1. Multiple Myeloma Serena Ezzeddine Morning Report May 30, 2009

2. Definition Multiple Myeloma is characterized by the neoplastic proliferation of a single clone of plasma cells producing a monoclonal immunoglobulin. This clone of plasma cells proliferates in the bone marrow and often results in skeletal destruction.

3. Epidemiology Accounts for approximately 1% of all malignant disease and slightly more than 10% of hematologic malignancies in the U.S. Annual incidence is 4 to 5 per 100,000 Occurs in all races and geographic locations, although incidence in various Asian populations is lower than in Caucasian. Slightly more common in men, and the incidence in blacks is almost twice that in whites Median age 66

4. Clinical Manifestations Bone pain -particularly back or chest and less often in the extremities, is present at the time of diagnosis in approximately 60% of patients. Pain is usually induced by movement and does not occur at night except when changing position. Weakness and fatigue are common, often associated with anemia. Fever <1%, and usually due to infection Weight loss in 24% of patients

5. Physical Findings Pallor is most frequent Palpable heptaomegaly, splenomegaly and lymphadenopathy are uncommon Neuro dx-Radiculopathy, usually thoracic or lumbarsacral is most common neuro complicarion Cord compression from extrameduallry plasmocytoma or fracture Peripheral Neuropathy-Uncommon and when present usually due to amyloidosis, with exception of osteosclerotic myeloma (POEMS) where 75-100% have it Infection due to immune dysfunciton from impaired lymphocyte function, suppression of normal plasma cell function and hypogammaglobulinemia

6. Laboratory Findings Anemia- usu. Normocytic normochromic is present in 73% of pts at diagnosis, but macrocytosis is present in 9% Rouleaux formation in more than one half-happens due to elevated serum protein levels. Elevated ESR Plasmacytosis Leukopenia/thrombocytopenia Hypercalcemia Monoclonal proteins -IgG,IgA,IgM,IgD Increased Total Protein Renal Failure with bland UA Reciprocal Immunoglobulin changes -the level of one or both of the major uninvolved immunoglobulins is reduced B2 microglobulin is elevated >2.7mg/L in 75 % of pts at time of diagnosis.Pt’s with higher levels have inferior survival

7. Rouleaux Formation

8. Diagnosis Multiple Myeloma (all 3 criteria must be met)  Presence of a serum or urinary monoclonal protein (not specific level of M-protein is used as cutoff value since ~40% of pts w/symptomatic myeloma will have M-protein <3g/dl  Presence of 10% clonal plasma cells in the bone marrow or a plasmacytoma. About 3% of pts may have less than 10% bone marrow plasma cells since focal involvement is possible  Presence of end organ damage felt related to the plasma cell dyscrasia, such as: Increased calcium concentration Lytic bone lesions-get Plain Films of skeleton Anemia Renal failure-serum Cr is increased in almost ½ of pts at diagnosis and is >2 in about 20 %

9. Related Disorders Asymptomatic (smoldering) multiple myeloma (SMM, both criteria must be met)  Serum monoclonal protein > 3 g/dL and/or bone marrow plasma cells >10 percent  No end organ damage related to plasma cell dyscrasia Monoclonal gammopathy of undetermined significance (MGUS, all 3 criteria must be met)  Serum monoclonal protein <3 g/dL  Bone marrow plasma cells <10 percent  No end organ damage related to plasma cell dyscrasia

10. Nonsecretory Myeloma ~3% of patients with multiple myeloma have no M-protein in the serum or urine on immunofixation at the time of diagnosis and are considered to have nonsecretory myeloma, and it usually remains nonsecretory in 76% of pts, but in about 60% of pts initially thought to have nonsecretory MM, there is detection of monoclonal free light chains in serum. The FLC assay measures serum kappa and lambda light chain levels, which can then be expressed in a ratio (pts with normal ratios will not have proliferative disorders)

11. Light Chain Myeloma Up to 20% of myeloma is characterized by only light chain in the serum or urine, lacking expression of the immunoglobulin heavy chain. Incidence of renal failure is much higher in light chain myeloma, as the creatinine is >2 in 1/3 of pts at presentation.

12. Bone Marrow Biopsy-Definitive Dx Plasma Cells

13. Staging A.Serum Creatinine <2mg/dl B.Serum Creatinne> 2mg/dl

14. International Staging System

15. Treatment Directed at eliminating the malignant plasma cell clone and correcting organ or tissue impairments, and the attempt is to achieve a complete response with early use of dose-intensive therapy with autologous hematopoetic stem cells. Pt has to be a transplant candidate and based on that, the chemo regimen is made, ie pts would be treated first with a regimen that is not toxic to hematopoietic stem cells (nonalkylating agents), induction then transplant Pts who are not eligible for transplant are receive standard therapy with alkylating agents. In most US centers, not eligible for transplant:  Age >77  Dbili>2.0  Serum Creatinine >2.5  ECOG performance status 3 or 4 unless due to bone pain  NYHA Class 3 or 4 HF Treat bone disease with Bisphosphonates (reduces incidence of skeletal events) and Ortho intervention Renal disease-dialysis, plasmapharesis, chemo, correct Ca

16. Treatment

17. MKSAP QUESTIONS 62 y/o F evaluated during f/u visit. Hx is significant for stage 3a MM that was dx 6 months ago and treated with oral thalidomide and intermittent high dose dexamethasone. She is not feeling well and now appears to be in partial remission. Lab values indicate monoclonal protein concentration of 3g/dl, and bone marrow aspirate smear shows 4% residual atypical plasma cells. Which of the following is the most appropriate treatment to optimize her disease-free and overall survival?  Continuation of oral thalidomide  Initiation of oral melphalan  Autologous stem cell transplant  Bisphosphonates

18. Treatment A disease –free and overall survival benefit is observed in patients receiving high dose chemotherapy and autologous stem cell transplantation during first remission from multiple myeloma

19. MKSAP QUESTIONS 64 y/o man is evaluated in ER with 3 day of progressive severe fatigue dyspnea, forgetfulness, inability to concentrate, and excessive thirst. He also had lower back pain for past 3 months. On PE, pt is somewhat confused, pulse 120, BP 110/75. Oral mucosa is dry and spine tender to light percussion. Labs HCT 27%, WBC 13.5 w/left shift, plts 160, Ca 13.5, Cr 3.5, a radiograph of LS shows osteopenia and compression fx T10 and L1. Bone marrow aspirate shows Which of the following is most likely dx? a.Megaloblastic anemia b.CLL c.Multiple Myeloma d.Metastatic small cell carcinoma of lung e.AML

20. References MKSAP Uptodate Blood. Treatment of multiple myeloma 2004 103:20-32 NEJM 351;18.October 2004 www.uspharmacist.com