Transcript MULTIPLE MYELOMA

MULTIPLE MYELOMA
(MM)
Curs an IV - limba engleza
2012-2013
MM - Background
• Definition:
B-cell malignancy characterised
by abnormal proliferation of
plasma cells able to produce a
monoclonal immunoglobulin (M
protein )
MM - Background
• Multiple myeloma : as myeloma or plasma cell
myeloma
• cancer of the plasma cell
• Multiple myeloma
– excessive numbers of abnormal plasma cells in the
bone marrow
– overproduction of intact monoclonal immunoglobulin
(IgG, IgA, IgD, or IgE) or Bence-Jones protein (free
monoclonal κ and λ light chains)
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
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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,
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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
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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 kappa M protein
Lambda Light Chains
Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 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:
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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
abnormalitie mus be present
a. Hb <8.5 g/dl, Hct < 25 %
b. Sr Ca > 12 gm/dl
c. 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
d. > 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 : β2-microglobulin (β2M) < 3.5 mg/L, albumin > 3.5
g/dL
– Stage II : β2M < 3.5 and albumin < 3.5; or β2M between 3.5
and 5.5
– Stage III : β2M > 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
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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 µmol/liter)
• Serum creatinine>2.5 mg/dL (221 µmol/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
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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)
 FLU, PNA, HIB
Multiple Myeloma = M-CRAB
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Monoclonal protein
Calcium
Renal failure
Anemia
Bone pain with lytic lesions