Multiple Myeloma

1. Multiple Myeloma By Dr.Sujith S.

2. Introduction Malignant proliferation of plasma cells derived from single clone. Osteoclasts Activating Factor

4. Plasma cell

6. A variety of chromosomal alterations - most common translocations are t(11;14)(q13;q32) and t(4;14)(p16;q32), Mutations in p53 and Rb-1 have also been described.

7. Myeloma increases in incidence with age. The median age at diagnosis is 68 years; it is uncommon under age 40. The yearly incidence is around 4 per 100,000 . Males are more commonly affected than females Blacks have twice the incidence of whites

8. Clinical Features Bone pain (70%) Mechanism of lytic lesion in the bone Site of involvement Back & Ribs,Pain precipitated by movement

9. Clinical features(cont.d) Complications Pathological fracture-persistent pain at the local site Spinal Cord Compression due to collapse of the vertebrae

10. Clinical features(cont.d) Increase susceptibility to bacterial infections. The most common infections are pneumonias and pyelonephritis Organisms in the lungs- Streptococcus pneumoniae, Staphylococcus aureus, and Klebsiella pneumoniae. Organisms in the urinary tract- Escherichia coli and other gram-negative

11. Contributory causes

12. Clinical features(cont.d) Renal failure occurs in nearly 25% of myeloma patients, Hypercalcemia Glomerular deposits of amyloid, hyperuricemia, recurrent infections, frequent use of nonsteroidal anti-inflammatory agents for pain control, use of iodinated contrast dye for imaging, bisphosphonate use, myeloma cells infiltrates Tubular damage associated with the excretion of light chains

13. Clinical Features(cont.d) The earliest manifestation of this tubular damage is the adult Fanconi syndrome (a type 2 proximal renal tubular acidosis),

14. Clinical features(cont.d) Glomerular function is usually normal Proteinuria is uncommon

15. Clinical features(cont.d) Decreased anion gap because the M component is cationic Hyponatremia (pseudohyponatremia) susceptible to acute renal failure if they become dehydrated

16. Clinical Features(cont.d) Anemia - 80% . It is usually normocytic and normochromic

17. Clinical Features(cont.d) Some have megaloblastic anemia due to either folate or vitamin B12 deficiency. Granulocytopenia and thrombocytopenia are very rare. Clotting abnormalities may be seen failure of antibody-coated platelets to function properly interaction of the M component with clotting factors I, II, V, VII, or VIII.

18. Clinical features(cont.d) Deep venous thrombosis is also observed Raynaud's phenomenon and impaired circulation may result if the M component forms cryoglobulins

19. Hyperviscosity Depends on the physical properties of the M component (most common with IgM, IgG, and IgA paraproteins). Paraprotein concentrations of ~40 g/L (4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA. Symptoms: headache, fatigue, visual disturbances, and retinopathy

20. Hypercalcemia - lethargy, weakness, depression, and confusion. Bony damage and collapse - cord compression, radicular pain, and loss of bowel and bladder control. Infiltration of peripheral nerves by amyloid- cause of carpal tunnel syndrome sensory ,motor mono and polyneuropathies. Sensory neuropathy is also a side effect of thalidomide and bortezomib therapy

21. Variants of Myeloma Solitary bone plasmacytomas may recur in other bony sites or evolve into myeloma. Extramedullary plasmacytomas submucosal lymphoid tissue of nasopharynx or paranasal sinus without marrow plasmacytosis rarely recur or progress Both highly responsive to local radiation theray

22. Diagnostic features Plasmacytosis in marrow Monoclonal protein in serum or urine Lytic disease of bone

27. Asymptomatic Multiple Myeloma M protein in serum>30g/L Bone marrow clonal plasma cells > 10% �� No myeloma-related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms

28. Symptomatic Multiple Myeloma M protein in serum and/or urine � Bone marrow (clonal) plasma cells or plasmacytoma Myeloma-related organ or tissue impairment (end organ damage, including bone lesions

29. Nonsecretory Myeloma No M protein in serum and/or urine with immunofixation �� Bone marrow clonal plasmacytosis 10% Myeloma-related organ or tissue impairment (end organ damage, including bone lesions)

30. Solitary Plasmacytoma of Bone No M protein in serum and/or urine Single area of bone destruction due to clonal plasma cells Bone marrow not consistent with multiple myeloma �� Normal skeletal survey (and MRI of spine and pelvis if done) �� No related organ or tissue impairment (no end organ damage other than solitary bone lesion

31. Myeloma-related organ or tissue impairment (ROTI) Calcium levels increased renal insufficiency anemia bone lesions symptomatic hyperviscosity, amyloidosis, recurrent bacterial infections (>2 episodes in 12 months)

32. Investigations CBC with differential may reveal anemia ESR is elevated. Rare patients (~2%) may have plasma cell leukemia with >2000 plasma cells/L. Serum calcium, urea nitrogen, creatinine, and uric acid levels may be elevated. Protein electrophoresis and measurement of serum immunoglobulins and free light chains.

33. Cont.d A 24-h urine specimen is necessary to quantitate protein excretion Serum alkaline phosphatase is usually normal It is also important to quantitate serum Beta2-microglobulin. Serum soluble IL-6 receptor levels and C-reactive protein may reflect physiologic IL-6 levels in the patient

34. Serum M Component IgG in 53% of patients, IgA in 25%, and IgD in 1% 20% of patients will have only light chains in serum and urine. Bence Jones protein is falsely negative in ~50% of patients with light chain myeloma.

35. Serum M Component Fewer than 1% of patients have no identifiable M component- have light chain myeloma About two-thirds of patients with serum M components -urinary light chains.

36. Criteria for Diagnosis of Multile Myeloma Durie Salmon Diagnostic Criteria Major Criteria I-Plasmacytoma on tissue biopsy. II-Bone marrow plasmacytosis(>30% plasma cells) III-Monoclonal immunoglobulin spike IgG>3.5g/dl or IgA>2g/dl kappa/lamda chain excretion>1g/dayin 24 hr UPEP

37. Minor Criteria a)Bone marrow plasmacytosis(10-30%plasma cells). b)Lesser magnitude of Ig spike c)Lytic lesions d)Normal IgM:<50mg/dl Normal IgA<100mg/dl or Normal IgG<600 mg/dl I plus b, c, or d II plus b, c, or d III plus a, c, or d a plus b plus c a plus b plus d

38. Durie-Salmon staging Staging system is based on the hemoglobin, calcium, M component, and degree of skeletal involvement low (stage I), intermediate (stage II), or high (stage III), stages are further subdivided on the basis of renal function [A if serum creatinine <2 mg/dL, B if >2 mg/dl]. stage IA have a median survival of >5 years and those in stage IIIB about 15 months. This staging system has been found not to predict prognosis after treatment with high-dose therapy or the novel targeted therapies that have emerged.

39. Stage I Estimated Tumor Burden < 0.6 (x 1012 cells/m2) Hemoglobin >100 g/L (>10 g/dL) Serum calcium <3 mmol/L (<12 mg/dL) Normal bone x-ray or solitary lesion Low M-component production IgG level <50 g/L (<5 g/dL) IgA level <30 g/L (<3 g/dL) Urine light chain <4 g/24 h

40. Stage III Hemoglobin <85 g/L (<8.5 g/dL) Serum calcium >3 mmol/L (>12 mg/dL) Advanced lytic bone lesions High M-component production IgG level >70 g/L (>7 g/dL) IgA level >50 g/L (>5 g/dL) Urine light chains >12 g/24 h

41. International Staging System Beta 2M < 3.5, alb 3.5 Beta 2M < 3.5, alb < 3.5 or Beta 2M = 3.5�5.5 Beta 2M > 5.5

42. Disorder Associated with Monoclonal Protein Neoplastic cell proliferation multiple myeloma solitary plasmacytoma Waldenstrom macroglobulinemia heavy chain disease primary amyloidosis Undetermined significance monoclonal gammopathy of undetermined significance (MGUS)

43. Disorder Associated with Monoclonal Protein Transient M protein viral infection post-valve replacement Malignacy bowel cancer, breast cancer Immune dysregulation AIDS, old age Chronic inflamation

44. Monoclonal gammopathy of undetermined significance ( MGUS) M protein presence, stable levels of M protein: IgG < 3.5g IgA < 2g LC<1g/day normal immunoglobulins - normal levels marrow plasmacytosis < 10% complete blood count - normal no lytic bone lesions no signs of disease

45. Monoclonal gammopathy of undetermined significance ( MGUS) M protein 3% of people > 70 years 15% of people > 90 years MGUS is diagnosed in 67% of patients with an M protein 10% of patients with MGUS develop multiple myeloma

46. Treatment Patients with symptomatic and/or progressive myeloma require therapeutic intervention. symptomatic supportive care to prevent serious morbidity from the complications of the disease. Therapy can significantly prolong survival and improve the quality of life for myeloma patients.

47. Treatment - Transplant Alkylating agents such as melphalan should be avoided since they damage stem cells, leading to decreased ability to collect stem cells for autologous transplant. High-dose pulsed glucocorticoids have been used either alone or VAD combination for 3 weeks for initial cytoreduction.

48. Treatment - Transplant Initial therapy is continued until maximal cytoreduction. Agents bortezomib, a proteasome inhibitor, and lenalidomide, an immunomodulatory derivative of thalidomide, have similarly been combined with dexamethasone and obtained high response rates without compromising collection of stem cells for transplantation

49. Treatment - Chemotherapy Only Intermittent pulses of an alkylating agent, L-phenylalanine mustard (L-PAM, melphalan) and prednisone administered for 4�7 days every 4�6 weeks. The usual doses of melphalan/prednisone (MP) are melphalan, 8 mg/m2 per day, and prednisone, 25�60 mg/m2 per day for 4 days.

50. Treatment - Chemotherapy Only In patients >65 years, combining thalidomide with MP (MPT) obtains higher response rates and overall survival than MP alone MPT is the standard therapy for patients who are not transplant candidates

51. High-dose melphalan therapy (HDT) with hematopoietic stem cell support have shown that HDT can achieve high overall response rates and prolonged progression-free and overall survival; Only few patients are cured. Complete responses are rare (<5%) with standard-dose chemotherapy, HDT achieves 25�40% complete responses.

52. Refractory Myeloma lenalidomide and/or bortezomib. These agents target not only the tumor cell but also the tumor cell�bone marrow interaction These agents in combination with dexamethasone can achieve up to 60% partial responses and 10�15% complete responses in patients with relapsed disease

53. Thalidomide, if not used as initial therapy, can achieve responses in refractory cases. High-dose melphalan and stem cell transplant, if not used earlier, can be used

54. Supportive Treatment

55. Supportive care directed at the anticipated complications of the disease may be as important as primary antitumor therapy. Hypercalcemia Dehydration ARF Hyperviscosity UTI Recurrent serious infection-Prophylactic IV globulin

56. Supportive Treatment Patients developing neurologic symptoms in the lower extremities, severe localized back pain, or problems with bowel and bladder control may need emergency MRI and radiation therapy for palliation. Most bone lesions respond to analgesics and chemotherapy The anemia associated with myeloma may respond to erythropoietin along with hematinics (iron, folate, cobalamin).

57. Prognosis The median overall survival of patients with myeloma is 5�6 years, Subsets of patients surviving over 10 years. The major causes of death are progressive myeloma, renal failure, sepsis, or therapy-related acute leukemia or myelodysplasia. intercurrent age related illnesses: myocardial infarction, chronic lung disease, diabetes, or stroke