Multiple Myeloma: A Comprehensive Guide To The Disease - Dr Ushang Kate

Multiple myeloma (MM) is a relatively rare form of cancer, accounting for approximately 1% of all cancers and 10% of all haematological malignancies. MM is a kind of cancer that affects the plasma cells in the bone marrow. Plasma cells are responsible for producing antibodies that help fight infections. When these cells become cancerous, they produce abnormal proteins called M proteins, which can cause a range of health problems.

Disease Presentation

The common features are characterised by the acronym “CRAB” which summarizes the most typical clinical manifestations of multiple myeloma ie. hypercalcaemia, renal insufficiency, anaemia, and bone disease along with the most recent SLiM CRAB diagnostic criteria. The characteristic of MM is a multistep transition process from monoclonal gammopathy of unknown significance (MGUS) to smouldering multiple to symptomatic myeloma via a succession of acquired genomic abnormalities.

It typically occurs in older adults, with the median age of diagnosis being 69 years old, and is slightly more common in men than women.

In India, the incidence rate of MM is estimated to be around 2.4-3.1 cases per 100,000 population, which is lower than the incidence rates reported in Western countries. However, due to the large population size of India, this still translates to a significant number of cases each year. The incidence of MM is also thought to be higher among certain ethnic groups, such as those of African descent.

Diagnostic workup

MM can be challenging, as the symptoms can be vague and nonspecific. Common symptoms include bone pain, fatigue, anaemia, and frequent infections. To diagnose MM, a variety of tests are done such as CBC differential serum albumin, beta2 microglobulin (ß<2M) level, serum protein electrophoresis, serum quantitative immunoglobulins levels, serum free light chain assay, urine tests, bone marrow aspiration and biopsies, imaging studies such as X-rays, CT, PET and MRIs.

Staging systems such as the Revised International Staging System (R-ISS) are used for stratifying the severity of patients’ diseases.

Molecular Cytogenetic for Risk Stratification

One important genetic test for prognostication in MM is the fluorescent in situ hybridization (FISH) test. FISH is a molecular cytogenetic test that can detect specific chromosomal abnormalities like translocations, copy number changes and ploidy associated with MM. These abnormalities are often used to predict outcomes for risk stratification that help guide treatment decisions.

There are specific chromosomal abnormal categories in MM. Immunoglobulin heavy-chain (IgH) translocations are early genetic events in MM. Several types of IGH abnormal markers can be detected using FISH testing. Recurrent translocations of immunoglobulin genes occur in ∼40% of multiple myeloma and occur during errors in the normal processes of B-cell development. The most common types of IGH translocations are the t(4;14),t(11;14),t(14;16) and t(14;20) occurring in 15%, 20-25%, 5-10%, 2-5% respectively. Among these t(11;14) carries a favourable outcome and other IGH translocations define a poor risk category.

Copy number alterations (CNA) are one of the most visible genomic changes in MM and ploidy status and are characterised by trisomy of specific odd-number chromosomes.

1. Deletion 17p: This abnormality is present in approximately 5-10% of MM cases and is associated with poor outcomes. It involves the deletion of genetic material on chromosome 17.
2. Deletion 13q/ Monosomy 13: This abnormality is present in approximately 15-20% of MM cases and is associated with poor outcomes. It involves the deletion of genetic material on chromosome 13.
3. Chromosome gains like hyper diploidy show 60% and 1p deletion/1q amplification show 5-10% frequency.

The prognosis for multiple myeloma depends on several factors, including the stage and aggressiveness of the disease, the patient's age, overall health, individual factors and genetic makeup.

Significant improvements in overall survival have been observed in MM, mainly due to the availability of novel drugs with variable mechanisms of action.

The following are some of the most commonly used treatments for multiple myeloma:

1. Chemotherapy: Chemotherapy refers to the use of medications to kill cancer cells. Chemotherapy medications can be administered orally, intravenously, or via injection.

2. Targeted therapy: Targeted therapy involves the use of drugs that target specific molecules or pathways involved in the growth and survival of cancer cells.

3. Immunomodulatory drugs: These drugs, such as thalidomide, lenalidomide, and pomalidomide, work by enhancing the immune system's ability to recognize and destroy cancer cells.

4. Corticosteroids: Corticosteroids, such as dexamethasone, are used to reduce inflammation and swelling and can help control symptoms of multiple myeloma.

5. Stem cell transplant: The restoration of damaged bone marrow with healthy stem cells is the goal of a stem cell transplant. This can be done using either the patient's stem cells (autologous transplant) or donor stem cells (allogeneic transplant).

6. Radiation therapy: Radiation therapy uses high-energy radiation to kill cancer cells.

7. Bisphosphonates: These drugs are used to reduce bone loss and the risk of fractures in patients with multiple myeloma.

However, standard treatment options do not benefit all and hence personalized targeted therapy approach is followed based on disease characteristics, among which assessing important genetic risk factors becomes important at diagnosis. The specific treatment plan for a patient with multiple myeloma will depend on the individual patient's condition, and treatment is typically managed by a team of healthcare professionals, including oncologists, haematologists, and other specialists. Overall, the median survival time for patients with MM is approximately 5 years. However, with advances in treatment, some patients may live much longer.

Take home message

The increasing availability of novel drugs and the better understanding of pathways involved in MM progression mandates accuracy in comprehensive prognostic and genetic workup to improvise on the risk stratification for a rationalized targeted treatment approach.

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