MULTIPLE MYELOMA

(MM)

MM

Definition:
B-cell malignancy characterised
by abnormal proliferation of
plasma cells able to produce a
monoclonal immunoglobulin (M
protein like IgG, IgA, IgD, or
IgE) or Bence-Jones protein

MM - Background
Normal Plasma Cell Function in the Immune
System
Stem cells can develop into B lymphocytes -- >travel to the
lymph nodes, mature, and then travel throughout the body.
When foreign substances (antigens) enter the body -- >B
cells develop into plasma cells that produce
immunoglobulins Ig (antibodies) to help fight infection and
disease.

Hematopoiesis

Figure legend: In multiple myeloma, the B cell is damaged and gives

rise to too many plasma cells (myeloma cells). These malignant cells
do not function properly and their increased numbers produce excess
immunoglobulins of a single type that the body does not need along
with reduced amounts of normal immunoglobulins.

MM Epidemiology (1)
Second most prevalent blood cancer
Approximately 1% of all cancers and 2% of all
cancer deaths.
45.000 currently have multiple myeloma
14.600 new cases of myeloma each year.
Responsible for more than 10.000 deaths in the
United States annually.
5 year survival rate

MM Epidemiology (2)
MM occurs in all races and all geographic
locations
African Americans and blacks from Africa is
two to three times the risk in whites
Risk is lower in Asians from Japan and in
Mexicans
Slightly more frequent in men than in women
(1.4:1)

MM Epidemiology (3)
MM is a disease of older adults
The median age at diagnosis is 66 years
Only 10 percent of patients are younger than
50 years
Only 2 percent of patients are younger than 40
years

MM Etiology
Genetic causes
Ongoing research is investigating whether HLA-Cw5 or
HLA-Cw2 may play a role in the pathogenesis of
myeloma.
Environmental or occupational causes
significant exposures in the agriculture, food, silicon,
Benzene, Nikel and petrochemical industries
Radiation:
Radiation has been linked to the development of myeloma.
In 109,000 survivors of the bombing of Nagasaki, 29 died
from myeloma from 1950-1976; however, some recent
studies do not confirm that these survivors have an
increased risk of developing myeloma.

MM - Pathophysiology
These myeloma cells travel through the bloodstream and
collect in the bone marrow, where they cause permanent
damage to healthy tissue.
As tumors grow, they invade the hard outer part of the bone,
the solid tissue.
In most cases, the myeloma cells spread into the cavities of all
the large bones of the body, forming multiple small lesions.
This is why the disease is known as "multiple" myeloma.

Figure legend: Bone marrow stromal cells and myeloma cells produce
cytokines that help myeloma cells grow and survive. Myeloma cells also
produce growth factors that stimulate new blood vessel formation through a
process called angiogenesis. New blood vessels provide nutrients and oxygen
to the tumor, allowing it to grow. The natural immune response that attacks
myeloma cells is suppressed.

Causes
Bone pains
Bone lesions

Involvment of immune
system

BONE MARROW
MONOCLONAL
PLASMA CELL
PROLIFERATION

Deformari
Fractures on
pathologic bone

Hypercalcemia

Cytopenia

Increased infectious
risk

Hypervascosity

Hyperproduction of
monoclonal
component

Renal clearance

Renal insuficiency

Auto-Antibody activity

eritrocite - hemaglutininelor la rece

trombocite afectarea functii
mielina - neuropatie senzitivo-motorie
factori ai coagulare - hemoragii
factorul von Willebrand
lipoproteina - hiperlipemii si xantoame
hormoni tiroidieni - hipotiroidie
structuri ale peretelui vascular

MM - Pathophysiology
Normally, plasma cells produce immunoglobulins to
fight infection
However, in MM and MGUS a single cloned plasma
cell proliferate and overproduce the same Ig (aka, the
"M-protein" or "paraprotein." )
o The M-protein is usually an IgG
MM cells can also just produce the light chain
component (Instead of the entire Ig)

MM - Pathophysiology
80% of cases of MM arise De Novo
20% percent from MGUS.
Risk factors for progression from MGUS to MM
include:
o An elevated M protein level > 1.5 g per dL
o A non-IgG MGUS
o Abnormal free light chain ratio
Patients with MGUS should be monitored closely q 6 to
12 months. (C-Level)

MM: Clinical Presentations

Anemia - 73 percent
Bone pain - 58 percent
Elevated creatinine - 48 percent
Fatigue/generalized weakness - 32 percent
Hypercalcemia- 28 percent
Weight loss - 24 percent, one-half of whom
had lost 9 kg

MM Clinical presentation
Clinical manifestations are related to malignant
behavior of plasma cells and abnormalities produced
by M protein
plasma cell proliferation:
multiple osteolytic bone lesions
hypercalcemia
bone marrow suppression ( pancytopenia )

monoclonal M protein
decreased level of normal immunoglobulins
hyperviscosity

MM Clinical presentation
Bone pain
Myeloma bone disease proliferation of tumor cells and
release of IL-6 (osteoclast activating factor :OAF)
stimulates osteoclasts to break down bone leading to
hypercalcemia
These bone lesions in plain radiographs-- > "punched-out" /
lytic bone lesion

MM Clinical presentation
Bone pain
Myeloma bone pain involves the rib ,sternum, spine ,
clavicle , skull , humerus & femur
The lumbar vertebrae are one of the most common sites of
pain -- >may lead to spinal cord compression.
Persistent localized pain may indicate a pathological
fracture.

MM Clinical presentation

MM Clinical presentation

MM Clinical presentation

MM Clinical presentation
Hypercalcemia - patients present with confusion,
somnolence, bone pain, constipation, nausea, and thirst.
Medical emergency

Anemia - normocytic and normochromic.

It results from the replacement of normal bone marrow by
infiltrating tumor cells and inhibition of normal red blood
cell production by cytokines.

MM Clinical presentation
Bleeding
bleeding resulting from thrombocytopenia.
In some patients, monoclonal protein may absorb clotting factors and
lead to bleeding, but this development is rare.

Hyperviscosity
high volume of monoclonal protein blood viscosity increases
complications such as stroke, myocardial ischemia, or infarction.
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
Medical emergency

MM Clinical presentation
Infection
Organism
:
polysaccharide
encapsulated
<strep.pneumoniae, H.influenzae>
Common pneumonia pathogens :S pneumoniae, S aureus,
and K pneumoniae
Common pathogens causing pyelonephritis : E coli and
other gram-negative organisms.
The increased risk of infection is due to immune deficiency
resulting from diffuse hypogammaglobulinemia, which is
due to decreased production and increased destruction of
normal antibodies.

MM Clinical presentation
Renal failure - Occurs in nearly 25% of myeloma
patients,
Hypercalcemia
Glomerular deposits of amyloid,
hyperuricemia,
recurrent infections, f
requent 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

MM Laboratory tests

ESR > 100

anaemia, thrombocytopenia
rouleaux in peripheral blood smears
marrow plasmacytosis > 10 -15%
hyperproteinemia
hypercalcemia
proteinuria
azotemia
osteolytic lesions in bones

Rouleaux Formation

MM Laboratory tests
total protein, albumin and globulin, BUN, creatinine, and
uric acid, which is high if the patient has high cell turnover
or is dehydrated
Serum
protein
electrophoresis,
electrophoresis, and immunofixation

urine

protein

Serum protein electrophoresis is used to determine the type of each

protein present and may indicate a characteristic curve (ie, where
the spike is observed).
Urine protein electrophoresis is used to identify the presence of the
Bence Jones protein in urine.
Immunofixation is used to identify the subtype of protein (ie, IgA
lambda).

SPEP: M-protein, M-spike

Immunofixation to Determine
Type of Monoclonal Protein

IgG
IgG kappa M protein

Lambda
Lambda Light
Light Chains
Chains

Kyle
Kyle RA
RA and
and Rajkumar
Rajkumar SV.
SV. Cecil
Cecil Textbook
Textbook of
of Medicine,
Medicine, 22nd
22nd Edition,
Edition, 2004
2004

MM Laboratory tests
A 24-hour urine collection for the Bence Jones protein (ie,
lambda light chains), protein, and creatinine
Quantification of proteinuria is useful for diagnosis (>1 g
of protein in 24 h is a major criterion) and for monitoring
the patient's response to therapy.
Creatinine clearance can be useful for defining the severity
of the patient's renal impairment.

MM - Imaging Work up
Skeletal Survey
o Skull, spine, long bones, ribs, pelvis
o Diffuse osteopenia may suggest myelomatous involvement
before discrete lytic lesions are apparent.
o Do not use bone scans to evaluate myeloma
MRI
o More sensitive
o But, generally reserved for suspected
spinal lesions

MM Laboratory tests
Procedures
bone marrow aspirate & biopsy
samples to calculate the percent of plasma cells in the
aspirate (reference range, <3%) and to look for sheets or
clusters of plasma cells in the biopsy specimen.

Bone marrow aspirate : plasma cells of multiple

myeloma.Note the blue cytoplasm, eccentric nucleus,
and perinuclear pale zone (or halo).

M M - Diagnostic Criteria
Major criteria
I. Plasmacytoma on tissue biopsy
II. Bone marrow plasma cell > 30%
III. Monoclonal M spike on electrophoresis IgG > 3,5g/dl,
IgA > 2g/dl, light chain > 1g/dl in 24h urine sample
Minor criteria
a. Bone marrow plasma cells 10-30%
b. M spike but less than above
c. Lytic bone lesions
d. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

M M - Diagnostic Criteria
Diagnosis:

I + b, I + c, I + d
II + b, II + c, II + d
III + a, III + c, I II + d
a + b + c, a +b + d

MM - Staging
Clinical staging
is based on level of haemoglobin, serum calcium,
immunoglobulins and presence or not of lytic bone
lesions
correlates with myeloma burden and prognosis
I. Low tumor mass
II. Intermediate tumor mass
III. High tumor mass
subclassification
A - creatinine < 2mg/dl
B - creatinine > 2mg/dl

MM - Staging
Durie-Salmon staging system
1. High tumor mass <stage III > one of following
a.
b.
c.

d.

abnormalitie mus be present

Hb <8.5 g/dl, Hct < 25 %
Sr Ca > 12 gm/dl
Very high Sr or Urine myeloma protein production rate
1. Ig G peak >7
gm/dl
2. IgA peak > 5
gm/dl
3. Bence
Joneprotein > 12 gm/ 24 hr
> 3 lytic bone lesion on bone survey

MM - Staging
Durie-Salmon staging system
2. Low tumor mass <stage I>
all of following must be present
a. Hb > 15 gm/dl, Hct> 32%
b. Sr Ca normal
c. Low Sr myeloma protein production rate
a.
b.
c.

d.

1. Ig G peak< 5 gm/dl
2. IgA peak < 3 gm/dl
3. Bence Jone protien < 4 g/ 24 hr

No bone lesion or osteoporosis

MM - Staging
Durie-Salmon staging system
3. Intermediate tumor mass <stage II>
a. no renal failure <Cr < 2 mg/dl>
b. Renal failure <Cr > 2 mg/dl>

MM - Staging
The International Staging System (ISS)
Stage I : 2-microglobulin (2M) < 3.5 mg/L, albumin > 3.5
g/dL
Stage II : 2M < 3.5 and albumin < 3.5; or 2M between 3.5
and 5.5
Stage III : 2M > 5.5
Median overall survival for patients with ISS stages I, II, and
III are 62, 44, and 29 months

MM: Treatment Decisions

Indications for treatment
Risk stratification
Eligibility for stem cell transplantation

MM: Treatment
Active care

Chemotherapy
Autologous / Allogenic stem cell transplamtation
Drug : Arsenic trioxide, Thalidomide & Immunomodulator
Interferon

Supportive care
Radiation therapy
Bisphosphonate
Kayphoplasty

Smoldering (asymptomatic)
myeloma
Deferral of chemotherapy until progression to
symptomatic disease
Follow these patients closely, every 3 to 4
months, with serum protein electrophoresis,
complete blood count, serum creatinine, and
serum calcium
Metastatic bone survey should be considered
annually because asymptomatic bone lesions
may develop

MM: Indications for Treatment

Anemia (hemoglobin <10 g/dL or 2 g/dL
below normal)
Hypercalcemia (serum calcium >11.5 mg/dL)
Renal insufficiency (serum creatinine>2
mg/dL)
Lytic bone lesions or severe osteopenia
Extramedullary plasmacytoma

MM: Risk stratification

FISH for detection of t(4;14), t(14;16), and del17p13
Conventional
cytogenetics
(karyotyping)
detection of del 13 or hypodiploidy

for

The presence of any of the above markers defines

high risk myeloma, which encompasses the 25
percent of MM patients who have a median survival
of approximately two years or less despite standard
treatment

Current Frontline Options

Conventional chemotherapy
Survival 3 yrs

Transplantation
Prolongs survival 4-5 yrs

Novel agents targeting stromal interactions and

associated signaling pathways have shown
promise

Chng WJ, et al. Cancer Control. 2005;12:91-104.

MM: initial therapy

The initial therapy of patients with
symptomatic myeloma varies depending on
whether patients are eligible or not to pursue
autologous hematopoietic cell transplantation

Initial Approach to Treatment of MM

Clearly not transplantation

candidate based on age, performance
score, and comorbidity

Potential transplantation
candidate

MPT, MPV, Len/dex

or clinical trial*

Nonalkylator-based
induction x 4 cycles

*Thal/dex or dex are additional options

especially if immediate response is
needed.

Stem cell harvest

NOT Eligible for Autologous

HCT
Age >77 years
Direct bilirubin>2.0 mg/dL (34.2 mol/liter)
Serum creatinine>2.5 mg/dL (221 mol/liter)
unless on chronic stable dialysis
Eastern Cooperative Oncology Group (ECOG)
performance status 3 or 4 unless due to bone
pain
New York Heart Association functional status
Class III or IV

Autologous Stem Cell Transplantation

Mel 200 mg/m2 standard conditioning regimen

Sufficient performance score, and adequate liver, pulmonary,
cardiac function needed
Higher PR and CR rates than conventional chemotherapy
Higher OS and EFS than conventional Rx
Advanced age and impaired renal function are, by themselves,
not contraindications

Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010.

Novel Frontline Options

Immunomodulatory drugs (IMiDs)

Thalidomide
Lenalidomide

Proteasome inhibitors
Bortezomib
Carfilzomib

Frontline Therapy in Elderly MM Patients

For elderly patients or those who are not suitable candidates
for transplantation, MP has been a standard treatment
ORR: 60%
Long-term CR: < 5%
Trials with MP-based combinations reported improved
response rates and time to progression
MPT
VMP

NCCN Practice Guidelines. Myeloma. V.3.2010.

Therapy Options: NonTransplant

Candidate

Melphalan + Prednisone (MP)

Melphalan + Prednisone + Thalidomide (MPT)
Dexamethasone (Dex)
Thalidomide + Dexamethasone (Thal/Dex)
Lenolidomide + Dexamethasone (Rev/Dex)
Bortezomib +/- Dexamethasone (Vel/Dex)

MM Supportive treatment
Supportive treatment
pain management
bone disease management
biphosphonates, calcitonin
recombinant erythropoietin
immunoglobulins
plasma exchange
radiation therapy

MM - Treatment of Bone Disease

Bisphosphonates
Surgical procedures
Vertebroplasty
Balloon Kyphoplasty

Radiotherapy
Treatment of myeloma

MM - Managing complications
Hypercalcemia
o Aggressive hydration, corticosteroids, lasix PRN
bisphosphonates
Renal Insufficiency
o Identifying reversible causes. Dialysis PRN.
o Plasmaphereis for hyperviscosity induced thrombosis
Anemia
o Erythopoetin, Transfusion
Infection
o Treat aggressively with broad spectrum antibiotics
o Vaccinations (B level)

Multiple Myeloma = M-CRAB

Monoclonal protein
Calcium
Renal failure
Anemia
Bone pain with lytic lesions