Multiple Myeloma

1. Multiple Myeloma By Dr. Navinee Vongsupathai

2. Multiple Myeloma • Definition • Causes and incidence • Clinical feature • Physical examination • Diagnosis • Classification and staging • Threatment • Prognosis

3. Definition • Multiple myeloma : as myeloma or plasma cell myeloma • cancer of the plasma cell • Multiple 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)

4. Definition • 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.

6. 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.

7. 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.

8. Definition • 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.

9. Incidence • Multiple myeloma is the second most prevalent blood cancer after non-Hodgkin's lymphoma • 1% of all cancers and 2% of all cancer deaths. • Age 60-65 years most common • Occurs in men > women • African Americans and Native Pacific Islanders have the highest reported incidence of this disease and Asians the lowest

10. Causes • 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.

11. Clinical features • common tetrad of multiple myeloma is CRAB • C = Calcium (elevated) • R = Renal failure • A = Anemia • B = Bone lesions

12. Clinical features • 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

13. Clinical features • 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.

14. Clinical features

15. Clinical features

16. Clinical features

17. Clinical features • Hypercalcemia • Pt. present with confusion, somnolence, bone pain, constipation, nausea, and thirst. • Anemia • The 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 (hematopoiesis) by cytokines.

18. Clinical features • Bleeding • bleeding resulting from thrombocytopenia. • In some patients, monoclonal protein may absorb clotting factors and lead to bleeding, but this development is rare. • Hyperviscosity • high volume of monoclonal protein -- > blood viscosity increases-- >complications such as stroke, myocardial ischemia, or infarction.

19. Clinical features • 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.

20. Clinical features • Renal failure • Renal failure may develop both acutely and chronically. • It is commonly due to hypercalcemia. • It may also be due to tubular damage from excretion of light chains, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). • Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.

21. Clinical features • Neurological symptoms • Common problems are weakness, confusion and fatigue due to hypercalcemia. • Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. • Finally, there may be radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome and other neuropathies (due to infiltration of peripheral nerves by amyloid). • It may give rise to paraplegia in late presenting cases.

22. Physical Examination • Pallor : anemia • Ecchymoses or purpura : thrombocytopenia • Bone pain without tenderness is typical : lytic destructive bone lesions or pathologic fracture.

23. Physical Examination • Neurologic findings • Sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal cord compression) • Weakness • Extramedullary plasmacytomas :soft tissue masses of plasma cells, are not uncommon.

24. Physical Examination • Amyloidosis • The shoulder pad sign is defined by bilateral swelling of the shoulder joints secondary to amyloid deposition-- >swelling as hard and rubbery. • Macroglossia is a common finding in patients with amyloidosis.

25. Diagnosis • Lab Studies: • CBC: anemia, thrombocytopenia, leukopenia • Peripheral blood smear : rouleaux formation

26. Rouleaux formation : high plasma protein

27. ภาพแสดงกลุ่มเซลล์ที่มีลักษณะคล้าย plasma cells คือ เซลล์มีลักษณะเป็นรูปไข่ ที่มี nucleus อยู่ชิดขอบด้านใดด้านหนึ่งของเซลล์ ลักษณะของ nucleus จะเห็น chromatin มาเรียงกันคล้ายล้อเกวียนหรือหน้าปัดนาฬิกา

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

30. Diagnosis • 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.

31. Diagnosis • Imaging Studies • Skeletal series • skull (a very common site ), the long bones ( for impending fractures), and the spine. • Diffuse osteopenia may suggest myelomatous involvement before discrete lytic lesions are apparent. • Do not use bone scans to evaluate myeloma • MRI scan • MRI to obtain a clear view of the spinal column and to assess the integrity of the spinal cord.

32. Diagnosis • 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.

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

34. Bone marrow biopsy : sheets of malignant plasma cells in MM

35. Diagnostic criteria • Durie-Salmon criteria Dx : 1 major & 1 minor or 3 minor criteria • Major criteria • Plasmacytoma on tissure biopsy • BM plasmacytosis with > 30% plasma cell • Monoclonal globulin spike on serum electrophoresis 3.5 g/dl for Ig G ,> 2g/dl for IgA • Or urine Bence Jones > 1g/24 hr

36. Diagnostic criteria • Durie-Salmon criteria • Minor criteria • Marrow plasmacytosis 10-29 % • Monoclonal globulin spike present ,but less than above • Lytic bone lesion • Normal Ig M< 0.05g/dl , IgA <0.1g/dl , IgG<0.6 g/dl

37. Staging • Durie-Salmon staging system • High tumor mass <stage III > one of following abnormalitie mus be present • Hb <8.5 g/dl, Hct < 25 % • Sr Ca > 12 gm/dl • 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 • > 3 lytic bone lesion on bone survey

38. Staging • Durie-Salmon staging system 2. Low tumor mass <stage I> all of following must be present • Hb > 15 gm/dl, Hct> 32% • Sr Ca normal • Low Sr myeloma protein production rate 1. Ig G peak< 5 gm/dl 2. IgA peak < 3 gm/dl 3. Bence Jone protien < 4 g/ 24 hr • No bone lesion or osteoporosis

39. Staging • Durie-Salmon staging system 3.Imtermediate tumor mass <stage II> a. no renal failure <Cr < 2 mg/dl> b. Renal failure <Cr > 2 mg/dl>

40. 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

41. Threatment • Active care • Chemotherapy • Autologous / Allogenic stem cell transplamtation • Drug : Arsenic trioxide, Thalidomide & Immunomodulator • Interferon • Supportive care • Radiation therapy • Bisphosphonate • Kayphoplasty

42. Threatment • Radiation therapy <palliative> • Rx : plasmacytoma post surgery • Chemotherapy • Melphalan & Prednisolone • VAD < vincristine, adriamycin, dexamethasone> • VMCP < vincristine , melphalan, cyclophosphamide, prednisolone>

43. Threatment • Arsenic trioxide : inhibit leukemic growth factor & + apoptosis • Thalidomide : Antiangiogenesis-- >apoptosis of MM cell • Bisphosphonate <Pamidronate,Zoledronic acid>-- > inhibit osteoclast

44. Prognosis • The International Staging System can help to predict survival • Stage 1 : 62 months • Stage 2 : 45 months • Stage 3 : 29 months