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 Afro-
Caribbean 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 Myeloma cells decrease

the RANKL expression 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 (M-

protein/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 M-
protein 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 Symptomatic myeloma

myeloma
M-protein in <30 g/l >30 g/l No specific level required
serum
Bone marrow <10% >10% >10%
clonal plasma
cells
Myeloma- No No Yes (hypercalcemia, renal
related organ insuff., anaemia, bone
or tissue lesions, symptomatic
impairment hyperviscosity, amyloidosis,
and/or recurrent bacterial infections
symptoms
 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
Asymptomatic Symptomatic
Active
Myeloma
M Protein (g/l)

Relapse
50
Refractory
MGUS* or Relapse
Smoldering
Myeloma
20 Plateau
Remission

Therapy Therapy Therapy

*Monoclonal
gammopathy ~19,000 ~15,000
~53,000
of uncertain New cases Annual patients in the EU2 Annual
significance
in EU2 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 March/April 2005

Bortezomib
1962 1999 approved for
Prednisone + First report on second-line
melphalan thalidomide in USA & Europe

2000s
Melphalan From 1980s
Tandem
Myeloablation +
ASCT
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 March/April 2005

Bortezomib
1962 1999 approved for
Prednisone + First report on second-line
melphalan thalidomide in USA & Europe

2000s
Melphalan From 1980s
Tandem
Myeloablation +
ASCT
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 M-
protein 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

Thaldex
MPT 2. Line VelDex,
MPV 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 2 microglobulin <3,5 mg/l 62
and se albumin >35 g/l
II Se 2 microglobulin between 3,5- 45
5,5 mg/l or Se 2 microglobulin
<3,5 mg/l but se albumin <35 g/l
III Se 2 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) 24,7 months
t(14;16)
p13-
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 Median survival time

diagnosis
Low 2-microglobulin level and > 111 months
absence of 13
High 2-microglobulin level
and absence of 13 or 47 months
Low 2-microglobulin and
presence of 13
High 2-microglobulin level 25 months
together with 13

Moreau P et al, Blood 2006;107:397-403.

 Approach to newly diagnosed symptomatic
myeloma

Low risk High risk

Transplant
Not a transplant candidate
candidate

Dex or Thal-Dex or
VAD x 4 cycles

Stem Cell Harvest for 2 transplants

Early Tx1; Tx2 in relapse Conventional chemother (HDC, melphalan

200 mg/m2) to plateau phase. Tx1 at relapse
Rajkumar SV 2004.
 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 March/April 2005

Bortezomib
1962 1999 approved for
Prednisone + First report on second-line
melphalan thalidomide in USA & Europe

2000s
Melphalan From 1980s
Tandem
Myeloablation +
ASCT
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+ Dex Dex+

prednisone Dex Interferon
Partial response 41% 70% 40% 42%

Complete 1% 3% 1% 1%
response
Median 21.1 mos 22.9 mos. 12.2 15.2 mos
progression-free mos.
survival
Severe pyogenic 11% 20% 13% 11%
infection
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
FGF(fibrobalst growth factor)
Inhibition of multiple myeloma growth
factors, including IL-6, TNF, 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
 Comparison of results of MP and MPT
treatment in older patients with newly
diagnosed multiple myeloma
Response quality Melphalan+ Melphalan+Prednisone
Prednisone (MP) + Thalidomide (MPT)
Facon T et al, J Clin Oncol 2006;24:1s

Complete response 2% 16%

At least a partial 40% 81%

response
Response durability
- Progression-free
survival 17.1 mos. 27.6 mos
- Overall survival 32.2 mos. 53.6 mos
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)
Adhesion Cytokine Angiogenesis
MM cells
TNFa
IGF-I
BMSC
VEGF X
IL-6 BM Vessels

IL-6, VEGF

Block IkB/NFkB Intracellular level

activation

Apoptosis Inhibitors
FAS (IAP, FLICE)

PI3K MAPK
Caspases antiapoptotic proliferation Inhibition
8,3
DNA-repair effectors

Increased Decreased Disruption of

Apoptosis Proliferation unfolded protein
response

San Miguel J. Hematol J. 2003;4(suppl 3):201-207.

 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 Day 4 Day 8 Day 11
10-day
REPEAT
Bortezomib Bortezomib Bortezomib Bortezomib REST
CYCLE
1.3 mg/m2 1.3 mg/m2 1.3 mg/m2 1.3 mg/m2 PERIOD

At least a 72-hr rest period between doses is

required
Allows for restoration of proteasome function
towards baseline Alkalmazsi elirat Janssen-Cilag 2005
 Clinical studies
SUMMIT CREST APEX
Study design Phase II, open- Phase II, open-label, Phase III,
label, multicenter multicenter, randomized; international, open-
two dose levels bortezomib label, randomized
dexamethasone to bortezomib or
dexamethasone
Patients Relapsed or Relapse during/following Relapsed MM;
refractory MM; front-line therapy for MM; n=669
n=202 n=54
Endpoints Primary: overall Overall response rate Primary: time to
response rate (CR + PR + MR) progression (TTP)
(CR + PR + MR) Secondary:
Secondary: overall/1-year
safety, quality of survival, response
life, clinical rate, duration, time
benefit 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.

 A hypothetical future treatment algorithm for
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
 Waldenstrms 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.
Waldenstrms 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: Waldenstrm 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 24% Lymphadenopathy 15%

neuropathy
Weight loss 17% Purpura 9%

Fever 15% Other bleedings 7%

(retinal hemorrhages)
Raynauds 11%
phenomenon
Tarkovcs G: Waldenstrm macroglobulinaemia. in Fkuszban az onkolgia s az
onkohematolgia, ed.: Dank M, Demeter J, 2006. Melinda Kiad
 Characteristic features of WM
Retinal hemorrhage BM showing increased numbers of BM showing IgM in cytoplasm of
from hyperviscosity 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 80/20
- >30 g/l 35%
-Cryoglobulins 10% of macroglobulins
Serum bta2-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 ( Raynauds
phenomenon)
 Treatment of WM
Major response Median
rate (>50% duration of
reduction of IgM response
concentration)
Chlorambucil 75% 46 months
Fludarabine BM depression,
-first-line treatment 75.5% 40-60 months opportunic infections,
-Salvage-treatment 33.7% 30-32 months Coombs + hemolysis
Cladribine
-first-line treatment 56.6% 20-39 months
-Salvage-treatment 42.6% 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