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