This document provides a comprehensive overview of multiple myeloma (MM) and its associated plasma cell disorders, detailing the biological mechanisms, clinical manifestations, epidemiology, and prognosis. It highlights key aspects such as the detection of monoclonal proteins (m components), organ dysfunction, susceptibility to infections, and renal failure linked to MM, as well as its differentiation from related conditions like monoclonal gammopathy of undetermined significance (MGUS) and Waldenström's macroglobulinemia. Additionally, the document explains diagnostic criteria, staging, and the significance of cytogenetic abnormalities for patient prognosis.

1. Dr E.Mohammadzadeh
Medical Oncologist & Hematologist;Internist
Kerman University of Medical Sciences
Multiple Myeloma

2. Multiple Myeloma: Introduction
 Plasma cell disorders are neoplastic or potentially
neoplastic diseases associated with the clonal proliferation
of plasma cells.
 They are characterized by the secretion of monoclonal
proteins that represent intact or incomplete IG molecules.
Monoclonal proteins are commonly referred to as M
proteins, myeloma proteins, or paraproteins.

3. MM: Introduction
 Syndromes associated with plasma cell disorders and monoclonal
proteins include premalignant disorders (monoclonal gammopathy
of undetermined signifcance, smoldering multiple
myeloma), malignant neoplasms (multiple myeloma,
Waldenström macroglobulinemia), and disorders primarily
related to the unique properties of the secreted monoclonal protein
(cryoglobulinemia, immunoglobulin light chain [AL] amyloidosis, light
chain deposition disease).

4. MM: Introduction
 Ab molecules are composed of two heavy chains and two
light chains. Each chain has a constant portion and a variable
region.There are five heavy chain isotypes (M, G,A, D, E)
and two light chain isotypes ( , ).
κ λ
 The variable region forms the Ag recognition site of the Ab;
its unique structural features form a particular set of
determinants, that are reliable markers for a particular
clone of cells.

6. MM: Introduction
 In most plasma cells, light chains are synthesized in slight
excess, are secreted as free light chains, and are cleared by
the kidney, but <10 mg of such light chains is excreted per
day.
 Electrophoretic analysis of components of the serum
proteins permits determination of the amount of
immunoglobulin in the serum.

7. MM: Introduction
 The Igs move heterogeneously in an electric field and form a
broad peak in the gamma region.The globulin region of the
γ
electrophoretic pattern is usually increased in the sera of
patients with plasma cell tumors.
 There is a sharp spike in this region called an M component
(M for monoclonal). Less commonly, the M component may
appear in the 2 or 2 globulin region.
β α
 The antibody must be present at a concentration of at least 5
g/L (0.5 g/dL) to be detectable by this method.This
corresponds to 109 cells producing the antibody.
∼

9. MM: Introduction
 Confirmation that such an M component is truly
monoclonal relies on the use of immunoelectrophoresis.
Hence immunoelectrophoresis and electrophoresis provide
qualitative and quantitative assessment of the M
component.
 In a given patient, the amount of M component in the
serum is a reliable measure of the tumor burden.This
makes the M component an excellent tumor marker.

12. MM: Introduction
 M components may be detected in other lymphoid neoplasms
such as CLL and lymphomas; nonlymphoid neoplasms such
as CML, breast and colon cancer; a variety of nonneoplastic
conditions such as cirrhosis, sarcoidosis, parasitic diseases,
Gaucher’s disease, and pyoderma gangrenosum; and a
number of autoimmune conditions, including RA,
myasthenia gravis, and cold agglutinin disease.
 At least two very rare skin diseases (lichenmyxedematosus,
or papular mucinosis, and necrobiotic xanthogranuloma)
are associated with a monoclonal gammopathy.

13. MM: Introduction
 The M component may be an intact Ab of any heavy chain
subclass, or it may be an altered Ab or fragment. Isolated light
or heavy chains may be produced.
 In 20% of myelomas, only light chains are produced and in
∼
most cases are secreted in the urine as Bence Jones proteins.
 The frequency of myelomas of a particular heavy chain class is
proportional to the serum concentration, and therefore IgG
myelomas are more common than IgA and IgD myelomas.

14. MM: Definition
 Multiple myeloma represents a malignant proliferation of
plasma cells derived from a single clone.
 MM is defined by the presence of 10% or more clonal plasma
cells on BM examination or biopsy-proven plasmacytoma;
and evidence of one or more myeloma defining events.
 The tumor, its products, and the host response to it result in
a number of organ dysfunctions and symptoms of bone pain
or fracture, renal failure, susceptibility to infection, anemia,
hypercalcemia, and occasionally clotting abnormalities,
neurologic symptoms, and manifestations of hyperviscosity.

15. MM: Epidemiology
 Multiple myeloma accounts for 1% of all malignant disease
and slightly more than 10% of hematologic malignant
neoplasms in the United States.
 Its incidence in blacks is almost twice that in whites and is
slightly more common in men than in women.
 The median age of patients at the time of diagnosis is about
65-70 years.

17. MM: Pathobiology
 The cause of MM is unclear. Exposure to radiation, benzene,
and other organic solvents, herbicides, and insecticides may
play a role.
 Almost all cases of myeloma evolve from a premalignant
MGUS phase, although the MGUS is clinically recognized
before the diagnosis of myeloma in only a small minority of
patients.

18. MM: Pathobiology
 The lytic bone lesions, osteopenia, hypercalcemia, and
pathologic fractures in patients with myeloma are a result of
abnormal osteoclast activity induced by the neoplastic plasma
cells as well as inhibition of osteoblast di erentiation
ff .
 The combination of osteoclast activation and osteoblast
suppression leads to the pure osteolytic bone disease that is
the hallmark of multiple myeloma.

20. MM: Clinical Manifestations
 Bone pain is the most common symptom, affecting nearly
70% of patients.The pain usually involves the back and ribs,
and unlike the pain of metastatic carcinoma, which often is
worse at night, the pain of MM is precipitated by movement.
 Persistent localized pain in a patient with myeloma usually
signifies a pathologic fracture.
 The bone lesions are caused by the proliferation of tumor
cells, activation of osteoclasts that destroy bone, and
suppression of osteoblasts.

22. MM: Clinical Manifestations
 The bone lesions are lytic and rarely associated with
osteoblastic new bone formation.Therefore radioisotopic
bone scanning is less useful in Dx than is plain radiography.
 The bony lysis results in hypercalcemia, and serious acute
and chronic complications of hypercalcemia may dominate
the clinical picture.
 Localized bone lesions may expand to the point that mass
lesions may be palpated, and the collapse of vertebrae may
lead to spinal cord compression

24. MM: Clinical Manifestations
 The next most common clinical problem in patients is
susceptibility to bacterial infections.
 The most common infections are pneumonias and
pyelonephritis, and the most frequent pathogens are
Streptococcus pneumoniae, Staphylococcus aureus, and
Klebsiella pneumoniae in the lungs and Escherichia coli and
other gram-negative organisms in the urinary tract.
 In 25% of patients, recurrent infections are the presenting
∼
features, and >75% of patients have a serious infection at
some time in their course.

25. MM: Clinical Manifestations
 The susceptibility to infection has several contributing causes.
First, patients have diffuse hypogammaglobulinemia if the M
component is excluded.The hypogammaglobulinemia is
related to both decreased production and increased
destruction of normal Abs.
 Some patients generate circulating regulatory cells in
response to their myeloma that suppress normalAb synthesis.
 In the case of IgG myeloma, normal IgGAbs are broken down
more rapidly than normal because the catabolic rate for IgG
antibodies varies directly with the serum concentration.

26. MM: Clinical Manifestations
 These patients have very poor Ab responses, especially to
polysaccharide Ags such as those on bacterial cell walls.
 A subset of CD4+T cells may be decreased.
 Granulocyte lysozyme content is low, and granulocyte
migration is slow.
 Abnormalities in complement functions is also responsible.
 Some commonly used therapeutic agents, suppress immune
responses and increase susceptibility to infection.

27. MM: Clinical Manifestations
 Renal failure occurs in nearly 25% of patients and
Hypercalcemia is the most common cause.
 Glomerular deposits of amyloid, hyperuricemia, recurrent
infections, frequent use of NSAIDs, use of iodinated contrast,
bisphosphonate use, and occasional infiltration of the kidney
by myeloma cells all may contribute to renal dysfunction.
 Tubular damage associated with the excretion of light chains
is almost always present.
 The proteinuria is not accompanied by hypertension, and the
protein is nearly all light chains.

28. MM: Clinical Manifestations
 Generally, very little albumin is in the urine because
glomerular function is usually normal.When the glomeruli
are involved, nonselective proteinuria is also observed.
 Patients with myeloma also have a decreased anion gap [i.e.,
Na+ – (Cl– + HCO3–)] because the M component is
cationic.
 Renal dysfunction due to light chain deposition disease, light
chain cast nephropathy, and amyloidosis is partially reversible
with effective therapy.

29. MM: Clinical Manifestations
 Normocytic & normochromic anemia occurs in ~80% of
patients:
 Replacement of BM by tumor cells,
 Inhibition of hematopoiesis by factors made by the tumor,
 Reduced EPO production by the kidney
 Effects of therapy
 Hemolysis
 Megaloblastic anemia
 ClottingAbnormalities
 Hyperviscosity

30. MM: Clinical Manifestations
 Neurologic symptoms occur in a minority of patients:
 Hypercalcemia
 Hyperviscosity
 Bony damage and collapse
 Infiltration of peripheral nerves by amyloid
 Sensory neuropathy due to therapy
 LAP & Splenomegaly are rare in MM.

34. MM: Dx & Staging
 The most important differential diagnosis in patients with
myeloma involves their separation from individuals with
MGUS or SMM.
 MGUS is vastly more common than myeloma, occurring in
1% of the population >50 years of age and in up to 10%
individuals >75 years.
 With long-term follow-up, 1% per year of patients with
∼
MGUS go on to develop myeloma and all myeloma is
preceded by MGUS.

39. MM: Dx & Staging
 Non-IgG subtype, abnormal kappa/lambda free light chain
ratio, and serum M protein >15 g/L (1.5 g/dL) are
associated with higher incidence of progression of MGUS to
myeloma.
 The features responsible for higher risk of progression from
SMM to MM are BM plasmocytosis >10%, abnormal
kappa/lambda free light chain ratio, and serum M protein
>30 g/L (3 g/dL).

42. MM: Dx & Staging
 Important variants of myeloma:
 Solitary bone plasmacytoma and extramedullary
plasmacytoma.
 These lesions are associated with an M component in <30%
of the cases, they may affect younger individuals, and both
are associated with median survivals of ≥10 years.
 Solitary bone plasmacytoma is a single lytic bone lesion
without marrow plasmacytosis.

43. MM: Dx & Staging
 Extramedullary plasmacytomas usually involve the
submucosal lymphoid tissue of the nasopharynx or paranasal
sinuses without marrow plasmacytosis.
 Both tumors are highly responsive to local RT.
 Solitary bone plasmacytomas may recur in other bony sites or
evolve into myeloma.
 Extramedullary plasmacytomas rarely recur or progress.

47. MM: Dx & Staging
 Rare patients ( 2%) may have
∼ plasma cell leukemia with
>2000 plasma cells/µL.This may be seen in
disproportionate frequency in IgD (12%) and IgE (25%)
myelomas.
 Serum alkaline phosphatase is usually normal even with
extensive bone involvement because of the absence of
osteoblastic activity.
 The serum M component will be IgG in 53% of patients, IgA
in 25%, and IgD in 1%; 20% of patients have only light
chains in serum and urine.

48. MM: Dx & Staging
 Patients secreting lambda light chains have a significantly
shorter overall survival than those secreting kappa.
 The heavy chain isotype may have an impact on patient
management: About half of patients with IgM paraproteins
develop hyperviscosity compared with only 2–4% of patients
with IgA and IgG M components.
 Among IgG myelomas, it is the IgG3 subclass that has the
highest tendency to form aggregates, leading to
hyperviscosity and cold agglutination at lower serum
concentrations.

49. MM: Prognosis
 Serum 2-microglobulin is the single most powerful
β
predictor of survival and can substitute for staging.
 Other factors that may influence prognosis are the presence
of cytogenetic abnormalities and hypodiploidy, chromosome
17p deletion, t(4;14), t(14;16) and t(14;20).
 The ISS system, along with cytogenetic changes is the most
widely used method of assessing prognosis

55. WALDENSTRÖM’S MACROGLOBULINEMIA
 WM is a malignancy of plasmacytoid lymphocytes that
secrete large quantities of IgM.
 It is a chronic disorder a ecting elderly patients (median age
ff
of 64 years) that shares features of the low-grade lymphomas
and myeloma.
 Unlike myeloma,WM is associated with LAP and
hepatosplenomegaly, and although bone marrow involvement
invariably occurs, lytic lesions and hypercalcemia are rare.

56. WALDENSTRÖM’S MACROGLOBULINEMIA
 The major clinical manifestations include anemia and the
hyperviscosity Syndrome.
 Epistaxis, retinal hemorrhages, dizziness, confusion, and
CHF may occur as a result of the hyperviscosity syndrome.
 About 10% of IgM proteins have properties of cryoglobulins,
and patients show symptoms of cryoglobulinemia or cold
agglutinin syndrome demonstrated as acrocyanosis,
Raynaud’s phenomenon, and vascular symptoms or hemolytic
anemia precipitated by exposure to cold.

57. WALDENSTRÖM’S MACROGLOBULINEMIA
 Some patients withWaldenström macroglobulinemia may
develop a peripheral neuropathy that may antedate the
appearance of the neoplastic process.
 The approach to and treatment ofWM are similar to those of
other low-grade B-cell lymphomas.