multiple myeloma Flashcards
Multiple myeloma definition
disseminated dx arising from malignant transformation of a terminally differentiated B cell
Features of MM
clonally rearranged immunoglobulin and usually secrete a monoclonal immunoglobulin
CRAB features of MM
C- hypercalcemia due to increased osteoclast activity
R- Renal dx
A- Anemia
B- Bone dx
Myeloma defining events
- 60% or more clonal plasma cells in bone marrow
- More than 1 focal lesion on MRI that is at least 5mm or greater in size
- Provided Involved free light chain at least 100mg/L, serum involved/ Uninvolved free light chain ratio should be 100 or greater
2nd most frequent hematological dx
Multiple myeloma
1% of cancers caused by
Multiple myeloma
Multiple myeloma account for these percent of hematological dx
10-13%
Age disease affects
Older people
70yrs median age
Asymptomatic phase in MM
May last for years undetected and can only be detected by MGUS
Asymptomatic or smouldering myeloma
Similar laboratory MM but no organ damage showing clinical features
MGUS
There is a peak of one particular immunoglobulin because that antibody is being clonally produced
Percentage of cases becoming symptomatic
10%
Aetiology of MM
Largely unknown
But myeloma cell has undergone immunoglobulin gene recombination, class switching, somatic hypermutation
Phenotype of malignant plasma cell
HIGH CD-38
HIGH CD138
LOW CD45
Overexpression of adhesion molecules on plasma cell clone, extracellular matrix proteins etc lead to
Secretion of interleukins
Hyperviscosity syndrome
iNCREASED immunoglobulin produced makes blood ver viscous. It produces CNS disturbances
Usually IgA and IgM caused
Severity of hyperviscosity depends on
immunoglobulin being cloned
the higher immunoglobulin size the higher the hyperviscosity
IGG- MONOMER
IGA- DIMER
IGM- PENTAMER..WILL BE WORSE
Why is there reduction in immunity in a person with MM
there is reduced production of normal immunoglobulin
Hallmarks of MM
Bone dx
What happens in bone dx
MM cells adhere to stromal cells induces osteoclast activating factors TNF alpha, IL-6,IL-1,RANK-L,VEGF, MIP alpha,etc
When RANK-L is increased, it promotes bone depletion, by stimylating osteoclast action
Cytogenic changes in MM
13q loss Hyperdiploidy Hypodiploidy loss of chromosome 8,13,14 Deletion at chromosome 17p
Clinal features
Skeletal
Marrow infiltration and marrow faluire
Infection due to decreased immunity
Renal failure usually due to obstruction by proteinaceous casts, hypercalcemia, infection, uric acid, amyloidosis
Symptoms of hyperviscosity
What causes thrombosis in MM
High factor 8
Acquired protein C resistance
Hypofibrinolysis
Immune modulatory drugs
Immune modulatory drugs include
Ledalidomide
Thallidomide
What causes bleeding in MM
Non functional platelets- proteins coat surface of platelets
interference with fibrin polymerization
Thrombocytopenia from bone marrow suppression
How to diagnose MM
FBC- ROULEAUX FORMATION, leucoerythroblastosis Increased ESR Plasma cells greater than 10% in bone marrow Paraprotein in serum Bence jones protein in urine normal IgG and albumin reduced Serum B2 macroglobulin increased C reactive protein increased Skeletal survey Myeloma related organ damage due to CRAB
Investigations in people with suspected MM
Serum and urine assessment for monoclonal protein Serum free light chain Bone marrow aspiration Serum beta 2 macroglobulin ALbumin serum imunoglobulins lactate dehydrogenase Fluorescent in situ hybridization MRI POSITRON EMMISSION TOMOGRAPHY Low dose whole body CT scan
Bad prognosis markers
Age greater than 65 Poor performance status Hb less than 8.5 Hypercalcemia Advanced lytic bone lesions Abnormal renal fxn Serum albumin < 30g/dl B2 macroglobulin> 6mg/l High C reactive protein high serum LDH High paraprotein cytogenetics t(4,14), del(17p), t(14,16) Hypodiploidy
International staging system
Stage 1- beta 2 microglobulin 3.5 and below and albumin 3.5 and greater
Stage 2- B2M less than 3.5 AND ALBUMIN less than 3.5G/DL
or greater than 3.5 and less than 5.5
Stage 3- B2M 5.5 and greater
Supportive treatment
Calcium- hydration, steroids lytic lesions -- bisphosphonates, radiotherapy Radiotherapy for pain and fracture Uric acid allopurinol Renal failure- hydration,steroids
Primary induction transplant therapy
Bortezomib/dexamethasone
Bortezomib/doxorubicin/dexamethasone
Bortezomib,/thallidomide/dexamethasone
Lenalidomide/ dexamethasone
Relapse treated with
Agents not previously used
Bortezomib/cyclophosphamide/dexamethasone
Carfilzomib
Thalidomide
Lenalidomide/cyclophosphamide/dexamethasone
Pamalidomide
Mean survival from diagnosis in MM
4-5 YRS
Differential diagnosis of MM
Monoclonal gammopathy of undetermined significance, no evidence of B cell disorder, M protein less than 30g/l, marrow plasma cells less than 10%
Smouldering multiple myeloma; no organ damage
Plasmacytoma
Amyloidosis
Waldestroms macroglobulinemia- IgM mediated
Heavy chain dx
What is amyloidosis
Disorder of protein folding where normally soluble protein are deposited as beta pleated sheets and deposited in organs leading to organ failure
Amyloid staining
Stains positive with congo red. and demonstrated in rectal, renal biopsies
Types of amyloidosis
AL
AA
Familial amyloid
Classical features of AL
macroglossia carpall tunnel syndrome peripheral neuropathy purpura malabsorption nephrotic syndrome cardiomyopathy
Waldestroms macroglobineamia characterised by
prescence of paraprotein IGM
Provides symptoms of tissue infiltration, hyperviscosity of blood,
Osteolytic lesions rare in
Waldestroms macroglobulineamia
