Pharma 9:Multiple Myeloma - med05.com

Multiple Myeloma and AmylodosisMultiple Myeloma and Amylodosis

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Dr. Fatin Al-Sayes, MSC and FRCPathDr. Fatin Al-Sayes, MSC and FRCPath

Vice Chairman Hematology DepartmentVice Chairman Hematology Department

Consultant HematologistConsultant Hematologist

Associate ProfessorAssociate Professor

King Abdulaziz University HospitalKing Abdulaziz University Hospital

Jeddah, K.S.A.Jeddah, K.S.A.

Multiple MyelomaMultiple Myeloma

● ● Definition: Definition:

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

●● Incidence:Incidence: - - 3 – 9 cases per 1000000 population / year, second most 3 – 9 cases per 1000000 population / year, second most

prevalent blood cancer prevalent blood cancer

approximately 9% of all cancer deaths.approximately 9% of all cancer deaths.

Multiple MyelomaMultiple Myeloma

Clinical manifestation are related to malignant behavior of plasma cells and Clinical manifestation are related to malignant behavior of plasma cells and abnormalities produced by M proteinabnormalities produced by M protein

● ● plasma cell proliferation:plasma cell proliferation:

multiple osteolytic bone lesions multiple osteolytic bone lesions

hypercalcemiahypercalcemia

bone marrow suppression (pancytopenia)bone marrow suppression (pancytopenia)

● ● monoclonal M proteinmonoclonal M protein

decreased level of normal immunoglobulinsdecreased level of normal immunoglobulins

hyperviscosityhyperviscosity• Bleeding tendency Bleeding tendency

Multiple MyelomaMultiple Myeloma

● ● M protein:M protein:

- - is seen in 99% of cases in serum and/or urine IgG>50%, IgA 20-25%, IgE I IgD 1-3%is seen in 99% of cases in serum and/or urine IgG>50%, IgA 20-25%, IgE I IgD 1-3%

light chain 20%light chain 20%

- 1% of cases are nonsecretory- 1% of cases are nonsecretory

Multiple MyelomaMultiple MyelomaClinical SymptomsClinical Symptoms

● ● bone pains, back ribs, pathologic fracturesbone pains, back ribs, pathologic fractures

● ● weakness and fatigueweakness and fatigue● ● serious infection – pneumonia, pyelonophritisserious infection – pneumonia, pyelonophritis● ● renal failurerenal failure● ● bleeding diathesisbleeding diathesis● ● weight lossweight loss● ● weakness & numbness in limbsweakness & numbness in limbs● ● high calcium level in bloodhigh calcium level in blood

● ● excessive thirst and urinationexcessive thirst and urination ● ● sleepinesssleepiness ● ● constipationconstipation ● ● nauseanausea ● ● loss of appetiteloss of appetite ● ● mental confusionmental confusion

Multiple MyelomaMultiple Myeloma

Laboratory TestsLaboratory Tests

● ● ESR > 100ESR > 100

● ● anaemia, thrombocytopeniaanaemia, thrombocytopenia

● ● rouleaux in peripheral blood smearsrouleaux in peripheral blood smears

● ● marrow plasmacytosis >10 by bone marrow examinationmarrow plasmacytosis >10 by bone marrow examination

● ● hyperproteinemiahyperproteinemia

● ● hypercalcemiahypercalcemia

● ● proteinuriaproteinuria

● ● azotemiaazotemia

● ● x-ray – skeletal survey ( osteopenia , pathlogical fracture , cord x-ray – skeletal survey ( osteopenia , pathlogical fracture , cord compression) compression)

Diagnostic Criteria for MultipleDiagnostic Criteria for Multiple

Major CriteriaMajor Criteria

I. Plasmacytoma on tissues biopsyI. Plasmacytoma on tissues biopsy II. Bone marrow plasma cell >(10%)II. Bone marrow plasma cell >(10%) III. Monoclonal spike on electrophoresis IgG>3.5g/dl, IgA>2g/dl, light chainIII. Monoclonal spike on electrophoresis IgG>3.5g/dl, IgA>2g/dl, light chain

>1g/dl in 24 h urine sample>1g/dl in 24 h urine sample

Minor CriteriaMinor Criteria

a. Bone marrow plasma cells less <10%a. Bone marrow plasma cells less <10%b. M spike but less than aboveb. M spike but less than abovec. Lytic bone lesionsc. Lytic bone lesionsd. Normal IgM<50mg.IgA<100mg. IgG<600mg/dld. Normal IgM<50mg.IgA<100mg. IgG<600mg/dl

What Causes Myeloma Cells to GrowWhat Causes Myeloma Cells to Grow??

● ● Adhesion moleculesAdhesion molecules

● ● Stromal cellsStromal cells

Interactions:Interactions:

- Cytokins (chemical messengers)- Cytokins (chemical messengers)

- Growth factors that promote angiogenesis- Growth factors that promote angiogenesis

- Inactivated immune system- Inactivated immune system

Staging of Multiple MyelomaStaging of Multiple Myeloma

Clinical StagingClinical Staging

● ● is based on level of haemoglobin, serum calcium, immunoglobulins and presence or is based on level of haemoglobin, serum calcium, immunoglobulins and presence or

not of lytic bone lesionsnot of lytic bone lesions

● ● correlates with myeloma burden and prognosiscorrelates with myeloma burden and prognosis

I. Low tumor massI. Low tumor mass

II. Intermediate tumor massII. Intermediate tumor mass

III. High tumor massIII. High tumor mass

● ● subclassificationsubclassification

A – creatinine <2mg/dlA – creatinine <2mg/dl

B - creatinine >2mg/dlB - creatinine >2mg/dl

Multiple MyelomaMultiple Myeloma

Poor Prognosis FactorsPoor Prognosis Factors

● ● cytogenetical abnormalities of 11 and 13 chromosomescytogenetical abnormalities of 11 and 13 chromosomes

● ● beta-2 microglobulines >2.5 ug/mlbeta-2 microglobulines >2.5 ug/ml

Treatment of Multiple MyelomaTreatment of Multiple Myeloma

● ● Patients <65 – 70 yearsPatients <65 – 70 years - high-dose therapy with autologous stem cell transplantation- high-dose therapy with autologous stem cell transplantation

- allogenic stem cell transplantation (conventional and ,,mini”)- allogenic stem cell transplantation (conventional and ,,mini”)

● ● Patients >65 yearsPatients >65 years - conventional chemotherapy- conventional chemotherapy

- non-myeloablative therapy with allogenic transplantation - non-myeloablative therapy with allogenic transplantation

(,,mini”) (,,mini”)

Treatment of Multiple MyelomaTreatment of Multiple Myeloma● ● Conventional chemotherapyConventional chemotherapy

- Melphlan + Prednisone- Melphlan + Prednisone

- M2 (Vincristine, Melphalan, Cyclophosphamid, BCNU, - M2 (Vincristine, Melphalan, Cyclophosphamid, BCNU,

Prednisone)Prednisone)

- VAD (Vincristin, Adriamycin, Dexamethasone)- VAD (Vincristin, Adriamycin, Dexamethasone)

● ● Response rate 50-60% patientsResponse rate 50-60% patients

● ● Long term survival 5-10% patientsLong term survival 5-10% patients

Treatment of Multiple MyelomaTreatment of Multiple Myeloma

● ● Autologous transplantationAutologous transplantation

- patients <65-70 years- patients <65-70 years

- treatment related mortality 10-20%- treatment related mortality 10-20%

- response rate 80%- response rate 80%

- long term survival 40-50%- long term survival 40-50%

● ● Conventional allogeneic transplantationConventional allogeneic transplantation

- patients < 45-50 years with HLA-in=dentical donor- patients < 45-50 years with HLA-in=dentical donor

- treatment related mortality 40-50%- treatment related mortality 40-50%

- long term survival 20-30% - long term survival 20-30%

Treatment of Multiple MyelomaTreatment of Multiple Myeloma

● ● New methodNew method

- non-myeloablative therapy and allogeneic - non-myeloablative therapy and allogeneic

transplantationtransplantation

- Thalidomid- Thalidomid

-Bortezomib (velcade)-Bortezomib (velcade)

Treatment of Multiple MyelomaTreatment of Multiple Myeloma

● ● Supportive treatmentSupportive treatment- - biphosphonates calcitonin biphosphonates calcitonin

- benefits include- benefits include ↓ ↓ fracturefracture ↓ ↓ radiotherapyradiotherapy

↓ ↓ bone pain improve quality of life.bone pain improve quality of life. - risks include- risks include

? Osteonocrosis of the jaw renal functions defect? Osteonocrosis of the jaw renal functions defect- recombinant erythropoietin- recombinant erythropoietin

- immunoglobulins- immunoglobulins- plasma exchange- plasma exchange- radiation therapy - radiation therapy

Disorder Associated with Monoclonal ProteinDisorder Associated with Monoclonal Protein● ● Neoplastic cell proliferationNeoplastic cell proliferation

- multiple myeloma- multiple myeloma- solitary plasmacytoma- solitary plasmacytoma- Waldenstrom macroglobulinemia- Waldenstrom macroglobulinemia- heavy chain disease- heavy chain disease- primary amyloidosis- primary amyloidosis

● ● Undetermined significanceUndetermined significance- monoclonal gammopathy of undetermined significance (MGUS)- monoclonal gammopathy of undetermined significance (MGUS)

● ● Transient M proteinTransient M protein- viral infection- viral infection- post-valve replacement- post-valve replacement

● ● MalignancyMalignancy- bowel cancer, breast cancer, lymphoma- bowel cancer, breast cancer, lymphoma

● ● Immune dysregulationImmune dysregulation- AIDS and connective tissue disease- AIDS and connective tissue disease

Monoclonal gammopathy of undetermined Monoclonal gammopathy of undetermined significance (MGUS)significance (MGUS)

●● M protein presence, stableM protein presence, stable

● ● levels of M protein: IgG<3.5g IgA<2g LC<1g/daylevels of M protein: IgG<3.5g IgA<2g LC<1g/day

● ● normal immunoglobulins – normal levelsnormal immunoglobulins – normal levels

● ● marrow plasmacytosis <5%marrow plasmacytosis <5%

● ● complete blood count – normalcomplete blood count – normal

● ● no lytic bone lesionsno lytic bone lesions

● ● no signs of diseaseno signs of disease

Monoclonal gammopathy of undetermined Monoclonal gammopathy of undetermined significance (MGUS)significance (MGUS)

● ● M proteinM protein

- 3% of people > 70 years- 3% of people > 70 years

- 15% of people > 90 years- 15% of people > 90 years

- MGUS is diagnosed in 67% of patients with an M protein- MGUS is diagnosed in 67% of patients with an M protein

- 10% of patients with MGUS develop multiple myeloma- 10% of patients with MGUS develop multiple myeloma

AmyloidosisAmyloidosis

- Homogenous protein deposit in tissues - Homogenous protein deposit in tissues stain pink with haematoxylin and red stain pink with haematoxylin and red with congo red and has green with congo red and has green

birefringence.birefringence.

- It has fibrillary structure. - It has fibrillary structure.

PathogenesisPathogenesis

______________________________________________________________________________________________________________Classification of AmylodiosisClassification of Amylodiosis

Type Chemical nature Organs involveType Chemical nature Organs involve______________________________________________________________________________________________________________Immunocyte-relatedImmunocyte-related

Myeloma Ig light chains and/or TongueMyeloma Ig light chains and/or TongueWaldenstrom’s parts of their Skin Waldenstrom’s parts of their Skin macroglobulianemia variable regions Heartmacroglobulianemia variable regions HeartHeavy-chain disease (AL) NervesHeavy-chain disease (AL) NervesPrimary amyloidosis Connective tissuePrimary amyloidosis Connective tissue Kidneys Kidneys LiverLiver

SpleenSpleenReactive systemicReactive systemicRheumatoid arthritis Protein A (acute LiverRheumatoid arthritis Protein A (acute LiverTuberculosis reactive, AA) SpleenTuberculosis reactive, AA) SpleenBronchiectasis Bronchiectasis Kidneys KidneysChronic osteomyetitis Bone marrowChronic osteomyetitis Bone marrowHodgkin’s diseaseHodgkin’s diseaseCarcinomasCarcinomasFamilial Mediterranean feverFamilial Mediterranean fever

LocalizedLocalizedInvolvement of a single Hormones EndocrineInvolvement of a single Hormones Endocrine organ Protein A with other tumoursorgan Protein A with other tumours constituents constituents Skin Skin

HeartHeart CNSCNS

(Alzheimer’s(Alzheimer’s disease) disease)