Multiple myeloma is a cancer of plasma cells that produces abnormal proteins. It most commonly affects people over age 65 and is more common in African populations. Symptoms include bone pain, infections, anemia, kidney problems, and neurological issues. Diagnosis requires the presence of clonal plasma cells in bone marrow, monoclonal proteins in blood or urine, or biomarkers of malignancy. Initial tests evaluate for paraproteins, organ damage, tumor burden, and prognosis.

1. Multiple Myeloma
Dr. Sayem Bin Latif
MD (Cardiology) Phase A Resident
Chittagong Medical College & Hospital
23 Sept 2018
sayembinlatif@gmail.com

2. Introduction
• Multiple myeloma is clonal plasma cell neoplasm
• Usually accompanied by monoclonal antibody production
• 1% of all cancer
• Median age 65 years
• Incidence higher in African populations

3. Etiology
• Familial clustering
• African Americans
• Radiation
• Agriculture ex. Benzene
• Sheet metal work
• Chronic inflammatory disorders

4. Gammopathy
• Gammopathy refers to over-production of one or more classes of
immunoglobulin.
• It may be polyclonal or monoclonal.

5. Monoclonal Gammopathy
• This term refers to the presence of a monoclonal immunoglobulin
band in the serum
• Monoclonal immunoglobulin band = M-protein or paraprotein
• Paraproteins are abnormal immunoglobulin produced by atypical
plasma cell.
• Monoclonal gammopathies/Paraproteinemia may occur in association
with normal or reduced levels of the other immunoglobulins.

6. Polyclonal Gammopathy
• A gammopathy in which there is heterogeneous increase in
immunoglobulins involving more than one cell line
• Normally serum immunoglobulin are polyclonal and represent the
combined output from millions of different plasma cells.

8. Diseases associated with M-proteins/Paraprotein
Malignant or
uncontrolled production
• Multiple myeloma
• Waldenstrom's
macroglobulinaemia
• MGUS
• NHL
• Solitary plasmacytoma
• CLL
• Primary amyloidosis
• Heavy chain disease
Benign or
stable production
• Chronic cold haemagglutinin
disease
• RA
• SLE
• Transient (e.g. with infections)
• AIDS
• Gaucher's disease
• Rarely with some solid tumor

9. Subject Benign Malignant
Bence-Jones proteinuria Absent May be Present
S paraprotein concentration Usually <20 g/L
and stationary
Usually >20 g/L & rising
Serum free light chain ratio Normal Abnormal
Immunoparesis
(hypogamaglobinaemia)
Absent Present
Underlying lympho
proliferative
disease or myeloma
Absent Present
Bone lesions Absent Present
Plasma cells in marrow < 10% > 10%
Features of benign and malignant paraproteinaemia

10. Normal Plasma Cell
 Derived from B cell.
 Large cell
 Oval or round
 Cytoplasm – basophilic with
small granule
 Nucleus - Round
- eccentric
- peri nuclear halo
- absent nucleoli
- Chromatin arranged in
coarse strand, gives rise to “cart
wheel” appearance.

11. Plasma Cell

12. Atypical plasma cell
 Large cell
 Cytoplasm – increased
- light blue
- vacuolation
- Russel bodies
- perinuclear halo
 Nucleus - eccentric
- loose or fine chromatin
- single prominent nucleoli

13. Bone Marrow

17. Plasma cell Neoplasm
 Monoclonal gammopathy of undetermined significance(MGUS)
 Plasma cell myeloma variants :
- Asymptomatic (smouldering) myeloma
- Non-secretory myeloma
- Plasma cell leukemia

18.  Plasmacytoma
- Solitary plasmacytoma of Bone
- Extra-osseous (extramedullary) plasmacytoma
 Immunoglobulin deposition disease
- Primary amyloidosis
- Systemic light & heavy chain deposition disease
 Osteosclerotic myeloma (POEMS syndrome)

19. MULTIPLE MYELOMA
 Multiple myeloma (myelomatosis) is a neoplastic proliferation of
plasma cells.
 Characterized by plasma cell accumulation in the bone marrow,
 The presence of monoclonal protein in the serum and/or urine and
 Related tissue damage in symptomatic pt.

20.  Normal plasma cells are derived from B cells and produce
immunoglobulins which contain heavy and light chains.
 Normal immunoglobulins are polyclonal, which means that a variety
of heavy chains are produced and each may be of kappa or lambda
light chain type.

21.  In myeloma, plasma cells produce immunoglobulin of a single heavy
and light chain, a monoclonal protein commonly referred to as a
paraprotein.
 In some cases only light chain is produced and this appears in the
urine as Bence Jones proteinuria.

22.  Annual incidence of MM is 4 per 1,00,000
 Blacks have nearly twice the incidence of whites.
 Myeloma accounts for 1% of all malignancies in whites and 2% in
blacks
 13% of all hematologic cancers in whites and 33% in blacks.
Etiology

23.  The incidence of myeloma is highest in African Americans and Pacific
islanders; intermediate in Europeans and North American whites; and
lowest in developing countries including Asia.
 Myeloma increases in incidence with age. The median age at diagnosis
is 70 years; it is uncommon under age 40.
 Male > females

24.  Myeloma occurred with increased frequency in those exposed to the
radiation of nuclear warheads in World War II after a 20-year latency.
 Myeloma has been seen more commonly than expected among
farmers who use herbicides & insecticides; wood workers, leather
workers, and those exposed to petroleum products & benzene.
 A variety of chromosomal alterations with prognostic significance has
been found in patients with myeloma; 13q14 deletions, 17p13
deletions, and translocations t(11;14)(q13;q32) and t(4;14)(p16;q32)
predominate.

29. C/F - Bone Lesion
 Bone pain Due to --
 Osteoporosis
 Pathologic fractures
 Lytic bone lesions
 Hypercalcaemia
* Tumor expansion
* Production of osteoclast
activating factor
by tumor cell
* Production of osteoblast
inhibitory factors

31.  Bone pain is the most common symptom in myeloma, affecting
nearly 70% of patients.
 The pain usually involves the back and ribs
 Unlike the pain of metastatic carcinoma, which often is worse at
night, the pain of myeloma is precipitated by movement.
 Persistent localized pain in a patient with myeloma usually signifies a
pathologic fracture.

32.  MM cell Several cytokines, including IL-1, lymphotoxin,
VEGF, receptor activator of NF- B (RANK) ligand, macrophage
inhibitory factor MIP-1 α, and TNF
Osteoclast activating factors
↑ osteoclast activity

33. Renal failure (25% pt of MM)
 The degree of renal failure is usually moderate, with a serum
creatinine lower than 4mg/dl.
 In 10% cases pts with newly diagnosed MM have renal failure severe
enough to require dialysis from the time of diagnosis.
 Tubular damage/ cast nephropathy associated with the excretion of
light chains is almost always present.

34.  Normally, light chains are filtered, reabsorbed in the tubules, and
catabolized.
 ↑ light chains in tubule  Tubular cells become overloaded
Light chain toxic effects
intracellular lysosomal enzymes.
Tubular damage results

35.  The earliest manifestation of this tubular damage is the adult Fanconi
syndrome (a type 2 proximal renal tubular acidosis), with loss of
glucose and amino acids, as well as defects in the ability of the kidney
to acidify and concentrate the urine.
 In myeloma kidney the typical feature consists of the presence of
myeloma casts, mainly composed of light chain in distal tubule &
collecting ducts.
 Cast formation ∝ severity of renal failure

36. Micrograph showing myeloma cast nephropathy in a kidney
biopsy. Hyaline casts are PAS positive (dark pink/red - right of
image). Myelomatous casts are PAS negative (pale pink - left of
image). PAS stain.

37. INFECTIONS
 Next to bone pain, most common clinical problem in patients with
myeloma is susceptibility to bacterial infections.
 The most common infections are pneumonia and pyelonephritis.
 Most frequent pathogens are Streptococcus pneumoniae,
Staphylococcus aureus, and Klebsiella pneumoniae in the lungs.

38. INFECTIONS - Why there is increased chance of
infection/ immune deficiency ?
Patients with myeloma have diffuse hypogammaglobulinemia if the M
component is excluded.
The hypogammaglobulinemia is related to both decreased production and
increased destruction of normal antibodies.
Some patients generate a population of circulating regulatory cells in
response to their myeloma that can suppress normal antibody synthesis.

39.  In the case of IgG myeloma, normal IgG antibodies are broken down
more rapidly than normal because the catabolic rate for IgG antibodies
varies directly with the serum concentration.
The large M component results in fractional catabolic rates of 8–16%
instead of the normal 2%.
 These patients have very poor antibody responses, especially to
polysaccharide antigens such as those on bacterial cell walls.

40. Granulocyte lysozyme content is low.
 Granulocyte migration is not as rapid as normal in patients with
myeloma, probably the result of a tumor product.
Abnormalities in complement functions in myeloma patients.
Some commonly used therapeutic agents, e.g., dexamethasone,
suppress immune responses and increase susceptibility to infection.

41. Anaemia & Bone marrow failure
 Normocytic and normochromic anemia occurs in 80% of myeloma
patients.
 A larger than expected fraction of patients may have megaloblastic
anemia due to either folate or vitamin B12 deficiency.

42.  Causes of anaemia -
 Replacement of normal marrow by expanding tumor cells
 Inhibition of hematopoiesis by factors made by the tumor
 Reduced production of erythropoietin by the kidney.
 Mild hemolysis.
 Chemotherapy with cytotoxic agents.

43.  Granulocytopenia and thrombocytopenia are very rare except when therapy-
induced.
 Clotting abnormalities may be seen due to -
 The failure of antibody-coated platelets to function properly or
 The interaction of the M component with clotting factors I, II, V,
VII, or VIII.
 Deep venous thrombosis is also observed with use of thalidomide or
lenalidomide in combination with dexamethasone.

44.  Raynaud's phenomenon and impaired circulation may result if the M component
forms cryoglobulins.
 Hyperviscosity syndromes may develop depending on the physical properties of
the M component (most common with IgM, IgG3, and IgA paraproteins).

45. Neurological Symptom
Neurological feature Cause
lethargy, weakness, depression, and
confusion.
Hypercalcemia
Headache, fatigue, visual
disturbances, and retinopathy.
Hyperviscosity
Radicular pain, and loss of bowel and
bladder control.
Cord compression due to Bony
damage and collapse
Sensory neuropathy side effect of thalidomide and
bortezomib therapy

46.  In case of spinal cord compression, dorsal spine is the most common
site of involvement, followed by the lumbar region.
 So clinical picture of spinal cord compression consists of back pain &
paraparesis.
 Lumbar involvement can cause a cauda equina syndrome ( LBP with
radicular distribution & leg weakness)

47. SPLEEN ?
LYMPH NODE?
Rarely causes enlargement of spleen, lymph nodes, or gut-associated
lymphatic tissue.

48. Rare presentations
• Soft tissue or solitary bone masses (plasmacytomas)
• Hyperviscosity-induced arterial infarctions or venous thrombosis
• Concomitant amyloidosis with gastrointestinal symptoms, peripheral
neuropathy, or cardiomegaly

49. Medical emergencies of MM
 Cord compression
 Pathologic fractures
 Hyperviscosity
 Sepsis
 Hypercalcemia

51. Classic triad of myeloma
 Marrow plasmacytosis (>10%)
- Bone marrow plasma cells are CD138+ and monoclonal
- If flow cytometry is performed, most plasma cells (>90%) will
show a "neoplastic" phenotype
 Lytic bone lesions
 A serum and/or urine M component.

52. INTERNATIONAL MYELOMA WORKING GROUP
(IMWG) CRITERIA FOR THE DIAGNOSIS OF
MULTIPLE MYELOMA

53.  The revised IMWG criteria allow, in addition to the classic CRAB
features, three “myeloma defining events” (MDEs).
 The presence of at least one of these markers is considered
sufficient for a diagnosis of multiple myeloma, regardless of the
presence or absence of symptoms or CRAB features.

54. The new definition of active multiple myeloma is:
• 1. Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or
extramedullary plasmacytoma and any one or more of the following
CRAB features and myeloma-defining events:
• 2. Evidence of end organ damage that can be attributed to the
underlying plasma cell proliferative disorder, specifically:
• Hypercalcemia: serum calcium >0.25 mmol/L (>1mg/dL) higher than
the upper limit of normal or >2.75 mmol/L (>11mg/dL)

55. • Renal insufficiency: creatinine clearance <40 mL per minute or serum
creatinine >177µmol/L (>2mg/dL)
• Anemia: hemoglobin valure of >20g/L below the lowest limit of
normal, or a hemoglobin value <100g/L
• Bone lesions: one or more osteolytic lesion on skeletal radiography,
CT, or PET/CT. If bone marrow has <10% clonal plasma cells, more
than one bone lesion is required to distinguish from solitary
plasmacytoma with minimal marrow involvement

56. • 3. Any one or more of the following biomarkers of malignancy (MDEs):
• 60% or greater clonal plasma cells on bone marrow examination
• Serum involved / uninvolved free light chain ratio of 100 or greater,
provided the absolute level of the involved light chain is at least 100mg/L
(a patient’s “involved” free light chain—either kappa or lambda—is the one
that is above the normal reference range; the “uninvolved” free light chain
is the one that is typically in, or below, the normal range)
• More than one focal lesion on MRI that is at least 5mm or greater in size.

57. Initial Investigations in Patients with Myeloma
 Screening tests
 Tests to establish diagnosis.
 Tests to estimate tumour burden and prognosis.
 Tests to assess myeloma related organ impairment (ROTI).
 Special tests indicated in some patients.

58. Ix – For Presence of a paraprotein
• Serum and urine should be screened by immunoglobulin
electrophoresis.

60. • CBC : - There is usually a normochromic normocytic or macrocytic
anaemia.
- Neutropenia and thrombocytopenia occur in advanced
disease
• PBF : -Rouleaux formation is marked in most cases.
- Abnormal plasma cells appear in the blood film in 15% of
patients and can be detected by sensitive flow cytometry in over 50%.
• ESR : Raised
• CRP : Raised

61.  Bone marrow Aspiration: Increased plasma cells (usually >20%)
often with abnormal forms
 Sermn calcium : elevation occurs in 45% of patients.
 Serum alkaline phosphatase : Typically normal, because of the
absence of osteoblastic activity (except following pathological
fractures).

62.  Serum creatinine : raised in 20% of cases.
 Serum albumin : decreased in advanced disease.
 Serum ϐ2-microglobulin: often raised and is a useful indicator of
prognosis. Levels less than 4 mg/L imply a relatively good prognosis.

63. Radiological investigation
 Reveals osteolytic areas without evidence of surrounding osteoblastic
reaction or sclerosis in 60% of patients.
 Generalized osteoporosis in 20%.
 Pathological fractures or vertebral collapse are common.

67. Tests to estimate tumour burden and
prognosis
 FISH analysis
 Quantification of Monoclonal protein in serum and urine
 Albumin
 β2-microglobulin
 Skeletal survey

71. Staging systems for patients with myeloma
 Based on a variety of clinical and laboratory tests, unlike the anatomic
staging systems for solid tumors.
 Serum β2-microglobulin is the single most powerful predictor of
survival and can substitute for staging.
 β2-Microglobulin is a protein of 11,000 mol wt with homologies to
the constant region of immunoglobulins that is the light chain of the
class I major histocompatibility antigens (HLA-A, -B, -C) on the
surface of every cell.

72. Durie & Salmon staging system

74.  Prognosis : Stage IA have a median survival of >5 years and
those in stage IIIB about 15 months.
 Limitation : This staging system has been found not to predict
prognosis after treatment with high-dose therapy or the novel targeted
therapies that have emerged.

75. Durie & Salmon plus staging system

76. International Staging Systems (ISS)/
International Prognostic Index (IPI)
for patients with myeloma
Factors Stage Median
Survival,
Months
β2M < 3.5,
alb ≥3.5
I (28%) 62
β2M < 3.5,
alb < 3.5 or
β2M = 3.5–5.5
II (39%) 44
β2M > 5.5 III (33%) 29