Multiple Myeloma  AbstractMultiple Myeloma (MM) also known as Myelomatosis, Kahler’s Disease & Plasma cell myeloma, is a neoplastic plasma cell disease that takes over the production of healthy plasma cells in the bone marrow. The proliferation of malignant plasma cells crowd out healthy blood cells, mainly in bones causing tumors. MM’s typical characterized problems include anemia, recurring infections, presence of M-protein in blood serum or urine, weak bones or lytic bone lesions, hypercalcemia, nerve damage and renal system failure. It is the second most common known Plasma Cell Disease that affects approximately 1 in 143 people per year in US [1]. There are no specific risk factors known yet, however some precursors that maybe involved in its development include age, gender, and life style factors.The initial evaluation to help confirm a diagnosis of myeloma includes blood and urine tests as well as an advanced bone marrow biopsy. Other tests include X-rays. MRIs, CT scans and PET scans for bone or skeletal surveys. The underlying pathogenesis of plasma cell malignancies is still under determined and under a series of research and clinical trials. MM is a treatable cancer but the survival rates are dependent upon factors such as age and general health. Once diagnosed, the individual treatment is based on the stage of disease progression. Some treatments of MM may include Chemotherapy, Biphosphonates, Radiation, Surgery, Stem cell transplant, Plasmapheresis, and other drugs [5].HistoryThe first documented case on MM was reported by Samuel Solley in 1844. The presence of protein in urine from patient Thomas Alexander McBean was studied and recorded by Dr. MacIntyre and Dr. Bence Jones. Hence, the urinary protein became known as Bence Jones Protein. McBean’s postmortem report’s described his bones to be soft, fragile with lesions and the bone marrow to be bloody and gelatinous.The term “Multiple Myeloma” was originated by Von Rustizky in 1873, who described his patient with multiple bone tumors. In 1889 major recognition of the disease was established by Professor Otto Kahler case of patient, Dr. Loos. Professor Kahler described some major characteristics of MM, which included anemia, skeletal pain, albuminuria and presence of monoclonal protein. These findings were linked as a part of clinical syndrome, giving MM the name Kahler’s disease [2]. The role of protein in MM was not recognized until 1956, during which 2 distinct groups of protein (Kappa and Lambda) were classified leading to the discovery of light chains from serum IgG monoclonal protein, which were identical to Bence Jones proteinuria. In the 1970s, Salmon, Durie and Smith developed a method to quantitate the total body burden of tumor cells and disease progression staging [2]. Early treatments included use of corticosteroids, cyclophosphamide, interferons, carmustine and thalimodine.   EpidemiologyMultiple Myeloma is a relatively uncommon cancer; occurrence is seen in about .7% of the worldwide population annually. Approximately 63,000 patients are reported to die from the disease each year [1]. In US the risk of getting MM is 1 in 143 [1]. The median age of MM being diagnosed is approximately 60-70+ years. Mortality rates are consistently higher in men than women and among blacks than whites [2].  The American Cancer Society’s estimates for Multiple Myeloma in US for 2015 are approximate 26,850 new cases diagnosed and about 11,240 death expectancy.Internationally, the highest rates of Multiple Myeloma mortality occurrence have been in Northern Europe, North America, Australia, and New Zealand and lowest rates in the Asian countries [2]. Other risk factors of myeloma include workplace exposure to hazardous chemicals and other substances, radiation exposure, and presence of other plasma cell diseases such as monoclonal gammapathy of undetermined significance (MGUS) and solitary plasmacytomas. 1% of people with these diseases end up developing multiple myeloma [2].Pathogenesis & PathophysiologyMM is a neoplastic plasma cell dyscrasia that is clinically characterized by a combination of systematic issues: Anemia, Hypercalcemia, bone abnormalities, renal system failure and presence of M-protein in blood serum or urine [2]. To this date no single molecular defect can account for the pathogenesis of MM. Malignant plasma cells reside in bone marrow and typically have low- proliferative rates.Somatically hypermutated rearranged immunoglobulin genes such as RAS is believed to account for the pathogenesis of myeloma cells. Abnormalities in bone marrow microenvironment, overproduction of Interleukin-6, which is an important hormone factor in growth of cells and antiapoptotic mechanisms, are known to excessively exceed the number of myeloma cells. Alterations in signaling pathways of cytokines and other molecules such as tumor necrosis factor, vascular derived endothelial growth factor (VEGF) and interleukin-1 (IL-1) play a key role in enhancement of multiple myeloma proliferation [6].Gene expression changes in cell adhesion molecules are shown to have osteoclast-activating factor, leading to lytic bone lesions and stimulation of bone marrow angiogenesis. Cytogenetic abnormalities of myeloma include deletion of chromosome 13 and 17 and translocation of one or more of the immunoglobulin gene, resulting in activation of oncogene [4]. These abnormalities can make the myeloma cells more resilient.Multiple myeloma progression has adverse physiologically effects, uncontrollable proliferation and cloning progressing into bone problems, cardiac and renal system dysfunctions, refractory cytopenia and immunological deficiencies. Monoclonal gammopathy of unknown significance (MGUS) is a benign condition that is speculated to be associated with the development of MM. It is characterized by the presence of an abnormal protein in the blood known as M-protein or Para-protein, produced by plasma cells. Patients with MGUS have a 1% chance of developing MM or other related blood disorders. Solitary plasmacytomas are also neoplasms that are highly likely to develop into MM [4]. [5] [6]   Clinical ManifestationThe initial symptoms of multiple myeloma are typically non-specific and vary by patients. Clinically Myeloma symptoms are characterized by anemia, abnormalities in bone marrow and skeletal disease, hypercalcemia, presence of M-protein, immunologic deficiency and renal failure [6].Bone DiseaseMyeloma bone pain is the most common symptom presented in patients with MM, typically in lumbar spine and pelvis, often onset with persistent localized pain, initially presented as osteoporosis. Most commonly myeloma may affect the mechanical integrity of the vertebral column resulting in spinal cord compressions. Lytic lesions of the vertebral column, ribs, sternum, skull, humerus and femur are specific to Multiple Myeloma manifestation [2].HypercalcemiaIs followed by the progressing bone degeneration, symptoms may include fatigue, constipation, nausea, dehydration, abdominal pain and loss of appetite [3]. Hypercalcemia can precipitate and aggravate renal insufficiency. Prognosis of hypercalcemia by itself is excellent but in MM its treatment does affect the rate of survival.AnemiaAnemia in multiple myeloma is multifactorial and is directly related to the concentration of malignant myeloma cells in the bone marrow. Myeloma cell proliferation interferes with production RBCs, tumor necrosis factor and IL-1 may inhibit erythropoiesis.Immunologic AbnormalitiesThe immune system is compromised due to low counts of WBCs and immunoglobulins. This increases the risk of opportunistic infection in MM patients. With the lowered resistance to fight infections, such as pneumonia and influenza, it is responsible for more than 90% of deaths amongst patients with MM.Effects of M-proteinM-protein represents overproduction of a homogenous immunoglobulin. Hypergammaglobulinemia increases serum viscosity and is the most common cause of hyperviscosity in MM. This results from elevated protein in serum and of large molecular size, abnormal polymerization, and abnormal shape of immunoglobulins such as IgA, IgD, IgG. This may lead to lymphoma, Waldenstrom macroglobulinemia, or light-chain amyloidosis. Increased serum viscosity interferes with functions of the circulatory system causing inefficient blood circulation to the brain and rest of the body. Hyperviscosity can cause dizziness, neurological symptoms and cardiovascular abnormalities [3]. Proteins of MM may interact with coagulation protein factors by inhibiting thrombin and fibrinogen, which can lead to risk of thrombosis or excessive bleeding.Renal FailureRenal dysfunction is presented in the majority of MM patients. High levels of creatinine present as a result of insufficient kidney activity. Contributing factors include hypercalcemia, light chain proteinuria, dehydration, and nephrotoxic drugs [2]. Myeloma kidney primarily affects the renal tubules by elevating the amount of immunoglobulin light chain protein excreted in urine. [2]           [2]  [6]     DiagnosisDiagnosis of multiple myeloma is determined by a number of different diagnostic tests. Because it cannot be diagnosed on the basis of any single laboratory test result, an accurate diagnosis is based on several factors, including physical evaluation, patient history, symptoms, and several diagnostic testing [4].  Laboratory tests that help confirm a diagnosis of myeloma include:Blood count test– compares the number of normal cells to MM cellsQuantitative Immunoglobulins– determines abnormality of immunoglobulin levels.Electrophoresis– detects levels of monoclonal immunoglobulin or M protein in the blood.Free light chain– measures the amount of light chains or the light chain ratio in the blood.Beta-2 microglobulin– high levels can determine prognosis.Blood chemistry test– levels of blood urea nitrogen, creatinine, albumin, calcium, and other electrolytes will be checked. Bone Marrow biopsy- determines the presence of myeloma cells in the bone marrow and detects abnormalities in normal cells. The bone biopsy sample can be used for other test including immunohistochemistry and flow cytometry, and chromosome analyses, including karyotype and fluorescent in situ hybridization.  Fine needle aspiration biopsy, core needle biopsy maybe required to confirm plasmacytomas.Imaging test- bone x-rays, Computed tomography scans, MRI scans, Positron emission tomography scans and Echocardiogram can detect bone destruction caused by myeloma cells.PrognosisOnce MM is diagnosed , the prognosis is based upon the advancement of the cancer, the signs and symptoms, and its progressive stage. The staging systems that are used are either the Durie-Salmon system, or the newer system called International Staging System for Multiple Myeloma [5]. These systems are based on factors such as:The amount of abnormal monoclonal immunoglobulin in the blood or urineLevels of Calcium in bloodSeverity of bone damage based on x-raysLevels of hemoglobinOther factors that may affect the prognosis include damage to kidney, age, rapid accumulation of MM cells, and genetic abnormalities. In the case of relapsed Multiple Myeloma, reoccurrence of MM, Refractory Multiple Myeloma,  or non-responsive myeloma different chemotherapeutic drugs, induction chemotherapy regimens and maintenance therapy can be introduced to delay the disease progression [5].[6] Treatment There is no standard treatment available for MM, the treatment is based upon factors such as age, health, lifestyle goals, previous interaction with myeloma drugs and disease stage. Multiple myeloma drug therapies consist of two types. One to control the disease progression and the other is management therapy [5]. At present there is only 1 category of MM, which requires treatment, and it is known as symptomatic myeloma [2].Multiple Myeloma Drug therapies– combination of chemotherapy drugs and corticosteroids to kill myeloma cells. Side effects- hair loss, nausea, vomiting, low blood count, permanent liver and kidney damage, immune deficiency.Immunomodulating agents- Thalimode, Lenalidomide and pomalidomide. Side effects- birth defects, risk of blood clotting, neurological dysfunction and muscle weakness.Proteasome inhibitors –to inhibit cell division. Side effects- Kidney insufficiency, low blood count, fever and peripheral neuropathy.Histone deacetylase inhibitors- interact with chromosomal histones. Side effects- weakness, nausea, vomiting, swelling, liver problems and cardiovascular myopathy. Stem Cell Transplants– peripheral blood stem cell transplant, commonly autologous transplants. Side effects- low blood count, infection, stem and GVHD (Graft Versus Host Disease).Biphosphonates– helps prevent further bone damage. Side effects- Osteonecrosis of the Jaw.Radiation therapy– used in cases of non-responsive chemo to destroy cancer cells.Side effects- similar to that of chemotherapy.Surgery– splinting of bones to repair or prevent fractures to weakened bones. Side effects- may not fix the initial cause and surgical complications.Supportive Treatments include:Intravenous Immunoglobulin (IVIG)- donor antibody transfusion, to raise levels of immunoglobulin to prevent risk of infection.Anemia treatment- whole blood transfusions or the use of drugs that raise red blood cell count such as Procrit (Erythropoietin) and Aranesp (darbapoietin).Plasmapheresis- prevents hyperviscosity by removing myeloma protein.Alternative therapies– Several relaxation techniques to reduce emotional stressConclusionMultiple Myeloma is a treatable cancer. Multiple Myeloma treatment options have increased significantly over the last 10 years. Clinical Trials of multiple myeloma are available to eligible patients and play an important part in development of newer treatment. New treatments have improved survival rates among myeloma patients.               Research on customized treatments based on genome mapping of the patient can help establish individual specific treatments [5].  Gene expression profiling present the chromosome alteration in myeloma cells. The ultimate goal of this research is to provide treatment on an individual basis. Arsenic Trioxide, histone deacetylase (HDAC) inhibitor, and dexamethasone are being used in combination to study their interactions. Making healthier choices, proper diet and rest is very important for patients with MM along with follow-up care with doctors for treatment [1].Works Cited[1] American Cancer Society. Cancer Facts and Figures 2015. Atlanta, GA: American Cancer Society; 2015[2] Dispenzeri, M.D., Angela, Martha Q. Lacy, M.D., and Philip R. Greipp, M.D. “Multiple Myeloma.” www.springer.com. Grant CA 91561-01, 2001. Web. 29 Apr. 2015.[3] Marieb, Elaine N., and Katja Hoehjn. Anatomy and Physiology. 9thth ed. Boston: Pearson, 2012. Print.[4] www.americancancersociety.com. Multiple Myeloma, 2006. Web. 29 Apr. 2015.[5] www.mmrf.org. N.p., n.d. Web. 29 Apr. 2015.[6] www.myclevelandclinic.org. N.p., n.d. Web. 29 Apr. 2015