Biology Assignment: Drug And Disease Project- Multiple Myeloma

Question

Task:
Prepare a well-researched and detailed biology assignment on any drug and disease project of your choice. Support the arguments with relevant references.

Answer

Introduction

The case of “Multiple myeloma” explored in the sections of biology assignment is the second most common haematological malignancy, resulting in 20% of the deaths from blood cancers and 2% of deaths from all cancers. It is part of a spectrum of disorders called ‘plasma cells neoplasms’. This illness is basically defined as an uncontrolled accummulation of bone marrow plasma cells which in turn results in instability of the genomes. These include point mutations in the DNA, genome deletions and amplifications, and chromosomal dislocation in immunoglobi chains, among other symptoms. Statistics in America shows that incidence of this illness is more in black people than while peoples, meaning that black people are more genetically predisposed to contract multiple myeloma. Blacks have double the prevalence that white people have, and also present at a younger age overall. It is also a disease more prevalent in old people, with the median age being 70 years and 85% of all diagnoses being people above 65 years (Blimark, et al., 2015). 

Doctors classify myelomas into two groups based on their malignacy, or how slowly or rapidly they grow in the body. They are classified as symptomatic and asymptomatic. Multiple myelomas manifest on different organs on the body at the same time. Asymptomatic myelomas can often be managed without treatment. Symptomatic ones, which shall be the focus on this research, has the mentioned related symptoms.

In simple terms, multiple myeloma is a malignancy of the plasma cells. These cells accumulate in the bone marrow leading to the overproduction of monoclonal protein. There are a spectrum of illnesses defined as plasma malignancies. They include monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), clinical multiple myeloma, and, on occasion it also includes plasma cell leukemia (Cowan, Allen, Barac, & Basaleem, 2018). The disease grows sneakily in the body, with damage occuring over time that can lead to damage of organs.

Causes

Risk factors

There are risk factors that increase the likelihood of one contracting myeloma (Leukemia nd lymphoma society webpage, 2021). Through statistical analysis of patient data, it has been found that there are marked demographics that have more infections of myeloma than others. These include;

• Age. Most cases of myeloma happen in people over 50. Under that age there are less infections.

• Sex. It is more prevalent in males than females.

• Race. Black people are twice as likely as white people to get myeloma.

• Medical history. People whose medical past has MGUS (monoclonal gammopathy of unknown significance) are at a higher risk.

• Obesity. Research suggests that obese people are more likely to get myeloma.

• Occupation. Some jobs, such as firefighting, put their practitioners at a higher risk of developing various types of cancer.

• Presence of known inflammatory illnesses such as type 2 diabetes and cardiovascular illness.

• People who are repestedly immunodeficient.

• Environment. Research has looked into the possibility that regular exposure to radiation and other chemicals such as pesticides and fertilizers might exascerbate the mutation of plasma cells.

Genetic factors

Genetic factors to an illness such as cancer refers to the existence of certain genes that increase the likelihood of one contacting the disease, or a genetic variation that might increase chances of the illness. This information is derived from the distribution of a disease among a population. While genetic causes of multiple myeloma have been few, there are some obvious glaring genetic conditions that predispose an individual to multiple myeloma (Franqui-Machin et al., 2015). In the case of cancers of the blood, the genes of focus are those that are involved in the generation of plasma cells in the bosy, as well as those that provide us protection from the environment, such as those involved in gene repair. These include family history of B-cell lymphoproliferative diseases, as well as African American ethnicity (Vangsted, Klausen, & Vogel, 2011).

Environmental risk factors

As has been mentioned earlier, exposure to chemicals like pesticides might predispose someone to myeloma. Exposure to radiation in general also increases the risk not only of multiple myeloma but also other cancers. 

Pathogenesis (how does the disease come about)

Myeloma develops upon the mutation of plasma cells. B lymphocytes are the cells that make up plasma cells. It is a type of white blood cell present in the marrow. When plasma cells are healthy, they help in the creation of antibodies which fight illness. The mutations when left untreated move into the bone marrow and proceed to crowd out the healthy cells. They are able to do this because unlike normal cells that mature and die on their own, cancer cells continually grow and become a crowd, ultimately being more than healthy cells (Gerecke, et al., 2016). These include the cells that when healthy are involved in the formation of red blood cells, white blood cells, and platelets. The effect of this is that white blood cells ar crowded out and therefore the body can no longer effectively protect itself from illness, the plasma builds up in bone leading to weak and sore bones, and a spike in protein released into the blood and urine, which might damage the kidney. The protein is because the myeloma cells attempt to produce antibodies as normal 

Symptoms

Clinical manifestation

Multiple myeloma often manifests as bone pains along ith other non specific symptoms such as nausea, vomiting, weakness, weight loss, malaise, recurrent infections, weigh loss, and geenral weakness. In modern times, this disease is scanned by looking for biomarkers instead of awaiting the onset of symptoms at which time it is difficult to rehabilitate a patient until remission. In some patients, abnormal results from laboratory results such as anemia, renal disease, and high protein levels might also be a symptom of multiple myeloma (Kariyawasan et al., 2007). The bone pains, as well as osteoporosis, pathological fractures, and hypercalcemia are caused by invasive lesions in the bones. When the bone marrow is invaded it results in anemia, and changes in the immunology cause reccurent infections. 

Detection/screening

For the identification of primary or obvious physical changes, a primary examination is done. However, most patients of myeloma have normal physical examination results. Laboratory examination has led to most diagnoses of multiple myeloma.

The year 2014 marked a major change in the study of myeloma, when the diagnosis of this illness changed from one based on symptoms to one based on biomarkers (Landgren & Rajkumar, 2016). When the illness was detected later as it was in earlier years, the treatment also began later, and the chances that patients would survive treatment were much slimmer thatn they are now. Early detection of this illness which has been made possible by all the new technology to support it has led to patients surviving for 10 more years than those who were only diagnosed when physical symptoms manifested.

There were at first four biomarkers used indiagnosis of multiple myeloma, which were referred to as the CRAB criteria (hypercalcemia, renal failure, anemia, and lytic bone lesions), but now three more have been added to bring it to seven biomarkers used in diagnostics for this illness. These are abnormal serum (s) FLCs which are used to denote abnormal sFLC ratio (involved/ uninvolved sFLC) of 100 or greater and the involved sFLC being 10 mg/dL or greater; in excess of 60% plasma cell infiltration of the bone marrow; and two or more focal lesions in the bone or bone marrow in the spine or pelvis at the very least.

For multiple myeloma to be diagnosed as needing therapy, a patient needs to have more than 10% plasma cells in the bone marrow; unusual immunoglobins in either blood or urine, or both ( which is always present except in the rare occasion of a non secreting patient); and at least one of the seven biomarkers (Landgren & Rajkumar, 2016).

This basis for diagnosis for multiple myeloma is based on the 2014 IMWG criteria (Leukemia and Lymphoma Society, 2021). This is by no means a perfect criteria, but it is meant to enable earlier detection of the illness, which goes a long way in increasing survival rates of people who receive a positive diagnosis.

A skeletal survey is doen either with a CT/PET scan, or a low dose CT scan. While there is no way to determine the concentration of plasma in the marrow, biomarkers are an effective way to diagnose myeloma.

Rates/stats/diagnosis/prognosis/morbidity

Multiple myeloma accounts for 1% of all cancers and 15% of haematological cancers. It is an illness maily found in old people, with the median age being 71 years for women and 74 years for men. It is less common than other haematological cancers like leukemia and lymphoma. 

According to Landgren and Rajkumar (2016), 25% of all diagnoses of myeloma are defined as high risk. Myeloma patients have seven time the hazard risk of developing infections as compared to people without myeloma. This means that they are 95% more likely to suffer from bacterial infections. In fact, Blimark, et al. (2015) notes that 22% of all deaths by multiple myeloma patients can be directly attributed to infections.

25% of all diagnoses result in death in 3 years. There have however been many improvements in this field medically, such that the survival rate to 5 years in 2010 was 45% as compare to the mediam survival rate in 2000 being 3 years. A 2007 study found that the mortality for multiple myeloma was as high as 10-20% within the first 2 months after physical symptoms present themselves (Kariyawasan et al., 2007). It is estimated that in the US there are 34920 people diagnosed in a year, and that 12410 patients will pass on from the illness.

Diagnosis

There is usually a procedure used before a patient is diagnosed with multiple myeloma. 

Blood tests. M proteins that are produced by myeloma cells are released into the bloodstream and might be discovered in a blood test for them. depending on the amounts of protein found, a doctor can deduce the severity of the myeloma. Blood tests furhter evaluate blood cell counts, levels of calcium and uric acid, as well as kidney functioning which might clue the doctor in on the presence of myeloma. 

Urine tests. The M proteins which are released in the blood stream might also be found in urine.

Bone marrow examination. This is done by inserting a long needle through the bone for testing in a laboratory. This sample is examined for myeloma cells, and also for gene mutations that might be responsible for the myeloma.

Imaging tests including X-ray, CT and PET (positron emission tomography) scan are used to find the bone problems that are a result of myeloma.

Treatments

In the 1960s, the treatment for this illness was mainly composed of chemotherapy and steroids, and it only begun once a patients body started to manifest symptoms (Michels & Petersen, 2017). Initial treatment incolves chemotherapy while the eligibility of a patient to a stem cell transplant is assessed.

Research has uncovered reasons why drugs that were expected to be effcetive in cancer cells were not performing as expected. The possibility of drug resistance was delved into in myeloma as it has been in other cancers. Undertanding drug reisitant multiple myeloma stem cells and other cells that resemble CSCs, is key to discovering how to treat cancer (Munshi & Anderson, 2013). Curing cancer should focus not only on gettig rid of myeloma cells, but also existing stem cells. Drug resistance in yeloma has been described as follows (Franqui-Machin et al., 2015);

1. Several drugs have been tested and implemented in the treatment of multiple myeloma. Examples of the drugs that have been tested include antineoplastic alkylating agents, cyclophosphamide, busulfan, BCNU and melphalan, the pleiotropic immunomodulator, thalidomide, and others (Franqui-Machin, Wendlandt, Janz, Zhan, & Tricot, 2015). A positive response is observed from their use at first, this isalways the precursor to an unfortunate relapse. This clued scientists into the fact that cancerous cells were acquiring immunity against the same drugs that were meant to destroy them. Alkylators applied in myeloablative doses are the only drug that reliably kill multiple myeloma cells.

2. In addition, flow cycrometric analysis has been done on multiple myeloma as with other cancers, and it has been found that there are a cluster of tumor cells thata re unique from the other cells. Multiple myeloma stem cells (MMSCs), as they are known, are multi drug resistant. 

Modern combination therapies are now being used in the treatment of multiple myeloma, and they have resulted in 60 to 80% of all patients achieving a full response to treatment (Landgren & Rajkumar, 2016). 

Drugs

• Statins 

The use of statins, which are also referred to as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, have been associated with less deaths in patients with multiple myeloma. When they were used in patients just before and shortly after a diagnosis with multiple myeloma, statins reduced the percentage of mortalities in studied populations by up to 24%. As an added advantage, statin reduced the likelihood of skeletal related events by 31% (Naymagon & Abdul-Hay, 2016). In general, the use of statins has been found to reduce incidence of both in cases multiple myeloma and all-cause deaths. In cancer patients, ststins were found to be able to arrest cell growth by reducing aniogenesis and the ability of tumor cells to metastasize.

• chemotherapy

This involves targeting high doses of drug to kill fast-growing cells. This is also doen before a bone marrow transplant.

• Corticosteroids

These play a regulatory role on the immune system thus stemming inflammation in the body. They also act on myeloma cells.

Therapies

1. Early palliative care- Palliative care as a treatment method for illnesses that might be deemed terminal in nature is used to assure patients a good quality of life (Porta-Sales et al., 2017). Several disciplines are combined in tbhis method to maximise the comfort of patients and consequently reduce incidences of pain in patients. 

2. Radiation therapy involves the application of high frequency beams and protons to kill cancer cells. This is a treatment that is used for all cancers.

3. Targeted therapy involves taking drugs that take advantage of any weaknesses in the structure of the cancer cells. The drugs are designed to focus on these anomalies, and subsequently kill the cancer cells.

4. Immunotherapy is a kind of treatment that aids your body in foghting cancer, which camouflages in the human body by producing proteins. It in essence interferes with the protein producing porocess of cancer cells.

Procedures

1. Bone marrow transplant involves replacing diseased bone marrow with healthy bone marrow froma a healthy donor. Before this procedure is done, stem cells involved in blood formation are harvested from the blood and high doses of chemotherapy are administered to kill diseased cells. It also needs a healthy and compatible donor of bone marrow.

Experimental approaches

In the article by Porta-Sales, Guerrero-Torrelles, and Moreno-Alonso (2017), the use of a therapeutic treatment used in the treatment of other cancers called palliative care is expounded upon. This therapy is used on a number of patients, and their response to it was studied.

Methodology

How is multiple myeloma understood currently

There are several studies that have been done on multiple myeloma. There is a huge difference between how informed the medical community is about the illness now and the information that was had in the 1960s. For example, we now know not to await the onset of physical symptoms to start diagnosing myeloma because the possibility of a full response is reduced when the cancer is more spread. In addition, we know that there are drugs against which the cancer cells have developed resistance, and that even if they seem to work on the short term, they will almost certainly result in a relapse. This data has been gathered over several years of observing the reaction of patients’ bodies to various treatment and correcting the diagnostic methods that did not enable early detection of myeloma. Field and natural experimental methods haveboth been used in the development of a behaviour profile for multiple myeloma. Conclusions have been based on data that has been collected over time in the past, and data analysis is finding more relations between crertain environmental and genetic issues and prevalence and severity of the illness. Below I have discussed two journal articles that made use of two different experimental methods, but which both drew important conclusions on myeloma.

Major experimental approaches

Randomised experimental design has been the method used in most of the research articles on multiple myeloma. Because the instances of this illness are not very many, it is possible for the medical practitioners to keep track of all cases and their bodies’ reaction to treatment. In most of the studies, the patients themselves might not have been aware of being studied for statistical purposes. In the study detailed by (Porta-Sales, Guerrero-Torrelles, & Moreno-Alonso, 2017), for example, palliative care as part of the treatment for haemolytic cancers is discussed. Palliative care as a treatment for blood cancers is yet to be embraced. This is despite it being used in treating other cnacers, where the maximum level of comfort is assured for the patient. The criteria by which patients were selected to join the palliative care programme was decided by the caregivers and medical personell in general. Data that was collected on patient response to this treatment was compared to secondary data on treatment methods without palliative care. This is a sensible approach because in medical care, to deny one batch of study subjects a treatment and give it to another ould not be received well and would seem unethical. The researcher made conclusions based off of a single research and they could not specify what sort of data to get from the experiment.

Non-randomised experimental design is used as well. The research by Sanfilippo et al. (2016), the administration of statin within three months of diagnosis to patients with multiple myeloma is described. The mortalities of patients who received statin treatment was compared to those who did not. The article is written in 2017, which is fourteen years after 2003 which is the time period within which treatment was studied. The data selected is from US veterans between 1997 and 2003, and focused on those patients who took statin versus those who did not. The research was preexperimental, as it occurred several years before the journal and its undertaking was out of the control of the researcher who studied the role of statins in multiple myeloma treatment.

The research by Franqui-Machin et al. (2015) does secondary research to find instances when stem cells seemed to inhibit the functionality of a cancer drug. Like all cancers, myeloma has clusters of stem cells which are always able to renew themselves and also manage to develop resistance against treatment. This research identifies that flow cytometric analysis of cancers often finds that there is a cluster of cancerous cells whose makeup is unique from other cells. This type of research constitutes non-randomised research. this is because in finding the data to be able to draw the final conclusions, the researcher could seek data which is as close to their requirements as possible. Research can be done only with data from a controlled group, or where the desired variable is controlled. Unlike randomised experimentation which finds data from a study group whose characteristics are not streamlined.

Results

The intensive research into the role that stem cells play in myeloma cells developing resistance against drugs proves that stem cells do in fact make cancer cells immune to treatment. Research also found that statins considerably lowered the mortality rates of patients, and that after treatment a full response was achieved in more patients. This means that both experimental methods which did not include the researcher going into a physical laboratory can still yield feasible results. The results have to be considered with the inevitable mutations in myeloma genes in mind. Randomised searches through literature create a basis for understanding changes in the medical field and in the genetic makeup of illnesses. These methods also unearth an entire database of information that can reveal where more research should be focused.

Major findings about multiple myeloma

The most important finding about multiple myeloma was the presence of biomarkers in the bloodstream and urine such that patients could be diagnosed as early as possible to increase their chances of survival. The seven biomarkers used to identify the presense of myeloma, as well as the presence of M proteins in the blood stream and urine, has revolutionised diagnostics and subsequently treatment of multiple myeloma. The understanding that a late diagnosis seriously affects the clinical progress of multiple myeloma as it does other cancers was very important. when diagnosis is early, which only happens 5% of the time, there is a 75% survival rate (Sanfilippo et al., 2016). When the cancer has spread to distant parts of the body, 5 year survival rate is 53%. This disparity is 5-year survival suggests that early discovery should be made a priority, a further research should go into it.

Cancer cells including myelomas can develop resistance to a drug scuh that it seems effective when it is first used but after some time its functioning ceases and the patient can relapse. With this knowledge, some medicines that were being used in the treatment of myeloma were eliminated from this use.

Mortality due to myeloma develops not only because of the spread of cancer in the bone marrow, but also because it makes patients more susceptible to bruises and therefore bacterial infections. This is important because with this information, medical practitioners can plan treatment and therapy for these patients with a very low likelihood of obtaining ijuries.

The discovery of stem cell transplants as treatment for multiple myeloma thirty years ago was a great discovery which has allowed young patients, diagnosed with an illness which in earlier times woiuld have been considered a death sentence, to live full and productive lives.

New research in multiple myeloma

1. Research has found that multiple myeloma is beginning to show new symptoms in patients, indicating a new frontier for this illness. This implies that for a better understanding i=od myeloma, further research should be done into tumor biology and therefore the subgroups of myeloma (Landgren & Rajkumar, 2016). All this should be done so that each subgroup of this illness can have its own specialised therapy and treatment for better results.

2. Definition of multiple myeloma patients using DNA technology, and their gene expressions based on geen expression is a new strategy that is helping to find out unique features in their genetic makeup. These two technologies should be merged so that the proper therapy can be selected for all patients.

3. While there has been research into biomarkers which gave us the 2014 directory for diagnostics, more research needs to go into biomarkers through randomised clinical trials. Many important strides have been made, but there are still people being diagnosed at advanced stages of the illness and this is not desired because the treatment procedure is delicate and expensive.

4. There is still a dilemma on how to treat recurrences of the illnesses. In cancers, relapses are always a possibility. For this reason, there should be clear plans on how to handle the replapse depending on which form it chooses to take.

Suggestions on further research

As has been mentioned before, only 5% of mujltiple myeloma cases are detected early enough for the survival rate to be at 75%. The fact that 95% of patients have only a 53% chance of surviving past 5 years after diagnosis is a grim statistic (Vangsted, Klausen, & Vogel, 2011). As more research is done on more effective treatment, it is also important that more biomarkers be found that can be detected in routine medical checks so that these statistics can be improved.

Conclusion 

Research still lags behind in the field of multiple myeloma. Granted, modern treatment and therapy has led to great strides being taken, treatment being more effective and reducing the cases of death even in instances formerly described as high risk. At the same time, a quarter of newly diagnosed cases die within 3 years of diagnosis. The survival rates in myelomas in general is much lower than other blood cancers like leukemia and lymphoma, meaning that there is possibly more that can eb done on the research front to improve the experience for patients. It is however worth noting that the diagnosis and treatment of myeloma, which is reflected in the survival rates, are greatly improved now when compared to the 1970s.

References

Blimark, C., Holmberg, E., Mellqvist, U.-H., Landgren, O., Björkholm, M., & Hultcrantz, M. (2015). Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. haematologica, 100(1), 107-113.

Cowan, A. J., Allen, C., Barac, A., & Basaleem, H. (2018). Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMAOncology, 4(9), 1221-1226.

Franqui-Machin, R., Wendlandt, E. B., Janz, S., Zhan, F., & Tricot, G. (2015). Cancer stem cells are the cause of drug resistance in multiple myeloma: fact or fiction? Oncotarget, 6(38), 40496-40506.

Gerecke, C., Fuhrmann, S., Strifler, S., Schmidt-Hieber, M., Einsele, H., & Knop, S. (2016). The Diagnosis and Treatment of Multiple Myeloma. Medicine, 470-477.

Kariyawasan, C., Hughes, D., Jayatillake, M., & Mehta, A. (2007). Multiple myeloma: causes and consequences of delay in diagnosis . Delays in diagnosing myeloma, 635–640.

Landgren, O., & Rajkumar, S. V. (2016). New Developments in Diagnosis, Prognosis, and Assessment of Response in Multiple Myeloma. CCR Focus, 22(22), 5428-5434.

Leukemia and Lymphoma Society. (2021, October 16). Retrieved from Leukemia and Lymphoma Society website: https://www.lls.org/facts-and-statistics/facts-and-statistics-overview

Leukemia nd lymphoma society webpage. (2021, October 16). Retrieved from Leukemia and Lymphoma Society: https://www.lls.org/myeloma/myeloma-overview

Michels, T. C., & Petersen, K. E. (2017). Multiple Myeloma: Diagnosis and Treatment. American Family Physician, 95(6), 373-384.

Munshi, N. C., & Anderson, K. C. (2013). New Strategies in the Treatment of Multiple Myeloma. Clinical Cancer Research, 3337-3345.

Naymagon, L., & Abdul-Hay, M. (2016). Novel agents in the treatment of multiple myeloma: a review about the future. Biology assignment Journal of Hematology & Oncology 9:52, 9(52), 1-20.

Pawlyn, C., & Davies, F. E. (2019). Toward personalized treatment in multiple myeloma based on molecular characteristics. Blood, 133(7), 660-675.

Porta-Sales, J., Guerrero-Torrelles, M., & Moreno-Alonso, D. (2017). Is Early Palliative Care Feasible in Patients With Multiple Myeloma. Journal of Pain and Symptom Management, 54(5), 692-700.

Sanfilippo, K. M., Keller, J., Gage, B. F., Luo, S., & Wang, T.-F. (2016). Statins Are Associated With Reduced Mortality in Multiple Myeloma. Journal of Clinical Oncology, 34(33), 4008-4020.

Sonneveld, P., Avet-Loiseau, H., Lonial, S., & Usmani, S. (2016). Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood, 127(24), 2955-2962.

Vangsted, A., Klausen, T. W., & Vogel, U. (2011). Genetic variations in multiple myeloma I: effect on risk of multiple myeloma. European Journal of Haematology, 8-30.

Wang, Y., Sanchez, L., Siegel, D. S., & Wang, M. L. (2016). Elotuzumab for the treatment of multiple myeloma. Journal of Hematology & Oncology, 1-8.