Multiple Myeloma – Symptoms And Causes

Plasma Cell Disorders

The plasma cell disorders are characterised by abnormal proliferation of immunoglobulin-producing cells and result in accumulation of monoclonal immunoglobulin in serum and urine. The group as a whole is known by various synonyms such as plasma cell dyscrasias, paraproteinaemias, dysproteinaemias and monoclonal gammopathies.

The group comprises the following entities:

1. Multiple myeloma
2. Localised plasmacytoma
3. Lymphoplasmacytic lymphoma (discussed above)
4. Waldenström’s macroglobulinaemia
5. Heavy chain disease
6. Primary amyloidosis
7. Monoclonal gammopathy of undetermined significance (MGUS).

The feature common to all plasma cell disorders is the neoplastic proliferation of cells derived from the B-lymphocyte lineage. These disorders constitute 16% of all B-cell malignancies.

• Normally B lymphocytes have surface immunoglobulin molecules of both M and G chains. Under normal circumstances, B-cells are stimulated by exposure to surface immunoglobulin-specific antigens and mature to form IgG-producing plasma cells.
• However, in plasma cell disorders, the control over this process is lost and results in abnormal production of immunoglobulin that appears in the blood and urine.
• These disorders differ from other B-cell lymphoid malignancies in having monoclonal synthesis of immunoglobulins and lack of prominent lymphadenopathy.
• In addition to the rise in complete immunoglobulins, plasma cell disorders synthesise excess light chains (kappa or lambda), or heavy chains of a single class (alpha, gamma, or mu). Bence-Jones proteins are free light chains present in blood and excreted in the urine of some plasma cell disorders.

Read And Learn More: General Pathology Notes

Multiple Myeloma:

Multiple myeloma is a multifocal malignant proliferation of plasma cells derived from a single clone of cells (i.e. monoclonal). The term multiple myeloma is used interchangeably with myeloma.

• The tumour, its products (M component), and the host response result in the most important and most common syndrome in the group of plasma cell disorders that produce osseous as well as extraosseous manifestations.
• Multiple myeloma primarily affects the elderly (peak incidence in 5th-6th decades) and increases in incidence with age. It is rare under the age of 40. Myeloma is more common in males than females.

Etiology And Pathogenesis:

Myeloma is a monoclonal proliferation of B-cells. The aetiology of myeloma remains unknown. However, the following factors and abnormalities have been implicated:

1. Radiation exposure: Large dose exposure to radiation with a long latent period has been seen in myeloma. For instance, survivors of a nuclear attack in World War II developed myeloma about 20 years later.

2. Epidemiologic factors: Myeloma has a higher incidence in blacks. Occupational exposure to petroleum products has been associated with higher incidence. Certain occupations such as farmers, wood workers and leather workers are more prone.

3. Karyotypic abnormalities:

Several chromosomal alterations have been observed in cases of myeloma, which include the following translocations and deletions:

1. Translocations t(11;14)(q13;q32) and t(4;14)(p16;q32).
2. Deletion of 13q.

4. Oncogenes-antioncogenes Overexpression and mutations in the following genes have been noted in the proliferation of tumour cells in myeloma:

1. Overexpression of myc and ras growth-promoting oncogenes in some cases.
2. Mutation in p53 and RB growth-suppressor genes in some cases.

Based on the above, the molecular pathogenesis of multiple myeloma and its major manifestations can be summed up as under and is schematically illustrated:

1. Cell-surface adhesion molecules bind myeloma cells to bone marrow stromal cells and extracellular matrix proteins.
2. This binding triggers adhesion-mediated signalling and mediates the production of several cytokines by fibroblasts and macrophages of the marrow.
   These include:
   IL-6, VEGF, TGF-β, TNF-α IL-1, lymphotoxin, macrophage inhibitory factor-1α (MIP-1α) and receptor activator of nuclear factor-κB (RANK) ligand.
3. Adhesion-mediated signalling affects the cell cycle via cyclin-D and p21 causing abnormal production of myeloma (M) proteins.
4. IL-6 cytokine plays a central role in cytokine-mediated signalling and causes proliferation as well as cell survival of tumour cells via its antiapoptotic effects on tumour cells.
5. Certain cytokines produced by myeloma cells bring about bony destruction by acting as osteoclast-activating factor (OAF). These are IL-1, lymphotoxin, VEGF, macrophage inhibitory factor-1α (MIF-1α), receptor activator of NF-κB ligand, and tumour necrosis factor (TNF).
6. Other effects of adhesion-mediated and cytokine-mediated signalling are the development of drug resistance and migration of tumour cells in the bone marrow milieu.

Morphologic Features:

Myeloma affects principally the bone marrow though during the disease other organs are also involved. Therefore, the pathologic findings are described below under two headings—osseous (bone marrow) lesions and extraosseous lesions.

1. Osseous (bone marrow) lesions: In more than 95% of cases, multiple myeloma begins in the bone marrow. In the majority of cases, the disease involves multiple bones. By the time the diagnosis is made, most of the bone marrow is involved.

• Most commonly affected bones are those with red marrow i.e. skull, spine, ribs and pelvis, but later long bones of the limbs are also involved.
• The lesions begin in the medullary cavity, erode the cancellous bone and ultimately cause destruction of the bony cortex. Radiographically, these lesions appear as punched-out, rounded, 1-2 cm-sized defects in the affected bone.

Grossly, the normal bone marrow is replaced by soft, gelatinous, reddish-grey tumours. The affected bone usually shows focal or diffuse osteoporosis.

Microscopically, the diagnosis of multiple myeloma can be usually established by examining bone marrow aspiration from an area of bony rarefaction. However, if the bone marrow aspiration yields dry tap or negative results, a biopsy of a radiologically abnormal or tender site is usually diagnostic.

The following features characterise a case of myeloma:

1. Cellularity: There is usually hypercellularity of the bone marrow.

2. Myeloma cells: Myeloma cells constitute ≥10% of the marrow cellularity. These cells may form clumps or sheets or may be scattered among the normal haematopoietic cells.

• Myeloma cells may vary in size from small, differentiated cells resembling normal plasma cells to large, immature and undifferentiated cells. Binucleate and multinucleate cells are sometimes present.
• The nucleus of a myeloma cell is commonly eccentric similar to plasma cells but usually lacks the cart-wheel chromatin pattern seen in classical plasma cells. Nucleoli are frequently present.
• The cytoplasm of these cells is abundant and basophilic with perinuclear halo, and vacuolisation and contains Russell bodies consisting of hyaline globules composed of synthesised immunoglobulin.
• In addition to neoplastic proliferation of plasma cells in multiple myeloma, reactive plasmacytosis in the bone marrow can occur in some other disorders; these include aplastic anaemia, rheumatoid arthritis, SLE, cirrhosis of the liver, metastatic cancer and chronic inflammation and infections such as tuberculosis.

However, in all these conditions the plasma cells are mature and they do not exceed 10% of the total marrow cells.

2. Extraosseous Lesions:

Late in the course of disease, lesions at several extraosseous sites become evident.

Some of the commonly involved sites are as under:

1. Blood: Approximately 50% of patients with multiple myeloma have a few atypical plasma cells in the blood. Other changes in the blood in myeloma are the presence of anaemia (usually normocytic normochromic type), marked red cell rouleaux formation due to hyperviscosity of blood, and an elevated ESR.

2. Myeloma kidney: Renal involvement in myeloma called myeloma nephrosis occurs in many cases (Chapter 714). The main mechanism of myeloma kidney is by filtration of light chain proteins (Bence Jones proteins) which are precipitated in the distal convoluted tubules in combination with Tamm-Horsfall proteins as tubular casts. The casts may be surrounded by some multinucleate giant-cells and a few inflammatory cells.

3. Myeloma neuropathy: Infiltration of the nerve trunk roots by tumour cells produces nonspecific polyneuropathy. Pathologic fractures, particularly of the vertebrae, may occur causing neurologic complications.

4. Systemic amyloidosis: Systemic primary generalised amyloidosis (AL amyloid) may occur in 10% cases of multiple myeloma and involve multiple organs and systems.

5. Liver, spleen involvement: Involvement of the liver and spleen by myeloma cells sufficient to cause hepatomegaly, and splenomegaly occurs in a small percentage of cases.

Morphologic  Clinical Features:

The clinical manifestations of myeloma result from the effects of infiltration of the bones and other organs by neoplastic plasma cells and from immunoglobulin synthesis.

The principal clinical features are as under:

1. Bone pain is the most common symptom. The pain usually involves the back and ribs. Pathological fractures may occur causing persistent localised pain. Bone pain results from the proliferation of tumour cells in the marrow and activation of osteoclasts which destroy the bones.

2. Susceptibility to infections is the next most common clinical feature. Particularly common are bacterial infections such as pneumonias and pyelonephritis. Increased susceptibility to infection is related mainly to hypogammaglobulinaemia, and partly to granulocyte dysfunction and neutropenia.

3. Renal failure occurs in about 25% of patients, while renal pathology occurs in 50% of cases. Causes of renal failure in myeloma are hypercalcaemia, glomerular deposits of amyloid, hyperuricaemia and infiltration of the kidney by myeloma cells.

4. Anaemia occurs in about 80% of patients of myeloma and is related to marrow replacement by the tumour cells (myelophthisis) and inhibition of haematopoiesis.

5. Bleeding tendencies may appear in some patients due to thrombocytopenia, deranged platelet function and interaction of the M component with coagulation factors.

6. Hyperviscosity syndrome owing to hyperglobulinaemia may produce headache, fatigue, visual disturbances and haemorrhages.

7. Neurologic symptoms occur in a minority of patients and are explained by hyperviscosity, cryoglobulins and amyloid deposits.

8. Biochemical abnormalities.

These include the following:

1. Hypercalcaemia due to destruction of bone;
2. Hyperuricaemia from necrosis of tumour mass and from uraemia related to renal failure; and
3. Increased β-2 microglobulins and other globulins in urine and serum.

9. Poems syndrome is seen in about 1% cases of myeloma and includes simultaneous manifestations of polyneuropathy, organomegaly, endocrinopathy, multiple myeloma and skin changes.

Morphologic Diagnosis:

The WHO criteria for diagnosis of symptomatic myeloma is based on classic triad of features:

1. Bone marrow clonal plasmacytosis of >10% or plasmacytoma on biopsy

2. presence of monoclonal proteins (M component) in serum or urine

3. Related organ or tissue impairment (CRAB= increased calcium level, renal insufficiency, anaemia, bone lesions)

Recently, revised criteria for diagnosis and management of multiple myeloma have been recommended. In addition to CRAB features, revised criteria include presence of at least one of the following 3 myeloma-defining events:

• ≥ 60% of clonal plasma cells on bone marrow examination
• ≥ 100 as the ratio of serum involved/uninvolved free light chain (either kappa or lambda)
• ≥ 5 mm-sized more than one focal lesion on MRI.

Diagnosis of asymptomatic or smouldering myeloma is made by the following criteria:

1. Presence of M-component in serum
2. Clonal plasma cells in the bone marrow >10%
3. No related organ impairment i.e. no CRAB.

There is rise in the total serum protein concentration due to paraproteinaemia but normal serum immunoglobulins (IgG, IgA and IgM) and albumin are depressed. Paraproteins are abnormal immunoglobulins or their parts circulating in plasma and excreted in urine.

• About twothird cases of myeloma excrete Bence Jones (light chain) proteins in the urine, consisting of either kappa (κ) or lambda (λ) light chains, along with presence of Bence Jones paraproteins in the serum.
• On serum electrophoresis, the paraprotein usually appears as a single narrow homogeneous M-band component, most commonly in the region of γ-globulin. Most frequent paraprotein is IgG seen in about 50% cases of myeloma, IgA in 25%, and IgD in 1%, while about 20% patients have only light chains in serum and urine (light chain myeloma).
• Nonsecretory myeloma is absence of M-band on serum and/or electrophoresis but presence of other two features out of triad listed above. Though the commonest cause of paraproteinaemias is multiple myeloma, certain other conditions which may produce serum paraproteins need to be distinguished.

These are as under:

1. Monoclonal gammopathy of undetermined significance (MGUS)
2. Waldenström’s macroglobulinaemia
3. Benign monoclonal gammopathy
4. B-cell lymphomas
5. CLL
6. Light chain disease
7. Heavy chain disease
8. Cryoglobulinaemia.

Multiple Myeloma Prognosis

Treatment Plan And Prognosis:

Treatment of multiple myeloma consists of systemic chemotherapy in the form of alkylating agents and symptomatic supportive care. Autologous stem cell transplantation and interferontherapy are the other modern treatment modalities offered.

Poor prognostic predictors for lower survival are:

Secretion of λ-light chain than those secreting κ-light chain, larger number of cytogenetic abnormalities, and increased β2 microglobulin level. The median survival is 2 years after the diagnosis is made. The terminal phase is marked by the development of pancytopenia, severe anaemia and sepsis.

Localised Plasmacytoma:

Two variants of myeloma which do not fulfil the criteria of classical triad are the localised form of solitary bone plasmacytoma and extramedullary plasmacytoma. Both these are associated with M component in about a third of cases and occur in young individuals.

• Solitary bone plasmacytoma is a lytic bony lesion without marrow plasmacytosis. Extramedullary plasmacytoma involves most commonly the submucosal lymphoid tissue of nasopharynx or paranasal sinuses.
• Both variants have better prognosis than the classic multiple myeloma. Plasma cell granuloma, on the other hand, is an inflammatory condition having admixture of other inflammatory cells with mature plasma cells, which can be easily distinguished by a discernible observer.

Multiple Myeloma Prognosis

Waldenström’S Macroglobulinaemia:

Waldenström’s macroglobulinaemia is an uncommon malignant proliferation of monoclonal B lymphocytes which secrete IgM paraproteins called macroglobulins as they have high molecular weight. The condition is more common in men over 50 years of age and behaves clinically like a slowly progressive lymphoma.

The exact etiology is not known but a possible relationship of IgM macroglobulin with myelin-associated glycoprotein which is lost in degenerating diseases has been suggested. The clinical evidence in favour is the appearance of peripheral neuropathy before the occurrence of macroglobulinaemia in some patients.

Morphologic Features: Pathologically, the disease can be regarded as the hybrid between myeloma and small lymphocytic lymphoma.

• Like myeloma, the disease involves the bone marrow, but unlike myeloma it usually does not cause extensive bony lesions or hypercalcaemia. The bone marrow shows pleomorphic infiltration by lymphocytes, plasma cells, lymphocytoid plasma cells, mast cells and histiocytes. Like in myeloma, serum M component is present.
• Unlike myeloma and more like small lymphocytic lymphoma, enlargement of lymph nodes, spleen and liver due to infiltration by similar type of cells is present more frequently.

Multiple Myeloma Prognosis

Clinical Features: The clinical features of the disease are due to both infiltration by the disease and paraproteins in the blood.

1. Hyperviscosity syndrome is the major clinical manifestation. It results in visual disturbances, weakness, fatiguability, weight loss and nervous system symptoms. Raynaud’s phenomenon may occur.
2. Moderate organomegaly in the form of lymphadenopathy, hepatomegaly and splenomegaly are frequently seen.
3. Anaemia due to bone marrow failure may be present.
4. Bleeding tendencies may occur due to interaction of macroglobulins with platelets and coagulation factors.

Diagnosis: Unlike myeloma, there are no characteristic radiologic findings.

The diagnosis rests on laboratory data as under:

1. Pleomorphic bone marrow infiltration
2. Raised total serum protein concentration
3. Raised serum monoclonal M component which is due to IgM paraprotein
4. Elevated ESR
5. Normocytic normochromic anaemia.

Multiple Myeloma Diagnosis

The management of the patients is similar to that of myeloma. Patients respond to chemotherapy with a median survival of 3-5 years.

Heavy Chain Diseases:

Heavy chain diseases are rare malignant proliferations of B-cells accompanied by monoclonal excess of one of the heavy chains. Depending upon the type of excessive heavy chain, three types—γ, α and µ, of heavy chain diseases are distinguished:

Gamma Heavy Chain Disease: Also called Franklin’s disease, it is characterised by excess of mostly γ1-paraprotein, both in the serum and urine and is demonstrated as M component.

Clinically, the condition may develop at any age and present with lymphadenopathy, splenomegaly, hepatomegaly, involvement of pharyngeal lymphoid tissue (Waldeyer’s ring) and fever. Patients have rapidly downhill course due to severe and fatal infection.

Alpha Heavy Chain Disease: This is the commonest of heavy chain diseases characterised by α-heavy chains in the plasma which are difficult to demonstrate in electrophoresis due to rapid polymerisation.

The patients present with bowel symptoms such as chronic diarrhoea, malabsorption and weight loss and may have enlargement of abdominal lymph nodes. Chemotherapy may induce long-term remissions.

Mu Heavy Chain Disease: This is the rarest heavy chain disease. The neoplastic B-cells produce m heavy chains which do not appear in the urine but κ light chains which are also produced appear in the urine.

Another feature that distinguishes this type of heavy chain disease from the others is the presence of vacuoles in the malignant B lymphocytes. The course and prognosis are like those of leukaemia or lymphoma.

Multiple Myeloma Diagnosis

Monoclonal Gammopathy Of Undetermined Significance (MGUS):

Due to longevity, monoclonal gammopathy of undetermined significance (MGUS) is now increasingly diagnosed in asymptomatic healthy ageing population—1% at 50 years of age and in 10% individuals older than 75 years. This makes it the most common form of plasma cell dyscrasia.

The defining criteria for MGUS are as under:

1. M-protein in serum <3 gm/dl
2. Marrow plasmacytosis <10%
3. No evidence of other B-cell proliferative disorder
4. Absence of myeloma-related end-organ tissue damage (i.e. absence of lytic bone lesions, high calcium level, anaemia).

The condition needs to be cautiously distinguished from myeloma and long term follow-up is required. In fact, MGUS has been considered as a forerunner of multiple myeloma in many studies because MGUS has been found to have the same chromosomal abnormalities as in myeloma.

Plasma Cell Disorders:

• Multiple myeloma is a multifocal malignant proliferation of plasma cells derived from a single clone of B cells (i.e. monoclonal).
• Prolonged radiation exposure and black race are some of the factors implicated in its etiology.
• The diagnosis of myeloma is made by osteolytic punched out osseous lesions, marrow plasmacytosis, and demonstration of M band in serum or urine electrophoresis
• Localised plasmacytoma may be solitary bone lesion or extramedullary. It is generally not associated with marrow plasmacytosis.
• Waldenström’s macroglobulinaemia is an uncommon malignant= proliferation of B cells.
• Heavy chain diseases due to malignant proliferation of B cells with monoclonal excess of one of heavy chains are rare.
• Monoclonal gammopathy of undetermined significance (MGUS) is common and is now increasingly diagnosed in asymptomatic healthy ageing population