Dr.P.

Sathyadharan MS(Ortho)
Assistant Professor - Orthopaedics

Introduction
Malignant proliferation of plasma cells derived

from SINGLE clone.

Plasma cell

 A variety of chromosomal alterations - most

common translocations are t(11;14)(q13;q32)

and t(4;14)(p16;q32),
Mutations in p53 and Rb-1 have also been

described.

Epidemiology
2nd most common blood cancer next to Non-Hodgkins

lymphoma.
Myeloma increases in incidence with age. The
median age at diagnosis is 68 years; it is uncommon
under age 40.
The yearly incidence is around 4 per 100,000 .
Males >>> females
Blacks have twice the incidence of whites

Clinical Features
Bone pain (70%)
Lytic lesion in the bone
Site of involvement

Back & Ribs,

Pain precipitated by movement

Clinical features(cont.d)
Complications

Pathological fracture-persistent pain at the local

site

Spinal Cord Compression due to collapse of the

vertebrae

Clinical features(cont.d)
Immuno compromised state
Increase susceptibility to bacterial infections.
The most common infections are pneumonias

and pyelonephritis
Organisms in the lungs- Streptococcus
pneumoniae, Staphylococcus aureus, and
Klebsiella pneumoniae.
Organisms in the urinary tract- Escherichia coli
and other gram-negative

Clinical features(cont.d)
Renal failure occurs in nearly 25% of myeloma
patients,
Hypercalcemia
Glomerular deposits of amyloid, hyperuricemia,

recurrent infections but Glomerular function is usually

normal
frequent use of nonsteroidal anti-inflammatory agents
for pain control, use of iodinated contrast dye for
imaging, bisphosphonate use,
myeloma cells infiltrates
Tubular damage associated with the excretion of light
chains

Clinical Features(cont.d)
The earliest manifestation of this tubular

damage is the adult Fanconi syndrome (a type

2 proximal renal tubular acidosis),
Proteinuria is uncommon
Hyponatremia (pseudohyponatremia)
susceptible to acute renal failure if they
become dehydrated

Clinical Features(cont.d)
Haematological
Anemia - 80% . It is usually normocytic and

normochromic
Some have megaloblastic anemia due to either folate

or vitamin B12 deficiency.

Granulocytopenia and thrombocytopenia are very rare.
Clotting abnormalities may be seen

failure of antibody-coated platelets to function properly

interaction of the M component with clotting factors I, II, V,
VII, or VIII.

Clinical features(cont.d)
Vascular
Deep venous thrombosis is also observed
Raynaud's phenomenon and impaired

circulation may result if the M component

forms cryoglobulins

Hyperviscosity
Depends on the physical properties of the M

component (most common with IgM, IgG, and

IgA paraproteins).
Paraprotein concentrations of ~40 g/L (4 g/dL)

for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7

g/dL) for IgA.
Symptoms: headache, fatigue, visual

disturbances, and retinopathy

 Hypercalcemia - lethargy, weakness,

depression, and confusion.

Bony damage and collapse - cord
compression, radicular pain, and loss of bowel
and bladder control.
Infiltration of peripheral nerves by amyloidcause of carpal tunnel syndrome sensory
,motor mono and polyneuropathies.
Sensory neuropathy is also a side effect of
thalidomide and bortezomib therapy

Variants of Myeloma
Solitary bone plasmacytomas may recur in

other bony sites or evolve into myeloma.

Extramedullary plasmacytomas
submucosal lymphoid tissue of nasopharynx
or paranasal sinus without marrow
plasmacytosis
rarely recur or progress
Both highly responsive to local radiation theray

Diagnostic features
Plasmacytosis in marrow
Monoclonal protein in serum or urine
Lytic disease of bone

Asymptomatic Multiple
Myeloma
M protein in serum>30g/L
Bone marrow clonal plasma cells > 10%
No myeloma-related organ or tissue

impairment (no end organ damage, including

bone lesions) or symptoms

Symptomatic Multiple
Myeloma
M protein in serum and/or urine
Bone marrow (clonal) plasma cells or

plasmacytoma
Myeloma-related organ or tissue impairment
(end organ damage, including bone lesions

Nonsecretory Myeloma
No M protein in serum and/or urine with

immunofixation
Bone marrow clonal plasmacytosis 10%
Myeloma-related organ or tissue impairment
(end organ damage, including bone lesions)

Solitary Plasmacytoma of
Bone
No M protein in serum and/or urine
Single area of bone destruction due to clonal

plasma cells
Bone marrow not consistent with multiple
myeloma
Normal skeletal survey (and MRI of spine and
pelvis if done)
No related organ or tissue impairment (no end
organ damage other than solitary bone lesion

Myeloma-related organ or tissue

impairment (ROTI)
Calcium levels increased
renal insufficiency
anemia
bone lesions
symptomatic hyperviscosity,
amyloidosis,
recurrent bacterial infections (>2 episodes in

12 months)

Investigations
CBC with differential may reveal anemia
ESR is elevated.
Rare patients (~2%) may have plasma cell

leukemia with >2000 plasma cells/L.

Serum calcium, urea nitrogen, creatinine, and
uric acid levels may be elevated.
Protein electrophoresis and measurement of
serum immunoglobulins and free light chains.

Cont.d
A 24-h urine specimen is necessary to

quantitate protein excretion

Serum alkaline phosphatase is usually normal
It is also important to quantitate serum Beta 2microglobulin.
Serum soluble IL-6 receptor levels and Creactive protein may reflect physiologic IL-6
levels in the patient

Serum M Component
IgG in 53% of patients, IgA in 25%, and IgD in

1%
20% of patients will have only light chains in
serum and urine.
Bence Jones protein is falsely negative in
~50% of patients with light chain myeloma.

Serum M Component
Fewer than 1% of patients have no identifiable

M component- have light chain myeloma

About two-thirds of patients with serum M
components -urinary light chains.

Criteria for Diagnosis of

Multiple Myeloma

Durie Salmon Diagnostic Criteria

Major Criteria
I-Plasmacytoma on tissue biopsy.
II-Bone marrow plasmacytosis(>30% plasma
cells)
III-Monoclonal immunoglobulin spike
IgG>3.5g/dl or IgA>2g/dl
kappa/lamda chain excretion>1g/dayin
24 hr UPEP

Minor Criteria
a)Bone marrow plasmacytosis(10-30%plasma cells).
b)Lesser magnitude of Ig spike
c)Lytic lesions
d)Normal IgM:<50mg/dl

Normal IgA<100mg/dl or
Normal IgG<600 mg/dl
I plus b, c, or d
II plus b, c, or d
III plus a, c, or d
a plus b plus c
a plus b plus d

Durie-Salmon staging
Staging system is based on the
hemoglobin, calcium, M component, and degree of
skeletal involvement
low (stage I), intermediate (stage II), or high (stage III),
stages are further subdivided on the basis of renal
function [A if serum creatinine <2 mg/dL, B if >2 mg/dl].
stage IA have a median survival of >5 years and those
in stage IIIB about 15 months.
This staging system has been found not to predict

prognosis after treatment with high-dose therapy or

the novel targeted therapies that have emerged.

Stage I
Estimated Tumor Burden < 0.6 (x 10 12 cells/m2)
Hemoglobin >100 g/L (>10 g/dL)
Serum calcium <3 mmol/L (<12 mg/dL)
Normal bone x-ray or solitary lesion
Low M-component production
IgG level <50 g/L (<5 g/dL)
IgA level <30 g/L (<3 g/dL)
Urine light chain <4 g/24 h

Stage III
Hemoglobin <85 g/L (<8.5 g/dL)
Serum calcium >3 mmol/L (>12 mg/dL)
Advanced lytic bone lesions
High M-component production
IgG level >70 g/L (>7 g/dL)
IgA level >50 g/L (>5 g/dL)
Urine light chains >12 g/24 h

International Staging
System
Beta 2M < 3.5, alb 3.5

Beta 2M < 3.5, alb < 3.5 or Beta 2M = 3.55.5

Beta 2M > 5.5

Disorder Associated with

Monoclonal Protein
Neoplastic cell proliferation

multiple myeloma
solitary plasmacytoma
Waldenstrom macroglobulinemia
heavy chain disease
primary amyloidosis
Undetermined significance
monoclonal gammopathy of

undetermined significance (MGUS)

Disorder Associated with

Monoclonal Protein
Transient M protein

viral infection
post-valve replacement
Malignacy
bowel cancer, breast cancer
Immune dysregulation
AIDS, old age
Chronic inflamation

Monoclonal gammopathy of
undetermined significance
( MGUS)
M protein presence, stable
levels of M protein: IgG < 3.5g IgA <

2g LC<1g/day
normal immunoglobulins - normal levels
marrow plasmacytosis < 10%
complete blood count - normal
no lytic bone lesions
no signs of disease

M protein

3% of people > 70 years

15% of people > 90 years
MGUS is diagnosed in 67% of

patients with an M protein

10% of patients
with MGUS develop
Monoclonal
gammopathy
of
multiple myeloma
undetermined
significance

( MGUS)

Treatment
Patients with symptomatic and/or progressive

myeloma require therapeutic intervention.

symptomatic supportive care to prevent
serious morbidity from the complications of
the disease.
Therapy can significantly prolong survival and
improve the quality of life for myeloma
patients.

Treatment - Transplant
Alkylating agents such as melphalan should

be avoided since they damage stem cells,

leading to decreased ability to collect stem
cells for autologous transplant.
High-dose pulsed glucocorticoids have been
used either alone or VAD combination for 3
weeks for initial cytoreduction.

Treatment - Transplant
Initial therapy is continued until maximal

cytoreduction.
Agents bortezomib, a proteasome inhibitor,
and lenalidomide, an immunomodulatory
derivative of thalidomide, have similarly been
combined with dexamethasone and obtained
high response rates without compromising
collection of stem cells for transplantation

Treatment - Chemotherapy
Only
Intermittent pulses of an alkylating agent, L-

phenylalanine mustard (L-PAM, melphalan)

and prednisone administered for 47 days
every 46 weeks.
The usual doses of melphalan/prednisone

(MP) are melphalan, 8 mg/m2 per day, and

prednisone, 2560 mg/m2 per day for 4 days.

Treatment - Chemotherapy
Only
In patients >65 years, combining thalidomide

with MP (MPT) obtains higher response rates

and overall survival than MP alone
MPT is the standard therapy for patients who
are not transplant candidates

 High-dose melphalan therapy (HDT) with

hematopoietic stem cell support have shown

that HDT can achieve high overall response
rates and prolonged progression-free and
overall survival;
Only few patients are cured.
Complete responses are rare (<5%) with
standard-dose chemotherapy, HDT achieves
2540% complete responses.

Refractory Myeloma
lenalidomide and/or bortezomib.
These agents target not only the tumor cell

but also the tumor cellbone marrow

interaction
These agents in combination with
dexamethasone can achieve up to 60% partial
responses and 1015% complete responses in
patients with relapsed disease

Thalidomide, if not used as initial therapy, can

achieve responses in refractory cases.

High-dose melphalan and stem cell
transplant, if not used earlier, can be used

Supportive Treatment

 Supportive care directed at the anticipated

complications of the disease may be as

important as primary antitumor therapy.
Hypercalcemia
Dehydration
ARF
Hyperviscosity
UTI
Recurrent serious infection-Prophylactic IV
globulin

Supportive Treatment
Patients developing neurologic symptoms in the

lower extremities, severe localized back pain, or

problems with bowel and bladder control may
need emergency MRI and radiation therapy for
palliation.
Most bone lesions respond to analgesics and
chemotherapy
The anemia associated with myeloma may
respond to erythropoietin along with hematinics
(iron, folate, cobalamin).

Prognosis
The median overall survival of patients with

myeloma is 56 years,
Subsets of patients surviving over 10 years.
The major causes of death are
progressive myeloma,
renal failure, sepsis, or
therapy-related acute leukemia or myelodysplasia.
intercurrent age related illnesses: myocardial

infarction, chronic lung disease, diabetes, or stroke