Post on 27-May-2015
description
Multiple Myeloma
Dr. Gajanan Pandit
Mb.P.T.Hospital, Mumbai
Definition
Multiple Myeloma (also k/a Myeloma, Plasma cell myeloma or Kahler disease )
is a progressive hematologic (blood) disease. It is a cancer of the plasma cell, an important part of the immune system that produces immunoglobulins (antibodies) to help fight infection and disease.
Pathology
Multiple myeloma is characterized by excessive numbers of abnormal plasma cells in the bone marrow and overproduction of intact monoclonal immunoglobulin (IgG, IgA, IgD, or IgE) or Bence-Jones protein (free monoclonal κ and λ light chains). Hypercalcemia, anemia, renal damage, increased susceptibility to bacterial infection, and impaired production of normal immunoglobulin are common clinical manifestations of multiple myeloma. It is often also characterized by diffuse osteoporosis, usually in the pelvis, spine, ribs, and skull.
When foreign substances (antigens) enter the body, B cells develop into plasma cells that produce immunoglobulins (antibodies) to help fight infection and disease.
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Immunoglobulins
Heavy chains
-IgG ( 60%-70% )
-IgA ( ~20% )
-IgM
-IgE
-IgD Light chains
-kappa ( -lambda ( l )
Bence Jones proteins
15% to 20% of patients with myeloma produce incomplete immunoglobulins, containing only the light chain portion of the immunoglobulin
Primarily in the urine, rather than in the blood (immunoelectrophoresis)
Different from monoclonal (M) protein or paraprotein
Absent in nonsecretory myeloma (1%)
cytokines IL-6,RANK,TNF
AngiogenesisVEGF
immune response
Multiple myeloma is the 2nd most prevalent blood cancer after non-Hodgkin's lymphoma.
Average age at diagnosis is 62 yrs for men and 61 yrs for women
Decline in the immune system, genetic factors, certain occupations, certain viruses, exposure to certain chemicals e.g.Agent Orange and exposure to radiation.
Kidney problems
* Excess protein in the blood filtered through kidneys kidney damagerenal failure.
* Hypercalcemia overworks the kidneys and can cause variety of symptoms ie. loss of appetite, fatigue, muscle weakness, restlessness, difficulty in thinking or confusion, constipation, increased thirst, increased urine production, and nausea and vomiting.
Hydration, steroids plus furosemide, bisphosphonates, avoid NSAIDs/ i.v.contrast.
Pain
Early sym. pain in the lower back or in the ribs. Due to tiny fractures by accumulation of plasma cells and weakened bone structures.
Proper positioning and support; increasing physical activity in consultation with physical/occupational therapists; bisphosphonates; radiation therapy; for spinal fractures: surgical procedures such as kyphoplasty or vertebroplasty
Hematological
Fatigue and Recurrent infection Erythropoietin therapy
Transfusions Appropriate antibiotic therapy
immunoglobulin therapy
Nervous system dysfunction
Root compression & hyperviscosity syndrome-- radiculopathy, breathlessness, confusion, and chest pain.
Treat as a medical emergency
Cryoglobulinemia,
Amyloidosis.
Diagnosis
Major criteria: A biopsy-proven plasmacytoma. A bone marrow sample showing 30% plasma cells. Elevated monoclonal Ig levels in the blood or urine
Minor criteria: A bone marrow 10%-30% plasma cells. Minor monoclonal Ig levels in blood or urine Imaging --- holes in bones due to tumor growth Antibody levels (not produced by the cancer cells) in the
blood are abnormally low.
Lab Investigations
CBC - Hb,TLC, DLC, PLT Biochem. -albumin, BUN, LDH, Ca, S.Creatinine S. beta-2 microglobulin (β2-M), CRP Quantitative immunoglobulins (QIGs) 24 hr urine protein & UPEP serum-based assay called FREELITE
(MGUS to MM )
Electrophoresis (EP) / Immunoelectrophoresis ( IEP )
a serum or urine sample
gel is stained and read
tall spike M proteins of identical
molecular size urine - B.J.Protein
Bone (skeletal) survey
Pathological fracture
Bone & Marrow
CT / MRI bone marrow
aspiration / biopsy (percentage of plasma cells )
Chromosomal analysis (karyotyping) and fluorescence in situ hybridization (FISH)
Classification of Myeloma
Monoclonal Gammopathy of Undetermined Significance (MGUS)
Asymptomatic Multiple Myeloma
[Smoldering (SMM) / Indolent (IMM) ] Symptomatic Multiple Myeloma (MM)
Monoclonal Gammopathy of Undetermined Significance (MGUS)
Serum M protein <3 g/dL
Bone marrow plasma cells <10%
Absence of anemia, renal failure, hypercalcemia, lytic bone lesions
1% of the general population and in about 3% of normal individuals over 70 years of age
16% -malignant plasma cell disorder
Disease Management - observation
Asymptomatic Multiple Myeloma
Smoldering Multiple Myeloma (SMM)
Serum M protein >3 g/dL and/or bone marrow plasma cells ≥10%
Absence of anemia, renal failure, hypercalcemia, lytic bone lesions
Indolent Multiple Myeloma (IMM)
Stable serum/urine M protein
Bone marrow plasmacytosis
Mild anemia or few small lytic bone lesions
Absence of symptoms
Asymptomatic Multiple Myeloma
Observation with treatment beginning at disease progression
Bisphosphonates Supportive care
Symptomatic Multiple Myeloma (MM)
Presence of serum/urine M protein
Bone marrow plasmacytosis (>30%)
Anemia, renal failure, hypercalcemia, or lytic bone lesions
chemotherapy, stem cell
transplantation, Thalidomide, Bortezomib, pamidronate, and Zoledronic acid,
Staging of Myeloma
Durie-Salmon systemclinical stage of disease
(stage I, II, or III) is based levels of M protein, number of lytic bone
lesions, hemoglobin values and serum calcium levels.Stages are further divided
(A/B) according to renal function
International Staging System (ISS)
new, simpler, more cost-effective
beta 2-micro globulin (β2-M) and
albumin
*Stage II = β2-M <3.5 or β2-M 3.5 – 5.5 mg/dL, and albumin <3.5 g/dL
sub classification A) S. Creat.<2.0 mg/dl & B) S. Creat.>2.0 mg/dl
Stage Durie-Salmon Criteria ISS Criteria
I • Hb >10 g/dL• S. Ca
++ ≤12 mg/dL
• x-ray, normal bone stru.
or solitary bone plasmacytoma• Low M-component production rate —
( IgG <5 g/dL; IgA <3 g/dL) • Bence Jones protein <4 g/24 h
β2-M < 3.5 mg/dL and
albumin ≥3.5 g/dL
II* Neither stage I nor stage III Neither stage I nor stage III
III •Hb <8.5 g/dL•S. Ca
++>12 mg/dL
•Advanced lytic bone lesions•High M-component production rate —
(IgG>7 g/dL; IgA>5 g/dL)•Bence Jones protein >12 g/24 h
β2-M ≥ 5.5 mg/dL
Prognostic indicatorsTest Values indicating favorable prognosis
B 2-M <3 μg/mL
Albumin ≥3.5 g/dL
PCLI < 1%
CRP <6 μg/mL
LDH Age ≤60 y: 100-190 U/L Age >60 y: 110-210 U/L
Plasmablastic morphology
Absence of plasmablastic morphology
Chromosomal analysis (FISH)
Normal chromosome 13
Genetic Expression Profiling in Myeloma
Varied response to therapy 50% deletion of chromosome 13 40% one of five specific translocations
e.g. translocation k/a t(4;14)
Myeloma bone disease
Rapid growth of myeloma cells inhibits normal bone-forming cells osteoblasts
production of substances that activate the cells that resorb bone called osteoclasts is increased
Normal Bone Cell ActivityProcess of bone
remodelingOsteoclasts are attracted to the
area of fatigued bone.
Osteoclasts remove the fatigued bone by breaking it down, creating a cavity in the bone.
Osteoblasts are attracted to the cavity in the bone.
Osteoblasts fill in the cavity with a matrix or framework.
Eventually, new bone forms.
Bone Cell Activity in Myeloma
Bone Marrow Microenvironment Tumor cells adhere to the bone marrow stromal cells (BMSCs),the
structural cells of BM.
Adherence increases the stromal cell production of the growth factor interleukin 6 (IL-6), >continued growth and survival of the myeloma cells.
Adherence also allows the myeloma tumor cells to produce other osteoclast-activating factors including interleukin 1-beta (IL-1β) and tumor necrosis factor-alpha (TNF-α).
Osteoclast-stimulating factors prompt the bone marrow stromal cells and the osteoblasts to produce growth factor-RANKL.
TNF induces osteoclast cells and increases osteoclast activity that results in the bone disease of myeloma.
Osteoclastic activity also results in the release of certain cytokines such as IL-6, which contribute to tumor cell growth and survival.
Treatment Decisions in Myeloma
results of the physical exam
results of laboratory tests
the specific stage or classification of their disease
their age and general health
their symptoms
whether complications of the disease are present
whether they have previously received treatment for their disease
their lifestyle and their view and philosophy on quality of life
Goals of Treatment Eradicating all evidence of disease, which may require
accepting higher levels of toxicity Controlling disease activity to prevent damage to other organs
of the body, using a regimen with an acceptable toxicity level Preserving normal performance and quality of life for as long
as possible with minimal intervention Providing lasting relief of pain and other disease symptoms When applicable, managing myeloma that is in remission over
the long-term
Treatment Approaches
Inactive DiseaseActive Disease
> Non-transplant Candidates
> Transplant Candidates Relapsed or Refractory Disease
Rajkumar et al. Mayo Clin Proc. 2002;77:814
Options for relapsed/refractory disease
Repeat initial therapy if relapse after 6mths of discontinuing therapy
Corticosteroids Thalidomide based regimens Bortezomib Salvage chemotherapy ( eg. VAD, Cyclophosphamide-
VAD, EDAP or oral cyclophosphamide Consider second transplant if stem cells available/
harvest possible investigation regimen in clinical trial
Potential Outcomes of Treatment
TreatmentOutcome
Definition
Molecularcomplete response
--No evidence of disease using the most sensitivetechniques available
Complete response(CR)
--No detectable M protein in the serum and urine andNormal percentage of plasma cells in the bone marrow orAbsence of myeloma cells by staining techniques
Near completeresponse
--As listed for CR, but with a positiveimmunofixation test
Very good partialresponse
--Greater than 90% decrease in M protein
Partial response(PR)
--Greater than 50% decrease in M protein
Minimal response --Less than 50% decrease in M protein
Stable disease (SD) --Stable disease parameters (including number and extentof lesions) with some decrease in M protein
Progressive disease --Greater than 25% increase in M protein, new bonylesions, or a new plasmacytoma