<p> MULTIPLE MYELOMA</p><p>Pathophysiology</p><p>Male predominant, African Americans, average age 68 at diagnosis. Risk factors: toxins, heredity</p><p>Immature B cells differentiate into plasma cells which secrete immunoglobulins. Chromosomal alteration in plasma cells leads to monoclonal proliferation of myeloma cells (IgG>A, usually heavy chains, 20% light chain, rarely nonsecretory). </p><p>Myeloma cells have low growth potential and are initially dependent on bone marrow environment for survival=Bone- CA interaction. They can later become stroma- independent and have extramedullary spread=Malignant Melanoma. In the initial phases, M cells bind to marrow cells which produce cytokines for Mcell growth and survival. Cytokines include OAFs, which damage the marrow by increasing resorption and decreasing bone formation, allowing M cell growth, and other cytokines which impair immune function.</p><p>Clinical Presentation reflects presence of plasma cells in bone and Ig in serum/urine</p><p>Bone: hypercalcemia in 30%, osteoporosis, lytic lesions (pain, fracture) due to increased osteoclasts. Not apparent on bone scan as process is destruction not formation.</p><p>Renal: 25%, impairment due to hypercalcemia /dehydration, or direct toxicity of light chains; see increased creatnine and proteinuria. Often cause of death.</p><p>Hematologic: anemia of chronic disease/CRI in 80%, hyperviscosity in IgA disease, abnormal platelet function</p><p>Infection: due to decrease in other circulating Ig, decreased APC function by cytokines. Typically gm negative/polysaccharide encapsulated organisms. Cause of death.</p><p>Extramedullary: metastatic myeloma can go to pleura, blood, skin</p><p>Spectrum of Disease/Subtypes</p><p>MGUS: probably precursor to MM- first chromosomal hit causes MGUS, second causes transformation to MM (transformation in 16% over about 10 years). Dx=hypergammaglobulinemia (monoclonal, IgG or A usually) with <10% plasma cells in marrow, no features of myeloma. Smoldering: not quite myeloma, monoclonal gammopathy with abnormal marrow cells Multiple Myeloma: 1 major and 1 minor criteria, or 3 minor criteria in patient with symptoms and progressive (bone) disease</p><p>Other: plasma cell leukemia (>5x10^9 plasma cells in peripheral blood), solitary plasmacytoma (solid tumor of monoclonal plasma cells on pathology), POEMS (bone sclerosis, demyelinating neuropathy, HSM, endocrinopathy, skin disease)</p><p>Diagnosis</p><p>Plasma cells in marrow, monoclonal Ig protein peripherally Criteria: Major- plasmacytoma, >30% plasma cells in marrow, monoclonal protein (IgG>3.5, IgA>2, or Bence Jones proteins >1 g/24 hour) Minor- lytic lesions, monoclonal hypergammaglobulinemia with others hypo, 10-30% plasmacytosis marrow</p><p>Evaluation</p><p>Laboratory: CBC, Calcium, Creatnine, 24hour urine protein (or ratio), LDH, U.A., CRP/ESR, beta2microglobulin (LMW protein HLA light chain, renally excreted)</p><p>Immunoglobulins in urine or serum Peripheral smear Immunoglobulin levels (one predominates), kappa to lambda ration Immunofixation- monoclonal spike in paraprotein. Serum: IgG 53%, IgA20%, k/l Immunofixation of urine: light chain disease- 20% bence jones proteins</p><p>Bone evaluation: BMAspirate/bx- plasma cells, cytogenetics Skeletal survey BMD</p><p>Staging</p><p>Stage 1- low tumor mass (Hb>10, IgG<5, IgA<3, BJ<4g, normal calcium, <2 lytic bone) Stage 2- int. tumor mass Stage 3- high tumor mass (any: Hb<8.5, IgG>7, IgA>5, BJ>12g, Ca>12, multiple lytic) Subclass by renal function (A if creatnine less than 2, B if greater)</p><p>Prognosis: poor if higher burden of tumor- LDH, UA, anemia, hypercalcemia, Beta2microglobulin, also if older, cytogenetics, extramedullary, increase CRP/ESR (cytokines) Treatment</p><p>Supportive: radiotherapy to fracture, RRT, analgesia, hypercalcemia, Epo, infection px</p><p>Bisphosphonates: Supportive for bone disease (improved QOL), possibly directly therapeutic. Indication= osteopenia, lytic lesion, fracture. Mechanism of action: inhibit osteoclast function by decreasing recruitment/ inhibiting maturation, also decrease IL production (OAF)- leads to decreased pain, fracture, and preservation of bone structure/integrity. Rx Clodronate 2400 mg/day, or monthly IV Pamidronate/Zolendronate. Duration uncertain, adjunct to chemotherapy as well.</p><p>Chemotherapy: Goal is remission (IF negative at 6 weeks, <5% plasmacytosis, no evidence dz progression). Median survival with conventional chemo 2-3 years, increased to 50% 5 year survival with high dose chemo and BMT. Drug resistance high.</p><p>Alkylating agents: Melphalan alone CR30%, Melph/Pred is standard. Combination chemo (VAD or CVAMP) 3-5 cycles induces remission faster but not more effective.</p><p>Induce with combination chemo, then HIGH DOSE MELPHALAN myeloablation with rescue autotransplantation of peripheral stem cells leads to 30-50% CR, 81% OR, 50% 5 year survival. OS is 6-9 years, in 21%. Tandem autotxp has 42%OS. Thalidomide if relapse.</p><p>Biologic/immunologic: Interleukins; PEG IFN toxic, 4 mos increased survival; Steroids to maintain remission also with side effects, Monoclonal Ab to B cells, Allogeneic transplant high mortality.</p>