Multiple Myeloma
MM
Plasma Cell Dyscrasias
Are characterized by clonal proliferation of
immunoglobulin-secreting differentiated B
lymphocytes and plasma cells.
*Multiple myeloma is the most common malignant
plasma cell dyscrasia.
Other common plasma cell dyscrasias include :
*monoclonal gammopathy of undetermined
significance (MGUS)
*immunoglobulin light-chain (AL) amyloidosis
* Waldenström macroglobulinemia
Introduction
*Myeloma (multiple myeloma, myelomatosis)
is due to the unregulated proliferation of monoclonal
plasma cells in the bone marrow
Their accumulation leads to:
- Anemia and Marrow Failure
- Bone Resorption resulting in Lytic Lesions, generalized
osteoporosis, and pathological fractures
- The cell of origin has not been conclusively
identified but may be a memory B-lymphocyte
- The cause is unknown.
MM - Definition
Accumulation of neoplastic plasma cells in the bones
and bone marrow.
These plasma cells generally produce a homogeneous
immunoglobulin protein that can be detected in the
serum (Paraprotein or M-component) or urine (as
the immunoglobulin light-chain component or
Bence-Jones protein).
Epidemiology
* Multiple myeloma occurs more commonly in
men than in women
* occurs rarely before the age of 40 years (median
age at presentation 60 years)
* Annual incidence: 12,500 new cases occurring
yearly in the Untied States.
Etiology
- The cause is unknown.
Clinical Manifestations
* Nonspecific symptoms as bone pain
(particularly in the back or the chest),
* Fatigue, infections, fractures, and weight loss.
The most common physical finding is pallor.
* Neurologic findings may also be present.
Large plasmacytomas can cause spinal cord or
nerve-root compression, and neuropathy can
develop because of the neuropathic effect of
the paraprotein.
Clinical features:
Marrow infiltration
Malignant plasma cells accumulate in the red marrow
of the axial skeleton and flat bones
Anemia is common, and frequently present at
diagnosis. It results from the combination of:
Renal impairment
Bone marrow suppression if the plasma cell burden is high
Overt bone marrow failure is more commonly a
feature of end-stage disease.
Clinical features:
Bone resorption
There is abnormal bone remodeling with :
1)- Increased osteoclastic bone resorption secondary to:
a)Increased levels of :
* RANKL produced by myeloma & marrow stromal
cells
* Interleukin-6
* Macrophage Inflammatory Protein 1α (MIP-1α)
b)Suppression of soluble osteoprotegerin (OPG) :
the receptor for RANKL
2)-Inhibition of osteoblastic bone formation
Clinical features:
Bone resorption
It Leads to :
1)- Lytic destruction of the skeleton
2)- Hypercalcaemia
3)- Normal alkaline phosphatase
Clinical features:
Bone resorption
Bone pain is the most common presenting complaint,
especially severe back pain
There may be fractures of proximal long bones, ribs,
sternum, and vertebral crush fractures
Hypercalcaemia and associated symptoms of thirst,
polyuria, nausea, constipation, drowsiness, and
even coma
Plain X-ray examination typically reveals osteoporosis
and typical lytic lesions that are often visualized on
skull films
(punched out lesions not surrounded by sclerosis).
Clinical features:
Secretion of paraprotein
Accumulation of M- protein in the plasma may result
in hyperviscosity with lethargy and confusion
There is a characteristic retinopathy in hyperviscosity
syndrome, with distension of retinal veins and
irregular vessel constrictions; hemorrhages and
papilledema may be present
IgA and IgM paraproteins are especially likely to
induce hyperviscosity though IgG also if in high level
Clinical features:
Secretion of paraprotein
Bence–Jones protein is deposited in the renal tubules
and leads to renal failure (cast nephropathy).
Other factors contributing to renal failure are:
Hypercalcemia and dehydration;
Amyloid deposition;
Infection.
Paraproteinemia is typically accompanied by
immune paresis, which contributes to the infection risk
Clinical features:
Other features
Plasmacytomas may be palpable and also cause pressure effects
Spinal cord compression is most frequent and constitutes a
medical emergency with the need for urgent assessment and
local radiotherapy and/or decompressive surgery
Amyloidosis may present as macroglossia, renal failure,
peripheral neuropathy, and cardiac failure
Very occasionally the sclerotic bone lesions appear, and this
variant of the disease is often accompanied by severe
progressive peripheral neuropathy
Clinical features:
Other features
Polyneuropathy: sensorimotor
Organomegaly (principally hepatomegaly);
Endocrinopathy (diabetes mellitus, amenorrhea,
gynecomastia);
M- protein;
Skin changes (predominantly pigmentation).
POEMS
Lab Invx
High concentrations of paraprotein, including positively charged
M protein, which can lead to expansion of plasma volume
and decreased anion gap, pseudohyponatremia, or
pseudohypoglycemia.
Hypercalcemia is present in 15% of patients at diagnosis and is
mediated by cytokines (osteoclast-activating factor, IL-6,
tumor necrosis factor β, and IL-1β) and immobilization caused
by inactivity.
Hematologic manifestations include rouleaux formation on
peripheral blood smear, anemia, thrombocytopenia, and the
coating of platelets by M protein, which causes platelet
dysfunction.
Abnormal serum creatinine, low potassium levels, and low
serum bicarbonate levels could also occur in patients with
renal manifestations of myeloma.
Suppression of normal immunoglobulin synthesis results in
recurrent infections in patients with multiple myeloma.
Anemia may be caused by bone marrow
infiltration, deficiency of erythropoietin levels,
and increased inflammatory cytokine levels.
Nephropathy may be caused by renal tubular
dysfunction due to tubular light-chain
deposition; proximal tubular dysfunction
leading to Fanconi syndrome, hypercalcemiainduced distal tubular dysfunction; amyloid
fibril deposition in glomeruli, resulting in the
nephrotic syndrome; urinary tract infections;
contrast agents; and nephrotoxic antibiotics
and drugs.
Diagnosis(1)
CBC.
ESR/CRP.
Urea, creatinine, electrolytes and serum calcium and
albumin.
Electrophoresis and immunofixation of serum and
urine proteins.
Quantification of intact paraprotein or free light chain
in serum.
β2 microglobulin quantification in the serum.
Bone marrow aspirates and trephine biopsy.
Skeletal survey.
Bone marrow aspirate: Plasma cell
infiltrate
Peripheral smear
Plasma cells
Rouleaux formation
Imaging
Plain radiography and MRI can detect the lytic
bone lesions in multiple myeloma, whereas
bone scan primarily detects osteoblastic
activity
Staging
The International Myeloma Working Group has agreed on three
simplified criteria for the diagnosis of symptomatic multiple
myeloma. The diagnostic criteria proposed by the World Health
Organization rely on major and minor diagnostic criteria . The
International Myeloma Working Group criteria distinguish
asymptomatic myeloma from symptomatic myeloma on the basis of
whether end-organ damage has occurred. Therapy is not required
in asymptomatic patients; however, they should undergo follow-up
monitoring every 3 to 4 months. Laboratory testing should include
serum protein electrophoresis, complete blood count, and serum
creatinine and calcium measurement. Bone survey should be
considered annually to evaluate for asymptomatic bone lesions.
Multiple myeloma used to be staged according to the levels of
monoclonal protein production, anemia, extent of bone disease,
presence of hypercalcemia, and renal failure. A simpler staging
scheme uses measurement of β2 microglobulin concentration, a
surrogate marker for myeloma tumor mass and renal function, and
serum albumin to identify patients with good, intermediate, and
poor prognosis
Standards for Diagnosis
Old Criteria
1 major and 2 minor criteria
or
3 minor criteria including 1 and 2 in a patient displaying
symptoms of myeloma.
Major criteria: •
1) biopsy-proven
plasmacytoma.
2) bone marrow sample
showing >30% plasma cells.
3) Elevated >30g/l
Monoclonal Ig levels in the
blood
Minor criteria:
1)A bone marrow sample
showing 10%-30% plasma
cells.
2) <30g/l Monoclonal Ig
levels in blood
3)Imaging studies revealing
lytic bone lesions
4)Low levels of normal Ig
in serum
Standards for Diagnosis
New Criteria
Standards for Diagnosis
New Criteria
International Myeloma Working Group Criteria for the Diagnosis
of Multiple Myeloma
1. Monoclonal plasma cells in the bone marrow >10%
and/or presence of a biopsy-proven plasmacytoma.
2. Monoclonal protein present in the serum and/or
urine.
3. Myeloma-related organ dysfunction (1 or more):
*Calcium elevation in the blood (serum calcium >10.5
mg/L [2.63 mmol/L] or upper limit of normal)
*Renal insufficiency (serum creatinine >2 mg/dL [152.6
µmol/L])
*Anemia (hemoglobin <10 g/dL [100 g/L] or 2 g < normal)
*Lytic bone lesions or osteoporosis
WHO Criteria for the Diagnosis of Multiple
Myeloma
Major Criteria
*Plasmacytoma on tissue biopsy
*Bone marrow clonal plasma cells >30%
*High M protein (IgG >3.5 g/dL [35 g/L], IgA >2.0 g/dL [20 g/L],
Bence-Jones proteinuria >1.0 g/24 h)
Minor Criteria
*Bone marrow clonal plasma cells 10%-30%
*M-protein less than above
*Lytic bone lesions
*Reduced normal immunoglobulins to <50% of normal
(The diagnosis of multiple myeloma requires a minimum of one
major criterion and one minor criterion or three minor
criteria, which must include bone marrow plasmacytosis of
10%-30% and the presence of a monoclonal protein ).
International Staging System for Multiple Myeloma
(Prognosis)
Stage
Criteria
MedianSurvival(months)
I Serum β2-microglobulin <3.5 mg/L,
serum albumin ≥3.5 g/dL (35 g/L)
62
II
Not stage I or III
44
III Serum β2-microglobulin ≥5.5 mg/L 29
Treatment
1- melphalan and prednisone or combinations with additional
alkylating agents or anthracyclines have yielded response
rates (>50% M protein reduction) in approximately 50% of
patients with multiple myeloma. Complete hematologic
remission, defined as an absence of monoclonal
gammopathy in serum or urine and normal bone marrow
aspirate/biopsy, occurs in no more than 5% of patients.
Median event-free survival and overall survival have not
exceeded 18 and 30 to 36 months, respectively; cures have
not been reported. The poor prognosis of patients with
multiple myeloma reflects the exquisite drug resistance of
even newly diagnosed multiple myeloma.
2- High-dose dexamethasone pulsing alone or in
combination with continuous infusions of
vincristine and doxorubicin (VAD) was
regarded an effective regimen for patients
whose disease has progressed while receiving
melphalan and prednisone.
As initial therapy, vincristine and doxorubicin
induce a more marked and rapid tumor
cytoreduction than standard melphalan and
prednisone or similar regimens. Overall
survival, however, is not improved.
Not given now (abandoned)
3- Interferon has been evaluated as part of
remission induction and maintenance therapy
as well as part of salvage therapy. Although
interferon results in prolonged event-free
survival, its impact on overall survival has
been negligible.
Randomized and historically controlled trials
have recently demonstrated the superiority of
high-dose chemotherapy and autologous stem
cell transplantation over standard treatment
in achieving remission rates of up to 40% to
50% and extending median event-free and
overall survival to 3 years and more than 5
years, respectively.
Supportive Therapy
Erythropoietin improves multiple myeloma–associated
anemia in about 75% of patients, even in the absence
of kidney disease, and is especially useful when anemia
persists because of irreversible renal failure.
An important adjunct in treatment, especially for bone
lesions, is parenteral bisphosphonate therapy, such as
pamidronate or zoledronic acid, which delays the
onset of skeletal-related events and seems to extend
survival. Renal dysfunction and osteonecrosis of the
jaw after dental procedures are potential adverse
effects of long-term parenteral bisphosphonate
therapy.
Hypercalcemia in patients with multiple myeloma is
managed with saline hydration, corticosteroids, and
bisphosphonates. Prophylactic immunizations for
pneumonia and influenza are mandatory. Patients with
recurrent bacterial infections may benefit from
prophylactic monthly immune globulin infusion.
Novel Therapies
Thalidomide is a novel treatment in multiple myeloma
that does not appear to act through a cytotoxic effect.
Instead, it may inhibit the growth and survival of tumor
cells, bone marrow stromal cells, or both; alter the
profile of adhesion molecules and interactions between
tumor cells and bone marrow stromal cells; modulate
the cytokine milieu; inhibit angiogenesis; or increase
the number of CD8 cells through its
immunomodulatory effects. Thalidomide-based
regimens have been evaluated in several trials and are
being used in relapsed, refractory, and front-line
settings. Therapy is generally well tolerated, and
toxicities include fetal malformations, constipation,
sedation, skin rash, peripheral neuropathy, fatigue, and
thromboembolism. Discontinuation of thalidomide is
not always required to manage toxicities.
Lenalidomide, a potent analogue of thalidomide, offers
great promise in myeloma. The toxicity profile is
different from that of thalidomide, with less
neuropathy, fatigue, and somnolence, but with
increased risk for neutropenia and thrombocytopenia.
Lenalidomide also can lead to thromboembolism.
Bortezomib, a proteasome inhibitor, inhibits cell growth,
induces apoptosis, and allows myeloma cells in vitro to
overcome drug resistance, and it has shown significant
activity in myeloma. This agent was U.S. Food and Drug
Administration approved as second-line therapy for
myeloma in 2004. Major toxicities are fatigue,
asthenia, peripheral neuropathy, and
thrombocytopenia.
Novel therapies, alone and in combination regimens,
have replaced oral melphalan and prednisone as well
as vincristine and doxorubicin and can be used for
initial treatment and in relapsed or refractory disease.
VMP vs. VTP
VT vs. VP in Elderly Newly Diagnosed Myeloma Patients
(Phase III)
1st randomization
Patients older
than 65 yrs of
age with newly
diagnosed
multiple
myeloma
(N = 260)
2nd randomization
Wk 31
VMP
Bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25,
29, 32 for one 6-wk cycle, then on Days 1, 8, 15, 22
for five 5-wk cycles +
Melphalan 9 mg/m2 QD on Days 1-4 each cycle +
Prednisone 60 mg/m2 QD on Days 1-4 each cycle
(n = 130)
VT
Bortezomib 1.3 mg/m2
on Days 1, 4, 8, 11 of
90-day cycle +
Thalidomide 50 mg/day
(n = 91)
VTP
Bortezomib 1.3 mg/m2 on Days 1, 4, 8, 11, 22, 25,
29, 32 for one 6-wk cycle, then on Days 1, 8, 15, 22
for five 5-wk cycles +
Thalidomide* 100 mg/day +
Prednisone 60 mg/m2 QD on Days 1-4 each cycle
(n = 130)
VP
Bortezomib 1.3 mg/m2
on Days 1, 4, 8, 11 of
90-day cycle +
Prednisone 50 mg every
48 hrs
(n = 87)
*Thalidomide dosed at 50 mg/day on Days 1-15 of first 6-wk cycle.
Primary endpoints: ORR in induction phase, CR in maintenance phase.
Secondary endpoints: PFS, OS, efficacy in patients with high-risk cytogenetics.
Mateos MV, et al. ASH 2009. Abstract 3.
Up to
3 yrs
PFS
100
Treatment Group
VMP VT
VMP VP
VTP VT
VTP VP
80
60
40
20
0
Median PFS, Mos
VTP VT: NR
VMP VT: NR
VTP VP: 26.5
VMP VP: 32
0 10 15 20 25 30 35 40 45
Mos
PFS significantly longer with VMP
Mateos MV, et al. ASH 2009. Abstract 3.
OS
100
Patients Surviving (%)
Patients Without Progression (%)
VMP → VT vs. VTP → VP in Elderly Newly Diagnosed Myeloma
Patients: Outcomes
80
60
40
20
0
2-Yr OS, %
VMP VT: 88
VMP VP: 88
VTP VT: 84
VTP VP: 81
0 10 15 20 25 30 35 40 45
Mos
VT vs. VTP VP at both first and second
randomizations (HR: 1.6; P = .008)
Addition of Lenalidomide to MP in Newly Diagnosed Elderly Myeloma
Pts (Phase III)
Stratified by age
(≤ 75 vs > 75 yrs)
and stage (ISS: 1.2 vs 3)
(N = 459)
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Lenalidomide 10 mg QD PO on Days 1-21
(n = 152)
Continued
lenalidomide
therapy
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Lenalidomide 10 mg QD PO on Days 1-21
(n = 153)
Lenalidomide
discontinued,
placebo added
Melphalan 0.18 mg/kg on Days 1-4 +
Prednisone 2 mg/kg on Days 1-4 +
Placebo on Days 1-21
(n = 154)
Double-blind treatment phase
Primary comparison: continuous therapy with MPR vs. MP
Palumbo A, et al. ASH 2009. Abstract 613.
Lenalidomide 25 mg QD +
Dexamethasone
Patients with
relapsed/
refractory
multiple
myeloma
Cycles 10 +
Disease progression
Cycles 1-9 (28-day cycles)
Open-label
extension/follow-up
phase
Patients Without Event (%)
Addition of Lenalidomide to MP in Newly Diagnosed Elderly
Myeloma Pts: Results
Addition of
lenalidomide
to MP plus
maintenance
lenalidomide
reduced risk of
progression by
50% vs MP alone
PFS
100
Median PFS
MPR-R Not reached
13.0 mos
MP
Median follow-up: 9.4 mos
75
50
HR: 0.499
95% CI: 0.330-0.755
Log rank: P < .001
25
0
0
5
10
15
20
25
30
Mos
ORR
CR
≥ VGPR
PR
MPR-R (n = 152), %
77
18
32
45
MPR (n = 153), %
67
13
33
34
MP (n = 154), %
49
5
11
37
< .001
< .001
< .001
--
Regimen
Palumbo A, et al. ASH 2009. Abstract 613.
P value
Monoclonal Gammopathy of
Undetermined Significance
Monoclonal gammopathy of undetermined significance (MGUS) is found in
approximately 1% to 2% of adults. The incidence is higher in patients older
than 70 years and in blacks. MGUS is defined by the criteria listed and is
characterized by a tendency towards development of multiple myeloma or a
related malignancy at the rate of 1% to 1.5% per year. Whether these
associations are pathogenetically related or are merely coincidental is not
clear. MGUS is always asymptomatic and is usually discovered through
incidental laboratory findings, most often, hyperproteinemia. A monoclonal
spike is identified on subsequent protein electrophoresis.
Laboratory evaluation should include a complete blood count and measurement
of serum calcium, creatinine, and electrolytes as well as immunoglobulin
quantitation, serum and urine protein electrophoresis, serum and urine
immunofixation electrophoresis, and a bone survey. Examination of the bone
marrow is not always required, but, if done, should show less than 10% plasma
cells.
IgG or IgA MGUS may progress to multiple myeloma, AL
amyloidosis, or a related plasma cell disorder, whereas
IgM MGUS may progress to a lymphoproliferative
disorder (non-Hodgkin lymphoma, chronic lymphocytic
leukemia, or Waldenström macroglobulinemia). A riskstratification model to predict the risk of progression of
MGUS uses three adverse risk factors: (1) a serum M
protein level greater than or equal to 1.5 g/dL, (2) nonIgG MGUS, and (3) an abnormal serum free light-chain
ratio. Using this model, the risk of disease progression
over 20 years for patients with various combinations of
risk factors is as follows:
three risk factors (high-risk MGUS) — 58%
two risk factors (high–intermediate-risk MGUS) — 37%
one risk factor (low–intermediate-risk MGUS) — 21%
no risk factors (low-risk MGUS) — 5%
MGUS may rarely be associated with nonmalignant
disorders, such as skin diseases (scleroderma,
pyoderma gangrenosum), liver diseases
(cirrhosis, primary biliary cirrhosis, hepatitis),
rheumatologic diseases (rheumatoid arthritis,
polymyositis, polymyalgia rheumatica), and HIV
infection.
Patients with MGUS should be evaluated every 3 to
6 months for symptoms suggestive of myeloma
and receive repeat laboratory tests every 6 to 12
months. Repeat bone marrow evaluation should
be done only if other laboratory features suggest
progression to multiple myeloma. Although there
is no treatment to prevent progression of MGUS
to multiple myeloma, monitoring for plasma cell
dyscrasias is important because early recognition
and treatment favorably affect outcome.
Monoclonal Gammopathy of
Undetermined Significance
The presence of a serum monoclonal protein
(M-protein, whether IgA, IgG, or IgM), at a
concentration ≤3 g/dL (30 g/L)
Bone marrow plasma cells <10%
The absence of lytic bone lesions, anemia,
hypercalcemia, and renal insufficiency related
to the plasma cell proliferative process or
related B-cell lymphoproliferative disorder
Waldenström Macroglobulinemia
Waldenström macroglobulinemia results from the proliferation of B
lymphocytes that show maturation to plasma cells and is
characterized by a lymphoplasmacytic infiltrate of the bone
marrow, lymphadenopathy, anemia, neuropathy, organomegaly,
IgM monoclonal gammopathy, and hyperviscosity syndrome.
Hyperviscosity syndrome, which is related to the physicochemical
properties of IgM, is identified by blurred vision; fatigue; mucosal
bleeding caused by impaired platelet function; heart failure;
headache; and altered mentation.
Funduscopic examination in these patients may show engorged retinal
veins.
Plasmapheresis temporarily relieves acute symptoms and should be
combined with specific treatment that may include chlorambucil,
rituximab, and fludarabine or cladribine.