Transcript Multiple myeloma - Semmelweis Egyetem I. sz

Multiple myeloma (MM)
The second most common adult
haematological malignancy. MM is
a clonal malignancy of terminally
differentiated plasma cells.
Multiple myeloma: Epidemiology and
incidence
• Annual incidence of approximately 30-50 per
million.
• Median age at presentation of about 70 years.
Approximately 15% of patients are aged <60
years and a further 15% are aged between 60
and 65 years. Fewer than 2% of myeloma
patients are under 40.
• Myeloma has a higher incidence in AfroCaribbean ethnic groups compared with
Caucasians.
• Median survival:
– From the diagnosis: 3-5 years
– From the first relapse: 1-3 years
– In case of refracter disease: 6-9 months
Myeloma: Clinical presentation
• Symptoms of bone disease: tipically persistent,
unexplained backache
• Impaired renal function
• Anaemia: typically normochromic, normocytic. Less
frequently leukopenia and thrombocytopenia
• Hypercalcaemia
• Recurrent or persistent bacterial infections
• Hyperviscosity
• Symptoms suggestive of spinal cord/nerve root
compression
• Features suggestive of amyloidosis
• Raised erythrocyte sedimentation rate
The role of RANKL/RANK/OPG system in
myeloma bone disease
Myeloma cells induce
the RANKL expression
Myeloma cells decrease
the OPG avaiability
Increased osteoclast activity,
decerased osteoblast function
Lateral skull X-ray with typical findings of multiple myeloma:
multiple "punched-out" holes. The arrow is pointing at one of the
larger holes
Spinal radiograph showing generalized osteopenia
and multiple compression fractures.
Renal impairment in multiple myeloma
• Prevalence in up to 30% of patients at
presentation and up to 50% of patients at
some stage of disease.
• Light-chain component of the
immunglobulin can cause proximal tubular
damage.
– Other factors: dehydration, hypercalcaemia,
hyperuricaemia, infection and use of
nephrotoxic drugs, amyloid, plasma cell
infiltration and use of NSAIDs
Anaemia and immundeficiency in MM
• Anaemia is present in two-thirds of patients at
presentation and becomes more common in
patients with progressive disease
• Myeloma patients have B-cell defects with
hypogammaglobulinaemia.
• Disturbed T-cell function has also been
demonstrated.
• During chemotherapy neutropenia may occur.
• High-dose corticosteroid treatment also
compromise defences against fungal and viral
infections.
Diagnostic criteria of multiple
myeloma
• Demonstration of a monoclonal protein (Mprotein/paraprotein) in the serum or urine
and
• lytic lesions on X-ray together with
• an increased number (>10%) of plasma
cells in the bone marrow.
Patients with multiple myeloma show a "spike"
in special regions of the serum protein
electrophoresis
Bone marrow smear in multiple
myeloma
Other conditions in which an Mprotein may be present
• Monoclonal gammopathy of undetermined
significance (MGUS; prevalence 3% in
those over 70 years old)
• AL amyloidosis
• Solitary plasmocytoma (skeletal or extra
medullary)
• B-cell non-Hodgkin lymphoma
• CLL
Diagnostic criteria for MGUS,
asymptomatic and symptomatic myeloma
MGUS
Asymptomatic
myeloma
Symptomatic myeloma
<30 g/l
>30 g/l
No specific level required
Bone marrow <10%
clonal plasma
cells
>10%
>10%
Myelomarelated organ
or tissue
impairment
and/or
symptoms
No
Yes (hypercalcemia, renal
insuff., anaemia, bone
lesions, symptomatic
hyperviscosity, amyloidosis,
recurrent bacterial infections
M-protein in
serum
No
Progression of MGUS and asymptomatic
myeloma to active disease
• The average risk of progression from
MGUS to active myeloma is about 1% per
year
– Only proven prognostic factor for progression
to myeloma is serum M-protein level. The risk
of progression in 10 years equal with
paraprotein level in g/l
• The median time to progression from
asymptomatic to symptomatic myeloma is
12-32 months
Multiple Myeloma Disease
1
Progression
100
Symptomatic
M Protein (g/l)
Asymptomatic
Active
Myeloma
Relapse
50
20
Refractory
Relapse
MGUS* or
Smoldering
Myeloma
Plateau
Remission
Therapy
*Monoclonal
gammopathy
of uncertain
significance
~19,000
New cases
in EU2
Therapy
~53,000
Annual patients in the EU2
Therapy
~15,000
Annual
deaths in EU
1. Adapted from International Myeloma Foundation; 2001. Reprinted with permission.
2. International Agency for Research on Cancer, World Health Organisation; Ferlay J, Bray F, Pisani, P and Parkin DM. Globocan 2000
Diagnostic Tests for Multiple Myeloma
• Blood and urine tests1
– Complete blood count (CBC) to detect if red blood cells, white blood cells,
or platelets are outside of normal range
– Chemistry profiles including blood urea nitrogen (BUN)2, calcium,
creatinine, and lactate dehydrogenase (LDH)
– 24-hour urine collection to measure levels of protein in the urine
– Serum protein electrophoresis or urine electrophoresis to measure levels of
immunoglobulins
– Immunoelectrophoresis or immunofixation to provide more specific
information about the type of abnormal immunoglobulins present
– ESR
• Bone tests1
– Bone (skeletal) survey utilizing X-ray or magnetic resonance imaging (MRI)
to assess bone involvement and number/size of lytic lesions
– Bone marrow aspiration/bone marrow biopsy to measure number of plasma
cells in the marrow
1. The Washington Manual of Oncology. Philadelphia, PA: Lippincott Williams & Wilkins; 2002. 2. The Merck Manual of Diagnosis and Therapy.
Sec II, ch 140, plasma cell dyscrasias. Available at: http://www.merck.com/pubs/mmanual/sectionII/chapter 140/140d.htm. Accessed March 25, 2003.
The use of imaging techniques in myeloma
• Plain radiographs is the standard method for
radiological screening at diagnosis
• CT scanning: higher sensitivity than plain X-ray
at detecting small lesions
• MR imaging: is useful for the assessment of the
extent and nature of soft tissue disease. For
investigation of patients with neurological
symptoms suggestive of cord compression.
Essential investigation in the differential
diagnosis of solitary plasmacytoma and
myeloma.
• PET scanning: Useful in detecting occult sites of
disease in myeloma and solitary plasmacytoma
The changes in the treatment of
multiple myeloma
1990s Supportive care
1962
Prednisone +
melphalan
Melphalan
1999
First report on
thalidomide
From 1980s
Myeloablation +
ASCT
March/April 2005
Bortezomib
approved for
second-line
in USA & Europe
2000s
Tandem
ASCT
Bortezomib
US licence 2003,
EU licence 2004
Treatment of hypercalcemia (occurs in up to
30% of myeloma patients, typically in active
disease)
• In mild hypercalcemia (se Ca:2,6-2,9
mmol/l) oral rehydration
• In moderate-severe hypercalcemia (se Ca
≥2,9 mmol/l)
– rehydrate with intravenous fluids and give
loop-diuretic drug.
– Start bisphosphonate immediately
– Additional therapy in refractory patients
General recommendation for
bisphosphonate therapy
• Bisphosphonate therapy is recommended for
all patients with myeloma requiring
chemotherapy, whether or not bone lesions are
evident.
• Treatment should be continued at least 2 years.
• Oral clodronate (1600 mg/day) and monthly iv.
pamidronate ( 90 mg) or zoledronic acid (4 mg)
are equivalent in efficacy.
• Renal function should be monitored, in case of
severe renal failure the dose should be reduced
• No proven indication of bisphosphonates in
asympromatic patients.
Prevention and management of renal
failure
•
•
•
•
•
Maintenance of a high fluid intake (3l/d)
Nephrotoxic drugs should be avoided
Hypercalcaemia must be corrected
Infection must be treated
In case of progressive renal failure plasma
exchange (theoretically beneficial in cast
nephropathy)
• Dialysis
Management of anaemia
• Anaemia usually improves with response
to chemotherapy.
• The use of EPO may be considered in
patients with symptomatic anaemia.
• Serum EPO concentration should be
measured (high EPO concentration, high
transfusion requirement and a low-platelet
count are negative prognostic factor for a
response to EPO)
Infections in myeloma
• Febrile myeloma patient should be treated
promptly with broad-spectrum antibiotics
that will cover S. pneumoniae, H.
influenzae and E. coli, which are the most
common causes of infections.
• Administration of immunglobulins should
be reserved for patients with recurrent
infections.
Other complications of multiple
myeloma
• Cord compression
– Occurs in 5% of patients. MRI, ther.: dexamethasone, local
radiotherapy
• Peripheral neuropathy
– Paraproteinaemic neuropathy should be considered in any
patients with monoclonal protein presenting with weakness,
numbness, paraesthesiae and hyporeflexia. IVIG therapy may
be effective.
• Hyperviscosity
– In patients with high paraprotein levels. Symptomatic patients
should be treated by plasma exchange. Chemotherapy should
be started promptly
• Amyloidosis
– Complications: cardiac failure, renal impairment and neuropathy,
lead to increased toxicity with various threpautic options
(anthracyclins, thalidomide, streoids)
The changes in the treatment of
multiple myeloma
1990s Supportive care
1962
Prednisone +
melphalan
Melphalan
1999
First report on
thalidomide
From 1980s
Myeloablation +
ASCT
March/April 2005
Bortezomib
approved for
second-line
in USA & Europe
2000s
Tandem
ASCT
Bortezomib
US licence 2003,
EU licence 2004
Measuring the response to therapy
Complete remission
No M-protein detected in serum or urine. Fewer
than 5% plasma cells in bone marrow, no
hypercalcemia
Partial remission
>50% reduction in serum paraprotein level and/or
90% reduction in urine free light chain excretion.
In non-secretory disease at least 75% reduction
in bone marrow plasma cells number
Minimal response
25-49% reduction in serum M-protein or <90%
reduction in urinary light chain excretion.
Plateau
No evidence of continuing myeloma-related organ
damage, less than 25% change in serum Mprotein levels for 3 months
Progressive disease
Organ damage continuing despite therapy or its
re-appearance in plateau-phase
Relapse
Reappearance of disease in patients previously in
CR
Treatment algorithms for patients with
multiple myeloma
MPT
MPV
Thaldex
2. Line VelDex,
VTD
1. The early intervention in asymptomatic patients has shown no benefit
2. Transplant candidate or not a transplant candidate
Criteria to decide which patient is eligible
for high dose chemotherapy followed by
stem cell rescue
• Age
– Initial studies tended to enroll patients younger than
65 years of age
– Recent studies indicate that transplant is safe in at
least same who are over the age of 70
• Co-morbid medical conditions
• Risk stratification
– Poor-risk chromosomal features have a short time to
progression after auotologous transplantation
Risk stratification:
International Staging System
Stage
Criteria
Median survival
(months
I
Se β2 microglobulin <3,5 mg/l
and se albumin >35 g/l
62
II
Se β2 microglobulin between 3,5- 45
5,5 mg/l or Se β2 microglobulin
<3,5 mg/l but se albumin <35 g/l
III
Se β2 microglobulin >5,5 mg/l
29
Greipp et al 2003.
For individual patients the best staging systems can predict survival outcome
with around 70% sensitivity and specificity.
Cytogenetics-based prognostic
grouping
Risk group
Cytogenetics
Median Overall
Survival
Poor
t(4;14)
t(14;16)
p13-
24,7 months
Intermediate
-13q14
42,3 months
Good
All others
50,5 months
The significance of cytogenetic information:
-Decision of possibility of stem cell transplantation
- indication of molecularly targeted approach of patients
Median survival time after transplantation
according to the presence or absence of risk
factors
Risk factor combinations at
diagnosis
Median survival time
Low β2-microglobulin level and > 111 months
absence of Δ13
High β2-microglobulin level
and absence of Δ13 or
Low β2-microglobulin and
presence of Δ13
High β2-microglobulin level
together with Δ13
Moreau P et al, Blood 2006;107:397-403.
47 months
25 months
Approach to newly diagnosed symptomatic
myeloma
Low risk
Not a transplant
candidate
High risk
Transplant
candidate
Dex or Thal-Dex or
VAD x 4 cycles
Stem Cell Harvest for 2 transplants
Early Tx1; Tx2 in relapse
Rajkumar SV 2004.
Conventional chemother (HDC, melphalan
200 mg/m2) to plateau phase. Tx1 at relapse
Induction therapy in transplant candidate
patients
• VAD (repeated monthly)
– Vincristin 0.4 mg 1-4. days.
– Adriamycin 9 mg/m2 1-4. days
– Dexamethason 40 mg 1-4., 9-12., 17-20. days
• Dex (repeated monthly)
– 40 mg/day on day 1 trough 4, 9 through 12, and 17
through 20
• Thal-Dex (repeated monthly)
– Thal 200 mg/d p.o. with Dex on day 1 trough 4, 9
through 12, and 17 through 20
The changes in the treatment of
multiple myeloma
1990s Supportive care
1962
Prednisone +
melphalan
Melphalan
1999
First report on
thalidomide
From 1980s
Myeloablation +
ASCT
March/April 2005
Bortezomib
approved for
second-line
in USA & Europe
2000s
Tandem
ASCT
Bortezomib
US licence 2003,
EU licence 2004
Melphalan + prednisone is the standard of care for
induction therapy in not transplant candidate elderly
patients with multiple myeloma
Melphalan+ Melphalan+
prednisone Dex
Dex
Dex+
Interferon
Partial response
41%
70%
40%
42%
Complete
response
1%
3%
1%
1%
Median
progression-free
survival
21.1 mos
22.9 mos.
12.2
mos.
15.2 mos
Severe pyogenic
infection
11%
20%
13%
11%
Any severe toxicity
18%
33%
31%
31%
Facon T et al. Blood 2006;107:1292-1298.
Induction therapy of multiple myeloma in
patients who are not candidate for stem
cell transplantation
• The dose of Melphalan = 7-12 mg/m2/day,
4-7 days, given on an every 4-6 weeks
schedule until plateau phase.
– Side effects: nephrotoxicity, myelotoxicity.
• Combined chemotherapy can improve the
remission rate together with higher
prevalance of side effects.
The story of thalidomide
• First marketed in the 1950s for the
treatment of pregnancy-related morning
sickness and later as a sedative.
• It was withdrawn because of serious
adverse events in pregnant women
including teratogenicity and dysmelia.
• Interest in the drug resurfaced in the
1990s because of its antiangiogenic and
immunmodulatory effects
Thalidomide in multiple myeloma:
mechanisms of action
• Antiangiogenic effects, mediated via inhibition
of VEGF (vascular endothelial growth factor) and
βFGF(fibrobalst growth factor)
• Inhibition of multiple myeloma growth
factors, including IL-6, TNFα, and VEGF
• Down-regulation of binding of myeloma cells
to bone marrow stromal cells
• Immunmodulatory effects, evidenced by
upregulation of natural killer cells (through the
release of interferon gamma and IL-2),
producing MM cell lysis
• Direct proapoptotic effects, arrests G1 growth
phase of myeloma cells
Richardson et al.: J Clin Oncology 2006;24(3):1-2., San Miguel JF, Haemat Rep, 2005;1(11):2-6
Facon T et al, J Clin Oncol 2006;24:1s
Comparison of results of MP and MPT
treatment in older patients with newly
diagnosed multiple myeloma
Response quality
Melphalan+
Prednisone (MP)
Melphalan+Prednisone
+ Thalidomide (MPT)
Complete response
2%
16%
At least a partial
response
40%
81%
17.1 mos.
32.2 mos.
27.6 mos
53.6 mos
Response durability
- Progression-free
survival
- Overall survival
More than 50% of patients reaching a PR within
the first 2 months of therapy
Regimens not based on MP
• Thal/dex 200-400 mg thalidomide/day +
dexamethasone 40 mg/day on 1-4., 9-12.
and 17-20. days. (remission rate: 64%) as
first-line therapy.
• Thalidomide+pegylated liposomal
doxorubicin+dexamethasone.
Comparable response rates (84%) in
untreated patients as well as those with
relapsed/refractery disease.
Thalidomide toxicity
• Thromboembolic episodes (involving
venous or arterial events)
• Neutropenia, thrombocytopenia
• Constipation
• Infections (pneumonia, herpes zoster)
• Peripheral neuropathy
• Psychiatrical problems (letargy, fatigue)
• Skin reactions and cardiac events
Lenalinomid: more potent thalidomide, and has a more favorable
toxicity profile than thalidomide
Proteasome inhibition is a new
second- or third-line treatment
possibility in multiple myeloma
Bortezomib seems able to
enhance chemosensitivity and
overcome chemoresistance
Summary: Mechanism of Action
of Bortezomib (VELCADE)
1 The 26S proteasome is a
large protein complex that
degrades tagged proteins
2 Bortezomib
is a reversible
inhibitor of the chymotrypsin-like
activity of the 26S proteasome
3 Inhibition of the 26S
4 Nonclinical studies
showed bortezomib to
be cytotoxic to a variety
of cancer cell types
proteasome prevents
proteolysis of tagged
proteins which can affect multiple
signaling cascades with the cell
Millennium Pharmaceuticals, Inc., 2003.
Adams J. Drug Discov Today. 2003;8:307-315.
Bortezomib (VELCADE)
 Cytokine
 Adhesion
MM cells
 Angiogenesis
 TNFa
 IGF-I
BMSC
X
 VEGF
 IL-6
BM Vessels
IL-6, VEGF
Block
activation
FAS
IkB/NFkB
Intracellular level
 Apoptosis Inhibitors
(IAP, FLICE)
PI3K
Caspases
8,3
antiapoptotic
Increased
Apoptosis
San Miguel J. Hematol J. 2003;4(suppl 3):201-207.
MAPK
proliferation
Decreased
Proliferation
Inhibition
DNA-repair effectors
Disruption of
unfolded protein
response
Normal Cells Survive Effects
of VELCADE™
• Normal cells can recover from transient
proteasome inhibition
– 72 hour rest period
• Cancer cells are more susceptible
– Pre-existing dysregulation of cell cycle, growth,
differentiation and apoptotic mechanisms
– Myeloma cells are 100-1000 times more sensitive
to effects of VELCADE™
• Absence of side-effects such as mucositis and
alopecia
– Common with other cytotoxic agents that target all dividing
cells
Velcade: Dosing and schedule
•
1.3 mg/m2 as a 3- to 5-second bolus IV
injection
via peripheral or central IV catheter
– Follow with a standard saline flush
Day 1
Bortezomib
1.3 mg/m2
•
Day 4
Bortezomib
1.3 mg/m2
Day 8
Bortezomib
1.3 mg/m2
Day 11
Bortezomib
1.3 mg/m2
10-day
REST
PERIOD
REPEAT
CYCLE
At least a 72-hr rest period between doses is
required
– Allows for restoration of proteasome function
towards baseline
Alkalmazási előirat Janssen-Cilag 2005
Clinical studies
SUMMIT
CREST
APEX
Study design
Phase II, openlabel, multicenter
Phase II, open-label,
multicenter, randomized;
two dose levels bortezomib
± dexamethasone
Phase III,
international, openlabel, randomized
to bortezomib or
dexamethasone
Patients
Relapsed or
refractory MM;
n=202
Relapse during/following
front-line therapy for MM;
n=54
Relapsed MM;
n=669
Endpoints
Primary: overall
response rate
(CR + PR + MR)
Secondary:
safety, quality of
life, clinical
benefit
Overall response rate
(CR + PR + MR)
Primary: time to
progression (TTP)
Secondary:
overall/1-year
survival, response
rate, duration, time
to response, safety
Richardson et al. N Engl J Med 2003;348:2609;
Jagannath et al. Br J Hematol 2004;127:165;
Richardson et al. ASH 2004 (abstract 336.5)
Updated Results of APEX Trial
►SURVIVAL
Overall and 1-Year Survival
P=.0272
– Bortezomib continues to demonstrate superior survival despite >
62% of HD dex pts crossing over to bortezomib
– Median OS: 29.8 months (95% CI: 23.2, not estimable) vs 23.7 months
(95% CI: 18.7, 29.1); hazard ratio = 0.77; P = 0.0272
 1-year survival rate: 80% vs 67%; P = 0.0002
Richardson P, et al. ASH 2005, abstract #2547
Velcade + Dexamethasone
The evidence of remission: PET Scan
Plasmacytomas
Pretreatment
After 4 Cycles
Jagannath et al. ASH 2004; Abstract 333
Past and current treatment algorithms for
not transplant candidate patients with
multiple myeloma
Orlowski RZ. Multiple Myeloma. Hematology 2006:338-347.
BP=: bendamustine+prednisone; MDT= Melphalan+Prednisone+Thalidomide;
MP=melphalan+prednisone; R-MP=melphalan+prednisone+lenalidomide;
ThaDD=thalidomide+pegylated liposomal doxorubicin+dexamethasone;
VMP=melphalan+prednisone+bortezomib
Orlowski RZ. Multiple Myeloma. Hematology
2006:338-347.
A hypothetical future treatment algorithm for
patients with multiple myeloma
Waldenström’s macroglobulinaemia
• Malignancy of lymphoplasmacytoid cells that
secrete IgM.
• Rare disease, 2% of hematological malignancies
• The disease associates with lymphadenopathy
and hepatosplenomegaly, but the major clinical
manifestation is the hyperviscosity syndrome.
• Slightly more common in men and occuring with
increased incidence with age (median age at
presentation is 63 year).
• The disease involves bone marrow, but unlike
myeloma, it does not cause bone lesion or
hypercalcaemia.
Waldenström’s macroglobulinaemia
• Malignant lymphocytes are present in the
peripheral blood.
• Like myeloma, a serum M component is present
in the serum in excess of 30 g/l, but inlike
myeloma, the size of the IgM paraprotein result
in little renal excretion. Therefore, renal disease
is not common.
• Median survival is about 5 years (in appr. 10% of
patients is more than 15 years).
The differential diagnosis of WM from
other B-lymphoproliferative disorders
Ghobrial I, Witzig T: Waldenström Macroglobulinemia. Current Treatment
Options in Oncology. 5(3):239-247.
Clinical symptoms and physical
abnormalities in patients with WM
Symptom
Frequency Physical abnormality Frequency
Weakness
66%
Hepatomegaly
20%
Loss of apetite
25%
Splenomegaly
19%
Peripheral
neuropathy
24%
Lymphadenopathy
15%
Weight loss
17%
Purpura
9%
Fever
15%
Other bleedings
(retinal hemorrhages)
7%
Raynaud’s
phenomenon
11%
Tarkovács G: Waldenström macroglobulinaemia. in Fókuszban az onkológia és az
onkohematológia, ed.: Dank M, Demeter J, 2006. Melinda Kiadó
Characteristic features of WM
Retinal hemorrhage
from hyperviscosity
BM showing increased numbers of BM showing IgM in cytoplasm of
lymphoid and plasmacytoid cells
lymphoid cells with
immunofluorescence
The serum protein
electrophoretic pattern is
characterized by a tall,
narrow peak (bottom
center) or dense band
Frequency of laboratory abnormalities at the
presentation of WM
Parameter
Frequency
Anaemia (Hb<120 g/l)
63%
Leukopenia (<3x109/l)
4%
Throbocytopenia (<100x109/l)
16%
IgM (monoclonal)
-kappa/lambda ratio
- >30 g/l
-Cryoglobulins
80/20
35%
10% of macroglobulins
Serum béta2-microglobulin >3 mg/l
62%
Serum viscosity >4
17%
Indications of the therapy in patients with
WM
• Appearence of general symptoms (fever, fatigue
caused by anaemia, loss of body weight)
• Progressive hepatosplenomegaly, symptoms
related to lymphadenomegaly
• Severe anaemia and/or thrombocytopenia
• Hyperviscosity (plasmapheresis)
• Amyloidosis (cardiomyopathy, nephrotic
syndrome, peripheral neuropathy)
• Cryoglobulinaemia with symptoms ( Raynaud’s
phenomenon)
Treatment of WM
Major response
rate (>50%
reduction of IgM
concentration)
Median
duration of
response
75%
46 months
Fludarabine
-first-line treatment
-Salvage-treatment
75.5%
33.7%
BM depression,
40-60 months opportunic infections,
30-32 months Coombs + hemolysis
Cladribine
-first-line treatment
-Salvage-treatment
56.6%
42.6%
20-39 months
8-12 months
Rituximab
44-48%
16-29 months In patients with
cytopenia. Temporary
IgM
Thalidomide
?
?
Corticosteroid
Mostly in patients with cryoglobulinaemia and iimmune
vasculitis
Chlorambucil