Multiple Myeloma

By Dr Sameh Shamaa

Multiple Myeloma

Epidemiology:

• 1% Of all malignant diseases.• Annual incidence: 3-4/100 000.• Age:

- Median age: 65y.- The diagnosis of MM in a patient < 30y

should only be made after careful evaluation of all data.

OPG/OCIF

OC precursor

OAF receptor (RANK)

OSTEOCLAST ACTIVATION

Osteoclast

RANKL/OAF

Osteoblast/ stromal cell/tumour cells/ myeloma

Teitelbaum Science 2000Teitelbaum Science 2000

RenalFailure

Hyperviscosity Am yloidosis

M onoclonalProtein

Anaem ia

LL 6

BonePains

Hypercalcaem ia

Bone Destruction

Release ofCytokines

M arrowInfiltration

Infections

Im m uneDeficiency

M M

MULTIPLE MYELOMA: Clinical Picture

Bone Marrow Failure:*Anemia:usually normocytic normochromic :due to marrow infiltration

and plasma volume expansion.

*Neutropenia is frequent(++ susceptibility to infection).

*Thrombocytopenia is rare.

Bone Disease:Skeletal lytic lesions,with or without osteoperosis,wedging or collapse of vertebral bodies or pathological fractures.

Renal Failure:In 20-40% of cases,due to:-BJP,and/0r hypercalcemia (in 95% of cases).-Other causes: hyperuricemia,hypeviscosity,sepsis& nephrotoxic drugs.

Hypercalcemia:Secondary to osteolysis----->polyurea,and polydypsia may lead to severe dehydration

Hyperviscosity:usually associated with IgM M-protein----ocular,hemostatic,and neurological disturbances.

Coagulopathy:either:-Hemorrhage: due to interference with action of clotting factors and platelets.-Thrombosis: due to acquired protein C deficiency.

Immune Paresis:-In 70% of patients with IgG MM, 40% of IgA MM and 20% of acses with BJP MMbut cell mediated immunity is intact. So----- incresed risk of bacterial sepsis.

Amyloidosis:In less than 5% of MM cases: more common with BJP and IgA MM-- deposition of amyloid material--congesive heart failure, Carpal tunnel syndrome, macroglossia, gastrointestinal disturbances and europathies., renal amyloidosis.

MULTIPLE MYELOMA

Lab investigation:

•ESR: very high.

•Serum protein electrophoresis: M-band.

•Immunofixation or immunoelectrophoresis: are confirmatory studies to define M-protein heavy and light chain classes.

MULTIPLE MYELOMA

Lab investigation:

•Serum Ca: often .

•Serum creatinine: often .

•Anaemia (not obligatory): (rouleaux formation of RBCs).

• In uninvolved immunoglobulins.

• +BJP in 24 hr urine collection (monoclonal light chains).

MULTIPLE MYELOMA

BM PICTURE:

(Aspirate & Trephine Biopsy)

• >10 % myeloma cells..• More basophilic cytoplasm.• Increased mitotic figures or multiple nuclei.• Coarse chromatin.• Plasma cell nests.

Immunophenotyping:

• CD 38 +ve.

• CD 19, 20, 22 -ve.

• Intracytoplasmic Ig +ve.

• sIg -ve.

MULTIPLE MYELOMA

MULTIPLE MYELOMA

RADIODIAGNOSIS:

•Radiological survey of the entire skeleton: is mandatory.•MRI: is superior to CT for screening the vertebral column for osteolytic lesions. •Bone scan: is not indicated (cold lesions).

•REMEMBER!! Iodine-containing contrast media may cause acute renal failure in case of paraproteinaemia.

MM: SWOG Criteria for Diagnosis:

(At least 1 major + 1 minor or 3 minors)

Major Criteria: (1) Plasmacytoma on tissue biopsy(2) Marrow plasmacytosis > 30 %.(3) Monoclonal protein:

Ig G > 3.5 g / dl.Ig A > 2 g / dl.BJP > 1 g / 24 hr.

Minor Criteria: (1) Marrow plasmacytosis 10-29 %.(2) Monoclonal protein present but less than the above levels(3) Lytic bone lesions(4) Decrease in uninvolved Ig:

Ig M < 50 mg / dl.Ig A < 100 mg / dl.Ig G < 600 mg / dl.

Prognostic Factors

(1) Staging (2) -2 microglobulin most significant) (3) CRP (reflect IL-6 activity) (4) PCLI (5) Cytogenetics (6) LDH

MULTIPLE MYELOMA

MM: Prognostic Factors

M.S. (mo)

Both 2M or CRP

Both

< 6

< 6

> 6

2M & CRP

54

27

6

Level(mg/l)

Risk Group

Low-risk Intermediate

High-risk

MM: Prognostic Factors

Cytogenetics:

• Cytogenetics abnormalities occur in 80-90% of patients.• FISH is the best technique to discover them.• Del 13 (partial or complete) & t involving 11q are associated with poor prognosis in ABMT patients only.• Hypodiploidy is associated with drug resistance.• Any abnormal karyotype leads to inferior outcome with standard therapy.

MM Treatment Options• Chemotherapy• High dose-therapy with transplant• Radiation• Maintenance therapy (e.g. alpha interferon, prednisone)• Supportive care for

– Anaemia– Pain– Bone disease (Bisphosphonates)– Hypercalcemia– Antibiotics– Emergency care (e.g. dialysis, plasmapheresis,

surgery)• Management of drug-resistant or refractory disease• New and emerging treatments

Treatment of MM

Use of Bisphosphonate in MM: Mechanism of action:

1. Decrease IL-6 release2. Direct effect on Myeloma (may slow tumor growth)3. Effect of angiogenesis

Treatment of MM

Radiotherapy: Indications:

• Big osteolytic lesions.• Significant osteolytic lesions in weight-bearing bone (for fear of pathological fracture).• Cord compression.• Extramedullary plasmacytoma.

TREATMENT PLAN IN MM

AB M T

N o H LA-IdenticalS ibling

M ini-Transplant

H LA-IdenticalS ibling

H LA-Typing

CR

C R

Another3 courses of VAD

PR

3 courses of VAD

Patients < 60 yrs of Age

TREATMENT PLAN IN MM

N o treatm ent

Asym ptom atic

2nd line

PD

VAD

Progression < 6 m onths

VAD

PD

R epeat M P

Progression >6 m onths

M P till C R or M ax. R esponse

Sym ptom atic or PD

Patients > 60 yrs

Survival of Multiple Myeloma patients

• No treatment: 3-6 months• Conventional chemotherapy: 3 years• Chemotherapy + IFN-α: 3 years ± 6 months• Auto transplant: 5 years• 25% dies within 1st year• 25% survival 8 years• No cure by conventional chemotherapy