Multiple Myeloma: Pathogenesis and Clinical Presentation

1. Multiple Myeloma: Pathogenesis and Clinical Presentation Tammy Weyer PA-C

2. Objectives: • Discuss Pathogenenesis • Review Clinical Presentation of Multiple Myeloma: • Diagnostic Work-Up • Criteria for diagnosis • Staging • Treatment Options

3. Multiple Myeloma Definition: A neoplasm of mature and immature plasma cells Normal plasma cells function as part of the immune system, secreting antibodies (proteins)

4. Clinical manifestations result from: Proliferation and accumulation of plasma cells Cytopenia’s Plasmacytoma’s Skeletal complications associated with disease pathologic fractures hypercalcemia Infections associated with disease Immune dysfuction from impaired lymphocyte fxn, suppression of normal plasma cell fxn, hypogammaglobulinemia Overproduction of M-proteins Renal disease hyperviscosity

5. Normal Plasma Cells in Bone Marrow

6. Multiple Myeloma: Bone Marrow

10. Initial Diagnostic Work-up: Labs • CBC w/diff, chem panel -Alb, LDH, β2MG, CR, Ca, UA • Quantitative IgS (especially IgA) • SPEP + IF • 24 hr urine for TP and M-protein quantity • SFLC assay (Freelite) • Bone marrow biopsy and aspirate - Std cyto and FISH 17p13, t(4:14), t(14:16)

11. Initial Diagnostic Work-up: Imaging • Skeletal survey • CXR (PA + lat) • Complete spine and pelvis • Calvarium • Femurs and humeri (other long bones) • MRI complete spine • Definitely in all pts presenting with back pain • PET/CT • Role less clear (not routine)

12. Normal SPEP

13. Alb a1 a2 bg Characterization of Myeloma-related M-Protein by SPEP and Immunofixation SPEP IF

14. Physical Properties of M-Proteins • Complete -globulin molecule or light-chain only: IgG most common • Varying mobility on SPEP • IgG:  • IgA:  • Light Chains: α-2 • Varying intrinsic viscosity: IgM highest • Amyloid formation • Cold-agglutinin activity

15. Clinical Manifestations Related to M-Proteins • Hyperviscosity syndrome • IgM >> IgA > IgG, IgD, IgE • Potential emergency • Also related to Hgb • Visual sxs, neurologic sxs, and bleeding • Mental status changes • Sxs start @ relative serum viscosity ~5 • Therapy: plasmapheresis (~q 1-2 wks)

16. Clinical Manifestations Related to M-Proteins • Renal Failure (2 major causes) 1. cast nephropathy ≈ myeloma kidney • M- protein (especially light-chain disease) • Certain filtered light chains are toxic to proximal tubular cells and signs of Fanconi syndrome can occur • tubular occlusion by non-absorbed light-chains bound to Tamm-Horsfall protein • parenchymal deposition of light-chains and/or amyloid result in a nephrotic syndrome (albumin spill) 2. Hypercalcemia

17. Clinical Manifestations Related to M-Proteins • Peripheral Neuropathy • amyloidosis • anti-MAG Abs (IgM) • Cold-Agglutinin Disease • Cryoglobulinemia

18. Suppression of non-M-protein Ig’s

19. Multiple Myeloma: Immune Dysregulation • Increased incidence of infection • Increased incidence of VZV reactivation and infection with encapsulated organisms • Decreased normal Igs • B-cell and T-cell functional abnormalities • Decreased CD4+/CD8+ ratio

20. Physical factors that play a role in increasing the risk of infection Neutropenia Steroid use Central venous catheters Chemo induced mucositis Hypoventalation 2/2 fracture of rib cage or spine

21. Multiple Myeloma: Lytic Skeletal Disease

22. Multiple Myeloma: Lytic Skeletal Disease • Result of osteoclast stimulation by “OAF” • TNF • IL-6 • IL-1 (?) • RANK / RANKL • NFB • OPG • MIP-1 Increased Osteoclast Proliferation IL-6 Increased Bone Resorption TNF NFB RANK IB RANK-L Myeloma cell (or stromal cells) Osteoclast OPG

23. Spinal cord compression • constitutes a medical emergency • occurs in 5% of pt’s with myeloma • severe back pain • weakness or paresthesias of the legs • bladder or bowel dysfunction or incontinence • MRI (avoid if dialysis dependent or GFR <30 mL/min) or CT myelogram • Start steroids

24. Less Common Findings • Plasmacytosis • Plasma cells in the peripheral blood > 2000/microL = plasma cell leukemia (1.5% of pt’s during the course of their dz). • Carries an ominous prognosis • CNS involvement • Intracranial plasmacytomas are rare • Leptomeningeal involvement with abnormal CSF is uncommon but being recognized more frequently (denotes poor prognosis)

25. 10-30% plasma cells in bone marrow • Monoclonal spike of lesser magnitude than major criteria • Lytic skeletal lesions • Suppression of normal Ig’s (IgG<6 g/L, IgA<1 g/L, IgM<500 mg/L) Diagnostic Criteria: Durie-Salmon Major: Minor: • Bone marrow plasmacytosis with >30% plasma cells • Plasmacytoma on tissue biopsy • Monoclonal immunoglobulin spike on SPEP: • IgG > 35 g/L • IgA > 20 g/L • Urine light chain > 1 g/24h (no amyloidosis) Diagnosis: 1 major + 1 minor (not 1+1) or 3 minor (including 1+2)

26. Criteria for Diagnosis of MM Durie BGM et al. Hematol J. 2003;4:379

27. Staging Criteria: Durie-Salmon • I: All of the following: • Hgb > 10 g/dL • Ca < 12 mg/dL • Bones WNL on XR (or solitary plasmacytoma) • IgG<50 g/L, IgA<30 g/L, urine LC<4 g/24 hr • II: Fitting Neither I nor III • III: Any of these: • Hgb < 8.5 g/dL • Ca > 12 mg/dL • Extensive skeletal destruction with fractures • IgG>70 g/L, IgA>50 g/L, urine LC > 12 g/24 hr

31. Cytogenetic abnormalities • Non-hyperdiploid tumors (associated with poorer prognosis) • t (4;14), t(14;16), del 17p13, p53 abnormality, and deletion of chromosome 13 areassociated with poorer prognosis • t (11;14) is associated with a favorable prognosis

32. Other Myeloma Variants: • Non-secretory myeloma (1%) • Biclonal Myeloma (0.5-2.5%) • Solitary plasmacytoma • Osteosclerotic myeloma (0.5-3%) • POEMS syndrome (Crow-Fukase) • polyneuropathy • organomegally • endocrinopathy • M-protein • skin changes

34. Multiple Myeloma: Treatment • Chemotherapy: • Oral • I.V. • High-Dose with Transplant • Bisphosphonates • Radiation Therapy • Transfusion Support and Hematopoietic Growth Factors

35. Goals of Therapy • Relief of symptoms • Quality of life • Immediate disease control • Complete remission? • Long-term disease control • Minimize disease complications • Improve survival?

39. Thalidomide • Biologic agent • Oral medication • Mechanism of action unknown • Blocks angiogenesis • Inhibits some myeloma growth factors

40. Thalidomide • 30 % response rate in previously treated myeloma • 65% response rate in combination with steroids (dexamethasone) as initial tx

45. Response Rates with NCCN Standards * *>VGPR

46. NOVEL AGENTS

47. Lenalidomide (Revlimid)

48. Revlimid CC-5013 • >1000x more potent in lab • Better side effect profile • Some blood count suppression • Oral • Being used in combination with other drugs

49. Revlimid CC-5013 • Revlimid alone 30 % response rate: even in pt’s previously transplanted and those who have had thalidomide • Current trials: Dexamethasone +/- Revlimid in relapsed and upfront patients.

50. SWOG S0232: Lenalidomide/Dex in Newly Dx’ed MM Induction Therapy Maintenance Therapy If PR, CR, SD on induction - repeat q 28 d until progression/relapse q 35 days x 3 courses in the absence of PD or unacceptable toxicity Lenalidomide 25 mg/d PO, d 1–28 Dex 40 mg/d PO, d 1–4, 9-12, 17-20 (n=250) Lenalidomide 25 mg/d PO, d 1–21 Dex 40 mg/d PO, d 1–4, 14-18 Newly dx’ed, untreated MM No ASCT planned (n=500) PD PD Placebo 25 mg/d PO, d 1–28 Dex 40 mg/d PO, d 1–4, 9-12, 17-20 (n=250) Placebo 25 mg/d PO, d 1–21 Dex 40 mg/d PO, d 1–4, 14-18 Endpoints: PFS, ORR, Overall Survival ***ASA 325 mg/day required