3.4 Multiple Myeloma Flashcards
Plasma cell dyscrasias are a spectrum of disorders characterized by the neoplastic proliferation of plasma cells.
- As such these are populations of plasma cells that belong to the same _________________.
Because it is in the nature of plasma cells to produce secrete immunoglobulins, these neoplastic plasma cells also secrete immunoglobulin/ a fragment of immunoglobulin molecule e.g. light chain. As these Igs come from the same clone of plasma cells, they can be identified as a monoclonal protein. Another name of the monoclonal protein is _____________.
About 2-3% of plasma cells dyscrasias are not associated with a paraprotein hence diagnosis of plasma cell dyscrasia cannot rely solely on the presence of a paraprotein.
It is also important to recognize that the presence of paraprotein does not imply plasma cell dyscrasias because many ______________ also secrete a paraprotein.
Plasma cell dyscrasias can be related with injury to tissues or organs. This can be because of direct organ infiltration e.g. plasma cells infiltrating the bones and bone marrow that causes fractures and development of cytopenias respectively. Organ injuries can occur due presence of paraproteins which disrupt function of organs e.g. kidneys due to the deposition of paraproteins in renal tubules.
clone/ monoclonal proliferation;
paraprotein;
B cells lymphomas
What is the progression of Plasma Cell Dyscrasias?
Post Germinal Centre B cell –> Monoclonal Gammopathy of Undetermined significance –> smoldering Multiple Myeloma –> symptomatic multiple myeloma
Diagnostic criteria for Symptomatic Multiple Myeloma (International Myeloma Working Group 2014)
Both criteria must be met:
- _________________ ≥10% or biopsy-proven bony or extramedullary plasmacytoma
- Plasmacytomas are collections of neoplastic collections of monoclonal cells - Any one or more of the following myeloma defining events:
End-organ damage attributed to underlying plasma cell disorder and not to another disorder e.g. diabetes
- (C) Hypercalcemia: ___________________
- (R) Renal insufficiency: _________________
- (A) Anemia: Hb >2 g/dL below the lower limit of normal, or <10 g/dL
- (B) Bone lesions: one or more ___________—- on skeletal Xray, CT
Biomarkers of malignancy that signify a high tumour load
- Clonal bone marrow plasma cell ≥60%
- ________________ ≥100 - (inv FLC≥100 mg/L)
>1 focal lesions on MRI studies (at least 5 mm)
*Presence of paraprotein is not essential for the diagnosis of symptomatic multiple myeloma as long as these 2 criterias listed are met
Clonal bone marrow plasma cells;
serum calcium > 2.75 mmol/L;
serum creatinine >177 umol/L;
osteolytic lesions;
Involved: uninvolved serum free like chain ratio
Diagnostic Criteria for Smoldering Multiple Myeloma (This category does not require treatment) . Both criteria must be met:
- Serum monoclonal protein (IgG or IgA) ≥_______ or urinary monoclonal protein ≥500 mg/24H and/or clonal bone marrow plasma cells ______________
- As opposed to Symptomatic Multiple Myeloma, a measurable paraprotein can form one of the required criteria - Absence of myeloma defining events or __________
30 g/L;
10–60%;
amyloidosis
Diagnostic Criteria for Monoclonal Gammopathy of Undetermined significance
All criteria must be met:
1. Serum monoclonal protein <30 g/L, urinary monoclonal protein _________
2. Clonal bone marrow plasma cells <10%*
3. Absence of myeloma defining events or amyloidosis
Most progress to ____________ at 1%/ year hence the patients can be monitored with yearly consultations
* Bone marrow examination may not be needed in patients with low-risk features (e.g. paraprotein is really low in quantity and it has an _____________, a bone marrow may not be strictly necessary)
500 mg/24 h;
symptomatic myeloma;
IgG isotype
Rarer types of Plasma Cell Dyscrasias
- Plasma cell dyscrasias that secrete paraprotein of other Ab isotypes (IgD, IgE and IgM) (IgG>IgA>light type). IgM paraprotein → more likely lymphoproliferative disorder then a plasma cell dyscrasia as many ______________ secrete IgM.
- Solitary plasmacytomas (collection of ___________, can be diagnosed in bone or soft tissue without the presence of same plasma cells in bone marrow and in the absence of end organ damage). Many of these patients, if the absence of myeloma defining events after an extensive search can be treated by ____________ and close follow up for future development of neo plasmacytomas or multiple myelomas
Amyloidosis : Amyloid protein is a fibrillary protein that can form sheets, that when deposited and accumulated in organs can lead to organ damage. The deposition of amyloid protein in tissues is called amyloidosis.
- One possible cause is from chronic inflammation such as RA, chronic osteomyelitis and the process of chronic inflammation results in the increased production of acute phase protein that over time accumulates in certain tissues. This is known as _____________.
B cell lymphomas;
clonal plasma cells;
local irradiation;
secondary amyloidosis
Amyloidosis associated with plasma cell dyscrasia is known as primary amyloidosis (result of accumulation of certain types of light chain, also known as AL Amyloidosis- Amyloid Light chains, _____ lamda type, ____ kappa type)
Deposited in kidneys, peripheral nerves, GI tract, myocardium
- In kidneys: _________________
- In nervous system: _______________
- Heart: ___________ form of cardiomyopathy/ restrictive form of cardiomyopathy
- GI tract: enlargement of the tongue (side of tongue indented by patient’s own teeth)
- Amyloid deposition in the ___________________ almost diagnostic of Amyloidosis type while other organ involvement seen in other types of amyloidosis.
AL amyloidosis seen with overt multiple myeloma, and 10% of symptomatic multiple myeloma patients suffer from amyloid deposition in very organs at the point where multiple myelomas are diagnosed. AL amyloidosis is also seen in certain patients with ___________________ but is most usually associated with plasma cell dyscrasia when plasma clone size is small.
¾; ¼
nephrotic syndrome;
Sensory- motor peripheral neuropathy ;
non ischaemic;
tongue, myocardium, bone marrow;
non Hodgkin lymphomas
Epidemiology of Multiple Myeloma
- 1% of all cancers, 10% of haematological cancers
- Median survival: 7 months in pre-chemotherapy era, 3 years with conventional chemotherapy, 5-7 years currently
- Not curable except for patient with _______________, most patients will still succumb to this disease
- Male : Female = 1.2-1.5 : 1
- Incidence rate of about 7/100,000 in the western world
- US – Non Asians: Asians = ~2:1
- ~ 150 to 200 diagnosed with all types of PCD in Singapore each year (Incidence rate ~3-4/100,000)
- Does not occur in children
- Incidence increases with age; median age at diagnosis is 70 (but have encountered occasional patients in 30s and late 20s
- Slightly increased in individuals with a ___________
allogeneic stem cell transplantation;
1st degree relative
Diagnosis of Multiple Myeloma- Peripheral blood film/ bone marrow aspirate
The diagnosis relies mainly on bone marrow aspirate, but sometimes there are clues in the peripheral blood film.
- Rbcs stacking together like a stack of coins (______________) due to high concentration of paraprotein neutralizing the electrical charges on the red cell surface which serves to keep the red cells apart. Plasma cells can occasionally be seen in peripheral blood, but this is more easily seen in bone marrow aspirate.
- Plasma cells with eccentrically placed nuclei and a basophilic cytoplasm with a ________________
- Bone marrow trephine biopsy is done as part of bone marrow examination and can give complimentary information on how ___________________
- Plasma cells are usually highlighted by the immunochemical stain ________
rouleaux formation;
perinuclear golgi apparatus. ;
densely infiltrated the marrow truly is;
CD138
The diagnosis relies on serum/ urine protein electrophoresis. This is the test that separates the different proteins in the serum/ urine/ any biological sample according to the charges and the molecular weight of the protein. The proteins are identified based on positions on the agarose gel bands that define albumin and the different globulin bands seen. Most immunoglobulins fall under the _______________ (seen as a _______ because Igs have a variety of molecular weight and charges due to different isotypes and specificity.
To identify the type of paraprotein that the patient has, this is elucidated by an added process called ________________. Added step is to place an ___________ at the top of these lanes. If there is a significant quantity of a particular isotype of antibody, it will react with the antiserum and precipitate out of solution. . The gel is then washed, getting rid of protein that has not been precipitated out of solution then stained the usual way.
gamma globulin band ;
smear;
immunofixation electrophoresis;
antiserum
International Staging System (ISS)
- Stage I: _______________ < 3.5 mg/L, ___________
- Stage II: not Stage I or III
- Stage III: β2M ≥ 5.5 mg/L
Certain genetic subtypes of multiple myeloma do poorly. Certain cytogenetic abnormalities are recurrently found in this poor risk genetic subtypes (¼ to ⅓ in patients)
- One is a deletion of the ______________ which results in a deletion in 1 out of 2 alleles of tumour suppressive gene.
- One is the translocation of _________________. This juxtaposes ____________ in chromosome 4 to enhance the heavy chain gene in chromosome 14. This results in overexpression of FGFR, which enhances proliferation of multiple myeloma cells.
Revised ISS
- Stage I: ISS stage I AND _______________ AND normal LDH
- Stage II : Not R-ISS stage I or III
- Stage III: ISS stage III AND either high-risk CA or high LDH
β2-microglobulin (β2M) ; albumin> 35 g/L;
short arm of chromosome 17 ;
4 and 14 chromosomes;
FGFR (fibroblast growth factor receptor gene);
standard-risk Chromosomal Abnormalities (CA);
Types of treatment (important when patients are newly diagnosed/ relapse)
Emergency treatment
- Severe hypercalcemia
- Mass effect, eg cord compression either from collapsed vertebrae or plasmacytomas that expand through vertebral bodies to compress spinal cord
- Renal failure: in some patients, this is to the extent that renal replacement is needed
- ____________: when paraproteins are higher than normal
Symptomatic/ Supportive treatment (for a good quality of life)
- Pain – Analgesia, _______________ (bone segments to restore height of collapsed vertebrae, very effective for pain relief) : for bone pain while waiting anti myeloma treatment to start working
- Anemia – Transfusions, ESAs → to increase sense of well being
Prophylactic treatment
- Infection – Antibiotics (anti myeloma treatment use __________________ which cause immunosuppression and myelomas suppress production of normal repertoire of antibodies), IVIg
- Frequent infection from encapsulated organisms like pneumococcal and haemophilus may benefit from the intravenous Ig while waiting for myeloma treatment to restore normal repertoire of antibodies
- Fractures – Surgery (_________________ may be recommended in new patients whose weight bearing bones have been so damaged by multiple myeloma that they are in state of impending fractures), _____________ (reduce risk of pathological fractures
Hyperviscosity;
kyphoplasty;
high dose of corticosteroids;
prophylactic intramedullary nailing of weight bearing bones;
Bisphosphonates
Anti-myeloma treatment
- Corticosteroids – ____________ (more potent than in the past when previously treated with prednisolone)
- Proteasome Inhibitors (PI) – _________ (1st gen, still used most commonly), Carfilzomib
- Immunomodulatory drugs (IMiD) – Thalidomide(1st gen, frequent side effects), __________ (backbone in many regiments)
- Monoclonal antibodies – ________ (anti-CD38) (both frontline treatment and treatment of relapse)
Chemotherapy (still in use in patients going for autologous stem cells transplant where both mobilisation regiment and conditioning regimen use chemotherapy)
Most patients (80-90%) will respond to the induction treatment and improve clinical, with biomarkers e.g. paraproteins also showing improvement in performance.
Those <70 years will be encouraged to undergo stem cell transplant. After transplant, they will be moved to a maintenance phase for as long as they can tolerate.
If transplant is ineligible (extremely old in age/ extreme comorbidities) will move to maintenance after sufficiently long induction phase.
As the disease progresses through a process of genomic instability, more and more mutations are accrued by clonal populations which makes the disease more resistant to treatment.
dexamethasone;
Bortezomib;
Lenalidomide;
Daratumumab;
What is the triple therapy/ quadraple therapy options for multiple myeloma?
- steroid + proteasome inhibitors + immunomodulatory drugs
- immunomodulatory drugs + steroid+ monoclonal antibodies
- immunomodulatory drugs + steroid+ monoclonal antibodies + proteasome inhibitors
