슬라이드 1

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1 Plasma Cell Disorders 이제중 화순전남대병원혈액종양내과

2 5 heavy chain isotypes (M, G, A, D, E) 2 light chain isotypes (kappa, lambda) Schematic structure of the immunoglobulin G (IgG) molecule

4 Serum protein electrophoresis showing a monoclonal (M) protein. A, Monoclonal pattern of serum protein as traced by densitometer after electrophoresis on agarose gel: tall, narrowbased peak of γ mobility. B, Monoclonal pattern from electrophoresis of serum on agarose gel (anode on left): dense, localized band representing monoclonal protein of γ mobility Immunofixation depicting an immunoglobulin G κ monoclonal protein.

5 Serom protein electrophoresis showing increased polyclonal immunoglobulins. A, Polyclonal pattern from a densitometer tracing of agarose gel: broad-based peak of γ mobility. B, Polyclonal pattern from electrophoresis of agarose gel (anode on the left). The band at the right is broad and extends throughout the γ area.

6 M components in other diseases Other lymphoid neoplasms (CLL, lymphomas of B or T cell origin) Nonlymphoid neoplasms (CML, breast cancer, colon cancer) Nonneoplastic conditions (cirrhosis, sarcoidosis, parasitic diseases, Gaucher disease, pyoderma gangrenosum) Autoimmune conditions (rheumatoid arthritis, myasthenia gravis, cold agglutinin disease)

7 Classification of Plasma Cell Proliferative Disorders I. Monoclonal Gammopathies of Undetermined Significance (MGUS) II. Malignant Monoclonal Gammopathies A. Multiple myeloma (IgG, IgA, IgD, IgE, and free light chains)) 1. Overt multiple myeloma 2. Smoldering multiple myeloma 3. Plasma cell leukemia 4. Non-secretory myeloma 5. IgD myeloma 6. Osteoclastic myeloma (POEMS syndrome) 7. Solitary plasmacytoma of bone 8. Extramedullary plasmacytoma B. Waldenström s macroglobulinemia III. Heavy-chain disease IV. Cryoglobulinemia V. Primary amyloidosis (AL)

Monoclonal gammopathy. A, Distribution of serum monoclonal proteins in 1311 patients seen at the Mayo Clinic during 2004.

8 Monoclonal gammopathy. A, Distribution of serum monoclonal proteins in 1311 patients seen at the Mayo Clinic during B, Diagnoses in 1423 cases of monoclonal gammopathy seen at the Mayo Clinic during Ig = immunoglobulin; MGUS = monoclonal gammopathy of undetermined significance; PC = plasmacytoma; SMM = smoldering multiple myeloma; WM = Waldenström's macroglobulinemia.

9 Monoclonal Gammopathy of Undetermined Significance (MGUS) Vastly more common than myeloma Occurring in 1% of population over age 50 years & in up to 10% over age 75 Diagnostic criteria < 10% BM plasma cells < 3 g/dl of M components no urinary Bence Jones protein no anemia, renal failure, lytic bone lesions, or hypercalcemia About 1% per year of patients with MGUS go on to develop myeloma Require no therapy serum M protein < 2 g/dl: electrophoresis repeated at 6 months annually if stable serum M protein > 2 g/dl: electrophoresis repeated at 3 months annually if stable About 2 year shorter survival than age-matched controls without MGUS

10 RISK OF PROGRESSION OF MGUS TO MYELOMA OR RELATED DISORDERS Risk Group Low risk: serum M protein <1.5 g/dl, IgG subtype, normal free light chain ratio ( ) Cumulative Absolute Relative Risk Cumulative Absolute Risk of Progression at 20 Years [*] Risk of Progression at 20 Years Accounting for Death as a Competing Risk [ ] 1 5% 2% Low intermediate risk: any 1 factor abnormal High intermediate risk: any 2 factors abnormal % 10% % 18% High risk: all 3 factors abnormal % 27% *Estimates in this column represent the risk of progression assuming that patients do not die of other causes during this period. Estimates in this column represent the risk of progression calculated by using a model that accounts for the fact that patients can die of unrelated causes during this time.

11 다발성골수종 (multiple myeloma) Etiology: unknown Exposure to radiation, benzene, and other organic solvents, herbicides, and insecticides may play a role. reported in familial clusters of two or more first-degree relatives and in identical twins. A variety of chromosome alterations 13q14 deletions, 17p13 deletions, 11q abnormalities t(11;14)(q13;q32) Overexpression of myc or ras gene Mutations in p53 & Rb-1 * Interleukin (IL)-6 may play a role in driving myeloma cell proliferation.

12 Pathogenesis of multiple myeloma. Multiple myeloma cells interact with bone marrow stromal cells and extracellular matrix proteins via adhesion molecules, triggering adhesion-mediated signaling as well as cytokine production. This triggers cytokine-mediated signaling that provides growth, survival, and anti-apoptotic effects as well as development of drug resistance. HSP, heparin sulfate proteoglycan.

13 Epidemiology of MM 1% of all malignant disease slightly more than 10% of hematologic malignancies in the USA Increases in incidence with age Median age at the time of diagnosis: 65 years * only 2% of patients are younger than 40. Annual incidence: 4 per 100,000 persons M > F

14 U.S, SEER 2002 OTHERS 4% CML 4% ALL 3% CLL 9% HD 7% NHL 48% AML 10% MM 14%

15 우리나라혈액암의호발비율 (2005) 기타 림프종 만성골수성백혈병 골수이형성증후군 급성림프모구성백혈병 다발성골수종 급성골수성백혈병

16 우리나라혈액암의사망률변화추이 ( ) X X 25 X 5 X 젂체암 다발성골수종 비호지킨림프종 백혈병

17 우리나라다발성골수종의년갂발생율 (1980s-2000s) 최근 20 년동안 30 배증가 Increased detection Carcinogen Aging Society

18 우리나라다발성골수종의유병율 현재 5,000 명정도로추정 계속증가추세!

19 Clinical Finding Clinical Features of Multiple Myeloma Underlying Cause and Pathogenetic Mechanism Hypercalcemia, osteoporosis, pathologic fractures, lytic bone lesions, bone pain Renal failure Easy fatigue anemia Recurrent infections Neurologic symptoms Nausea and vomiting Bleeding/clotting disorder Tumor expansion, production of osteoclast activating factor by tumor cells, osteoblast inhibitory factors Hypercalcemia, light chain deposition, amyloidosis, urate nephropathy, drug toxicity (nonsteroidal antiinflammatory agents, bisphosphonates), contrast dye Bone marrow infiltration, production of inhibitory factors, hemolysis, decreased red cell production, decreased erythropoietin levels Hypogammaglobulinemia, low CD4 count, decreased neutrophil migration Hyperviscosity, cryoglobulinemia, amyloid deposits, hypercalcemia, nerve compression, anti-neuronal antibody, POEMS syndrome, therapy-related toxicity Renal failure, hypercalcemia Interference with clotting factors, antibody to clotting factors, amyloid damage of endothelium, platelet dysfunction, antibody coating of platelet, therapy-related hypercoagulable defects * pneumonia: S. pneumoniae, S. aureus, K. pneumoniae **UTI: E. coli, other Gram (-) organisms

20 초기진단을위한검사 H & P CBC, differential, platelets BUN/creatinine, electrolytes LDH Calcium/albumin Beta-2 microglobulin Serum quantitative immunoglobulins, serum protein electrophoresis (SPEP) serum immunofixation electrophoresis (SIFE) 24h UPEP & immunofixation Skeletal survey Unilateral bone marrow aspirate + biopsy Cytogenetics FISH [del 13, del 17, t(4;14), t(11;14), t(14;16)] Bone marrow immunohistochemistry AND/OR Bone marrow flow cytometry Useful Under Some Circumstances MRI for suspected vertebral compression CT scan (avoid contrast) PET/CT scan Tissue biopsy to diagnosis a solitary osseous or extraoesseous plasmacytoma Bone densitometry Plasma cell labeling index Staining of marrow & fat pad for amyloid Serum free light chain assay Serum viscosity HLA typing C-reactive protein

22 Definition of multiple myeloma Smoldering myeloma (Asymptomatic) Active (symptomatic) myeloma a M-protein in serum 3 g/dl &/or Bone marrow clonal plasma cell 10%, No related organ or tissue impairment (no end organ damage, including bone lesions) or symptoms Require one or more of the following: Calcium elevation (> 11.5 g/dl) Renal insufficiency (creatinine > 2 mg/dl) Anemia (hemoglobin < 10 or 2 g < normal) Bone disease (lytic or osteopenic) Monoclonal Gammopathy of Undetermined Significance (MGUS) : 혈청 M 단백 < 3 g/dl, 골수형질세포 <10%, 장기침범증거 (-) C R A B a Other examples: Repeated infection Secondary amyloidosis Hyperviscosity Hypogammogulobulinemia

26 Staging systems for multiple myeloma Stage Durie-Salmon Criteria ISS Criteria I All of the following: Hb > 10 g/dl Serum calcium value 12 mg/dl Bone x-ray, normal bone structure (scale 0) or solitary bone plasmacytoma only Low M-component production rate IgG value < 5 g/dl IgA value < 3 g/dl Bence Jones protein < 4 g/24 h serum β 2 -microglobulin <3.5 mg/l and albumin 3.5 g/dl II Neither stage I nor stage II Neither stage I nor stage II III All of the following: Hb < 8.5 g/dl Serum calcium value > 12 mg/dl Advanced bone lytic lesions (scale 3) High M-component production rate IgG value > 7 g/dl IgA value > 5 g/dl Bence Jones protein > 12 g/24 h Subclassification Criteria A Normal renal function (serum creatinine level < 2.0 mg/dl) B Abnormal renal function (serum Cr level 2.o mg/dl) serum β 2 -microglobulin 5.5 mg/l

27 다발성골수종의발젂사 (1980 현재 ) Blood 2008

28 형질세포종 (Plasmacytoma) 에대한치료법

29 형질세포종 (Plasmacytoma) 에대한치료법 Solitary Osseous Solitary Extraosseous RT ( 45 Gy) RT ( 45 Gy) Surgery Primary progressive or response followed by progression 다발성골수종에대한검사및병기 Active (symptomatic) myeloma 다발성골수종 + 형질세포종 다발성골수종에대한치료 +/- 방사선치료

30 초기임상상황에따른치료법 Smoldering (asymptomatic) or Stage I myeloma Observe at 3-6 mo intervals 병기 II 이상진행 반응군 Active (symptomatic) all other stages of myeloma Induction therapy Bisphosphonates + adjunctive treatment as indicated 이식대상자 : 조혈모세포채집 (2 번이식가능용량 ) 진행성질환 Quantitative immunogloulins + quantitation of M protein every month CBC, differential, platelets BUN, creatinine, calcium Bone survey annually or for symptomss Bone marrow biopsy as clinically indicated Consider free light chain Consider MRI Consider PET/CT scan

31 일차치료반응에따른치료법 Active (symptomatic) myeloma: Response after induction therapy Stem cell transplantation Continue induction therapy to plateau Postinduction therapy Active (symptomatic) myeloma: Progressive disease Stem cell transplantation salvage therapy or Clinical trial Quantitative immunogloulins + quantitation of M protein at least every 3 month CBC, differential, platelets BUN, creatinine, calcium Bone survey annually or for symptomss Bone marrow biopsy as clinically indicated Consider free light chain Consider MRI Consider PET/CT scan

32 새로진단된다발성골수종에대한치료접근법 (2008) 새로진단된다발성골수종 이식비적응환자 이식적응환자 Melphalane + Prednisone + Thalidomide X 12 주기 or VMP 관찰 자가이식 ( 일차이식후완전반응이나 VGPR 이유도되지않으면이차이식 ) 비알킬화제가포함된 2-4 주기유도요법 안정화될때까지지속치료 : 재발시에자가이식

34 이식이적합한환자에서일차치료요법 Bortezomib/dexamethasone (Category 1) Bortezomib/doxorubicin/dexamethasone (Category 1) Bortezomib/lenalidomide/dexamethasone (Category 2B) Bortezomib/Thalidomide/dexamethasone (Category 1) Lenalidomide/dexamethasone (Category 1) Dexamethasone (Category 2B) Thalidomide/dexamethasone (Category 2B) Liposomal doxorubicin/vincristine/dexamethasone (Category 2B) Cyclophosphamide/thalidomide/dexamethasone (CTD) Exposure to myelotoxic agents (including alkylating agents and nitrosureas) should be limited to avoid compromising stem-cell reserve prior to stem-cell harvest in patients who may be candidates for transplant

35 이식이적합하지않는환자에서일차치료요법 Dexamethasone (Category 2B) Lenalidomide/low-dose dexamethasone (Categroy 1) Liposomal doxorubicin/vincristine/dexamethasone (DVD) (Cate 2B) Melphalan/prednisone (MP) Melphalan/prednisone/bortezomib (MPB) (Category1) Melphalan/prednisone/thalidomide (MPT) (Category 1) Thalidomide/dexamethasone Vincristine/doxorubicin/dexamethasone (VAD) (Categroy 2B)

36 Maintenance therapy Interferon (Category 2B) Steroids (Category 2B) Thalidomide (Category 1) prednisolone (Category 2B) Consider herpes zoster prophylaxis for patients treated with bortezomib. Prophylactic anticoagulation recommended for patients receiving thalidomide-based therapy or lenalidomide with dexamethasone.

37 구제요법 Repeat primary induction therapy (if relapse at > 6 mo) Bortezomib (Category 1) Bortezomib/dexamethasone Bortezomib/liposomal doxorubicin (Category 1) Bortezomib/lenalidomide/dexamethasone (Category 2B) Lenalidomide/dexamethasone (Category 1) Lenalidomide Cyclophosphamide-VAD High-dose cyclophosphamide Thalidomide Thalidomide/dexamethasone Dexa, thalido, cisplastin, doxorubicin, cytoxan, etoposide (DT-PACE) Dexamethasone Dexamethasone, cyclophosphamide, etoposide, cisplatin (DCEP)

38 탈리도마이드독성 최기성, 선천성기형유발 : 파미온유해관리프로그램가장흔한이상반응 : 변비, 기면, 무력증기타 : 감각말초신경병증, 발진, 기립성저혈압, 호중구감소증, 스티븐슨-존슨증후군및중독성표피괴상증과같은피부이상반응, 두통호산구증가증말초부종, 호흡곤란, 어지러움, 저혈압, 서맥, 증후성갑상선부젂증, 혈소판수의증가혹은감소빈혈심부정맥혈젂증

39 Bortezomib (Velcade, 벨케이드 ): 부작용 무력상태 (65%) 위장관증상 오심 (64%), 설사 (51%), 변비 (43%), 구토 (36%) 혈소판감소증 (43%) 말초신경병증 (37%) 구토, 발열, 혈소판감소증, 정신장애 ( 각 35%) 식욕부진과식욕감소 (34%) 감각이상및감각장애 (27%) 빈혈과두통 ( 각 26%) 기침 (21%) 호흡곤란및폐렴 (4%) 대상포진 (15-20%)

40 부가적인치료 Adjuvant (I) Bone disease Bisphosphonates (pamidronate/zoledronic acid) All patients with documented bone disease including osteopenia Monitor for renal dysfunction with use of bisphosphonate Monitor for osteonecrosis of the jaw (ONJ) Radiation therapy Low-dose radiation therapy (10-30Gy): palliative treatment for uncontrolled pain, for impending pathologic fracture or impending cord compression Limited involved fields: to limit the impact of irradiation on stem-cell harvest or impact on potential future treatments Orthopedic consultation for impending or actual long-bone fractures or bony compression of spinal cord or vertebral column instability Consider vertebroplasty or kyphoplasty for symptomatic vertebral compression fractures

42 Osteonecrosis of the Jaw (ONJ) complicating Bisphosphonate treatment Established ONJ The moth-eaten appearance of ONJ on plain x-ray

43 부가적인치료 Adjuvant (II) Hypercalcemia Hydration/furosemide, bisphosphonates, steroids and or calcitonin Hyperviscosity Plasmapheresis should be used as adjuvant therapy for symptomatic hyperviscosity Anemia Consider erythropoietin for anemic patients Infection Intravenous immunoglobulin therapy should be considered in the setting of recurrent life-threatening infection Consider pneumovax and influenza vaccine Consider PCP, herpes, and antifungal prophylaxis if high dose dexamethasone regimen

45 부가적인치료 Adjuvant (III) Renal dysfunction Maintain hydration to avoid renal failure Avoid use of NSAIDs Avoid IV contrast Plasmapheresis Not a contraindication to transplant Monitor for renal dysfunction with chronic use of bisphosphonate Coagulation/thrombosis Prophylactic anticoagulation recommended for patients receiving thalidomidebased, or lenalidomide with dexamethasone therapy

46 IMW Group Uniform Response Criteria Response Category scr, Stringent complete response Response Criteria CR as defined below plus Normal free light chain (FLC) ratio & absence of clonal cells in bone marrow by immunohistochemistry or immunofluorescence CR, complete response Negative immunofixation on the serum & urine & disappearance of any soft tissue plasmacytomas and 5% plasma cells in bone marrow VGPR, very good partial response PR, partial response SD, stable disease Serum & urine M-protein detectable by immunofixation but not on elctrophoresis or 90% reduction in serum M-protein plus urine M-protein level <100 mg/24 h 50% reduction of serum M-protein & reduction in 24h urinary M-protein by 90% or to < 200 mg/24 h If the serum & urine M-protein are unmeasurable, a 50% decrease in the difference between involved & uninvolved FLC level is required in place of the M- protein criteria If serum & urine M-protein are unmeasurable, and serum free light assay is also unmeasurable, 50% reduction in plasma cells a 30% In addition to the above listed criteria, if present at baseline, a 50% reduction in the size of soft tissue plasmacytoma is also required Not meeting criteria for CR, VGPR, PR or progressive disease

47 다발성골수종의병기및예후결정인자 I. International Staging System Stage I (serum β 2 -microglobulin <3.5 mg/l and albumin 3.5 g/dl) Stage II (not fitting stage I or II) Stage III (serum β 2 -microglobulin 5.5 mg/l) II. Performance status III. Myeloma risk stratification IV. Other independent prognostic factors Serum lactate dehydrogenase (LDH) Plasmablastic morphology Circulating plasma cells V. Other Advanced age Durie Salmon stage C-reactive protein Serum creatinine Platelet count

49 62 세남자 : 수주전부터시작된요통으로내원, 어지러움 (+) 과거력상특이질환없었음 증례 혈액검사 : CBC WBC 6,100/uL, Hb 9.6 g/dl, Platetelet 83,000/uL T-protein 12.8 g/dl, albumin 3.1 g/dl, AST 20 IU/L, ALT 15 IU/L BUN 22.2 mg/dl, Cr 1.4 mg/dl Sodium 128 meq/l, Potassium 4.7 meq/l, Total calcium 8.6 mg/dl Uric acid 7.4 mg/dl, LDH 402 IU/L, CRP 6.7 mg/dl b2-microglobulin 2,954 ug/l(n:670-1,310) aptt 61.3 sec, PT 1.82 (INR) 진단을위해서수행해야할검사들은?

50 초기진단을위한검사

51 Skull AP/Lat

52 Femur/Tibia

53 L-spine MRI

54 증례 검사결과가아래와같았다. IgG 8,540 mg/dl (N: 700-1,600), IgA 32.8 mg/dl (N: ) IgM 17.6 mg/dl (N: ) FLC quantitation-kappa 160 mg/l (N: ) FLC quantitation-lambda 7.97 mg/l (N: ) Kappa/Lambda ratio (N: , ) serum M-protein: 8.71 g/dl, SIF: IgG, Kappa type BM: Plasma cell 17%, 46 XX 이환자의진단과병기는? 이환자에서시행되어야할응급치료 / 일차치료 / 보조요법은?

55 증례 이환자의진단과병기는? Symptomatic multiple myeloma: ISS 2 이환자에서시행되어야할응급치료, 1차치료, 보조치료? 1) Plasmapheresis 2) induction therapy 3) Bisphosphonate & erythropoietin 4) Pain control with NSAID, opioid palliative radiotherapy 5) Vertebroplasty or kyphoplasty

56 M-protein (g/dl) 증례 차 CTD 차 CTD PBSC 채집 1 차자가이식 차자가이식유지요법

58 Individualizing Treatment of Patients With Myeloma in the Era of Novel Agents Progress in MM cell biology Discovery of New Drugs Prognostic factors & Myeloid subtypes Singular mechanism of action Individualize and tailor treatment

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