Multiple Myeloma

What is multiple myeloma (MM)?

Multiple myeloma is a neoplastic proliferation characterised by plasma cell accumulation in the bone marrow, presence of monoclonal immunoglobulins in the serum and/or urine and related tissue damage. 

What are plasma cells?

Plasma cells are a type of white blood cell that produces antibodies. Antibodies are proteins that help the body fight infection. Plasma cells are produced in the bone marrow and then travel to the lymph nodes and spleen.

Plasma cells are formed from B cells, another type of white blood cell. When a B cell encounters an antigen, a foreign substance that the body does not recognize, it becomes activated and begins to divide. One of the daughter cells from this division becomes a plasma cell.

Plasma cells are highly specialized for antibody production. They have a large cytoplasm, which contains a lot of ribosomes, the organelles that produce proteins. Plasma cells also have a well-developed Golgi apparatus, which is responsible for packaging and secreting proteins. Plasma cells can produce a large number of antibodies, each of which is specific to a particular antigen. When an antibody encounters the antigen that it is specific for, it binds to it and marks it for destruction by other immune cells.

Plasma cells play a vital role in the immune system. Antibodies help to protect the body from a wide range of infections, including bacteria, viruses, and parasites. Antibodies also play a role in other immune functions, such as allergy and autoimmunity.In addition to their role in the immune system, plasma cells also play a role in other bodily functions, such as bone remodeling and wound healing.

How do plasma cells produce antibodies?

Normally, the plasma cells, representing the final stage of B-cell maturation produce polyclonal immunoglobulins to fight infections. The maturation of B lymphocytes occurs in the bone marrow and afterwards migrates to secondary lymph nodes, where antigens are presented to B cells. 

Immature plasma cells are characteristically short-lived cells and producers of IgM involved in the primary immune response. In some circumstances, plasma cells experience hypermutations of the Ig light and heavy chains variable genes, secreting other Ig isotypes such as IgG and IgA or infrequently IgE and IgD or paraproteins. Later, these cells migrate to the bone marrow to differentiate into long-lived plasma cells, lasting for days or months.

Here are some examples of diseases that can affect plasma cells:

• Multiple myeloma: A cancer of the plasma cells
• Waldenström’s macroglobulinemia: A cancer of the plasma cells that produce a type of antibody called IgM
• Amyloidosis: A disease in which abnormal proteins called amyloid fibrils accumulate in the tissues, including the plasma cells
• Common variable immunodeficiency (CVID): A disorder in which the body does not produce enough antibodies

How does multiple myeloma occur?

 The characteristic immunophenotype of malignant plasma cells is CD38high, CD138high and CD45low. Paraproteinemia refers to the presence of a monoclonal immunoglobulin band (M-protein) in the serum. M-protein reflects the synthesis of immunoglobulin from only a single clone of plasma cells. Tumour cells have very complex genetic changes but dysregulated or increased expression of cyclin D is believed to be an early unifying event. Aberrations include hyperdiploidy, translocations of immunoglobulin heavy-chain gene and monoallelic loss of 13q. These myeloma cells produce pathogenic antibodies or antibody fragments. 

Multiple myeloma cells most commonly secrete IgG or IgA antibodies. However, in addition to complete antibodies, they usually also secrete free, unpaired Ig light chains which are small in size and can pass from the blood through the filtration slits of the renal glomeruli and into the renal tubules. The Ig light chains are toxic to renal epithelial cells and tend to form precipitates and obstructive casts which contribute to renal dysfunction. 

Free lambda light chains are also prone to form amyloids which are fibrillar deposits that may be found in the renal glomeruli and the perivascular spaces of many tissues including the liver, spleen and heart. Renal amyloidosis often causes nephrotic syndrome which is the spilling of albumin and other plasma proteins into the urine. 

Bone resorption is caused by myeloma cells that stimulate the maturation and function of osteoclasts both directly, via release of factors such as macrophage inflammatory protein-1 alpha (MIP-1 alpha) and IL-3, and indirectly by stimulating marrow stromal cells to release osteoclastogenic factors such as receptor activator of NF-kappa B ligand (RANKL) and IL-6. At the same time, myeloma cells also release factors such as Dickkopf-1 (DKK-1) that suppress the activity of osteoblasts. The net effect of these alterations strongly favour bone resorption. The proliferation of malignant plasma cells also inhibits normal B-cell function and the production of normal antibodies resulting in an increased susceptibility to bacterial infections. 

What are the clinical features of multiple myeloma (MM)?

98% of cases occur over the age of 40 years with a peak incidence at 70 years old. 

Myeloma usually presents with symptoms related to anemia, renal failure, bone resorption, or hypercalcemia.

• Bone pain: Bone pain is the most common symptom of MM, occurring in about 70% of patients at diagnosis. The pain is often located in the back, ribs, or pelvis. Occasionally patients experience bone pain especially backache due to vertebral collapse and pathological fractures. 
• Anemia: Anemia is present in about 50% of patients at diagnosis. There may be abnormal bleeding tendency as myeloma protein may interfere with platelet function and coagulation factors. 
• Hypercalcemia: Hypercalcemia is present in about 20% of patients at diagnosis.
• Immunosuppression: Immunosuppression is present in about 50% of patients at diagnosis. Recurrent infections are related to deficient antibody production, abnormal cell-mediated immunity and neutropenia. 
•  Amyloidosis and hyperviscosity syndrome may occur too.

Other clinical features of MM may include:

• Fatigue: Fatigue is a common symptom of MM, occurring in about 80% of patients.
• Shortness of breath: Shortness of breath is a common symptom of anemia, which is a common complication of MM.
• Dizziness: Dizziness is a common symptom of anemia, which is a common complication of MM.
• Nausea and vomiting: Nausea and vomiting can be symptoms of hypercalcemia, which is a common complication of MM.
• Constipation: Constipation can be a symptom of hypercalcemia, which is a common complication of MM.
• Frequent infections: Frequent infections can be a sign of immunosuppression, which is a common complication of MM.

What are the laboratory investigations for multiple myeloma (MM)?

The diagnostic indicators of MM are hypercalcemia, renal disease, anemia and bone lesions which give the abbreviation (CRAB). 

• Characteristic “punched out” lytic skeletal lesions are produced by expanding masses of plasma cells. 
• Rouleaux formation is marked in peripheral blood film. 
• Bone marrow examination shows more than 10% plasma cells.
• Serum protein electrophoresis shows IgG in 60% of cases. Free light chains or Bence Jones proteins can be detected using the same methods. 
• Raised serum beta-2 microglobulin is a useful indicator of prognosis. 
• Cytogenetics are becoming more and more important in staging and prognostic purposes. 

What are the different stages of multiple myeloma (MM)?

Multiple myeloma (MM) is staged for treatment purposes to help doctors determine the best treatment plan for each patient.

For myeloma, staging-wise it is important to begin with whether the patient is experiencing symptoms. It is common to classify people with newly diagnosed myeloma as either:

• Asymptomatic. This means the person does not have symptoms and signs of the disease. This is called smoldering myeloma.
• Symptomatic. This means the person has symptoms and signs of the disease. Patients with symptoms, or who are about to develop symptoms, need treatment. The symptoms related to myeloma are described with the mnemonic acronym “CRAB.”

The Revised International Staging System (R-ISS) is now used more commonly to classify multiple myeloma. It defines the factors that affect a person’s survival of the disease. The system has 3 stages based 

• Serum albumin level: Albumin is a protein that is produced by the liver. It helps to regulate the fluid balance in the blood and tissues. A low albumin level is a sign of advanced MM.
• Beta-2 microglobulin (β2-M) level: β2-M is a protein that is produced by all cells in the body. It is removed from the blood by the kidneys. A high β2-M level is a sign of advanced MM.
• Lactodehydrogenase (LDH) level: LDH is an enzyme that is found in all cells in the body. It is responsible for converting lactate to pyruvate, which is a source of energy for the cells.Elevated serum LDH levels are associated with a more aggressive form of MM and a worse prognosis. Patients with elevated serum LDH levels are more likely to have bone marrow involvement, and they are more likely to develop complications from MM, such as hypercalcemia and renal failure.
• Cytogenetic risk: Cytogenetics is the study of chromosomes. Certain chromosomal abnormalities are associated with a worse prognosis in MM. Recent efforts have been made to further classify myeloma based on patterns of gene expression in myeloma cells. This is an ongoing area of research. 

Based on these three factors, patients are assigned to one of three stages:

• Stage I: All of the following apply, β2-M less than 3.5 mg/L, serum albumin of 3.5 g/dL or more, normal LDH, no high-risk chromosome changes in myeloma cells found by FISH test.
• Stage II: Not stage I or stage III.
• Stage III: β2-M is more than 5.5 mg/L, plus one of the following: Myeloma cells that have high-risk chromosome changes found by FISH test or high LDH. 
• Recurrent or relapsed myeloma is myeloma that returns after a period of being in control after treatment is called recurrent myeloma or relapsed myeloma. If there is a recurrence, the cancer may need to be staged again (called re-staging) using one of the systems above.

Patients with stage I MM have the best prognosis, while patients with stage III MM have the worst prognosis.

The ISS staging system is used to guide treatment decisions in MM. Patients with stage I MM are typically treated with less aggressive regimens, while patients with stage III MM are typically treated with more aggressive regimens.

In addition to the ISS staging system, there are a number of other staging systems that are used in MM. These staging systems are more complex, but they may be more accurate in predicting prognosis.

What are the current treatments for multiple myeloma (MM)?

The current treatment for multiple myeloma (MM) depends on a number of factors, including the stage of the disease, the patient’s age and health, and the patient’s preferences.

The main goal of treatment for MM is to achieve remission, which is a state in which there is no evidence of the disease. Remission can be achieved with a variety of treatments, including:

• Chemotherapy: Chemotherapy uses drugs to kill cancer cells. Chemotherapy is often used in combination with other treatments, such as stem cell transplantation and immunotherapy. Currently, newly diagnosed multiple myeloma patients are treated with induction therapy that usually includes triple combinations such as bortezomib, lenalidomide and dexamethasone. Other preferred regimens may be selected depending on the eligibility of the candidates for transplants. This first phase of treatment has the objective of reducing tumour burden and improving the haematopoietic stem cell collection. After achieving response, this primary therapy is followed by high dose melphalan and autologous stem cell transplantation, consolidation and or maintenance using bortezomib or lenalidomide. For relapse multiple myeloma patients, the situation has also improved with new treatment options being recently approved, new strategies for therapy sequence and novel double or triple combinations. To date, no treatment has been proven to be curative in myeloma, but these new treatments have roughly doubled the median survival, providing reason for optimism. 
• Stem cell transplantation: Stem cell transplantation is a procedure in which healthy stem cells are transplanted into the patient’s body. Stem cells are the immature cells that develop into different types of blood cells. Stem cell transplantation can help to restore the patient’s immune system and to kill cancer cells.
• Immunotherapy: Immunotherapy uses the patient’s own immune system to fight cancer. Immunotherapy drugs can help to activate the immune system to kill cancer cells. It uses materials made either by the body or in a laboratory to improve, target, or restore immune system function. In CAR T-cell therapy, some T cells are removed from a patient’s blood. Then, the cells are changed in a laboratory so they have specific proteins called receptors. The receptors allow the changed T cells to recognize the cancer cells. In the case of idecabtagene vicleucel, the cells recognize BCMA on the myeloma cells. The changed T cells are grown in large numbers in the laboratory and returned to the patient’s body. Once there, they seek out and destroy cancer cells. 
• Immunomodulatory drugs: Thalidomide, lenalidomide , and pomalidomide are classified as immunomodulatory drugs, which stimulate the immune system. These drugs also keep new blood vessels from forming and feeding myeloma cells. Thalidomide and lenalidomide are approved to treat newly diagnosed patients. Lenalidomide and pomalidomide are also effective for treating recurrent myeloma. Steroids, such as prednisone and dexamethasone, are very effective at reducing the burden of plasma cells, but this effect is only temporary. 

In addition to these main treatments, there are a number of other treatments that may be used for MM, including:

• Targeted therapy: Targeted therapy drugs target specific proteins or molecules that are involved in the growth and survival of cancer cells. Targeted therapy is a treatment that targets the cancer’s specific genes, proteins, or the tissue environment that contributes to cancer growth and survival. This type of treatment blocks the growth and spread of cancer cells and limits damage to healthy cells. Targeted therapy for multiple myeloma includes proteasome inhibitors, histone deacetylase inhibitors, monoclonal antibodies, nuclear export inhibitors and B-cell maturation antigen (BCMA) targeting agent. 
• Radiation therapy: Radiation therapy uses high-energy rays to kill cancer cells. Radiation therapy is often used to treat specific areas of bone pain or to treat tumors that are blocking the flow of urine.
• Bisphosphonates: Bisphosphonates are drugs that help to strengthen bones and reduce the risk of bone fractures.
• Bone marrow stimulants: Bone marrow stimulants are drugs that help to stimulate the production of blood cells. Bone marrow stimulants may be used to treat patients with anemia caused by MM.

The best treatment plan for each patient will vary depending on the individual factors listed above. It is important to work with a doctor to develop a treatment plan that is right for you.

In recent years, there have been a number of advances in the treatment of MM. New drugs and treatment regimens have been developed that have improved the outcomes for patients with MM.

Current research on the treatment of MM is focused on developing new and more effective treatments, as well as on finding ways to improve the quality of life for patients with MM.

Key Points of Multiple Myeloma (MM)

Definition

Malignant disorder of plasma cell in the bone marrow

Incidences

Slightly more common in males than females and most common between 50 – 80 years old.

Clinical features

• Bone pain or pathological fractures
• Bone marrow failure (marrow infiltration)
• Infections (immune paresis & neutropenia)
• Renal failure 
• Hypercalcemia
• Amyloidosis

Pathophysiology

Laboratory investigations

Full blood count and Peripheral blood characteristics

Anemia, neutropenia & thrombocytopenia in advanced disease. Rouleaux formation and leucoerythroblastic picture may be present.

Bone marrow characteristics

>15% plasma cells

Other important investigations and expected results

• Serum paraproteinemia &/or Bence Jones protein in the urine
• ↑ ESR, CRP, serum light chain, β2M, 
• Bone lytic lesions in CT scan, X-rays, MRI
• Hypercalcemia
• M band in serum electrophoretic studies
• Renal function test: ↑ blood urea, serum creatinine and uric acid levels

Treatment and management

• Chemotherapy
• Corticosteroid e.g. dexamethasone, prednisolone
• Thalidomide or Bortezomib
• Bone-modifying drugs
• Immunotherapy
• Stem cell transplantation
• Radiation therapy

Disclaimer: This article is intended for informational purposes only and is specifically targeted towards medical students. It is not intended to be a substitute for informed professional medical advice, diagnosis, or treatment. While the information presented here is derived from credible medical sources and is believed to be accurate and up-to-date, it is not guaranteed to be complete or error-free. See additional information.

References

1. Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008 Mar 15;111(6):2962-72. doi: 10.1182/blood-2007-10-078022. PMID: 18332230; PMCID: PMC2265446.
2. Wallington-Beddoe, C.T., Mynott, R.L. Prognostic and predictive biomarker developments in multiple myeloma. J Hematol Oncol 14, 151 (2021). https://doi.org/10.1186/s13045-021-01162-7