Multiple Myeloma

3. Multiple Myelomaa diagnostic approach J. Ryan Altman, MD UNC Dept of Internal Medicine Morning Report 9 December 2008

4. Multiple Myeloma Definition Malignant proliferation of plasma cells producing a monoclonal Ig = “M component” Etiology Cause unknown May be 2/2 exposure to radiation, benzene, other organic solvents, herbicides, or insecticides Genetics Family h/o cancer in 1st degree relatives found in 42% Before dx of MM, >1/3 of pts had recognized plasma cell proliferative process (MGUS, smoldering, indolent, or evolving myeloma, solitary plasmacytoma of bone or extramedullary plasmacytoma, or AL amyloidosis. Epidemiology Accounts for appx 1% of all malignant disease and slightly more than 10% of all hematologic malignancies in the US Occurs in all races and all geographic locations Affects M>F Incidents in blacks:whites, 2:1 Median age 66 Survival: 5 yrs (31%), 10 yrs (10%), 20 yrs (4%) About 14,600 new cases and about 10,900 deaths/yr

5. Multiple Myeloma Clinical manifestations Back pain Esp back or chest, present appx 60% Usually induced by movement Does not occur at night except with change in position Patients height may be reduced by several inches b/c of vertebral collapse. Weakness and fatigue Anemia Fever, if present usually 2/2 infection Weight loss Complications of myeloma: hypercalcemia, renal insufficiency, or amyloidosis PE findings Pallor Palpable hepatomegaly, splenomegaly and LAD (all uncommon)

6. Multiple myeloma Neurologic manifestations Radiculopathy (thoracic or lumbosacral area) is most common complication Cord compression (from extramedullary plasmacytoma or bone fragment occurs in appx 5%; is a medical emergency, so get an MRI or CT myelography of entire spine immediately) Peripheral neuropathy (uncommon and when present usually 2/2 amyloidosis) Exception: POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, M protein, Skin changes) is an osteosclerotic myeloma CNS involvement intracranial plasmacytomas are rare Encephalopathy 2/2 hyperviscosity or high blood levels of ammonia, in absence of liver involvement

7. Multiple Myeloma Infection Pts at incr risk due to combination of immune dysfunction and physical factors Immune dysfunction Impaired lymphocyte function Suppression of normal plasma cell function Hypogammaglobulinemia Neutropenia (during tx with chemo or steroids) Physical factors Indwelling central venous catheters Chemo-induced mucositis Hypoventilation 2/2 pathologic fx involving rib cage and spine Other PE findings Plane xanthomas (involving creases of palms and/or soles) may represent paraneoplastic phenomenon Plasmacytomas of ribs may present as expanding costal lesions or soft tissue masses Pleural effusions 2/2 plasma cell infiltration Diffuse pulmonary involvement 2/2 plasma cell infiltration

8. Multiple myeloma Bone disease Bone pain present in appx 60% of pts at time of dx Focal lytic lesion (60%) Osteoporosis, pathologic fx, compression fx (20%) Development of osteolytic lesions Via production of cytokines: leads to stimulation of osteoclastic activity and inhibition of osteoblastic activity. Imaging Skeletal surveys Reveals punched-out lesions, diffuse osteopenia or fx in nearly 80% at time of dx CT or MRI Helpful in pts with bone pain but no abnormalities on routine x-ray Bone scan Inferior to conventional x-ray for detection of lytic lesions and should not be used.

9. Multiple myeloma Renal Disease Cr >2 (20%) May be presenting manifestation 2 major causes of renal insufficiency: cast nephropathy and hypercalcemia Cast nephropathy Large, waxy, laminated casts in distal and collecting tubules Mainly composed of precipitated monoclonal light chains Urine dipstick typically negative for protein Primary (AL) amyloidosis and Light Chain Deposition Disease Amyloid fibrils composed of monoclonal light chains Present with minimal Bence-Jones proteinuria and large amounts of albumin Acute renal failure after radiocontrast media Filtered light chains induce proximal tubular dysfunction Signs of Fanconi syndrome (prox renal tubular acidosis, aminoaciduria, hypouricemia, and phosphate wasting)

10. Multiple Myeloma Lab findings Anemia Normocytic, normochromic anemia Due to myelophthisis, decr bone marrow production, and autoimmune Ab Rouleaux Found in >50% Red cells take appearance of stack of coins in diluted suspensions of blood and is seen in pts with elevated serum protein levels Associated with incr ESR Plasmacytosis Leukopenia Thrombocytopenia Hypercalcemia Found appx 20% of the time Can act as unmeasured cation and thereby result in LOW anion gap A decr anion gap may also be 2/2 presence of cationic IgG molecule.

11. Multiple Myeloma Labs Monoclonal proteins Present in serum and/or urine in 97% of pts M protein measured by serum or 24h UPEP with immunofixation Free light chain assays can detect monoclonal proteins in absence of M protein What monoclonal proteins? IgG (52%), IgA (21%), light chain (Bence Jones) only (16%), IgD (2%), biclonal (2%), IgM (0.5%), no monoclonal protein (7%) Kappa is predominant light chain isotype by factor of 2:1 Exception: Lambda more common in IgD myeloma Reciprocal Ig changes Nonsecretory myeloma: 3% have no M-protein in SPEP or UPEP Bone Marrow MM confirmed by bone marrow examination. Involvement may be more focal than diffuse, may require aspiration/biopsy at multiple sites to establish dx Beta-2 microglobin Elevated in 75% of pts at time of diagnosis Pts with high values have inferior survival

12. Multiple myeloma Treatment Combination of oral alkylating agent (i.e. melphalan) and prednisone or vincristine/doxorubicin/dexamethasone Local radiation therapy for painful bone lesions Zoledronic acid (4mg IV monthly) decr skeletal complications Thalidomide (an immunomodulatory agent) may be combined with dexamethasone Bortezomid (a protease inhibitor that degrades ubiquitinated proteins) approved for tx that has progressed despite 2 prev tx After induction chemotherapy, consolidation with high-dose therapy and autologous stem cell transplant improves survival. Adjuvant treatment Bone: bisphosphonates decr skeletal complications Renal: avoid NSAIDS and IV contrast; plasmapheresis for ARF Hyperviscosity syndrome: plasmapheresis Infections: consider IVIg for recurrent infections

13. Multiple Myeloma Sources Clinical and Laboratory Manifestations of Multiple Myeloma. www.uptodateonline.com Pocket Medicine. 2nd ed. The Washington Manual of Medical Therapeutics. 32nd ed.