; S/E: opthalmologic toxicity 9. Idecabtagene vicleucel: anti BCMA CAR transduced T-cell : fourth line therapy ; S/E: cytokine release syndrome and neurotoxicity
59
Therapy endpoint in MM
Serum M component half life : 3 weeks Serum and urine light chain half life: 6 hours Urine light chain levels: relate to renal tubular function (not a reliable measure of tumor cell kill)
60
Definition of complete remission in MM
Disappearance of serum and urine monoclonal protein with normal bone marrow by light microscopy (this is the standard goal of therapy)
61
Supportive therapy for Bortezomib 1. Give herpes zoster prophylaxis 2 Neuropathy is decreased if given subcutaneously and on a weekly administration Supportive therapy for Lenalidomide 1. Require DVT prophylaxis (aspirin, warfarin, LMWH, DOAK)
Suportive therapy for anti-BCMA CAR-T cell therapy 1. Supplementation with intravenous y globulin due to induction of prolonged hypogammaglobulinemia
62
Treatment for hypocalcemia 1. Bisphosphonates 2. Glucocorticoid therapy 3. Hydration 4. Natriuresis 5. Calcitonin (rarely)
Bisphosphonates: reduce osteoclastic bone reabsortion Pamidronate 90 mg or Zoledronate 4 mg (once a month x12-24 months) S/E of bisphosphonate: osteonnecrosis of the jaw and renal dysfunction Denosumab 120 mg IV monthly Has similar effect to bisphosphonates Prevent bone-related complications of myeloma
63
Plasmapheresis
1. 10x more effective at clearing light chains than peritoneal dialysis 2. Treatment of choice for hyperviscosity syndrome
64
Pneumococcal vaccines
Pneumococcal POLYSACCARIDE vaccine: not elicit antibody response Pneumococcal CONJUGATE vaccine: more protective
65
66
For cord compression
MRI and local radiation therapy and glucocorticoids
67
Bone lesions: Respond to analgesics and systemic therapy
Painful bone lesions: respond to localized radiation

For orals By Princess (6 decks)

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