Multiple myelomaMultiple myeloma

Dr. Sabir M. AminDr. Sabir M. Amin

DefinitionDefinition

characterized by neoplastic proliferation characterized by neoplastic proliferation of a clone of plasma cells producing aof a clone of plasma cells producing a

monoclonal immunoglobulinmonoclonal immunoglobulin

• •usually single clone of plasma cells, usually single clone of plasma cells, although biclonal myeloma has been although biclonal myeloma has been reportedreported

EpidemiologyEpidemiology

incidence 3 per 100,000incidence 3 per 100,000

• •increased frequency with age, median increased frequency with age, median age of diagnosis is 68age of diagnosis is 68

PathophysiologyPathophysiology

malignant plasma cells secrete malignant plasma cells secrete monoclonal antibodymonoclonal antibody

95%95% produce M protein (a monoclonal Ig produce M protein (a monoclonal Ig = identical heavy chain + identical = identical heavy chain + identical lightlight

chainchain))

• •IgG 55%, IgA 20%, IgD 2%, IgM 0.5%IgG 55%, IgA 20%, IgD 2%, IgM 0.5%

pathophysiologypathophysiology

15-20%15-20% produce only light chains, found produce only light chains, found in eitherin either::

• •serum as an increase in the quantity of serum as an increase in the quantity of either kappa or lambda light chaineither kappa or lambda light chain

• •urine as Bence-Jones Proteinurine as Bence-Jones Protein

<<5%5% are non-secretorsare non-secretors

Clinical featuresClinical features

Bone diseaseBone disease - pain (usually back), bony tenderness. - pain (usually back), bony tenderness. pathologic fractures, lytic lesions are classical pathologic fractures, lytic lesions are classical (skull, spine, proximal long bones, ribs)(skull, spine, proximal long bones, ribs)

increased bone resorption secondary to osteoclast increased bone resorption secondary to osteoclast activityactivity

AnemiaAnemia - weakness, fatigue. Pallor (secondary to BM - weakness, fatigue. Pallor (secondary to BM suppression)suppression)

• •weight lossweight lossInfectionsInfections::

usually S. pneumoniae and Gram-negativesusually S. pneumoniae and Gram-negatives( ( secondary to suppression of normal plasma cell secondary to suppression of normal plasma cell

functionfunction))

Lytic lesions & pathologicalLytic lesions & pathological##

C/FC/F

HypercalcemiaHypercalcemia – N/V, confusion, – N/V, confusion, constipation, polyuria, polydipsia, secondary constipation, polyuria, polydipsia, secondary to increased bone turnoverto increased bone turnoverRenal disease/renal failureRenal disease/renal failure

• •most frequently causes cast nephropathymost frequently causes cast nephropathy BleedingBleeding::

secondary to thrombocytopenia. may see secondary to thrombocytopenia. may see petechiae, purpurapetechiae, purpura

Extramedullary plasmacytomaExtramedullary plasmacytoma:: soft tissue mass composed of monoclonal soft tissue mass composed of monoclonal

plasma cells, purplish colourplasma cells, purplish colour

C/FC/F

HyperviscosityHyperviscosity - may manifest as headaches, - may manifest as headaches, stroke, angina, Ml secondary to increased stroke, angina, Ml secondary to increased viscosity caused by M (monoclonal) proteinviscosity caused by M (monoclonal) protein

AmyloidosisAmyloidosis:: may cause Factor X deficiency if fibrils bind may cause Factor X deficiency if fibrils bind

Factor X →bleedingFactor X →bleeding NeurologicNeurologic disease - muscle weakness, pain disease - muscle weakness, pain

paresthesias radiculopathy caused by paresthesias radiculopathy caused by vertebral fracture, extramedullary vertebral fracture, extramedullary plasmacytomaplasmacytoma..

spinal cord compression (in 10-20% of pts) is spinal cord compression (in 10-20% of pts) is a medical emergencya medical emergency

InvestigationInvestigation

CBCCBC • •normocytic anemia, thrombocytopenia, normocytic anemia, thrombocytopenia,

leukopenialeukopenia • •rouleaux formation on peripheral film, ↑ ESRrouleaux formation on peripheral film, ↑ ESR

BiochemistryBiochemistry • •increased Ca, increased Cr, proteinuria (24 hour increased Ca, increased Cr, proteinuria (24 hour

urine collection)urine collection)Serum protein electrophoresisSerum protein electrophoresis - demonstrates - demonstrates monoclonal protein spike in serum, in 80% - i.e. monoclonal protein spike in serum, in 80% - i.e. M proteinM protein

• •urine protein electrophoresis - demonstrates light urine protein electrophoresis - demonstrates light chains in urine =Bence-Jones Protein (20% )chains in urine =Bence-Jones Protein (20% )

InvestigationInvestigation

bone marrow biopsybone marrow biopsy

• •greater than 10% plasma cellsgreater than 10% plasma cells

Skeletal series (Skeletal series (x.raysx.rays), MRI if ), MRI if symptoms of cord compressionsymptoms of cord compression

• •presence of lytic lesions and areas at presence of lytic lesions and areas at risk of pathologic fracturerisk of pathologic fracture

• •beta-2 microglobulinbeta-2 microglobulin, , LDHLDH and and CRPCRP are poor prognosticatorsare poor prognosticators

BM aspirate: infiltrate of BM aspirate: infiltrate of abnormal plasma cellsabnormal plasma cells

DiagnosisDiagnosis

Minimal diagnostic criteria for myeloma •10% plasma cells in BM or plasmacytoma

on biopsy •Plus at least one of:

1.Serum paraprotein (IgG 30 g/l; IgA 20 g/l) 2.Urine paraprotein (Bence Jones

proteinuria)

3 .Osteolytic lesions on skeletal survey

TreatmentTreatment

Treatment is non curativeTreatment is non curative Treatment goals areTreatment goals are::

• •improvement in quality of life (improve anemia, improvement in quality of life (improve anemia, reverse renal failure, bony pains, prevent reverse renal failure, bony pains, prevent progression of disease and complications)progression of disease and complications)

• •increase in overall survivalincrease in overall survival • •autologous stem cell transplant if <70 year oldautologous stem cell transplant if <70 year old

usually preceded by 4-6 months of tumour usually preceded by 4-6 months of tumour reducing therapy utilizing a regimen thatreducing therapy utilizing a regimen thatincludes steroids (prednisone or includes steroids (prednisone or dexamethasone)dexamethasone)

TreatmentTreatment

chemotherapy if >70 years old or chemotherapy if >70 years old or transplant-ineligibletransplant-ineligibleconsider melphalan + prednisone alone if consider melphalan + prednisone alone if >75 yrs>75 yrsMelphalan + prednisone + thalidomide or Melphalan + prednisone + thalidomide or melphalan + prednisone + bortezomibmelphalan + prednisone + bortezomibif 65-75 yrsif 65-75 yrsdexilmethilsone ± thalidomide, dexilmethilsone ± thalidomide, bortezomib if ARFbortezomib if ARF

TreatmentTreatment

supportive management withsupportive management with::

BisphosphonatesBisphosphonates for osteoporosis or lytic lesions for osteoporosis or lytic lesions

Local XRTLocal XRT for bone pain, spinal cord compression for bone pain, spinal cord compression

Kyphoplasty/vertebroplastyKyphoplasty/vertebroplasty for vertebral for vertebral fractures to improve pain relief and regain fractures to improve pain relief and regain height(kyphoplasty)height(kyphoplasty)

HydrationHydration for hypercalcemia and renal failure, for hypercalcemia and renal failure, bisphosphonates (e.g. pamidronate) for severe bisphosphonates (e.g. pamidronate) for severe hypercalcemia, hypercalcemia, prophylactic antibioticsprophylactic antibiotics, , erythropoietinerythropoietin for anemia for anemia

Monoclonal Gammopathy of Monoclonal Gammopathy of Unknown SignificanceUnknown Significance (MGUS) (MGUS)

• •presence of M protein in serum in presence of M protein in serum in absence of any clinical or laboratory absence of any clinical or laboratory evidence of aevidence of a

plasma cell dyscrasia or plasma cell dyscrasia or lymphoproliferative disorderslymphoproliferative disorders

• •incidence: 0.15% in general population, incidence: 0.15% in general population, 5% of people >70 years of age5% of people >70 years of age

• •asymptomaticasymptomatic

DiagnosisDiagnosis

Presence of a serum (M-protein) at a concentration <30 g/LPresence of a serum (M-protein) at a concentration <30 g/L< •< •10%10% plasma cel[s in bone marrowplasma cel[s in bone marrow

• •absence of hyperabsence of hyperCCalcemia, and alcemia, and RRenal insufficiency, enal insufficiency, AAnemia, nemia, BBony disease related to the plasma cell proliferative process ony disease related to the plasma cell proliferative process (absence of "CRAB")(absence of "CRAB")

. .0.3-1%0.3-1% of patients develop a hematologic malignancy each yearof patients develop a hematologic malignancy each year • •patients with M protein peak ≥15 g/L, or patients with IgA or patients with M protein peak ≥15 g/L, or patients with IgA or

IgM MGUS are at higher risk of malignant transformationIgM MGUS are at higher risk of malignant transformation • •patients with a normal free light chain ratio are at low riskpatients with a normal free light chain ratio are at low risk

monitor with annual history, physical, CBC, Cr, Calcium, albumin. monitor with annual history, physical, CBC, Cr, Calcium, albumin. serum protein electrophoresis (considered pre-malignant)serum protein electrophoresis (considered pre-malignant)

Waldenstrom’s Waldenstrom’s macroglobulinemiamacroglobulinemia

proliferation of lymphoplasmacytoid proliferation of lymphoplasmacytoid cells (a hybrid of lymphocytes and cells (a hybrid of lymphocytes and plasma cells)plasma cells)

• •secrete large quantities of monoclonal secrete large quantities of monoclonal lgM paraproteinlgM paraprotein

C/FC/F

chronic disorder of elderly patients, median age 64 chronic disorder of elderly patients, median age 64 symptoms: weakness, fatigue, bleeding (oronasal), symptoms: weakness, fatigue, bleeding (oronasal), weight loss, recurrent infections, dyspnea, CHFweight loss, recurrent infections, dyspnea, CHF

( ( triad of anemia, hyperviscosity, plasma volume triad of anemia, hyperviscosity, plasma volume expansionexpansion .) .)Neurological symptoms: peripheral Neurological symptoms: peripheral

neuropathy, cerebral dysfunctionneuropathy, cerebral dysfunction • •signs: pallor, splenomegaly. hepatomegaly. signs: pallor, splenomegaly. hepatomegaly.

lymphadenopathy, retinal lesionslymphadenopathy, retinal lesions • •key complication to avoid: Hyperviscosity Syndromekey complication to avoid: Hyperviscosity Syndrome

because IgM (unlike IgG) confined largely to because IgM (unlike IgG) confined largely to intravascular spaceintravascular space

Investigation & DxInvestigation & Dx

bone marrow shows plasmacytoid bone marrow shows plasmacytoid lymphocyteslymphocytes

• •bone lesions usually not presentbone lesions usually not present • • rarely hypercalcemiararely hypercalcemia

• •cold hemagglutinin disease possible - cold hemagglutinin disease possible - Raynaud's phenomenon. hemolytic Raynaud's phenomenon. hemolytic anemia precipitated by cold anemia precipitated by cold weather weather ..normocytic anemia, rouleaux, normocytic anemia, rouleaux, high ESR if hyperviscosity not presenthigh ESR if hyperviscosity not present

TreatmentTreatment

alkylating agents (chlorambucil). alkylating agents (chlorambucil). nucleoside analogues (fludarabine). nucleoside analogues (fludarabine). thalidomidethalidomide,,

rituximab. or combination therapyrituximab. or combination therapy

• •corticosteroidscorticosteroids

• •plasmapheresis for hyperviscosityplasmapheresis for hyperviscosity