Plasma Cell Disorders Flashcards
Epidemiology of Multiple Myeloma
Median Age - 69, It is uncommon Under the age of 40.
Males > Females
Blacks have twice the incident than whites
accounts 13 % of all hematological disorder in whites, and 33% in blacks
Higher incidence in developed countries than developing countries
Pathogenesis of MM
MM cells bind via cell-surface adhesion molecules to bone marrow stromal cells (BMSC) which triggers:
- MM cell growth
- Drug resistance
- Migration in the bone marrow milieu
Variant cytokines play a role: IL-6, Insulin-like growth factor I (ILF-I), Vascular endothelial growth factor (VEGF), Stromal cell-derived growth factor (SDF)-1alpha.
Clinical manifestations of MM
- Bone pain- affecting 70% of patients.
- Recurrent infections with increased susceptibility to bacterial infections. presenting feature in 25% of patients.
- Renal Failure- occurs in 25% in patients.
- Normocytic and normochromic Anemia- occurs in 80% of patients.
- Neurological symptoms, occurs in a minority of patients.
Bone lesions- mechanism
- Proliferation of tumor cells
- Activation of osteoclasts, mediated by OAF osteoclast activating factors by MM cells.
- suppression of osteoblasts, mediated by Dickhoff-1 DKK-1 produced by MM cells.
Susceptibility to infections - common sites and pathogens.
- Most common infections are Pneumonia and Pyelonephritis.
- In case of Pneumonia the most frequent pathogens are Streptococcus Pneumoniae, staphylococcus aureus, and Klebsiella pneumoniae.
- In case of pyelonephritis, the most frequent pathogens are Escherichia coli, ang gram negative bacteria
Susceptibility to infections- contributing factors
- Diffuse hypogammaglobulinemia- decreased production and increased destruction of normal antibodies.
- Abnormalities in T cell function
- Immunosuppressive therapy
Renal failure- Contributing Factors.
- Hypercalcemia
- Deposit of amyloid
- hyperuricemia
- recurrent infections
- frequent use of NSAIDs fore pain control
- use of contrast for imaging
- bisphosphonate use
- Infiltration of the kidney by MM cells
*Tubular damage is cause by increased excretion of light chains- leading to Fanconi’s Syndrome type 2 (proximal).
Anemia in MM- mechanism
- Replacement of normal marrow by expanding tumor cells.
- Inhibition of hematopoiesis by factors made by the tumor
- Reduced production of erythropoietin
- Long term therapy
- Mild hemolysis
Neurological manifestations - mechanism
- Hypercalcemia - causing lethargy, weakness, depression, and confusion.
- Hyper-viscosity - causing headache, fatigue, shortness of breath, exacerbation or precipitation of heart failure, visual disturbances, ataxia, vertigo, retinopathy, somnolence, and coma.
- bony damage and collapse may lead to cor compression leading to to radicular pain and loss of bowel and bladder control.
- Infiltration of peripheral nerves by amyloid, may cause carpal tunnel syndrome, and mono/polyneuropathy.
- Therapy side effects of Thalidomide and bortezomib.
Diagnosis of MM Criteria
Clonal bone marrow plasma cells or biopsy-proven or extramedullary plasmocytoma, and any of the following myeloma defining events:
- Evidence of one or more end-organ damage taht can be attributed to the underlying plasma cell proliferative disorder:
- Hypercalcemia: calcium 1 mg/dl higher than the upper limit, or higher than 11 mg/dl
- Renal inssufisciency: creatinine clearence < 40 ml per minute, or serum creatinine > 2 mg.
- Anemia: hemoglobin 2 mg below the lowr limit of norma, or Hb below 10 mg/dl.
- Bone lesions: One or more osteolytic lesions on skeletal radiography, CT/ PET-CT.
- Any one or more of the following biomarkers of malignancy:
* Clonal bone marrow plasma cell percentage > 60 %/
* Involved: uninvolved serum free ligh chain ratio > 100.
* > 1 focal lesions on MRI studies
Smoldering MM criteria
Both criteria must be met:
- serum monoclonal protein (IgG or IgA) > or equal to 30 g/l, or urinary monoclonal protein > or equal to 500 mg per 24 hours, and/or clonal bone marrow plasma cells > 10-60%.
- Absence of myeloma defining events or amyloidosis.
Monoclonal Gammopathy of Undetermined significance criteria
- Serum monoclonal protein (non IgM type) < 30 g/l
- Clonal bone marrow plasma cells < 10%.
- Absence of myeloma defining events or amyloidosis that can be attributed to the plasma cell proliferative disorder
Solitary Plasmacytoma - Diagnostic criteria
- 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 survey
- Absence of end-organ damage (CRAB).
Role of Beta 2 Microglobulin and albumin in MM
Predictors of survival.
Combination of B2 and albumin levels form the basis for a three-stage International Staging system ISS.
- Circulating Plasma cells, high levels of LDH are associated with poor prognosis.
Treatment of MM
1- Systemic Therapy to control Myeloma:
* Newly diagnosed MM with myeloma defining events:
- Transplant eligible:
Induction Therapy with:
* RVD ( Lenalidomide (Immunomodulatory agent), Bortezomib (Proteasome Inhibitor), Dexamethasone)
* VCD ( Bortezomib, Cyclophosphamide (Alkylating agent), Dexamethasone)
* VD
* LD
If response have been achieved, HDT high dose therapy with Autologous stem cell transplantation. If there was no response alternate regimes are advised.
2- Supportive care to control symptoms of the disease
