Management of Multiple Myeloma

Irza WahidSubdivision of Hematology – Medical Oncology

Departement of Internal MedicineMedical Faculty, Andalas University

Management of Multiple Myeloma

Irza WahidSubdivision of Hematology – Medical Oncology

Departement of Internal MedicineMedical Faculty, Andalas University

Blok Muskuloskeletal

Bone Metastases

Blok Muskuloskeletal

Bone Metastases

PA-3

Disease prevalence, Disease prevalence, Bone mets. Bone mets. MedianMedianU.S. (in thousands)U.S. (in thousands) incidence (%)incidence (%) survival (mo) survival (mo)

MyelomaMyeloma 75 - 100 75 - 100 70 - 9570 - 95 2424RenalRenal 198 198 20 - 2520 - 25 1212MelanomaMelanoma 467 467 14 - 4514 - 45 66BladderBladder 582 582 4040 6 - 96 - 9ThyroidThyroid 207 207 6060 4848LungLung 386 386 30 - 4030 - 40 77BreastBreast 1,993 1,993 65 - 7565 - 75 2424ProstateProstate 984 984 65 - 7565 - 75 3636

Clinical Importance and Prognosis of Bone Metastases

Clinical Importance and Prognosis of Bone Metastases

NCI, 197; International Myeloma Foundation, 2001.

Multiple MyelomaMultiple Myeloma

• Definition

B-cell malignancy characterised by abnormal proliferation of plasma cells able to produce a monoclonal immunoglobulin ( M protein )

• Definition

B-cell malignancy characterised by abnormal proliferation of plasma cells able to produce a monoclonal immunoglobulin ( M protein )

Greenlee RT. CA Cancer J Clin 2001;51:15. Bergsagel DE. Blood 1999;94:1174Greenlee RT. CA Cancer J Clin 2001;51:15. Bergsagel DE. Blood 1999;94:1174

MM EpidemiologyMM Epidemiology

• 19,900 new cases per yr, 50,000 total cases, 2% cancer deaths in U.S.

• Higher incidence in African Americans, Pacific Islanders

• Median age 71 yrs

• Exposure to radiation, petroleum products, pesticides & Agent Orange

• 19,900 new cases per yr, 50,000 total cases, 2% cancer deaths in U.S.

• Higher incidence in African Americans, Pacific Islanders

• Median age 71 yrs

• Exposure to radiation, petroleum products, pesticides & Agent Orange

StatisticsStatistics

• Second most prevalent blood cancer• Approximately 1% of all cancers and 2%

of all cancer deaths.• 45,000 currently have multiple myeloma• 14,600 new cases of myeloma each year. • Responsible for more than 10,000 deaths

in the United States annually.

• Second most prevalent blood cancer• Approximately 1% of all cancers and 2%

of all cancer deaths.• 45,000 currently have multiple myeloma• 14,600 new cases of myeloma each year. • Responsible for more than 10,000 deaths

in the United States annually.

http://www.multiplemyeloma.org/about_myeloma/2.03.asp

How Plasma Cells WorkHow Plasma Cells Work

• Develop from stem cells in bone marrow• Stem cells develop into B cells (B

lymphocytes)• Antigens enter body then B cells develop

into plasma cells • Produce antibodies

• Develop from stem cells in bone marrow• Stem cells develop into B cells (B

lymphocytes)• Antigens enter body then B cells develop

into plasma cells • Produce antibodies

Normal Cell (5%)Normal Cell (5%)

Myeloma Cells (10%)Myeloma Cells (10%)

What Causes Myeloma Cells To Grow?

What Causes Myeloma Cells To Grow?

• Adhesion molecules• Stromal cells

Interactions:– Cytokins (chemical messengers)– Growth factors that promote angiogenesis– Inactivated immune system

• Adhesion molecules• Stromal cells

Interactions:– Cytokins (chemical messengers)– Growth factors that promote angiogenesis– Inactivated immune system

Multiple MyelomaMultiple Myeloma

Clinical manifestations are related to malignant behavior of plasma cells and abnormalities produce by M protein

• plasma cell proliferation:multiple osteolytic bone lesionshypercalcemiabone marrow suppression ( pancytopenia )

• monoclonal M proteindecreased level of normal immunoglobulinshyperviscosity

Clinical manifestations are related to malignant behavior of plasma cells and abnormalities produce by M protein

• plasma cell proliferation:multiple osteolytic bone lesionshypercalcemiabone marrow suppression ( pancytopenia )

• monoclonal M proteindecreased level of normal immunoglobulinshyperviscosity

Symptoms Symptoms

• Anemia• Fatigue• Bone pain

– Back– Ribs

• Unexplained bone fractures• Repeated infections

– Pneumonia– Bladder and kidney infection– Urinary tract infection

• Weight loss• Weakness and numbness in limbs

• Anemia• Fatigue• Bone pain

– Back– Ribs

• Unexplained bone fractures• Repeated infections

– Pneumonia– Bladder and kidney infection– Urinary tract infection

• Weight loss• Weakness and numbness in limbs

SymptomsSymptoms

• Abnormal proteins– Blood and urine– Polyclonal to Monoclonal proteins

• High level of calcium in blood– Excessive thirst and urination– Sleepiness– Constipation– Nausea– Loss of appetite– Mental confusion

• Abnormal proteins– Blood and urine– Polyclonal to Monoclonal proteins

• High level of calcium in blood– Excessive thirst and urination– Sleepiness– Constipation– Nausea– Loss of appetite– Mental confusion

Signs & Symptoms in 1027 Newly Diagnosed Myeloma Patients Signs & Symptoms in 1027 Newly Diagnosed Myeloma Patients

00

1010

2020

3030

4040

5050

6060

7070

8080

BoneBone

lesionslesions

FatigueFatigue Cr >2Cr >2

mg/dLmg/dL

Ca >11Ca >11

mg/dLmg/dL

Wt lossWt loss

(>9 kg) (>9 kg)

% p

atie

nts

% p

atie

nts

79

Hb<12Hb<12

g/dLg/dL

73

BoneBone

painpain

66

32

1319

12

Kyle RA. Mayo Clin Proc 2003;78:21-33Kyle RA. Mayo Clin Proc 2003;78:21-33

Screening and DiagnosisScreening and Diagnosis

• Blood and urine tests• X-rays• Magnetic Resonance Imaging (MRI)• Computerized Tomography (CT)• Bone marrow examination

• Blood and urine tests• X-rays• Magnetic Resonance Imaging (MRI)• Computerized Tomography (CT)• Bone marrow examination

Diagnostic Criteria for Multiple MyelomaDiagnostic Criteria for Multiple Myeloma

Major criteria

I. Plasmacytoma on tissue biopsy

II. Bone marrow plasma cell > 30%

III. Monoclonal M spike on electrophoresis IgG > 3,5g/dl,

IgA > 2g/dl, light chain > 1g/dl in 24h urine sample

Minor criteria

a. Bone marrow plasma cells 10-30%

b. M spike

c. Lytic bone lesions

d. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

Major criteria

I. Plasmacytoma on tissue biopsy

II. Bone marrow plasma cell > 30%

III. Monoclonal M spike on electrophoresis IgG > 3,5g/dl,

IgA > 2g/dl, light chain > 1g/dl in 24h urine sample

Minor criteria

a. Bone marrow plasma cells 10-30%

b. M spike

c. Lytic bone lesions

d. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

Diagnostic Criteria for Multiple MyelomaDiagnostic Criteria for Multiple Myeloma

Diagnosis:

• I + b, I + c, I + d • II + b, II + c, II + d• III + a, III + c, I II + d• a + b + c, a +b + d

Diagnosis:

• I + b, I + c, I + d • II + b, II + c, II + d• III + a, III + c, I II + d• a + b + c, a +b + d

Staging of Multiple MyelomaStaging of Multiple Myeloma

Clinical staging • is based on level of haemoglobin, serum

calcium, immunoglobulins and presence or not of lytic bone lesions

• correlates with myeloma burden and prognosis

I. Low tumor mass II. Intermediate tumor mass

III. High tumor mass• subclassification

A - creatinine < 2mg/dlB - creatinine > 2mg/dl

Clinical staging • is based on level of haemoglobin, serum

calcium, immunoglobulins and presence or not of lytic bone lesions

• correlates with myeloma burden and prognosis

I. Low tumor mass II. Intermediate tumor mass

III. High tumor mass• subclassification

A - creatinine < 2mg/dlB - creatinine > 2mg/dl

Myeloma Prognostic FactorsMyeloma Prognostic Factors

• Serum 2 microglobulin

• Cytogenetics - del13 or 13q-, t(4;14), 17p-, hypodiploid

• C-reactive protein

• LDH

• Plasmablastic morphology

• Peripheral blood plasma cells

• Gene expression profile

• Serum 2 microglobulin

• Cytogenetics - del13 or 13q-, t(4;14), 17p-, hypodiploid

• C-reactive protein

• LDH

• Plasmablastic morphology

• Peripheral blood plasma cells

• Gene expression profile

Incidence of Chromosomal Abnormalities in MM Incidence of Chromosomal Abnormalities in MM

Genomic Aberrations Incidence of aberration

Del (13) 48%

Del (17p) 11%

t(4;14) (p16;q32) 14%

Hyperdiploidy 39%

t(11;14) (q13;q32) 21%

• n = 1064 patients• Chromosomal changes observed in 90% of patients• n = 1064 patients• Chromosomal changes observed in 90% of patients

International Staging System (ISS)for Symptomatic MyelomaInternational Staging System (ISS)for Symptomatic Myeloma

*β2m < 3.5 mg/L and albumin < 3.5 g/dL or β2m 3.5 - < 5.5 mg/L, any albumin *β2m < 3.5 mg/L and albumin < 3.5 g/dL or β2m 3.5 - < 5.5 mg/L, any albumin

Greipp et al. J Clin Oncol 2005; 23: 3412-20Greipp et al. J Clin Oncol 2005; 23: 3412-20

Stage CriteriaMedian Survival (mo)

Iβ2m < 3.5 mg/L

albumin ≥ 3.5 g/dL62

II* Not stage I or III 44

III β2m ≥ 5.5 mg/L 29

Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004Kyle RA and Rajkumar SV. Cecil Textbook of Medicine, 22nd Edition, 2004

NormalNormal Monoclonal Protein in Myeloma

Monoclonal Protein in Myeloma

Serum Protein ElectrophoresisSerum Protein Electrophoresis

Distribution of Monoclonal ProteinsDistribution of Monoclonal Proteins• M protein found in serum or urine

or both at time of diagnosis: 97%

• Serum M spike by protein electrophoresis: 80%

• Abnormal serum immunofixation: 93%

• Abnormal urine immunofixation: 75%

• Non-secretory myeloma: 3%

• M protein found in serum or urine or both at time of diagnosis: 97%

• Serum M spike by protein electrophoresis: 80%

• Abnormal serum immunofixation: 93%

• Abnormal urine immunofixation: 75%

• Non-secretory myeloma: 3%

Malignant Plasma Cells in MarrowMalignant Plasma Cells in Marrow

Normal Bone BiologyNormal Bone BiologyBone is always in an active state of

remodeling (build up/break down)

• Resorption: stimulated osteoclasts erode bone, creating a cavity

• Reversal: bone surface is prepared for osteoblasts to begin forming bone

• Formation: osteoblasts replace resorbed bone and fill the cavity with new bone

• Resting: bone surface rests until a new remodeling cycle begins

Bone is always in an active state of remodeling (build up/break down)

• Resorption: stimulated osteoclasts erode bone, creating a cavity

• Reversal: bone surface is prepared for osteoblasts to begin forming bone

• Formation: osteoblasts replace resorbed bone and fill the cavity with new bone

• Resting: bone surface rests until a new remodeling cycle begins

Adapted from Novert's Pharmaceuticals

Vicious cycle of Bone MetastasesVicious cycle of Bone Metastases

Mineralized bone matrix

Tumor Cells in Bone

Osteoblasts

New bone

Osteoclasts

Osteolytic factors• RANKL• PTH-rp• Interleukins 1,6,8• TNFs• M-CSF

Osteoblastic factors• Endothelin-1• Fibroblast growth factor• Bone morphogenic proteins• Insulin-like growth factors

Bone-derived tumorgrowth factors

• Transforming growth factor • Insulin-like growth factors• Fibroblast growth factors• Platelet-derived growth factor• Bone morphogenic proteins

Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.

Osteolytic metastasesOsteolytic metastases• Tumor cells produce growth factors

that stimulate bone destruction• i.e. RANK ligand

• Osteoclasts are activated and break down bone

• Osteoblasts cannot build bone back fast enough

• Decreased bone density and strength; high risk for fracture

• Tumor cells produce growth factors that stimulate bone destruction• i.e. RANK ligand

• Osteoclasts are activated and break down bone

• Osteoblasts cannot build bone back fast enough

• Decreased bone density and strength; high risk for fracture

Patel, B. and DeGroot, H. Orthopedics Journal. 2001;24:612-7.

Osteoblastic MetastasisOsteoblastic Metastasis

• Osteoblasts are stimulated by tumors to lay down new bone

• Bone becomes abnormally dense and stiff

• Paradoxically bones are also at risk of breaking

• Osteoblasts are stimulated by tumors to lay down new bone

• Bone becomes abnormally dense and stiff

• Paradoxically bones are also at risk of breaking

Bone Imaging in MMBone Imaging in MM

• Skeletal radiography is the primary diagnostic test to detect destructive bony lesions in multiple myeloma

• MRI is useful in assessing whether spinal compression fractures are due to a focal mass or from osteopenia due to increased osteolysis

• PET scans can be used to detect soft tissue or bone metastases

• Skeletal radiography is the primary diagnostic test to detect destructive bony lesions in multiple myeloma

• MRI is useful in assessing whether spinal compression fractures are due to a focal mass or from osteopenia due to increased osteolysis

• PET scans can be used to detect soft tissue or bone metastases

Angtuaco EJ et al. Radiology. 2004;231:11-23.Angtuaco EJ et al. Radiology. 2004;231:11-23.

Treatment OptionsTreatment Options

• Goals:– Attack the cancer– Strengthen the bone– Reduce symptoms

• Includes:– Systemic therapy– Local therapy

• Goals:– Attack the cancer– Strengthen the bone– Reduce symptoms

• Includes:– Systemic therapy– Local therapy

Clearly not a transplant candidate

Can include melphalan-based combinations

Potential transplant candidate

Non-alkylator based induction

Stem cell harvest

Initial Approach to TreatmentInitial Approach to Treatment

Therapy Options: NonTransplant CandidateTherapy Options: NonTransplant Candidate

• Melphalan + Prednisone (MP)

• Melphalan + Prednisone + Thalidomide (MPT)

• Dexamethasone (Dex)

• Thalidomide + Dexamethasone (Thal/Dex)

• Lenolidomide + Dexamethasone (Rev/Dex)

• Bortezomib +/- Dexamethasone (Vel/Dex)

• Melphalan + Prednisone (MP)

• Melphalan + Prednisone + Thalidomide (MPT)

• Dexamethasone (Dex)

• Thalidomide + Dexamethasone (Thal/Dex)

• Lenolidomide + Dexamethasone (Rev/Dex)

• Bortezomib +/- Dexamethasone (Vel/Dex)

NCCN Practice Guideline-v.2.2008NCCN Practice Guideline-v.2.2008

• Alternative chemotherapy– M2 ( Vincristine, Melphalan,

Cyclophosphamid, BCNU, Prednisone)

– VAD (Vincristin, Adriamycin, Dexamethasone)

• Response rate 50-60% patients• Long term survival 5-10% patients

• Alternative chemotherapy– M2 ( Vincristine, Melphalan,

Cyclophosphamid, BCNU, Prednisone)

– VAD (Vincristin, Adriamycin, Dexamethasone)

• Response rate 50-60% patients• Long term survival 5-10% patients

Bortezomib (Velcade®)Bortezomib (Velcade®)

• Reversible inhibitor of chymotrypsin-like activity of 26-S proteasome

• Prevents proteolysis of ubiquitinated proteins & can lead to apoptosis of tumor cells

• Dosing: 1.3 mg/m2 IV bolus d 1, 4, 8, & 11 (21-d treatment cycle) for a maximum of 8 cycles

• FDA approved for MM that has relapsed after ≥1 prior standard therapies

• Reversible inhibitor of chymotrypsin-like activity of 26-S proteasome

• Prevents proteolysis of ubiquitinated proteins & can lead to apoptosis of tumor cells

• Dosing: 1.3 mg/m2 IV bolus d 1, 4, 8, & 11 (21-d treatment cycle) for a maximum of 8 cycles

• FDA approved for MM that has relapsed after ≥1 prior standard therapies

Systemic TherapiesSystemic Therapies

Pain control– Pain medication

• Tylenol, NSAIDs (ibuprofen), narcotics, steroids• Success can be limited by side effects

– Radiopharmaceuticals• Strontium-89 and samarium-153: radioactive

particles travel directly to tumor in bone• Can reduce pain refractory to other measures• Infrequently used

Pain control– Pain medication

• Tylenol, NSAIDs (ibuprofen), narcotics, steroids• Success can be limited by side effects

– Radiopharmaceuticals• Strontium-89 and samarium-153: radioactive

particles travel directly to tumor in bone• Can reduce pain refractory to other measures• Infrequently used

Systemic Therapies: BisphosphonatesSystemic Therapies: Bisphosphonates

• Bind to and inhibit osteoclast action – Inhibit bone breakdown– Prevent bone damage– Improve bone density and strength

• Recommended for almost everyone with

cancer bone metastases

• Bind to and inhibit osteoclast action – Inhibit bone breakdown– Prevent bone damage– Improve bone density and strength

• Recommended for almost everyone with

cancer bone metastases

Thank YouThank You