Multiple Myeloma Multiple Myeloma is a form of cancer which affects the plasma cells of the body, which are white blood cells. Multiple Myeloma, first described in 1848, is a disease “characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein.” To understand how Multiple Myeloma affects an infected person’s plasma cells, it helps to have a general understanding of how normal blood cells are formed and how they act. Most blood cells develop from stem cells, which can be found in bone marrow (soft material inside our bones – the “filling”). Stem cells mature into white blood cells, red blood cells, or platelets.2 The purpose of white blood cells is to fight off infection, while red blood cells carry oxygen and platelets aid in blood clotting, which controls bleeding. Plasma cells make antibodies, which are parts of the immune system and help the body protect itself from germs and other harmful substances (Exhibit 1).2 Myeloma begins when a plasma cell begins dividing uncontrollably, which sets off a chain reaction of abnormal cell divisions. These abnormal plasma cells are called myeloma cells. Eventually, there is a large buildup of myeloma cells in the bone marrow, potentially damaging the outer, solid part of the bone. The reason the disease is called multiple myeloma because it usually affects several bones in any given infected person. The myeloma cells, instead of creating the normal antibodies, create M proteins, which can collect in the urine, blood, or even in organs as blood spreads it throughout the body (Exhibit 2).2 Whether or not Multiple Myeloma has genetics roots which are traceable is still up for debate, but there isn’t much evidence to suggest that there is a genetic component in multiple myeloma diagnoses. A research study done by the Centre for Haematological Oncology at The General Infirmary at Leeds in England looked at 23 patients diagnosed with multiple myeloma. The test showed that of those, only 1 patient (3.2%) had a detected p53 mutation. P53 is a tumor suppressor gene, meaning its purpose is to stop the formation of tumors by regulating the cell cycle (Exhibit 3). While there are instances where a child inherits only one functional p53 gene from their parents (known as Li-Fraumeni syndrome), this is a very rare instance and the more common form of p53 deficiencies is the mutation of the p53 gene. More than 50% of all adult cancers involve a mutated p53 gene; however, as shown above, multiple myeloma normally does not involve a mutated p53 gene. There some risk factors involved with multiple myeloma that increase one’s chances of being diagnosed, which are discussed in the subsequent section, along with multiple myeloma case data. While there are several risk factors for multiple myeloma, it is generally unknown as to why a particular person develops multiple myeloma.3 The first risk factor for multiple myeloma is age – most people diagnosed with multiple myeloma are over 65, and the disease is very rare amongst people younger than 40. 3 Another risk factor is race – the risk of multiple myeloma is highest for those of African descent, and lowest amongst those of Asian descent. The disease is significantly more common in men than in women – each year, approximately 11,200 men are diagnosed with multiple myeloma, as opposed to 8,700 women. The reason for the race and gender risk factors of multiple myeloma, however, is unknown.3 While there is no consistent statistical data, it is widely accepted amongst doctors that family history, especially of a 1st level relative (parents, siblings), is a risk factor for multiple myeloma. Monoclonal gammopathy of undetermined significance (MGUS) is “a benign condition in which abnormal plasma cells make M proteins.”3 There are usually no symptoms, but it has been found that there is an increase in probability of someone being diagnosed with multiple myeloma if there have been previously diagnosed with MGUS. There are more suspected risk factors, including exposure to certain chemicals and viruses, certain gene alterations (although none have been proven to be risk factors), certain diets, and obesity.3 This section will focus on the symptoms and complications of multiple myeloma. Below is a list of the most prevalent symptoms of multiple myeloma: * * Bone pain (esp. back/ribs) * Broken bones (esp. spine) * Weak and tired * Constantly thirsty * Frequent Infections and fevers3 * Weight loss * Frequent urination * Constipation * Nausea

The diagnosis of multiple myeloma can occur after a routine blood test with your doctor. However, the most common diagnosis occurs when doctors take an x-ray of a broken bone and suspect the cancer has caused or is a contributing factor to the broken bone. When analyzing the blood tests, the following are considered when diagnosing multiple myeloma: people with multiple myeloma have high levels of proteins in the blood, especially M and other immunoglobulin, albumin, and beta-2-microglobulin. Also, the blood exam tests for high levels of calcium and for creatinine levels (to assure that the kidneys are working properly).3 Other ways to test for multiple myeloma include urine tests, x-rays, biopsies (test the bone marrow itself from a large bone - a painful procedure). Unfortunately, Multiple myeloma is a very fatal cancer, where only 35% of patients diagnosed with multiple myeloma living 5 years past their diagnosis.3 There are three general treatment options for patients diagnosed with multiple myeloma – (1) watchful waiting (regular checkups every few months), (2) induction therapy, and (3) stem cell transplant. Those experiencing symptoms should and normally do choose the latter two. Induction therapy includes treatment through many different types of drugs. The first one is chemotherapy, which kills myeloma cells using radiation; however, this method also kills normal cells, including unaffected stem cells in the bone marrow, and can lead to the need for a painful bone-marrow transplant, which will be discussed later.3 Another is target therapy, which use drugs to block the growth of the malignant cells by targeting the abnormal protein that stimulates said growth. Steroids can also be used, as they can trigger the death of myeloma cells.3
There are some cases where a stem cell transplant is needed, as it allows the affected person to be treated with a high dose of drugs (as shown in the above section, normal stem cells can die from treatment along with the cancerous cells, sometimes requiring a stem cell transplant).3 The new cells you get through a stem cell transplant are to replace the cells destroyed by treatment. Stem cell transplants can either come from yourself or a family member (in rare cases, other donors may work). When the stem cells are donated by yourself, it is called an auitologous stem cell transplant, where before the treatment is started, stem cells are removed from the bone marrow and frozen or stored. After the treatment (usually Chemotherapy), the cells are returned to your body. When the stem cells come from an outside source (family member), it is called an allogenic stem cell transplant.3
Gene profiling is a pressing issue for many diseases. The question is, however, does it make sense for us to provide genetic screen-testing for multiple myeloma? Researchers at the Myeloma Institute for Research and Therapy at the University of Arkansas for Medical Sciences have found a small segment of genes whose activity could potential predict those with a very high risk for multiple myeloma, and could help with treatment in the near future. The study, done over a seven-year period, followed 532 patients who were diagnosed with multiple myeloma. At the beginning of the study, research doctors from the Institute performed a “blood stem cell transplant to create a genetic profile to chart the severity of the disease” amongst each individual patient.4 The study narrowed the number of genes possibly involved with multiple myeloma to as few as 17. It was determined that the activity in these 17 genes could mean the difference between high or low risk for developing multiple myeloma.4 Of those 17 genes, 5 are located on chromosome 1, leading researchers to suggest that the defects on chromosome 1 could be directly related to a higher risk for multiple myeloma, as well as more severe cases of multiple myeloma.4 The next section will explain what genes are involved in Multiple Myeloma. There has been a recent discovery of a new type of RNA, called microRNA’s (miRNA’s), which are noncoding RNAs’. In order to determine whether or not the miRNA’s play a significant role in the transformation of plasma cells into a malignant tumor (and therefore a diagnosis of multiple myeloma), researchers have used miRNA microarrays to track them.5 A study done by the National Center for Biotechnology Information revealed that those with multiple myeloma had an overexpression of miR-21, the miR-106b~25 cluster, miR-181a, miR-181b, miR-32 and the miR-17~92 cluster, as compared with those in healthy individuals and individuals diagnosed with MGUS.5 The same study identified two miRNA’s (miR-19a and b) that down regulated gene expression of SOCS-1 (found on Chromosome 16, full name - suppressor of cytokine signaling 16) (Exhibit 3). It is not known exactly what the purpose of this gene is in terms of multiple myeloma, but the general role of the SOCS-1 gene is a modulator of IFN-gamma action, which is required for normal postnatal growth and survival.7
In July 2009, the Multiple Myeloma Research Foundation (MMRD) and the Multiple Myeloma Research Consortium (MMRC) announced that it had completed sequencing the entire multiple myeloma genome.9 By making this information public, the MMRD and MMRC have made great strides towards coming up with new treatments, as well as identifying specific genes that are associated with the onset of multiple myeloma. I think that we should offer diagnostic genetic testing for Multiple Myeloma risks to patients who fall under any of the risk factor categories (especially those diagnosed with monoclonal gammopathy of undetermined significance (MGUS), as there is a very significant advantage in identifying individuals who have high-risks for multiple myeloma at an earlier age. For those with MGUS, it is important to test for Multiple Myeloma as well as other cancers, because while MGUS is usually dormant and can go untreated for years, approximately 25% of those with MGUS are ultimately diagnosed with Multiple Myeloma or another cancer.10 While this progression cannot be prevented, there are treatments that, when enacted early enough can lead to increased chances of remission and decreased symptoms. Those with MGUS should undergo genetic testing to determine whether or not the 17 genes described earlier in this memo, especially those located on Chromosome 1, are mutated, deleted, or not working properly.9
By testing early for the mutations in the 17 genes that are found in their mutated state in patients with multiple myeloma, we can extract stem cells from the individual with a high-risk or with a new onset of the disease through an auitologous stem cell transplant before treatment begins, which will allow for a higher rate of success for the drugs. In addition, there are many cases of multiple myeloma which go untreated for months, sometimes years, because there are no physical symptoms. By running genetic testing for patients with a high-risk, or those with monoclonal gammopathy of undetermined significance, treatments can be begun earlier, which could lead to increased survival rates.

Works Cited 1. Sarah J. Grenthlein, MD. Multiple Myeloma. October 4, 2010. http://emedicine.medscape.com/article/204369-overview (accessed 11.17.2010). 2. MedicineNet. Multiple Myeloma. 2010. http://www.medicinenet.com/multiple_myeloma/article.htm#1whatis (accessed 11.8.2010). 3. U.S. Department of Health and Human Services. "What you Need to Know About Multiple Myeloma." National Cancer Institute, September 2008. 4. National Center for Biotechnology Information. The p53 Tumor Suppressor Protein. 2008. http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gnd&part=thep53tumorsuppressorprotein (accessed 11 19, 2010). 5. American Association for Cancer Research (2007, September 20). Gene Profiling Can Single Out The Worst Cases Of Multiple Myeloma And Guide Therapy. ScienceDaily. Retrieved November 21, 2010, from http://www.sciencedaily.com/releases/2007/09/070918105425.htm 6. Services, U.S. Department of Health and Human. MicroRNA's Regulate Critical Genes Associated with Muiltiple Myeloma Pathogenesis. National Center for Biotechnology Information, 2008. 7. GeneCards. Suppressor of Cytokine Signaling 1. 2009. http://www.genecards.org/cgi-bin/carddisp.pl?gene=Socs1 (accessed November 10, 2010). 8. GenWay. SOCS1 Anitbody. 2010. http://www.genwaybio.com/product_info.php?products_id=43725 (accessed November 20, 2010). 9. Multiple Myeloma Research Foundation. Multiple Myeloma Genomics Initiative First to Sequence Complete Myeloma Genomes. July 27, 2009. http://www.themmrf.org/about-the-mmrf/powerful-news/press-releases/mmrc-multiple-myeloma-genomics-initiative-first-to-sequence-complete-myeloma-genomes.htmlhttp://www.themmrf.org/about-the-mmrf/powerful-news/press-releases/mmrc-multiple-myeloma-genomics-i (accessed November 10, 2010). 10. University of Arkansas for Medical Sciences. Gene Expression Signatures of High Risk MGUS to Multiple Myeloma. March 9, 2009. http://www.ibridgenetwork.org/uams/micro-array-screening (accessed November 21, 2010).

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