Key Notes on Multiple Myeloma and Its Management

Overview of Multiple Myeloma

Definition: Cancer arising from plasma cells.
Plasma cells produced at the very end of the pathway on the lymphoid line of hematopeiesis
Usually incurable, variable prognosis.
Incidence:
- Approximately 6,000 newly diagnosed cases per year in the UK.
- Second most common hematological malignancy.
- Accounts for at least 2% of all cancer-related deaths.
- 44% of new cases are in individuals aged 75 years or older; less than 2% are under 40 years.
- Slightly more prevalent in men than in women.
Key clinical features:
- bone/back pain
Fatigue/ mailase / weight loss
recurring infection
pathological features
unexplained breathlessness

Immunoglobulins

Types: IgG, IgA, IgD, IgE, IgM.
Structure of Immunoglobulin Molecules: Include light chains classified as either Kappa or Lambda.
Heavy chains- IgG, A,D,E,M
Plasma cells are responsible for producing immunoglobulins- key component of the immune system.

Free Light Chains

Types:
- Free Kappa Chains
- Free Lambda Chains
- Bound forms found in plasma cells, including bound Kappa and bound Lambda chains.
- Measure the number of each of these chains and proportion of these together in the blood- get ratio.
- There are normal ranges for free kappa, free lambda and the ratio of both.
- I ration ratio higher/ lower than normal, cna be a sign of plasma cell dyscrasia- one of these is multiple myeloma.
- MGUS- plasma cell dyscrasia producing abnormal amount of serum free light chains, but the significance is unknown- it is not a cancer, no signs/ sx and a lot of people don’t know that they have it - but it does give increased risk of multiple myeloma.

Paraproteinaemia

Indicator: Presence of a monoclonal protein spike (M-band) visible on protein electrophoresis.
In myeloma there can be a type od paraprotein- protein that is overproduced and functionless.
Immunofixation can be done when identified paraprotein.

Diagnostic Tests

Routine tests include:
- Full Blood Count (FBC)
- Chemistry tests (e.g., creatinine, adjusted calcium)
- Immunoglobulin quantification and electrophoresis
- Serum Free Light Chain (sFLC) assay
Immunofixation- measures the numbers and types of proteins in the blood.Electrophoreisis.
Additional diagnostic measures:
- Bone marrow biopsy
- Radiological imaging (e.g., PET-CT, CT, MRI)
- Tests to be conducted in primary care and hospital settings.

Symptomatic/Active Myeloma- myeloma is not always symptomatic.

Diagnosis criteria include: (to qualify for active treatment)
- Bone marrow showing ≥10% plasma cells or presence of extramedullary plasmacytoma plus one or more of the following symptoms:
- End-organ damage (e.g., hypercalcaemia >2.75 mmol/L) - have to have end organ damage. (without symptoms of end organ damage, still have myeloma but don’t need treatment. Without sx of end organ damage, still have myeloma but dont need treatment.
- Renal impairment (CrCl < 40 mL/min or serum creatinine >177 µmol/L)
- Anemia (hemoglobin < 100 g/L or >20 g/L below lower limit of normal)
- Bone lesions
- only need one of these as well as 10% plasma on bone marrow.
- Biomarkers:
  - Bone marrow >60% plasma cells
  - Involved:uninvolved serum free light chain ratio ≥100
  - Presence of >1 focal lesion measuring ≥5 mm.
Key Clinical Features:
- Bone or back pain
- General fatigue or unwellness (including weight loss)
- Recurring infections
- Pathological fractures
- Unexplained breathlessness.

Treatment Timeline

Key Treatments Over the Years:
- 1960-80s: Melphalan; introduction of combination chemotherapy with vincristine, doxorubicin, and dexamethasone (VAD).
- 2000 onwards: Progression to high-dose chemotherapy followed by autologous stem cell transplant (ASCT).
- Introduction of novel therapies such as Thalidomide, Bortezomib, Panobinostat, Isatuximab, and other targeted treatments including Lenalidomide, Pomalidomide, Carfilzomib, Ixazomib, Daratumumab, Elranatamab, and Teclistamab.
- Strict commission on NHS, can only use certain drugs at certain points.

Immunomodulatory agents- teratogenic. Risk of thrombosis, need anticoagulant

alongside.

mAbs- bind to myeloma cells and cause cell mediated death

proteasome - targeted treatment that prevents breakdown of protein- damage myeloma cells and cause cell death.

BCMA- antibody conjugate- on surface on myeloma cell, once bound releases cytotoxic agent to cause cell death - is not delivered to normal cells.

Bispecific T cell engagers- only become available v recently. Only for 4th line treatment- need to have failed 3 other classes of drug before this. They bind to BCMA on one end and also cd3 on t cells- to bring cancer cell in line with the patients immune system to destroy cancer cells.

all these drugs are combined with dexamethasone, which has anti myeloud effect.

Considerations at relapse: