MULTIPLE MYELOMA(MM)

Curs an IV - limba engleza2012-2013

MM - Background

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

MM - Background

• Multiple myeloma : as myeloma or plasma cell myeloma

• cancer of the plasma cell

• Multiple myelomaMultiple myeloma– excessive numbers of abnormal plasma cells in

the bone marrow – overproduction of intact monoclonal

immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal κ and λ light chains)

MM - Background

• Normal Plasma Cell Function in the Immune System– Stem cells can develop into B lymphocytes -- >travel to the

lymph nodes, mature, and then travel throughout the body.

– When foreign substances (antigens) enter the body -- >B cells develop into plasma cells that produce immunoglobulins Ig (antibodies) to help fight infection and disease.

Hematopoiesis

Figure legend: In multiple myeloma, the B cell is damaged and gives rise to too many plasma cells (myeloma cells). These malignant cells do not function properly and their increased numbers produce excess immunoglobulins of a single type that the body does not need along with reduced amounts of normal immunoglobulins.

MM – Epidemiology (1)

• 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. • 5 year survival rate

MM – Epidemiology (2)

• MM occurs in all races and all geographic locations

• African Americans and blacks from Africa is two to three times the risk in whites

• Risk is lower in Asians from Japan and in Mexicans

• Slightly more frequent in men than in women (1.4:1)

MM – Epidemiology (3)

• MM is a disease of older adults

• The median age at diagnosis is 66 years

• Only 10 percent of patients are younger than 50 years

• Only 2 percent of patients are younger than 40 years

MM – Etiology

• Genetic causes– Ongoing research is investigating whether HLA-Cw5 or

HLA-Cw2 may play a role in the pathogenesis of myeloma.

• Environmental or occupational causes– significant exposures in the agriculture, food, silicon,

Benzene, Nikel and petrochemical industries

• Radiation:– Radiation has been linked to the development of myeloma.– In 109,000 survivors of the bombing of Nagasaki, 29 died

from myeloma from 1950-1976; however, some recent studies do not confirm that these survivors have an increased risk of developing myeloma.

MM - Pathophysiology• These myeloma cells travel through the bloodstream and

collect in the bone marrow, where they cause permanent damage to healthy tissue.

• As tumors grow, they invade the hard outer part of the bone, the solid tissue.

• In most cases, the myeloma cells spread into the cavities of all the large bones of the body, forming multiple small lesions. This is why the disease is known as "multiple" myeloma.

Figure legend: Bone marrow stromal cells and myeloma cells produce cytokines that help myeloma cells grow and survive. Myeloma cells also produce growth factors that stimulate new blood vessel formation through a process called angiogenesis. New blood vessels provide nutrients and oxygen to the tumor, allowing it to grow. The natural immune response that attacks myeloma cells is suppressed.

Causes

BONE MARROW BONE MARROW MONOCLONAL MONOCLONAL PLASMA CELL PLASMA CELL

PROLIFERATIONPROLIFERATION

Bone lesions

Hypercalcemia

Cytopenia

Deformari

Fractures on pathologic bone

Bone pains

Involvment of immune system

Increased infectious risk

Hyperproduction of monoclonal component

Hypervascosity

Auto-Antibody activityeritrocite - hemaglutininelor la recetrombocite – afectarea functiimielina - neuropatie senzitivo-motoriefactori ai coagulare - hemoragiifactorul von Willebrandlipoproteina - hiperlipemii si xantoamehormoni tiroidieni - hipotiroidiestructuri ale peretelui vascular

Renal clearance

Renal insuficiency

MM - Pathophysiology

• Normally, plasma cells produce immunoglobulins to fight infection 

• However, in MM and MGUS a single cloned plasma cell proliferate and overproduce the same Ig (aka, the "M-protein" or "paraprotein." )o The M-protein is usually an IgG

• MM cells can also just produce the light chain component (Instead of the entire Ig)

MM - Pathophysiology

• 80% of cases of MM arise De Novo• 20% percent from MGUS.• Risk factors for progression from MGUS to MM

include:o An elevated M protein level > 1.5 g per dLo A non-IgG MGUSo Abnormal free light chain ratio 

• Patients with MGUS should be monitored closely q 6 to 12 months. (C-Level)

MM: Clinical Presentations

• Anemia - 73 percent• Bone pain - 58 percent• Elevated creatinine - 48 percent• Fatigue/generalized weakness - 32 percent• Hypercalcemia- 28 percent• Weight loss - 24 percent, one-half of whom

had lost ≥ 9 kg

MM – Clinical presentationClinical manifestations are related to malignant

behavior of plasma cells and abnormalities produced by M protein

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

• monoclonal M proteindecreased level of normal immunoglobulinshyperviscosity

MM – Clinical presentation

• Bone pain– Myeloma bone disease proliferation of tumor cells and

release of IL-6 (osteoclast activating factor :OAF) stimulates osteoclasts to break down bone leading to hypercalcemia

– These bone lesions in plain radiographs-- > "punched-out" /

lytic bone lesion

MM – Clinical presentation

• Bone pain – Myeloma bone pain involves the rib ,sternum, spine ,

clavicle , skull , humerus & femur

– The lumbar vertebrae are one of the most common sites of pain -- >may lead to spinal cord compression.

– Persistent localized pain may indicate a pathological fracture.

MM – Clinical presentation

MM – Clinical presentation

MM – Clinical presentation

MM – Clinical presentation• Hypercalcemia - patients present with confusion,

somnolence, bone pain, constipation, nausea, and thirst. – Medical emergency

• Anemia - normocytic and normochromic.– It results from the replacement of normal bone marrow by

infiltrating tumor cells and inhibition of normal red blood cell production by cytokines.

MM – Clinical presentation• BleedingBleeding

– bleeding resulting from thrombocytopenia. bleeding resulting from thrombocytopenia. – In some patients, monoclonal protein may absorb clotting factors and In some patients, monoclonal protein may absorb clotting factors and

lead to bleeding, but this development is rare.lead to bleeding, but this development is rare.

• HyperviscosityHyperviscosity– high volume of monoclonal protein high volume of monoclonal protein blood viscosity increases blood viscosity increases

complications such as stroke, myocardial ischemia, or infarction.complications such as stroke, myocardial ischemia, or infarction.– Depends on the physical properties of the M component (most

common with IgM, IgG, and IgA paraproteins). – Paraprotein concentrations of ~40 g/L (4 g/dL) for IgM, 50 g/L (5

g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA.– Symptoms: headache, fatigue, visual disturbances, and retinopathy– Medical emergencyMedical emergency

MM – Clinical presentation• Infection

– Organism : polysaccharide encapsulated <strep.pneumoniae, H.influenzae>

– Common pneumonia pathogens :S pneumoniae, S aureus, and K pneumoniae

– Common pathogens causing pyelonephritis : E coli and other gram-negative organisms.

– The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies.

MM – Clinical presentationRenal failure - Occurs in nearly 25% of myeloma

patients, – Hypercalcemia – Glomerular deposits of amyloid, – hyperuricemia, – recurrent infections, f– requent use of nonsteroidal anti-inflammatory agents

for pain control, use of iodinated contrast dye for imaging, bisphosphonate use, myeloma cells infiltrates

– Tubular damage associated with the excretion of light chains

MM – Laboratory tests

• ESR > 100• anaemia, thrombocytopenia• rouleaux in peripheral blood smears• marrow plasmacytosis > 10 -15%• hyperproteinemia• hypercalcemia• proteinuria• azotemia • osteolytic lesions in bones

Rouleaux Formation

MM – Laboratory tests– total protein, albumin and globulin, BUN, creatinine, and

uric acid, which is high if the patient has high cell turnover or is dehydrated

– Serum protein electrophoresis, urine protein electrophoresis, and immunofixation

• Serum protein electrophoresis is used to determine the type of each protein present and may indicate a characteristic curve (ie, where the spike is observed).

• Urine protein electrophoresis is used to identify the presence of the Bence Jones proteinBence Jones protein in urine.

• Immunofixation is used to identify the subtype of protein (ie, IgA lambda).

SPEP: M-protein, M-spike

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

Immunofixation to Determine Type of Monoclonal Protein

IgG kappa M protein Lambda Light Chains

MM – Laboratory tests• A 24-hour urine collection for the Bence Jones protein (ie,

lambda light chains), protein, and creatinine

– Quantification of proteinuria is useful for diagnosis (>1 g of protein in 24 h is a major criterion) and for monitoring the patient's response to therapy.

– Creatinine clearance can be useful for defining the severity

of the patient's renal impairment.

MM - Imaging Work up• Skeletal Survey

o Skull, spine, long bones, ribs, pelviso Diffuse osteopenia may suggest myelomatous involvement before

discrete lytic lesions are apparent. o Do not use bone scans to evaluate myeloma

• MRI o More sensitiveo But, generally reserved for suspected

spinal lesions

MM – Laboratory tests

• Procedures – bone marrow aspirate & biopsy

• samples to calculate the percent of plasma cells in the aspirate (reference range, <3%) and to look for sheets or clusters of plasma cells in the biopsy specimen.

Bone marrow aspirate : plasma cells of multiple myeloma.Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo).

M M - Diagnostic CriteriaMajor 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 criteriaa. Bone marrow plasma cells 10-30%b. M spike but less than abovec. Lytic bone lesionsd. Normal IgM < 50mg, IgA < 100mg, IgG < 600mg/dl

M M - Diagnostic Criteria

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

MM - StagingClinical 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

• subclassificationA - creatinine < 2mg/dlB - creatinine > 2mg/dl

MM - Staging

• Durie-Salmon staging system1. High tumor mass <stage III > one of following

abnormalitie mus be presenta. Hb <8.5 g/dl, Hct < 25 %b. Sr Ca > 12 gm/dlc. Very high Sr or Urine myeloma protein production rate

1. Ig G peak >7 gm/dl 2. IgA peak > 5 gm/dl 3. Bence Joneprotein > 12 gm/ 24 hr

d. > 3 lytic bone lesion on bone survey

MM - Staging

• Durie-Salmon staging system2. Low tumor mass <stage I>

all of following must be presenta. Hb > 15 gm/dl, Hct> 32%b. Sr Ca normalc. Low Sr myeloma protein production rate

a. 1. Ig G peak< 5 gm/dl b. 2. IgA peak < 3 gm/dl c. 3. Bence Jone protien < 4 g/ 24 hr

d. No bone lesion or osteoporosis

MM - Staging

• Durie-Salmon staging system3. Intermediate tumor mass <stage II>a. no renal failure <Cr < 2 mg/dl>b. Renal failure <Cr > 2 mg/dl>

MM - Staging• The International Staging System (ISS)

– Stage I : β2-microglobulin (β2M) < 3.5 mg/L, albumin > 3.5 g/dL

– Stage II : β2M < 3.5 and albumin < 3.5; or β2M between 3.5 and 5.5

– Stage III : β2M > 5.5

Median overall survival for patients with ISS stages I, II, and III are 62, 44, and 29 months

MM: Treatment Decisions

• Indications for treatment• Risk stratification• Eligibility for stem cell transplantation

MM: Treatment

• Active care– Chemotherapy– Autologous / Allogenic stem cell transplamtation– Drug : Arsenic trioxide, Thalidomide & Immunomodulator– Interferon

• Supportive care– Radiation therapy– Bisphosphonate– Kayphoplasty

Smoldering (asymptomatic) myeloma

• Deferral of chemotherapy until progression to symptomatic disease

• Follow these patients closely, every 3 to 4 months, with serum protein electrophoresis, complete blood count, serum creatinine, and serum calcium

• Metastatic bone survey should be considered annually because asymptomatic bone lesions may develop

MM: Indications for Treatment

• Anemia (hemoglobin <10 g/dL or 2 g/dL below normal)

• Hypercalcemia (serum calcium >11.5 mg/dL)• Renal insufficiency (serum creatinine>2

mg/dL)• Lytic bone lesions or severe osteopenia• Extramedullary plasmacytoma

MM: Risk stratification• FISH for detection of t(4;14), t(14;16), and del17p13

• Conventional cytogenetics (karyotyping) for detection of del 13 or hypodiploidy

• The presence of any of the above markers defines high risk myeloma, which encompasses the 25 percent of MM patients who have a median survival of approximately two years or less despite standard treatment

Current Frontline Options

• Conventional chemotherapy– Survival ≤ 3 yrs

• Transplantation– Prolongs survival 4-5 yrs

• Novel agents targeting stromal interactions and associated signaling pathways have shown promise

Chng WJ, et al. Cancer Control. 2005;12:91-104.

MM: initial therapy

• The initial therapy of patients with symptomatic myeloma varies depending on whether patients are eligible or not to pursue autologous hematopoietic cell transplantation

*Thal/dex or dex are additional options especially if immediate response is needed.

Clearly not transplantation candidate based on age, performance

score, and comorbidity

MPT, MPV, Len/dexor clinical trial*

Potential transplantation candidate

Nonalkylator-based induction x 4 cycles

Stem cell harvest

Initial Approach to Treatment of MM

NOT Eligible for Autologous HCT

• Age >77 years• Direct bilirubin>2.0 mg/dL (34.2 µmol/liter)• Serum creatinine>2.5 mg/dL (221 µmol/liter)

unless on chronic stable dialysis• Eastern Cooperative Oncology Group (ECOG)

performance status 3 or 4 unless due to bone pain

• New York Heart Association functional status Class III or IV

Autologous Stem Cell Transplantation

Mel 200 mg/m2 standard conditioning regimen Sufficient performance score, and adequate liver, pulmonary,

cardiac function needed Higher PR and CR rates than conventional chemotherapy Higher OS and EFS than conventional Rx Advanced age and impaired renal function are, by themselves,

not contraindications

Attal M, et al. N Engl J Med. 1996;335:91-97. NCCN Practice Guidelines. Myeloma. V.3.2010.

Novel Frontline Options

• Immunomodulatory drugs (IMiDs)– Thalidomide– Lenalidomide

• Proteasome inhibitors– Bortezomib– Carfilzomib

Frontline Therapy in Elderly MM Patients

• For elderly patients or those who are not suitable candidates for transplantation, MP has been a standard treatment– ORR: 60%– Long-term CR: < 5%

• Trials with MP-based combinations reported improved response rates and time to progression– MPT– VMP

NCCN Practice Guidelines. Myeloma. V.3.2010.

Therapy Options: NonTransplant Candidate• Melphalan + Prednisone (MP)• Melphalan + Prednisone + Thalidomide (MPT)• Dexamethasone (Dex)• Thalidomide + Dexamethasone (Thal/Dex)• Lenolidomide + Dexamethasone (Rev/Dex)• Bortezomib +/- Dexamethasone (Vel/Dex)

MM – Supportive treatment

• Supportive treatment– pain management– bone disease management– biphosphonates, calcitonin– recombinant erythropoietin– immunoglobulins– plasma exchange – radiation therapy

MM - Treatment of Bone Disease• Bisphosphonates• Surgical procedures

– Vertebroplasty– Balloon Kyphoplasty

• Radiotherapy• Treatment of myeloma

MM - Managing complications• Hypercalcemia

o Aggressive hydration, corticosteroids, lasix PRN bisphosphonates

• Renal Insufficiency o Identifying reversible causes. Dialysis PRN. o Plasmaphereis for hyperviscosity induced thrombosis

• Anemiao Erythopoetin, Transfusion

• Infectiono Treat aggressively with broad spectrum antibioticso  Vaccinations (B level)

FLU, PNA, HIB

Multiple Myeloma = M-CRAB

• Monoclonal protein• Calcium• Renal failure• Anemia• Bone pain with lytic lesions