Multiple Myeloma and Prostate Cancer Flashcards
1
Q
Multiple Myeloma (MM)
A
- Neoplastic proliferation of plasma cells producing a monoclonal immunoglobulin malginant disease of plasma cells in bone marrow
- Plasma cells proliferate in the bone marrow and often results in extensive skeletal destruction with osteolytic lesions, osteopenia, and/or pathologic fractions
2
Q
Monoclonal Antibodies
A
- Antibodies made by identical immune cells that are clones of a unique parent cell
3
Q
When is a diagnosis of MM suspected?
A
Suspected when there is one or more of the following:
- Bone pain with lytic lesions discovered on routine skeletal films or other imaging modalities
- An increased total serum protein concentration and/or presence of a monoclonal protein in urine or serum
- Systemic signs of symptoms suggestive of malignancy, such as unexplained anemia
- Hypercalemia - either symptomatically or incidentally discovered
- Acute renal failure with a bland urinalysis or rarely the nephrotic syndrome due to concurrent immunoglobulin light chain (AL) amyloidosis
4
Q
Epidemiology MM
A
- Accounts for 1-2% of all cancers and slightly more than 17% of hematogolic malignancies
- Higher incidence in African Americans
- Occurs more often in older adults - median age of diagnosis is 66years
- Familial component - risk of developing MM is 3.7X higher in those that have a frist degree relative with MM
5
Q
Clinical Presentation of MM
A
Most signs and symptoms are related to infiltration of plasma cells into bone or other organs or kidney damage from excess light chains.
- Anemia
- Bone pain - esp. back and chest
- Elevated creatinine - mainly due to light cast nephropathy or hypercalcemia
- Fatigue/generalized weakness
- Hypercalcemia
- Weight loss
- Infection
- Neuroligc disease - radiculopathy (pinched nerve), cord compression, peripheral neuropathy, CNS involvement
6
Q
Pathogenesis of MM
A
- Pathogenesis of MM is a complex process leading to the replication of a malignant clone of plasma cell origin.
- Almost all cases of MM are produced by a premalinant plasma cell proliferative disorders known as monoclonal gammopathy of undetermined signifcance (MGUS).
- Pathogenesis of MM can be thought of as a 2-step process:
- Establishment of MGUS
- Progression of MGUS to MM
7
Q
Establishment of MGUS
A
- Appears to develop as the result of cytogenic abnormalities, which are thought to be the product of an abnormal plasma cell response to antigenic stimulation. Results in plasma cell clone producing monoclonal immunoglobulin.
- Risk factors: older age, immunosuppresssion, environmental exposure, genetic predisposition/
- Cytogenic abnormalities - translocation events involving the immunoglobulin heavy chain (likely occurs during class switiching) results in oncogene next to a promoter region; or a genetic instability manifested by trisomies resulting in overexpression of genes that promote growth.
8
Q
Progession of MGUS to MM
A
- Further insults to the plasma cell clone, either through additional genetic abnormalities or changes in the bone marrow microenvironment, result in progression of MGUS to MM.
- Progression is thought to be due to a “random second hit”
- Additional genetic changes
- Increased cell proliferation due to cell cycle dysegulation
- Evasion of programmed cell death
- Changes in bone marrow microenvironment
9
Q
Abnormal Plasma Cells in MM
A
In the bone marrow some hematopoietic stems cells will differentiate into plasma cells
- Normally, bone marrow contains <5% plasma cells which secrete antibodies
- In MM, the hematopoietic stem cell shifts its production to produce more plasma cells (>10% plasma cells in bone marrow). Futhermore, these plasma cells secrete abnormal antibodies in a majority of MM cases (ex. heavy chains + light chains, light chains alone, or niether). The abnormal proteins produced and secreted by the malignant plasma cells can be detected by protein electrophoresis.
10
Q
End Organ Damage in MM
A
- Osteolytic bone lesions, hypercalcemia, bone pain, pathologic fractures - Increased RANKL produced by plasma cells and decrease in OPG results in increased osteoclast activity (bone breakdown) and decrease osteoblast activity (bone buildup).
- Renal insufficency - accumulation of Ig light chains in the tubules of the kidney results in blockage of tubules by light chain casts.
- Anemia - Due to replacement of normal hematopoietic tissue by tumours and by disruption of bone marrow microenvironment.
11
Q
Laboratory Studies MM
A
- Urinalysis - Findings in MM depend on the etiology of the kindey damage:
- Myeloma cast nephropathy - presence of large, waxy, laminated casts in distal and collecting tubules. Casts are mainly make up of precipitated monoclonal light chains. Urine dipstick is typically negative for protein, since most of the proteinuria is comprise of urinary monoclonal protein rather than albumin.
- Patients may also present with amyloidosis, these patients would be positive on dipstick.
- Peripheral smear
- Rouleaux formation (RBCs take on appearance of a stack of coins in diluted suspensions of blood), leukopenia, and thrombocytopenia. Rarely able to detect monoclonal plasma cells on peripheral smear.
- Bone marrow
- Bone marrow aspirate and biopsy are key in MM diagnosis
- Bone marrow contains >10% clonal plasma cells
- Free light chain assay
- Measures kappa and lambda light immunoglobulin chains that are unbound to heavy chains in the serum. In MM you may see excess production of one type of light chain
- Serum Protein electrophoresis
- Will see a large gamma spike in the gamma region indicating a clonal population of Igs.
- Imaging
- Cross-sectional imaging is preferred as they are more sensitive than plain radiogrpahs for detection of most skeletal lesion in myeloma
- MRI is most sensitive for bone involvement
- PET/CT is more sensitive for extramedullary involvement
- Cross-sectional imaging is preferred as they are more sensitive than plain radiogrpahs for detection of most skeletal lesion in myeloma
12
Q
Diagnostic Criteria MM
A
- Diagnosis requries fulfillment of the following:
- Clonal bone marrow plasma cells ≥ 10% or biopsy - proven boney or soft tissue plasmacytoma
- Plus ONE of the following:
- Presence of related organ or tissue impairment - Increased Calicum level; Renal insufficiency; Anemia; and Bone lesions
- Presence of a biomarker associated with near inevitable progression to end-organ damage: ≥ 60% clonal plasam cells in the bone marrow; involved/uninvolved FLC ratio of 100 or more (presence of light chains); or MRI with more than one focal lesions
13
Q
Treatment MM
A
MM is incurable
- Induction therapy
- Patients eligible for HCT receive induction therapy for 2-4 months prior to stem cells collection to reduce number of tumour cells
- Patients ineligible for HCT generally continue treatment until progression
- Maintenance
- All patients will eventually relapse. Maintenance therapy prolongs progessions - free survival but unclear if it improves overall survival
14
Q
Proteasome inhibitors
A
- Proteasome - small protein complexes in cells which degrade unneeded or damaged proteins by porteolysis. Once these proteins are broken up the cell can use them to make new proteins.
- Cancerous plasma cells make much larger amounts of ineffective proteins. Proteasome inhibitors work by preventing the “protein recycling process” allowing the proteins to build up in the cell. The cell then dies of build-up of accumulated wasts.
- Overall, proteasome inhibitors have shown efficicant in both front-lin and relapse setting, but the development of resistence and side effects like peripheral neuropathy can limit its use. However, newer version are effective at lower doses can have lower incidence of neuropathy.
15
Q
Bisphosophates and Cancer
A
- Bisphosophates bind avidly to bone and are ingested by osteoclasts, resulting in inhibition of osteoclast-mediated bone resorption
- Certain cancers (breast, lung, prostate, MM) are prone to the development of bone disease. Once the tumour is in the bone marrow they alter the function of osteoclasts and osteoblsts to enhance bone resportion and inhibit bone formation, leading to skeletal destruction (cord compression, hypercalcemia, loss of mobility).
- Due to antiresorptive acitivty, bisphophonates are used in the treatment of malginant bone disease to prevent or delay skeletal morbidty associated with bone mets.
- Frist generation - induce osteoclast apoptosis
- Second and third generation - suppress osteoclast mediated bone resorption.
