Multiple Myeloma.pptx diagnostic criteria

treatment

1. Multiple Myeloma 2080.08.27 Presented by: Dr sandeep oli 2 nd year resident, Department of Orthopaedics , PoAHS Moderator: Dr Kathit Raj Ghimire Consultant orthopaedics surgeon, Department of Orthopaedics , PoAHS

2. Contents: Introduction Classification Pathogenesis Variants of PCM Clinical features Diagnosis Management

3. Immunoglobulin

4. Light chains Kappa chain 2. Lambda chain Normal ratio of k:L= 2:1 Free light chain ratio: 0.26 to 1.65

5. Hematopoetic tumor: classification

6. Introduction Plasma cell myeloma (PCM) is a monoclonal, neoplastic proliferation of plasma cells that involves the bone marrow and occasionally involves extraskeletal site commonly  results in multiple b one lesions, hyper c alcemia , r enal insufficiency, and a nemia

7. 1 % of all malignant neoplasms in white patients and approximately 2% in black patients 2 nd m/c hematopoetic malignancy (10%) m/c malignacy occuring in skeletal sites

8. Male: female = 2:1 median age at diagnosis: 70 years

9. Risk factors Chronic infections (like chronic osteomyelitis ), Systemic inflammatory disease as eg . rheumatoid arthritis Persistent radiation exposure Other : asbestos, pesticides, petroleum products, rubber, plastic and wood products HHV- 8 ( in POEMS syndrome) MGUS ( risk 1 % per year)

10. Mayo group risk stratification: Standard risk : t(11;14) or t (6;14) Intermediate risk : t(4;14), deletion of 13q14 , hypodiploidy , and a plasma cell labeling index greater than 2 High risk : deletion of 17p13, t(14;16), t(14;20 ), or a high risk signature by gene expression profiling M edian overall survival for high risk, intermediate risk, and standard risk is 3 years, 4 to 5 years, and 8 to 10 years, respectively

11. Pathogenesis: Stimulate the production of RANKL and other pro- osteoclastic mediators (macrophage colony-stimulating factor (M-CSF, IL-6 , IL-11, ) Osteoprotegerin (OPG) synthesis is suppressed, resulting in further osteoclast activation Inhibition of Osteoblastic differentiation ( TNF and Dickkopf-1 (DKK-1) down regulate osteoblast function)

12. P athogenesis

13. F orms of PCM

14. Solitary plasmacytoma of bone:

15. Symptomatic multiple myeloma

16. “CRAB”

17. POEMS syndrome: P olyneuropathy M onoclonal plasma cell proliferative disorder Any one of the 3 other major criteria: sclerotic bone lesions, Castleman's disease, elevated levels of VEGFA Any one of the following 6 minor criteria : O rganomegaly Extravascular volume overload E ndocrinopathy S kin changes Papilloedema Thrombocytosis/polycythemia

18. TEMPI syndrome P araneoplastic syndrome associated with a plasma cell neoplasm. T elangiectasias , E levated erythropoietin and E rythrocytosis , M onoclonal gammopathy , P erinephric fluid collection, and I ntrapulmonary shunting. Rare disease

19. Clinical features Bone disease: severe bone pain: 70 % Cord compression: neurologic features D iffuse osteoporosis, H ypercalcaemia and P athological fractures : 40% of patients Medical complications: Anaemia , Hypercalcaemia , H yperuricaemia , Hypoalbuminaemia Hyperviscosity , Immunosuppression R enal dysfunction:

20. Myeloma bone disease Skeletal related events due to multiple myeloma bone pain, osteoporosis, pathological fractures, osteolytic bone lesions, spinal instability, spinal cord and nerve root compression and extramedullary plasmacytoma

21. Myeloma defining events: ( SLiM features) 1. 60 % or greater clonal plasma cells on bone marrow examination ( s ixty ) 2. Serum involved / uninvolved free li ght chain ratio of 100 or greater 3 . More than one focal lesion on M RI that is at least 5mm or greater in size.

22. International staging system (ISS) Stage B2- microglobulin albumin Overall survival 1 <3.5 mg/dl ≥ 3.5 mg/dl 62 months 2 3.5 – 5.5 mg/dl - 44 months 3 > 5.5 mg/dl - 29 months Revised- ISS

23. Blood investigations: CBC, ESR Peripheral smear: rouleax formation To asses renal function : RFT, eGFR , BUN To assess protein and other substance in blood: calcium levels, total protein test, serum beta-2 microglobulin (s β2 M), lactate dehydrogenase (LDH), C-reactive protein, and blood sugar

24. 5. To assess serum monoclonal protein : serum protein electrophoresis (SPEP), electrophoresis of blood or urine (IFE), quantitative immunoglobulins testing ( QIg ), serum free light chain assay and serum heavy/light chain assay 6. Immunophenotype

25. Immunophenotype

26. Bone marrow examination Bone marrow aspirate plus trephine biopsy To Test for cytogenetics , fluorescent in situ hybridization (FISH), and immunophenotyping

27. Microscopic

28. Imaging Principle of imaging: ( nccn 2024) Suspected MM: whole body LD CT/ FDG PET OR CT Osseous plasmacytoma : whole body MRI Extra osseous plasmacytoma : FDG PET CT Follow up for MM: WB LD CT/FDG PET/ WB MRI

29. Imaging: Plain radiography : spine, pelvis, chest, skull , humerus and femur One of the: PET-CT, LDWB-CT if negative then MRI of the whole body or spine be done in all patients - clear evidence of one or more sites of osteolytic bone destruction (≥5mm in size ) - Increased uptake on PET-CT alone is not adequate - Bone densitometry studies are not sufficient  

30. Radiography: M ultifocal, sharply demarcated, lytic foci and with cortical thinning: punched-out lesions Skull: peper - pot appearance No sclerosis No periosteal new bone formation Negative on bone scan

31. CT scan: superior for demonstrating fractures, osteolytic lesions, and soft-tissue masses and may aid in distal staging of disease MRI : extent of marrow infiltration, visualization of focal masses and areas most at risk of fracturing, and to highlight response to treatment

32. Differential diagnosis Primary lymphoma of bone Metastatic bone disease Waldenstorm macroglobulinemia

33. Treatment:

34. Drugs for MM

35. Novel drugs:

36. Stages of Treatment: Induction stage: Stem cell transplantation: if eligible c ) Consolidation stage: d) Maintenance stage :

37. Regimen: VTD: bortezomib -thalidomide-dexamethasone; VRD : bortezomib - lenalidomide -dexamethasone; VCD : bortezomib cyclophosphamide-dexamethasone ; PAD : bortezomib - adriamycin -dexamethasone

38. Bisphosphonates E ffective in reducing vertebral fractures and pain No role in decreasing non vertebral fracture ( Mhaskar et al ; 2017) R ole in improving overall survival (OS) remains unclear ( improved OS - Aviles; 2013) Antitumor effects ( Aparacio ; 1998)

39. J Orthop Surg Res . 2021;16(1):400. Published 2021 Jun 22 O verall analysis showed that denosumab was superior to zoledronic acid in delaying time to first skeletal-related event

40. Factors to consider for ASCT:

41. ( 2022 ) cornerstone of treatment in eligible patients PFS and OS rate varies Kulkarni et al (2019) 5-year overall survival (OS) and progression-free survival (PFS) was 61.6% ± 3.8% and 37.2% ± 3.9% respectively

42. MGUS: annual follow up Solitary plasmacytoma : wide resection and external beam irradiation therapy

43. Newer agents: Peferisone : synthetic alkylphospholipid inhibiting the Akt /protein kinase B activity (important for MM cell survival and antiapoptosis ) Geldanamycin and Tanespimycin : HSP-90 (heat shock protein) inhibitors that show promising results with bortezomib NPI-0052 : proteasome inhibitor like bortezomib but with earlier onset of action and different kinetics Tocilizumab : is an IL-6 inhibitor   Idecabtagene vicleucel ( Abecma ®); 2021 Ciltacabtagene autoleucel ; 2022 Talquetamab-tgvs ( Talvey ™) and Elranatamab ( Elrexfio ™) ; 2023

44. Surgical intervention If life expectancy > 3 months Benefits: Relief from pain Provide stability Restoration of bone continuity Easy mobilization of patient Improved quality of life

45. Surgical intervention : MBD Indications: spinal instability potential or existing pathological fracture Progressive neurological impairment Intractable pain clearly attributable to a site of MBD; solitary plasmacytoma of bone soft tissue plasmacytoma in limbs or spine needle or open biopsy

46. Contraindications : P oor physical condition ; Untreatable dysfunction of heart, lungs and kidney ; S evere coagulation disturbance that is difficult to correct; and U ncontrollable serious infection

47. Spine : Percutaneous: vertebroplasty / kyphoplasty + biopsy Open: for decompression and fixation/ reconstruction Combined approaches - Fixation methods: plates, pedicle screw, lateral mass screw fixation , 360 degree stabilization - Reconstruction: artificial vertebral bodies, titanium mesh, bone cement and allograft bone

48. Long bones: Procedures : curettage/ resection of lesions and filling of bone cavity with bone cement fixation with titanium Intramedullary devices/ plate ? Solitary plasmacytoma : wide resection and radiotherapy

49. Pelvis: If pelvic ring not involved: resection of lesion and filling with bone cement If pelvic ring unstable: resection and pelvic reconstruction Periacetabular lesions with intact acetabular subchondral plate: currettage , PMMA and modified Harrington pins P eriacetabular lesions where acetabular subchondral plate is violated: complex THA with acetabular cage If sacrum involved: partial total sacrectomy +reconstruction

50. Harrington technique

51. Median survival: 1992: 1 year 2000: 2-3 year Currently: 8 year

52. C onclusion Incurable but disease free interval are possible Timely suspicion and treatment is vital

53. References Campbell’s operative orthopaedics-14 th edition Apley and solomon’s system of orthopaedics and trauma- 10 th edition Miller’s review of orthopaedics- 8 th edition Orthopedic Knowledge update: musculoskeletal tumors NCCN guidelines 2024 Milavec H et al. Surgical Management of Multiple Myeloma With Symptomatic Involvement of the Spine.  Int J Spine Surg . 2020;14(5): 785-794 Surgeon's Committee of the Chinese Myeloma Working Group of the International Myeloma Foundation. Consensus on Surgical Management of Myeloma Bone Disease.  Orthop Surg . journal 2016;8(3): 263-269

54. Thank you