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Multiple myeloma
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Multiple MyelomaGamal Abdul Hamid MD
Definition
A malignantmalignant proliferationproliferation of plasma cellsplasma cells derived from a single clonesingle clone involving more than 10 percent of the bone marrow
The multiple myeloma cell produces monoclonal monoclonal immunoglobulinsimmunoglobulins that may be identified on serum or urine protein electrophoresis.
As a result !
Tumor, its products, and the patients response to it, result in a number of organ dysfunctions
Fracture/bone pain Renal failure Susceptibility to infection Anemia Hypercalcemia Clotting abnormalities Neurologic symptoms Vascular manifestations of hyperviscosity
Etiology
Cause not known !
More commonly than expected among Low socioeconomic class Farmers (DDT exposure) Wood workers Leather workers Sheet metal workers Nuclear industry workers Those exposed to petroleum products (??benzene)
Incidence
Increases with age Ages from 45 up to 68 years
Males > Females (slightly)
Accounts for about 1% of all malignancies in whites 13% of all hematologic cancers in whites
MULTIPLE MYELOMA: Pathophysiology
The pathological and clinical features of myeloma are due to:
1. Tissue infiltration 2. Production of large amount of
paraprotein3. Impairment of immunity.
Clinical Manifestations of Multiple Myeloma
•Pain in the lower back, long bones or ribs
•Generalized malaise
•Infections
•Fever
•Bleeding
•Symptoms of hypercalcemia •Nausea •Fatigue •Thirst
•Symptoms of hyperviscosity •Headaches •Bruising •Ischemic neurologic symptoms
•Other neurologic symptoms •Peripheral neuropathy •Meningitis
Pathogenesis and Clinical Manifestations Bone Symptoms
Bone pain (most common symptom affecting 70% of patients )Involves back , ribs , long bones, skull and pelvisPrecipitated by movement (unlike the pain of
metastatic carcinoma, which often is worse at night)If persistent & localized usually signifies a pathologic
fracture
Pathogenesis and Clinical Manifestations Susceptibility to bacterial infections
Recurrent infections are the presenting features in 25% of patients
Most common infections are Pneumonias (Streptococcus pneumoniae,
Staphylococcus aureus, and Klebsiella pneumoniae)Pyelonephritis ( Escherichia coli and other gram-
negative organisms )
Pathogenesis and Clinical ManifestationsRenal failure / pathology
Failure occurs in nearly 25%
Some renal pathology is noted in > 50%
Factors contributing to renal dysfunction Hypercalcemia ( most common cause of renal failure)Glomerular deposits of amyloidHyperuricemiaRecurrent infections Infiltration of the kidney by myeloma cellsTubular damage associated with the excretion of light chains
(almost always present )
Pathogenesis and Clinical ManifestationsAnemia
Occurs in 80% of myeloma patients
TypesUsually normocytic and normochromicCan be megaloblastic due to either folate or vitamin B12
deficiency
Due to Replacement of normal marrow by expanding tumor cells Inhibition of hematopoiesis by factors made by the tumorMild hemolysis
Diagnosis
30% of new cases are diagnosed incidentally during evaluation for seemingly unrelated problems
In 30 % a pathologic fracture is the presenting feature
In 25% of patients recurrent infections are the presenting features
Diagnosis
The classic triad of myeloma Marrow plasmacytosis (>10%)Lytic bone lesionsSerum and/or urine M component
The diagnosis may be made in the absence of bone lesions if the plasmacytosis is associated with a progressive increase in the M component over time or if extramedullary mass lesions develop
Confirmation of 1 major and 1 minor criterion or 3 minor criteria in symptomatic patientsMajor Diagnostic Criteria Minor Diagnostic Criteria
Biopsy-proven plasmacytoma
Bone marrow sample = 10% to 30% plasma cells
Bone marrow sample = 30% plasma cells
Minor monoclonal immunoglobulin levels in blood or urine (< 3 g/dL)
Elevated monoclonal immunoglobulin levels in blood or urine
Osteopenia/lytic bone lesions (confirmed through imaging studies)
Abnormally low antibody levels (not associated with malignant cells) in the blood
Myeloma classification
Monoclonal Gammopathy of Undetermined Significance Serum M-protein < 3 g/dLBone marrow plasma cells < 10%
Absence of anemia, renal failure, hypercalcemia, lytic bone lesions
Asymptomatic Multiple Myeloma
Smoldering Multiple Myeloma Indolent Multiple MyelomaSerum M-protein > 3 g/dL and/or bone marrow plasma cells ≥ 10%
Bone marrow plasmacytosis
No anemia, renal failure, hypercalcemia, lyticbone lesions
Mild anemia or few small lytic bone lesions
Stable serum/urine M-proteinNo symptomsPresence of serum/urine M-protein
Symptomatic Multiple MyelomaBone marrow plasmacytosis (> 10%) Anemia, renal failure, hypercalcemia, or lytic bone lesions
Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone
Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma
Clinical evaluationCareful physical examination
Tender bones and masses Enlargement of the spleen and lymph nodes, the physiologic sites of
antibody production (minority) Exudative macular detachment, retinal hemorrhage or "cotton-wool"
spots Amyloid deposition on the tongue, causing macroglossia Cardiomegaly related to deposition of immunoglobulin. Positive Tinel sign, Phalen sign for carpal tunnel compression due to
amyloid deposition.
Imagings Chest and bone radiographs ( lytic lesions or diffuse osteopenia ) MRI
To depict myeloma tumors To document cord or root compression in patients with pain syndromes. To assess efficacy of therapy (Radiographic improvement occurs in 30 %
of treated patients)
Clinical evaluation
Blood studies CBC (anemia , pancytopenia ,)ESR (elevated)Ca, BUN , Cr and uric acid (elevated)Serum alkaline phosphatase is usually normal
(absence of osteoblastic activity) Hypoalbuminemia
Clinical evaluation Protein electrophoresis In Monoclonal gammopathies &
Myeloma the single clone of plasma cells produce a homogeneous monoclonal immunoglobulin ( M protein) characterized by the presence of a sharp, well-defined band with a single heavy chain and a similar band with a kappa or lambda light chain
The M protein is identified as a narrow peak or "spike" in the g, ß or a 2 regions
StageInternational Staging System
Criteria
I β2-microglobulin < 3.5; albumin ≥ 3.5
II Neither stage I nor stage III values
III β2-microglobulin > 5.5
Staging:Durie-Salmon system: widely used since 1975Stage based on M-protein levels, bone lesions, Hb values, serum calcium—many variablesInternational Staging SystemSimplified staging based on serum β2-microglobulin
Staging
For predicting survival
Based on clinical and laboratory tests (unlike the anatomic staging systems for solid tumors)Hemoglobin, CalciumM componentDegree of skeletal involvement
Stages(I , II , III ) further subdivided into A & B based on renal functionStage IA (median survival > 5 years) Stage IIIB about 15 months.
STAGE I (low cell mass, <0.6 x 1012 cells/m2)
All of the following:Haemoglobin value < 10 g/dLSerum calcium value normal or < 10.5 mg/dLBone X-ray, normal bone structure (scale 0) or solitary bone plasmacytoma
onlyLow M-component production rates
IgG value < 5.0 g/dLIgA value < 3.0 g/dL
Urine light chain M-component on electrophoresis < 4 g/24 hours
STAGE II (intermediate cell mass 600 - 1,200 x 1012 cells/m2) Fitting neither stage I nor stage III.
STAGE III (high cell mass > 1,200 x 1012 cells/m2)One or more of the following:
Haemoglobin value < 8.5 g/dLSerum calcium value > 12 mg/dLAdvanced lytic bone lesions (scale 3)High M-component production rates
IgG value > 7.0 g/dLIgA value > 5.0 g/dL
Urine light chain M-component on electrophoresis >12 g/24 hours
Disease Phases
Asymptomatic Symptomatic
MGUS or Smouldering Myeloma
Active Myeloma Relapse
Refractory relapse
Plateau remission
Therapy IIII IIII IIII
M P
rotein
g/d
L
Go!
Goals of MM Therapy
Goals of treatment Address pain relief & other disease
symptoms Control disease activity
prevent further organ damage Extend disease-free survival (DFS) Prolong overall survival (OS) Preserve normal performance and QOL for
as long as possible
Multiple Myeloma: Current Status
Relapsed Disease• Transient Response to Therapy• Survival 1-3 years
Diagnosis• Survival 3-5 yrs• Survival <12mo without therapy
Relapsed andRefractory
• Resistant to all therapy• Universally fatal • Survival 6-9 months
First-Line:• VAD • MP• Transplant (depending on age)
5-year Mortality: 75%; 10-year Mortality: 95-98%
Second Line:• VAD • Dexamethasone • Thalidomide• Transplant• Investigational Therapy
Refractory:• Supportive or palliative care• Investigational Therapy• Deaths 12,000/yr.
50 - 75% Response RateAll patients relapse
Unmet Medical Need
Choice of therapy at relapse dependent on duration of response & previous therapies. Response rate & duration reduced with each sequential regimen
1960
1970
1980
1990
2000
Melphalan
MP MEDIAN OS 3 years
First reports on High-dose Treatment 1983VAD 1984
ASCT 1996
Thalidomide 1999
Double ASCT > single 2003Bortezomib 2004 Median OS Lenalidomide 2005 not reached at 7 years
History Of MM Treatment
Novel Therapies
Bortezomib
Thalidomide and analogues
Trisenox (Arsenic Trioxide)
Genasense (bcl-2 antisense)
Farnesyl Transferase Inhibitors
Bortezomib Mechanism of Action
• First in class
• Novel mechanism of action
• Reversibly inhibits the proteasome
• One target, multiple downstream pathways:
• The cell cycle
• Apoptosis
• Angiogenesis
• Gene transcription
• Interaction of cell with microenvironment
Bortezomib
[(1R)-3-methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic acid.
Bortezomib - Indication
Bortezomib is approved as front-line treatment for multiple myeloma patients unsuitable for bone marrow transplantation in combination with melphalan and prednisone
Bortezomib is also indicated as
Monotherapy for the treatment
of progressive MM in patients who
have received at least one
prior treatment
35
Recent Clinical Data: VISTA VMP (Velcade+Melphalan+Prednisolone) significantly prolongs
survival in the largest MP-based phase III studyConsistency of treatment effect Rapid and durable responses with very high Complete
Response rate (similar to transplantation)Prolonged Time To Progression
VMP consistently superior across all prognostic subgroups including patients with poor prognostic characteristics
VMP well tolerated
Results establish VMP as a new standard of care for MM patients not eligible for HDT-ASCT, based on the highest level of evidence1
1. Anderson et al. Leukemia 2008;22:231-9.
VISTA : VELCADE as Initial Standard Therapy in multiple myeloma: Assessment with melphalan and prednisone San Miguel et al. ASH 07
VMPVMPCycles 1-4Cycles 1-4
Bortezomib 1.3 mg/mBortezomib 1.3 mg/m22 IV: days 1,4,8,11,22,25,29,32 IV: days 1,4,8,11,22,25,29,32
Melphalan 9 mg/mMelphalan 9 mg/m22 and prednisone 60 mg/m and prednisone 60 mg/m22 days 1-4 days 1-4
Cycles 5-9Cycles 5-9
Bortezomib 1.3 mg/mBortezomib 1.3 mg/m22 IV: days 1,8,22,29 IV: days 1,8,22,29
Melphalan 9 mg/mMelphalan 9 mg/m22 and prednisone 60 mg/m and prednisone 60 mg/m22 days 1-4 days 1-4
MPMPCycles 1-9Cycles 1-9
Melphalan 9 mg/mMelphalan 9 mg/m22 and prednisone 60 mg/m and prednisone 60 mg/m22 days 1-4 days 1-4
9 x 6-week cycles (54 weeks) in both arms
Primary endpoint:
TTP
Newly diagnosed
MM patients; age >65 years
High CR rate with MPV
MPVMPV MPMP PP
CR + PRCR + PR
CR+VGPRCR+VGPR
82%82%
45%45%
50%50%
10%10%
<.0001<.0001
<.0001<.0001
CR (IF-)CR (IF-) 35%35% 5%5% <.0001<.0001
VISTA : Response to TreatmentVISTA : Response to Treatment
Thank you
Thank you