1. Plasma Cell Disorders Kristi McIntyre M.D. Texas Oncology 2004 Monoclonal Gammopathies

3. Classification of Monoclonal Gammopathies Monoclonal Gammopathy of Undetermined Significance Malignant Monoclonal Gammopathies Multiple Myeloma Smolderimg Multiple Myeloma Plasma cell leukemia IgD myeloma POEMS Plasmacytoma Malignant Lymphoproliferative disorders Heavy Chain disease Amyloidosis

4. Patient Profile 61 year old female presented with rash to dermatologists in 2001. SPEP revealed 0.2 IgGlambda M-protein. Asymptomatic otherwise. 2001200220032004 2 1 M-protein Breast ca

5. MGUS Denotes presence of an M-protein in a patient without a plasma cell or lymphoproliferative disorder M-protein < 3g/dL < 10% plasma cells in bone marrow No or small amounts of M-protein in urine Absence of lytic bone lesions,anemia,hypercalcemia or renal insufficiency No evidence of B cell lymphoproliferative disorder Stability of M-protein over time

6. MGUS Monoclonal Gammopathy of Undetermined Significance 1% of adults in US 3% of adults over age 70 years 11% of adults over age 80 years 14% of adults over age 90 years

7. MGUS MGUS can progress to monoclonal disease: IgA or IgG Multiple Myeloma Primary Amyloidosis or related plasma cell disorder IgM NHL CLL Waldentroms macroglobulinemia

8. MGUS 1,384 patients MGUS Kyle, R. A. et al. N Engl J Med 2002;346:564-569 IgG : 70% IgM :15% IgA :12% Heavy chain Light chain Kappa : 61% Lambda : 39% Concentration of uninvolved immunoglobulins reduced in 39%

9. MGUS prognosticators( predictors of progression): 1.Age 2.sex 3.Size of initial M-protein 4.Type of immunoglobulins 5.Hemoglobin 6.# of bone marrow plasma cells 7.Reduction of uninvolved imunoglobulins 8.Urinary light chains Kyle, R. A. et al. N Engl J Med 2002;346:564-569

10. Initial Monoclonal Protein Values in 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy of Undetermined Significance Was Diagnosed from 1960 through 1994

11. Kyle, R. A. et al. N Engl J Med 2002;346:564-569 Probability of Progression among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy of Undetermined Significance (MGUS) Was Diagnosed from 1960 through 1994  Risk of progression to serious disease 1% per year

12. Kyle, R. A. et al. N Engl J Med 2002;346:564-569 Patterns of Increase in Monoclonal Protein among 1384 Residents of Southeastern Minnesota in Whom Monoclonal Gammopathy Was Diagnosed in 1960 through 1994

13. MGUS The size of the M-protein at the time of recognition of MGUS is the most important predictor of progression IgM & IgA monoclonal proteins have a greater risk of progression than an IgG M-protein Reduction in uninvolved immunoglobulins & urine protein not significant

14. MGUS Management: Periodic monitoring of serum protein electrophoresis Interval of monitoring based on initial M-protein level Monitoring should be at least annually LIFELONG Risk does not go away with time “cumulative” probability of progression ( 10% at 10 years, 25% at 25 years)

15. Patient Profile 64 year old female hospitalized with severe low back pain for 3 weeks. Spine films negative MRI scan showed path fracture at L2. Fatigue x 2 months ESR: 28mm/hr Creat : 0.6 Calcium 9.4 SPEP : M-protein : IgG kappa 4.8 g/dl

16. SPEP Multiple Myeloma 3-4 % patients have no serum or urine M-protein “non-secretory myeloma”

17. Multiple Myeloma

20. Patient Profile Skeletal survey : diffuse osteoporosis Bone marrow : 48% atypical plasma cells L2 biopsy: plasmacytoma

21. Multiple Myeloma Diagnostic definition: M-protein in serum >3 g/dL M-protein in urine Lytic bone lesions Minimal criteria for diagnosis include a bone marrow containing > 10% plasma cells (or plasmacytoma) plus at least one of the following:

22. Multiple Myeloma International Myeloma Working Group: Presence of an M-protein in serum Presence of bone marrow clonal plasma cells Presence of related tissue or organ impairment (“CRAB”) C calcium R renal failure A anemia B bone lesions

24. Multiple Myeloma Bone Disease Conventional radiographs abnormal 80% of patients who present with multiple myeloma Osteopenia or osteoporosis 20% Focal lytic bone 57% Pathologic fractures 20% Vertebral body compression fractures 20%

25. Multiple Myeloma MRI scan:  MRI scans of spine are an excellent assessment of bone marrow and myelomatous involvement.  >95% of patients with multiple myeloma have MRI abnormalities: Diffuse involvement of bone marrow Focal bone marrow lesions Heterogeneous bone marrow

26. Multiple Myeloma Stimulation of osteoclastic activity Osteolytic lesions occur through 2 mechanisms via production of cytokines by myeloma cells adjacent to bone: Inhibition of osteoblastic activity IL-6

27. NEJM Tian,E Dec 2003 The Role of Wnt-Signaling Antagonist DKK1 on the development of Osteolytic Lesions in Multiple Myeloma Gene expression analysis

28. Multiple Myeloma Bone disease: mechanism for osteolytic lesions BM microenvironment Myeloma cell overexpress DKK1 osteoblast Osteoclasts Tian,EDec 2003 NEJM

29. Multiple Myeloma Oncologic emergency Spinal cord compression occurs in 5 % of patients with multiple myeloma Managed with urgent: 1. Corticosteroids 2.neurosurgical intervention (laminectomy or anterior decompression) + radiation therapy to preserve neurological function 3. Radiation therapy alone

30. Multiple Myeloma Normochromic /normocytic anemia occurs in 75% patients at diagnosis

31. Multiple Myeloma Renal disease Serum creatinine increased in > 50% at diagnosis Creatinine >2g/dL in 20% of patients Renal failure may be presenting manifestation Major causes: Myeloma cast nephropathy Hypercalcemia Amyloidosis Radiocontrast dye in a patient with myeloma

32. Multiple Myeloma

34. Prognosticators: Serum beta2 microglobulin- small protein synthesized by all nucleated cells;light chain moiety of HLA antigen LDH reflects cell turnover C-reactive protein reflects IL-6 levels

35. Multiple Myeloma Cytogenetics Abnormalities associated with chromosome 13 carry a particularly unfavorable prognosis & respond poorly to therapy

36. Multiple Myeloma Management SMM –smoldering multiple myeloma : M-protein >3g/dl,bone marrow plasma cells >10%, but asymptomatic with no organ related problems MGUS Multiple myeloma SMM SMM requires no intervention but close surveillance to assess stability

37. Multiple Myeloma Treatment:Bisphosphonates: Pamidronate given monthly IV has been demonstrated to significantly reduce skeletal events in patients with Multiple Myeloma. 21%41%Skeletal events Pamidronate* Placebo  Also reduces bone pain

38. Multiple Myeloma Management Multiple Myeloma Age <70 Transplant eligible Age > 70 Transplant ineligible Melphalan 0.15mg/kg x 7 d Prednisone 20mg po tid x 7d MP produces reponse rates of 50-60% & median survival of 2-3 years

39. Multiple Myeloma Conventional chemotherapy for induction: VAD -Vincristine Adriamycin Dexamethasone ORR CR* 84% 27% Modification of this regimen now with VDD(pegylated lipasomal doxirubicin) *Anderson,H:Br J Cancer 1995

40. Multiple Myeloma Thalidomide IMiDs (immunomodulatory agent )with antiangiogenic properties old drug 1950’s for sedation & pregnancy induced nausea/vomiting Withdrawn 1961-tetratogenic causing phocomelia Deformities later found to be due to inhibition of developing fetal limbs vessels (anti-angiogenic)

41. Multiple Myeloma Thalidomide & dexamethasone Myeloma patients with refractory disease underwent clinical trials producing 50% response rate (CR =PR ) Median survival from start of therapy 38 months Relatively minor side effects and taken orally Major clinical trials now testing thalidomide /Dex as induction regimen

42. Multiple Myeloma Proteosome inhibitors (Velcade) FDA approval May 2003 Interferes with intracellular pathway that degrades proteins regulating cell cycle, apoptosis,angiogenesis

43. Multiple Myeloma Autologous transplantation – recommended for advanced stage myeloma after induction therapy = age <70, good PS, normal renal function Allogeneic transplantation- insufficient evidence currently nonmyeloblative “mini” transplants as salvage Tandem double better than single (41 vs 21 mos OS)

44. Poems(osteosclerotic myeloma) Polyneuropathy dominating feature(100%),motor Organomegaly -hepatosplenomegaly (50%) Endocrinopathy hypogonadism, hypothyroidism (66%) Monoclonal gammopathy Skin changes hyperpigmentation, hypertrichosis Sclerotic bone lesions –97% Etiology of symptoms related to proinflammatory cytokines (VEGF)

45. Poems(osteosclerotic myeloma) Treatment : 5000cGy to osteosclerotic bone lesion

46. Patient Profile 54 year old high profile male trial attorney went skiing with the “firm” in March 2002. Fell & fractured left humerus. Saw orthopedic surgeon on return to Dallas.”Pathologic fracture”bone survey otherwise negative: MRI spine negative. Lab: BM : <10% plasma cells SPEP 0.52% IgGkappa UPEP -negative DX : Solitary Plasmacytoma left humerus

47. Solitary plasmacytoma Presence of single plasmacytoma without evidence of multiple myeloma Younger median age at presentation (55yrs) 50-60% will convert multiple myeloma within 10 years Treatment: tumoricidal radiation to site (5000cGy) Possible bone marrow collection/storage