Latest revision as of 22:47, 29 July 2020

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Hannan Javed, M.D.[2]; Haytham Allaham, M.D. [3]; Shyam Patel [4]; "sandbox:SN"

Template:Pernicious Anemia

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [5]; Associate Editor(s)-in-Chief:

Overview

Pernicious anemia (also called Addison's anemia) is a type of red blood cell disorder caused by impaired vitamin B12 metabolism. Vitamin B12 is primarily absorbed by the small intestine, after being bound to intrinsic factor secreted by parietal cells of gastric mucosa. When this process is disrupted by conditions like atrophic gastritis, celiac disease, small bowel resection etc, B12 deficiency ensues.

Historical perspective

Pernicious anemia was first discovered by Thomas Addison, hence it is also known as addison's anemia.
Loss of life from large volume blood loss in the people fighting in the first world war inspired George Whipple to investigate blood forming components such as arsenic, iron pills etc, but found liver to be the most effective. He bled dogs until they had clinical anemia and fed them cooked liver which showed an improvement in symptoms and hematopoeisis. ^[1]
In 1948, Smith, Rickles et al., isolated the anti-pernicious factor from liver extract and named it Vitamin B12. They showed that even small amounts of this factor can be used to treat and to prevent pernicious anemia. ^[2]

Pathophysiology

Vitamin B12 is an essential vitamin for humans and animals because we cannot synthesise it on our own. B12 is a cofactor in DNA synthesis and other important biochemical reactions. Vitamin B12 deficiency manifests as anemia because hematopoetic stem cells in the bone marrow which are rapidly dividing need B12 for division and DNA production. This process is impaired leading to ineffective hematopoeisis. Vitamin B12 is also necessary for production of myelin which is an important component in the covering sheath of nerves. Deficiency results in improper nerve conduction due to nerve destabilisation. ^[3]

Physiology

Vitamin B12 is also called cobalamin because it contains cobalt at the core of its structure. Dietary sources of vitamin B12 include meat, fish and eggs.^[4]
When consumed through its dietary source, B12 is bound to protein till it enters the stomach.
In the stomach, B12 is uncoupled from its carrier protein due to the presence of gastric acid, which is why vitamin B12 deficiency is so commonly seen among those on chronic antacid medication. ^[5]
Once in the stomach, it is then bound to gastric R binder, a glycoprotein secreted by the salivary glands till it reaches the duodenum.^[6]
In the duodenum and jejunum, the pancreatic enzymes digest the gastric R binder and cobalamin is bound to intrinsic factor (IF).
Intrinsic factor is secreted by the gastric parietal cells. Once bound to IF, vitamin B12 travels up to the ileum where IF is removed and B12 binds with carrier proteins called transcobalamins and this complex is taken up by the liver and bone marrow, among other tissues.
Inside the cells, the transcobalamin-B12 complex is dissolved and cobalamin is reduced to methylcobalamin which serves as a cofactor and coenzyme in many important biochemical reactions^[7].

The two major reactions involving B12 in the human body are:

Vitamin B12 in the from of cyanocobalamin is required in the synthesis of methionine. Methionine is produced from homocysteine and is catalysed by the enzyme methionine synthase. This enzyme utilises cyanocobalamin as a cofactor. Deficiency of vitamin B12 causes a decreased production of methionine and buildup of homocysteine. Hyperhomocysteinemia is implicated as a risk factor in cardiovascular disease.^[8]
The Kreb's cycle utilises vitamin B12 in the reaction converting methylmalonyl-CoA to succinyl-CoA. Thus vitamin B12 deficiency causes a buildup of methylmalonic acid, the substrate for the enzyme methylmalonyl coenzyme A mutase. Methylmalonic acid levels are elevated in the urine of people affected with pernicious anemia and other forms of B12 deficiency.

Storage

The human body can store anywhere from 2-5mg of vitamin B12. Most of this is stored in the liver and is recycled via enterohepatic circulation.

Pathogenesis

Pernicious anemia is a type of megaloblastic anemia caused due to improper vitamin B12 absorption by the body. Impaired absorption occurs because of deficiency of intrinsic factor which is produced by the parietal cells of the stomach. The etiology of pernicious anemia can be due to autoimmune causes or genetic disease. In autoimmune disease, the antibodies attack most of the gastric mucosa, but the antrum is spared.

Autoimmune causes of pernicious anemia

This is the most common cause of pernicious anemia. In autoimmune pernicious anemia, the body produces antibodies against parietal cells or intrinsic factor.

Antibodies against parietal cells of the gastric mucosa work to inhibit the H+/K(+)-ATPase which is the proton pump present in the parietal cells. The proton pump serves as an auto antigen and activates the cytotoxic CD4+ T cells which proceed to destroy gastric mucosal cells.^[9]^[10]
Intrinsic factor antibodies are present in fewer cases of pernicious anaemia but are highly specific. There are 2 types of IF antibodies. They prevent the binding and absorption of cobalamin in the ileum via its receptor.^[11]

Clinical features

The symptoms of pernicious anemia take months, and often years to manifest. Patients most commonly present with symptoms of anemia like lightheadedness, dizziness, shortness of breath etc. The population affected with pernicious anemia is usually the elderly (>60 years) owing to its insidious onset.
Pernicious anemia has hematological, gastrointestinal and neurological manifestations.
Hematological signs are the earliest manifestation of the disease while neurological signs are seen much later.
Patients with pernicious anemia usually have very low levels of hydrochloric acid in the stomach (achlorhydria) and high levels on gastrin (hypergastrinemia).

Differentiating pernicious anemia from other diseases

Pernicious anemia shares many similarities with other forms of megaloblastic anemia like B12 and folate deficiency.

Vitamin B12 deficiency due to insufficient intake (eg veganism) has all the features of pernicious anemia like megaloblasts, hypersegmented neutrophils, neuropsychiatric manifestations. But atrophic gastritis is absent, so achlorhydria, parietal cell antibodies or IF antibodies are absent. Intrinsic factor levels are also normal.^[6]
Folic acid deficiency also results in megaloblastic anemia and similar hematological changes as pernicious anemia, but urinary excretion of methylmalonic acid is absent, so are features of pernicious anemia like achlorhydria, antibodies and normal IF levels.
Ileal resection causes B12 deficiency due to decreased absorption.
Certain drugs such as methotrexate, azathioprine cause folate deficiency and result in megaloblastic anemia. This is usually seen in patients taking chemotherapy or other chronic conditions such as rheumatoid arthritis. ^[12]
Chronic proton pump inhibitor therapy also results in B12 deficiency as vitamin B12 cannot dissociate from its carrier protein in the absence of an acidic environment.^[13]
Long term use of metformin, such as in diabetics, is linked to vitamin B12 deficiency and symptoms similar to pernicious anemia, but this can be differentiated from pernicious anemia as it is seen in diabetics on chronic therapy.^[14]

Associated Conditions

People affected with pernicious anemia might have other coexisting autoimmune conditions such as autoimmune thyroiditis, autoimmune diabetes, vitiligo etc. Autoimmune thyroiditis is most commonly seen in patients with pernicious anemia, particularly females. HLA DR3 has been implicated in the development of autoimmune diseases such as pernicious anemia^[15].

Epidemiology and demographics

Pernicious anemia is a disease of the elderly. The mean age of patients who are symptomatic is >60.^[16]
An exception is the genetic form of the disease which is a congenital deficiency of intrinsic factor and is seen in children <10 years of age.
Men and women are equally affected
Prevalence of pernicious anemia is estimated at 0.1% of the population.^[17]

Genetics

Some forms of pernicious anemia are congenital and a genetic link has been postulated because of a higher incidence in certain populations.
Affected people have a complete or near total absence of intrinsic factor and the presence of antibodies against intrinsic factor.
The genetic variant is transmitted through an autosomal recessive pattern.^[18]

Risk factors

People who have autoimmune conditions like diabetes mellitus, autoimmune thyroiditis are at higher risk of developing pernicious anemia.

Natural History, Complications and Prognosis

In most cases, patients affected with pernicious anemia remain asymptomatic for many years.
Early manifestations include fatigue, shortness of breath, pallor and weakness.
Long standing untreated pernicious anemia results in irreversible neurological damage such as subacute combined degeneration of the spinal cord.
Neurological changes are irreversible once they set in and do not resolve with cobalamin supplementation.

Diagnosis

A diagnosis of pernicious anemia is made by a history and physical examination, along with hematological and neurological examination.

Diagnostic criteria

The only specific criteria to diagnose pernicious anemia is an intrinsic factor output of less than 200U/h after pentagastrin stimulation, where normal levels would be >2000U/h. ^[19]

Symptoms

Symptoms of pernicious anemia are summarised below

Hematological symptoms	Gastrointestinal symptoms	Neurological symptoms
Fatigue	Loss of appetite	Parasthesias
Weakness	Weight loss	Depression
Shortness of breath	Nausea	Gait problems
Dizziness	Burning sensation on tongue	Weakness
Tachycardia	Diarrhea	Loss of balance
Lightheadedness	Vomiting	Confusion

Physical examination findings

Most important physical examination findings are the neurological findings of long standing B12 deficiency which leads to subacute combined degeneration of the spinal cord.

Hematological signs include pallor and icterus.^[20]
Neurological signs: Vitamin B12 deficiency causes nerve demyelination. B12 deficiency also causes a buildup of methylmalonic acid which is toxic to neuronal cells and causes apoptosis.^[21].

The main neurological manifestation of pernicious anemia and vitamin B12 deficiency is subacute combined degeneration. The posterior and lateral columns of the spinal cord are affected. Lateral column demyelination manifests as hyperreflexia and spasticity, while posterior column defects are loss of proprioception and vibration sense. Ataxia and loss of tandem gait are also manifestations of posterior column demyelination. Recreational or accidental inhalation of nitrous oxide gas (laughing gas) can precipitate subacute combined degeneration in people with low levels of vitamin B12.^[22]

Gastrointestinal signs: Upto 25% of people affected with pernicious anemia develop glossitis. The tongue appears red, "beefy" and smooth due to atrophy and blunting of the lingual papillae.^[23]

Subacute combined degeneration

Laboratory findings

The first step in diagnosis is a blood vitamin B12 level. Blood levels less than 200 pg/ml are seen in pernicious anemia.
Intrinsic factor antibodies and Parietal cell antibodies.
Low intrinsic factor level.^[24]
Gastric mucosal sampling shows parietal cell atrophy with antral sparing.^[25]
Increased level of gastrin.
Increased levels of homocysteine and methylmalonyl-CoA.
Decreased folate levels are seen due to "folate trapping" in the form of methyltetrahydrofolate.

Shilling Test

The Shilling test is no longer done to detect an IF deficiency but has historical importance. After a vitamin B12 deficiency is noted, the patient is given radioactively tagged cobalamin to take orally. Soon after this step, the patient is injected with unlabelled cobalamin intramuscularly. Urine is checked for radioactive cobalamin for the next 24 hours. In pernicious anemia, there is an intrinsic factor deficiency, therefore the orally consumed radioactive cobalamin will not be absorbed and can be detected in the urine. In the next step, the patient is given radioactive cobalamin along with intrinsic factor and their urine is checked for traces of radioactive cobalamin. Absence of radioactive cobalamin in the urine points to the deficiency of intrinsic factor in the patients stomach which is the cause of vitamin B12 deficiency^[26]. If the cobalamin absorption does not increase even with intrinsic factor supplementation, patient can be given a course of antibiotics as bacterial overgrowth may hinder absorption.

Peripheral smear findings

The most obvious peripheral smear finding is megaloblasts and macrocytes.

Megaloblastic anemia results due to the lagging behind of nuclear development when compared to cytoplasmic development. This is known as nuclear-cytoplasmic asynchrony. Such defective cells are destroyed in the bone marrow (intramedullary hemolysis).

Decreased number of RBCs (erythopenia)
Macrocytosis- the RBCs in pernicious anemia are very large. Macrocytosis is defined as cells that have an MCV >100 femtolitres (normal :80-100fL)
Hypersegmented neutrophils : Neutrophils containing ≥ 6 lobes. ^[27]
Poikilocytosis and anisocytosis
Low reticulocyte count (reticulopenia)
Howell-Jolly bodies

Atrophic gastritis
Hypersegmented neutrophil

Treatment

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Standard treatment for pernicious anemia is replacement of cobalamin via intramuscular injection. ^[28]
1000 mcg IM everyday for one week, followed by weekly injections the next month and then monthly once injections.
Response to treatment is measured by an increase in reticulocyte count within 5 days of starting therapy.
Patient also experience a sense of wellbeing shortly after beginning therapy.
If reticulocytosis is not observed within the first week of therapy, other factors such as hypothyroidism, folate deficiency should be considered.
Intramuscular therapy can be replaced by high dose oral therapy.^[17]
Neurological disease always warrants parenteral treatment.
Within the first 3-4 weeks of treatment, marrow changes revert and there is resolution in macrocytosis.
Most patients require lifelong monthly therapy.
Routine follow up should be done with a CBC every few months.
A small percentage of patients develop gastric carcinoma, particularly in the elderly. Regular surveillance helps in early detection and treatment. ^[29]

Prevention

There is no primary preventive measure for pernicious anemia.
Once sucessfully diagnosed and treated, patients with pernicious anemia are followed up every year for development of stomach cancer^[30], or symptoms of anemia.

References

Overview

Multiple myeloma was first reported by Dr. Samuel Solly in the mid-19th century. The Bence Jones protein was first discovered by Dr. Henry Bence Jones around that time and was found to be associated with multiple myeloma. In the mid-20th century, chemotherapy was first used to treat multiple myeloma. Over the ensuing years, various agents were approved by the U.S Food and Drug administration. In the late 20th century, it was shown that high-dose therapy and autologous stem cell transplantation could improve survival. The International Myeloma Working Group recently revised the criteria for a diagnosis of multiple myeloma in 2014 to better define the disease.

Historical Perspective

Discovery

In 1844, Dr. Samuel Solly reported the first case of multiple myeloma. He was a surgeon working in St. Thomas Hospital at London. ^[31]^[32]
In 1845, William MacIntyre observed abnormal urinary proteins to be associated with multiple myeloma. These were eventually coined as Bence Jones proteins.^[33]
In 1848, Dr. Henry Bence Jones first described the Bence Jones protein and found it to be associated with multiple myeloma.^[34]
In 1850, William MacIntyre published the features of the first case of multiple myeloma.
In 1856, Dr. Heller described precipitation of urinary protein above a temperature of 50 degrees Celsius. This was eventually found to be the Bence Jones protein.^[32]
In 1875, Waldeyer used the term "plasma cell" for the first time.^[35]
In 1880, Fleischer used the term Bence Jones protein for the first time.^[32]
In 1895, plasma cells were first described. It was later found that plasma cell proliferation was the cellular basis for multiple myeloma.^[32]
In 1900, Wright stated that the tumor cells in myeloma were either plasma cells or their descendants.^[32]^[35]
In 1922, Bayne-Jones and Wilson reported 2 groups of Bence Jones protein.^[32]
In 1928, Perlzweig first described the presence of hyperproteinemia in multiple myeloma patients.^[32]^[36]
In 1928, Copeland and Geschickter reported the first large case series of multiple myeloma patients. They described 412 patients from 1848 to 1928 and noted that these patients had pathologic fractures, Bence Jones protein in the urine, renal dysfunction, and anemia.^[32]^[32]
In 1929, Arinkin introduced bone marrow aspiration for the diagnosis of multiple myeloma that led to significantly increase in diagnosed cases.^[32]
In 1939, the monoclonal protein spike (M-spike) was described on protein electrophoresis. The M-spike was noted to be the gamma-globulin region.^[32]
In 1956, light chains were recognized to be a component of multiple myeloma.^[32]
In 1956, Korngold and Lipari described different classes of Bence Jones protein that were later named as kappa and lambda in their honor.^[32]^[37]
In 1961, Jan Waldenström described the concept of monoclonal and polyclonal gammopathies.^[32]^[38]
In 1962, Gally and Edelman recognized that Bence Jones protein and the serum immunoglobulin light chain had the same amino acid composition.^[32]^[39]
In 2005, the International Staging System (ISS) was developed and cytogenetic classification was described.
In 2014, the International Myeloma Working Group (IMWG) revised the diagnostic criteria for active multiple myeloma to include bone marrow plasma cell burden of 60% or greater, serum free light chain ratio of involved-to-uninvolved light chain of 100 or greater, and greater than 1 bony lesion on MRI measuring at least 5 mm. The advent of the 2014 diagnostic criteria increased the proportion of patients diagnosed with active multiple myeloma.
In 2015, In June 2015, the International Myeloma Working Group (IMWG) released the Revised International Staging System for multiple myeloma.

Development of Treatment Strategies

In 1844, Dr. Solly treated patients with rhubarb pill and orange peel.^[34]^[40]
In 1845, phlebotomy, leeches, steel and quinine were attempted to treat Thomas Alexander McBean.^[40]^[41]
In 1947, Dr. N. Alwall treated multiple myeloma patients with urethane.^[42]
In 1958, Dr. N. Blokhin first used melphalan as a chemotherapy agent to treat multiple myeloma.^[32]
In 1961, the use of thalidomide was prohibited since it was found to be associated with birth defects.^[43]
In 1962, the chemotherapy agent melphalan was shown to improve overall survival in multiple myeloma.^[43]^[44]
In 1967, Maas reported improvement in 8 patients treated with prednisone.^[35]
In 1969, Alexanian conducted a randomized trial that showed improved survival with combination of prednisone and melphalan than melphalan alone.^[35]^[45]
In 1975, Krall, Uthoff, and Harley used a combination of steroids and alkylating agents such as carmustine, melphalan, cyclophosphamide.^[32]^[46]
In 1987, Selby reported complete remission in 11/41 myeloma patients treated with single high dose of intravenous melphalan but majority of those 11 patients relapsed.^[32]^[47]
In 1999, Singhal and colleagues showed that thalidomide had a 32% response rate in a phase II clinical trial of relapsed/refractory multiple myeloma.
In 2003, the proteasome inhibitor bortezomib was approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma.

History of stem-cell transplantation

In 1957, Thomas treated 6 human patients with intravenous infusion of bone marrow cells after total body irradiation or chemotherapy, of these 6 patients 1 patient had multiple myeloma.^[32]^[35]^[48]
In 1975, the Durie-Salmon staging system was developed to help guide the treatment.^[32]
In 1982, a physician were reported to be the recipient of the first successful syngeneic bone marrow transplant for myeloma. The donor was his identical twin brother.^[32]^[49]
In 1983, T.J. McElwain and R.L. Powles showed that autologous stem cell transplant could be used to treat multiple myeloma.^[32]
In 1986, Fefer reported five myeloma patients who were recipients of syngeneic bone marrow transplant.^[32]^[50]
In 1987, Gahrton reported median survival of 1 year in 10 patients of multiple myeloma who received allogeneic bone marrow transplant.^[32]^[51]
In 1987, Barlogie treated 7 patients of multiple myeloma refractory to alkylating agents with combination of high-dose melphalan with total body irradiation, followed by autologous or allogeneic bone marrow transplantation. Of these 7 patients, 6 achieved tumor mass reduction >90%. This played a critical role in developmental of future transplantation strategies in myeloma patients.^[32]^[35]^[52]
In the 1990s, it was shown that high-dose therapy with autologous stem cell rescue led to improved patient outcomes.^[43]

References

↑ Sinclair L (2008). "Recognizing, treating and understanding pernicious anaemia". J R Soc Med. 101 (5): 262–4. doi:10.1258/jrsm.2008.081006. PMC 2376267. PMID 18463283.
↑ SMITH EL (1948). "Purification of anti-pernicious anaemia factors from liver". Nature. 161 (4095): 638. doi:10.1038/161638a0. PMID 18856623.
↑ Miles LM, Allen E, Clarke R, Mills K, Uauy R, Dangour AD (2017). "Impact of baseline vitamin B12 status on the effect of vitamin B12 supplementation on neurologic function in older people: secondary analysis of data from the OPEN randomised controlled trial". Eur J Clin Nutr. 71 (10): 1166–1172. doi:10.1038/ejcn.2017.7. PMID 28225050.
↑ Watanabe F (2007). "Vitamin B12 sources and bioavailability". Exp Biol Med (Maywood). 232 (10): 1266–74. doi:10.3181/0703-MR-67. PMID 17959839.
↑ Jung SB, Nagaraja V, Kapur A, Eslick GD (2015). "Association between vitamin B12 deficiency and long-term use of acid-lowering agents: a systematic review and meta-analysis". Intern Med J. 45 (4): 409–16. doi:10.1111/imj.12697. PMID 25583062.
↑ ^6.0 ^6.1 Del Corral A, Carmel R (1990). "Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice". Gastroenterology. 98 (6): 1460–6. doi:10.1016/0016-5085(90)91076-i. PMID 2110915.
↑ Harrington DJ (2017). "Laboratory assessment of vitamin B12 status". J Clin Pathol. 70 (2): 168–173. doi:10.1136/jclinpath-2015-203502. PMID 27169753.
↑ Tinelli C, Di Pino A, Ficulle E, Marcelli S, Feligioni M (2019). "Hyperhomocysteinemia as a Risk Factor and Potential Nutraceutical Target for Certain Pathologies". Front Nutr. 6: 49. doi:10.3389/fnut.2019.00049. PMC 6491750. PMID 31069230.
↑ Callaghan JM, Khan MA, Alderuccio F, van Driel IR, Gleeson PA, Toh BH (1993). "Alpha and beta subunits of the gastric H+/K(+)-ATPase are concordantly targeted by parietal cell autoantibodies associated with autoimmune gastritis". Autoimmunity. 16 (4): 289–95. doi:10.3109/08916939309014648. PMID 7517707.
↑ Toh BH, Sentry JW, Alderuccio F (2000). "The causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis". Immunol Today. 21 (7): 348–54. doi:10.1016/s0167-5699(00)01653-4. PMID 10871877.
↑ Schade SG, Abels J, Schilling RF (1967). "Studies on antibody to intrinsic factor". J Clin Invest. 46 (4): 615–20. doi:10.1172/JCI105563. PMC 442045. PMID 6021209.
↑ Green R, Datta Mitra A (2017). "Megaloblastic Anemias: Nutritional and Other Causes". Med Clin North Am. 101 (2): 297–317. doi:10.1016/j.mcna.2016.09.013. PMID 28189172.
↑ Heidelbaugh JJ (2013). "Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications". Ther Adv Drug Saf. 4 (3): 125–33. doi:10.1177/2042098613482484. PMC 4110863. PMID 25083257.
↑ Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ; et al. (2016). "Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study". J Clin Endocrinol Metab. 101 (4): 1754–61. doi:10.1210/jc.2015-3754. PMC 4880159. PMID 26900641.
↑ Zulfiqar AA, Andres E (2017). "Association pernicious anemia and autoimmune polyendocrinopathy: a retrospective study". J Med Life. 10 (4): 250–253. PMC 5771255. PMID 29362601.
↑ Carmel R (1996). "Prevalence of undiagnosed pernicious anemia in the elderly". Arch Intern Med. 156 (10): 1097–100. PMID 8638997.
↑ ^17.0 ^17.1 Andres E, Serraj K (2012). "Optimal management of pernicious anemia". J Blood Med. 3: 97–103. doi:10.2147/JBM.S25620. PMC 3441227. PMID 23028239.
↑ Gordon MM, Brada N, Remacha A, Badell I, del Río E, Baiget M; et al. (2004). "A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency". Hum Mutat. 23 (1): 85–91. doi:10.1002/humu.10297. PMID 14695536.
↑ Cattan D (2011). "Pernicious anemia: what are the actual diagnosis criteria?". World J Gastroenterol. 17 (4): 543–4. doi:10.3748/wjg.v17.i4.543. PMC 3027024. PMID 21274387.
↑ Seynabou F, Fatou Samba Diago N, Oulimata Diop D, Abibatou Fall S, Nafissatou D (2016). "Biermer anemia: Hematologic characteristics of 66 patients in a Clinical Hematology Unit at Senegal". Med Sante Trop. 26 (4): 402–407. doi:10.1684/mst.2016.0625. PMID 28073728.
↑ Han L, Wu S, Han F, Gu X (2015). "Insights into the molecular mechanisms of methylmalonic acidemia using microarray technology". Int J Clin Exp Med. 8 (6): 8866–79. PMC 4538064. PMID https://www.ncbi.nlm.nih.gov/pubmed/26309541 Check |pmid= value (help).
↑ Choi C, Kim T, Park KD, Lim OK, Lee JK (2019). "Subacute Combined Degeneration Caused by Nitrous Oxide Intoxication: A Report of Two Cases". Ann Rehabil Med. 43 (4): 530–534. doi:10.5535/arm.2019.43.4.530. PMC 6734019 Check |pmc= value (help). PMID 31499607.
↑ Stoopler ET, Kuperstein AS (2013). "Glossitis secondary to vitamin B12 deficiency anemia". CMAJ. 185 (12): E582. doi:10.1503/cmaj.120970. PMC 3761039. PMID 23359038.
↑ Lahner E, Annibale B (2009). "Pernicious anemia: new insights from a gastroenterological point of view". World J Gastroenterol. 15 (41): 5121–8. doi:10.3748/wjg.15.5121. PMC 2773890. PMID 19891010.
↑ Korman MG, Strickland RG, Hansky J (1972). "The functional 'G' cell mass in atrophic gastritis". Gut. 13 (5): 349–51. doi:10.1136/gut.13.5.349. PMC 1412218. PMID 5036089.
↑ "StatPearls". 2020. PMID 29939561.
↑ Farrelly SJ, O'Connor KA (2017). "Hypersegmented neutrophils and oval macrocytes in the setting of B12 deficiency and pancytopaenia". BMJ Case Rep. 2017. doi:10.1136/bcr-2016-218508. PMC 5612428. PMID 28821482.
↑ Annibale B, Lahner E, Fave GD (2011). "Diagnosis and management of pernicious anemia". Curr Gastroenterol Rep. 13 (6): 518–24. doi:10.1007/s11894-011-0225-5. PMID 21947876.
↑ Murphy G, Dawsey SM, Engels EA, Ricker W, Parsons R, Etemadi A; et al. (2015). "Cancer Risk After Pernicious Anemia in the US Elderly Population". Clin Gastroenterol Hepatol. 13 (13): 2282-9.e1-4. doi:10.1016/j.cgh.2015.05.040. PMC 4655146. PMID 26079040.
↑ Venerito M, Link A, Rokkas T, Malfertheiner P (2016). "Gastric cancer - clinical and epidemiological aspects". Helicobacter. 21 Suppl 1: 39–44. doi:10.1111/hel.12339. PMID 27531538.
↑ Moehler T, Goldschmidt H. Multiple Myeloma. Springer Science & Business Media; 2011. https://books.google.com/books?isbn=3540857729
↑ ^32.00 ^32.01 ^32.02 ^32.03 ^32.04 ^32.05 ^32.06 ^32.07 ^32.08 ^32.09 ^32.10 ^32.11 ^32.12 ^32.13 ^32.14 ^32.15 ^32.16 ^32.17 ^32.18 ^32.19 ^32.20 ^32.21 ^32.22 ^32.23 ^32.24 Kyle RA, Rajkumar SV (2008). "Multiple myeloma". Blood. 111 (6): 2962–72. doi:10.1182/blood-2007-10-078022. PMC 2265446. PMID 18332230.
↑ Rosenfeld L (September 1987). "Henry Bence Jones (1813-1873): the best "chemical doctor" in London". Clin. Chem. 33 (9): 1687–92. PMID 3304718.
↑ ^34.0 ^34.1 Kyle RA, Steensma DP (2011). "History of multiple myeloma". Recent Results Cancer Res. 183: 3–23. doi:10.1007/978-3-540-85772-3_1. PMID 21509678.
↑ ^35.0 ^35.1 ^35.2 ^35.3 ^35.4 ^35.5 Rajkumar SV (2009). "Multiple myeloma". Curr Probl Cancer. 33 (1): 7–64. doi:10.1016/j.currproblcancer.2009.01.001. PMC 2743983. PMID 19254626.
↑ KUNKEL HG, TISELIUS A (September 1951). "Electrophoresis of proteins on filter paper". J. Gen. Physiol. 35 (1): 89–118. PMC 2147300. PMID 14873923.
↑ KORNGOLD L, LIPARI R (1956). "Multiple-myeloma proteins. III. The antigenic relationship of Bence Jones proteins to normal gammaglobulin and multiple-myeloma serum proteins". Cancer. 9 (2): 262–72. PMID 13304841.
↑ WALDENSTROM J (1960). "Studies on conditions associated with disturbed gamma globulin formation (gammopathies)". Harvey Lect. 56: 211–31. PMID 14004528.
↑ EDELMAN GM, GALLY JA (August 1962). "The nature of Bence-Jones proteins. Chemical similarities to polypetide chains of myeloma globulins and normal gamma-globulins". J. Exp. Med. 116: 207–27. PMC 2137388. PMID 13889153.
↑ ^40.0 ^40.1 Solly S (1844). "Remarks on the pathology of mollities ossium; with cases". Med Chir Trans. 27: 435–498.8. PMC 2116942. PMID 20895811.
↑ Kyle RA (December 2000). "Multiple myeloma: an odyssey of discovery". Br. J. Haematol. 111 (4): 1035–44. PMID 11167737.
↑ ALWALL N (September 1947). "Urethane and stilbamidine in multiple myeloma report on two cases". Lancet. 2 (6472): 388. PMID 20263550.
↑ ^43.0 ^43.1 ^43.2 Hong J, Lee JH (2016). "Recent advances in multiple myeloma: a Korean perspective". Korean J Intern Med. 31 (5): 820–34. doi:10.3904/kjim.2015.408. PMC 5016289. PMID 27604794.
↑ Hoogstraten B, Sheehe PR, Cuttner J, Cooper T, Kyle RA, Oberfield RA, Townsend SR, Harley JB, Hayes DM, Costa G, Holland JF (July 1967). "Melphalan in multiple myeloma". Blood. 30 (1): 74–83. PMID 6028709.
↑ "Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group". J. Clin. Oncol. 16 (12): 3832–42. December 1998. doi:10.1200/JCO.1998.16.12.3832. PMID 9850028.
↑ Lee BJ, Sahakian G, Clarkson BD, Krakoff IH (February 1974). "Proceedings: Combination chemotherapy of multiple myeloma with alkeran, cytoxan, vincristine, prednisone, and BCNU". Cancer. 33 (2): 533–8. PMID 4812771.
↑ Selby PJ, McElwain TJ, Nandi AC, Perren TJ, Powles RL, Tillyer CR, Osborne RJ, Slevin ML, Malpas JS (May 1987). "Multiple myeloma treated with high dose intravenous melphalan". Br. J. Haematol. 66 (1): 55–62. PMID 3593657.
↑ THOMAS ED, LOCHTE HL, LU WC, FERREBEE JW (September 1957). "Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy". N. Engl. J. Med. 257 (11): 491–6. doi:10.1056/NEJM195709122571102. PMID 13464965.
↑ Osserman EF, DiRe LB, DiRe J, Sherman WH, Hersman JA, Storb R (1982). "Identical twin marrow transplantation in multiple myeloma". Acta Haematol. 68 (3): 215–23. doi:10.1159/000206984. PMID 6215815.
↑ Fefer A, Cheever MA, Greenberg PD (June 1986). "Identical-twin (syngeneic) marrow transplantation for hematologic cancers". J. Natl. Cancer Inst. 76 (6): 1269–73. PMID 3520068.
↑ Gahrton G, Tura S, Flesch M, Gratwohl A, Gravett P, Lucarelli G, Michallet M, Reiffers J, Ringdén O, van Lint MT (April 1987). "Bone marrow transplantation in multiple myeloma: report from the European Cooperative Group for Bone Marrow Transplantation". Blood. 69 (4): 1262–4. PMID 3548846.
↑ Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G, Jagannath S, Horwitz L (September 1987). "High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma". Blood. 70 (3): 869–72. PMID 3304465.

[pmid18463283-1] Sinclair L (2008). "Recognizing, treating and understanding pernicious anaemia". J R Soc Med. 101 (5): 262–4. doi:10.1258/jrsm.2008.081006. PMC 2376267. PMID 18463283.

[pmid18856623-2] SMITH EL (1948). "Purification of anti-pernicious anaemia factors from liver". Nature. 161 (4095): 638. doi:10.1038/161638a0. PMID 18856623.

[pmid28225050-3] Miles LM, Allen E, Clarke R, Mills K, Uauy R, Dangour AD (2017). "Impact of baseline vitamin B12 status on the effect of vitamin B12 supplementation on neurologic function in older people: secondary analysis of data from the OPEN randomised controlled trial". Eur J Clin Nutr. 71 (10): 1166–1172. doi:10.1038/ejcn.2017.7. PMID 28225050.

[pmid17959839-4] Watanabe F (2007). "Vitamin B12 sources and bioavailability". Exp Biol Med (Maywood). 232 (10): 1266–74. doi:10.3181/0703-MR-67. PMID 17959839.

[pmid25583062-5] Jung SB, Nagaraja V, Kapur A, Eslick GD (2015). "Association between vitamin B12 deficiency and long-term use of acid-lowering agents: a systematic review and meta-analysis". Intern Med J. 45 (4): 409–16. doi:10.1111/imj.12697. PMID 25583062.

[pmid2110915-6] 6.0 ^6.1 Del Corral A, Carmel R (1990). "Transfer of cobalamin from the cobalamin-binding protein of egg yolk to R binder of human saliva and gastric juice". Gastroenterology. 98 (6): 1460–6. doi:10.1016/0016-5085(90)91076-i. PMID 2110915.

[pmid27169753-7] Harrington DJ (2017). "Laboratory assessment of vitamin B12 status". J Clin Pathol. 70 (2): 168–173. doi:10.1136/jclinpath-2015-203502. PMID 27169753.

[pmid31069230-8] Tinelli C, Di Pino A, Ficulle E, Marcelli S, Feligioni M (2019). "Hyperhomocysteinemia as a Risk Factor and Potential Nutraceutical Target for Certain Pathologies". Front Nutr. 6: 49. doi:10.3389/fnut.2019.00049. PMC 6491750. PMID 31069230.

[pmid7517707-9] Callaghan JM, Khan MA, Alderuccio F, van Driel IR, Gleeson PA, Toh BH (1993). "Alpha and beta subunits of the gastric H+/K(+)-ATPase are concordantly targeted by parietal cell autoantibodies associated with autoimmune gastritis". Autoimmunity. 16 (4): 289–95. doi:10.3109/08916939309014648. PMID 7517707.

[pmid10871877-10] Toh BH, Sentry JW, Alderuccio F (2000). "The causative H+/K+ ATPase antigen in the pathogenesis of autoimmune gastritis". Immunol Today. 21 (7): 348–54. doi:10.1016/s0167-5699(00)01653-4. PMID 10871877.

[pmid6021209-11] Schade SG, Abels J, Schilling RF (1967). "Studies on antibody to intrinsic factor". J Clin Invest. 46 (4): 615–20. doi:10.1172/JCI105563. PMC 442045. PMID 6021209.

[pmid28189172-12] Green R, Datta Mitra A (2017). "Megaloblastic Anemias: Nutritional and Other Causes". Med Clin North Am. 101 (2): 297–317. doi:10.1016/j.mcna.2016.09.013. PMID 28189172.

[pmid25083257-13] Heidelbaugh JJ (2013). "Proton pump inhibitors and risk of vitamin and mineral deficiency: evidence and clinical implications". Ther Adv Drug Saf. 4 (3): 125–33. doi:10.1177/2042098613482484. PMC 4110863. PMID 25083257.

[pmid26900641-14] Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ; et al. (2016). "Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study". J Clin Endocrinol Metab. 101 (4): 1754–61. doi:10.1210/jc.2015-3754. PMC 4880159. PMID 26900641.

[pmid29362601-15] Zulfiqar AA, Andres E (2017). "Association pernicious anemia and autoimmune polyendocrinopathy: a retrospective study". J Med Life. 10 (4): 250–253. PMC 5771255. PMID 29362601.

[pmid8638997-16] Carmel R (1996). "Prevalence of undiagnosed pernicious anemia in the elderly". Arch Intern Med. 156 (10): 1097–100. PMID 8638997.

[pmid23028239-17] 17.0 ^17.1 Andres E, Serraj K (2012). "Optimal management of pernicious anemia". J Blood Med. 3: 97–103. doi:10.2147/JBM.S25620. PMC 3441227. PMID 23028239.

[pmid14695536-18] Gordon MM, Brada N, Remacha A, Badell I, del Río E, Baiget M; et al. (2004). "A genetic polymorphism in the coding region of the gastric intrinsic factor gene (GIF) is associated with congenital intrinsic factor deficiency". Hum Mutat. 23 (1): 85–91. doi:10.1002/humu.10297. PMID 14695536.

[pmid21274387-19] Cattan D (2011). "Pernicious anemia: what are the actual diagnosis criteria?". World J Gastroenterol. 17 (4): 543–4. doi:10.3748/wjg.v17.i4.543. PMC 3027024. PMID 21274387.

[pmid28073728-20] Seynabou F, Fatou Samba Diago N, Oulimata Diop D, Abibatou Fall S, Nafissatou D (2016). "Biermer anemia: Hematologic characteristics of 66 patients in a Clinical Hematology Unit at Senegal". Med Sante Trop. 26 (4): 402–407. doi:10.1684/mst.2016.0625. PMID 28073728.

[pmidhttps://www.ncbi.nlm.nih.gov/pubmed/26309541-21] Han L, Wu S, Han F, Gu X (2015). "Insights into the molecular mechanisms of methylmalonic acidemia using microarray technology". Int J Clin Exp Med. 8 (6): 8866–79. PMC 4538064. PMID https://www.ncbi.nlm.nih.gov/pubmed/26309541 Check |pmid= value (help).

[pmid31499607-22] Choi C, Kim T, Park KD, Lim OK, Lee JK (2019). "Subacute Combined Degeneration Caused by Nitrous Oxide Intoxication: A Report of Two Cases". Ann Rehabil Med. 43 (4): 530–534. doi:10.5535/arm.2019.43.4.530. PMC 6734019 Check |pmc= value (help). PMID 31499607.

[pmid23359038-23] Stoopler ET, Kuperstein AS (2013). "Glossitis secondary to vitamin B12 deficiency anemia". CMAJ. 185 (12): E582. doi:10.1503/cmaj.120970. PMC 3761039. PMID 23359038.

[pmid19891010-24] Lahner E, Annibale B (2009). "Pernicious anemia: new insights from a gastroenterological point of view". World J Gastroenterol. 15 (41): 5121–8. doi:10.3748/wjg.15.5121. PMC 2773890. PMID 19891010.

[pmid5036089-25] Korman MG, Strickland RG, Hansky J (1972). "The functional 'G' cell mass in atrophic gastritis". Gut. 13 (5): 349–51. doi:10.1136/gut.13.5.349. PMC 1412218. PMID 5036089.

[pmid29939561-26] "StatPearls". 2020. PMID 29939561.

[pmid28821482-27] Farrelly SJ, O'Connor KA (2017). "Hypersegmented neutrophils and oval macrocytes in the setting of B12 deficiency and pancytopaenia". BMJ Case Rep. 2017. doi:10.1136/bcr-2016-218508. PMC 5612428. PMID 28821482.

[pmid21947876-28] Annibale B, Lahner E, Fave GD (2011). "Diagnosis and management of pernicious anemia". Curr Gastroenterol Rep. 13 (6): 518–24. doi:10.1007/s11894-011-0225-5. PMID 21947876.

[pmid26079040-29] Murphy G, Dawsey SM, Engels EA, Ricker W, Parsons R, Etemadi A; et al. (2015). "Cancer Risk After Pernicious Anemia in the US Elderly Population". Clin Gastroenterol Hepatol. 13 (13): 2282-9.e1-4. doi:10.1016/j.cgh.2015.05.040. PMC 4655146. PMID 26079040.

[pmid27531538-30] Venerito M, Link A, Rokkas T, Malfertheiner P (2016). "Gastric cancer - clinical and epidemiological aspects". Helicobacter. 21 Suppl 1: 39–44. doi:10.1111/hel.12339. PMID 27531538.

[31] Moehler T, Goldschmidt H. Multiple Myeloma. Springer Science & Business Media; 2011. https://books.google.com/books?isbn=3540857729

[pmid18332230-32] 32.00 ^32.01 ^32.02 ^32.03 ^32.04 ^32.05 ^32.06 ^32.07 ^32.08 ^32.09 ^32.10 ^32.11 ^32.12 ^32.13 ^32.14 ^32.15 ^32.16 ^32.17 ^32.18 ^32.19 ^32.20 ^32.21 ^32.22 ^32.23 ^32.24 Kyle RA, Rajkumar SV (2008). "Multiple myeloma". Blood. 111 (6): 2962–72. doi:10.1182/blood-2007-10-078022. PMC 2265446. PMID 18332230.

[pmid3304718-33] Rosenfeld L (September 1987). "Henry Bence Jones (1813-1873): the best "chemical doctor" in London". Clin. Chem. 33 (9): 1687–92. PMID 3304718.

[pmid21509678-34] 34.0 ^34.1 Kyle RA, Steensma DP (2011). "History of multiple myeloma". Recent Results Cancer Res. 183: 3–23. doi:10.1007/978-3-540-85772-3_1. PMID 21509678.

[pmid19254626-35] 35.0 ^35.1 ^35.2 ^35.3 ^35.4 ^35.5 Rajkumar SV (2009). "Multiple myeloma". Curr Probl Cancer. 33 (1): 7–64. doi:10.1016/j.currproblcancer.2009.01.001. PMC 2743983. PMID 19254626.

[pmid14873923-36] KUNKEL HG, TISELIUS A (September 1951). "Electrophoresis of proteins on filter paper". J. Gen. Physiol. 35 (1): 89–118. PMC 2147300. PMID 14873923.

[pmid13304841-37] KORNGOLD L, LIPARI R (1956). "Multiple-myeloma proteins. III. The antigenic relationship of Bence Jones proteins to normal gammaglobulin and multiple-myeloma serum proteins". Cancer. 9 (2): 262–72. PMID 13304841.

[pmid14004528-38] WALDENSTROM J (1960). "Studies on conditions associated with disturbed gamma globulin formation (gammopathies)". Harvey Lect. 56: 211–31. PMID 14004528.

[pmid13889153-39] EDELMAN GM, GALLY JA (August 1962). "The nature of Bence-Jones proteins. Chemical similarities to polypetide chains of myeloma globulins and normal gamma-globulins". J. Exp. Med. 116: 207–27. PMC 2137388. PMID 13889153.

[pmid20895811-40] 40.0 ^40.1 Solly S (1844). "Remarks on the pathology of mollities ossium; with cases". Med Chir Trans. 27: 435–498.8. PMC 2116942. PMID 20895811.

[pmid11167737-41] Kyle RA (December 2000). "Multiple myeloma: an odyssey of discovery". Br. J. Haematol. 111 (4): 1035–44. PMID 11167737.

[pmid20263550-42] ALWALL N (September 1947). "Urethane and stilbamidine in multiple myeloma report on two cases". Lancet. 2 (6472): 388. PMID 20263550.

[pmid27604794-43] 43.0 ^43.1 ^43.2 Hong J, Lee JH (2016). "Recent advances in multiple myeloma: a Korean perspective". Korean J Intern Med. 31 (5): 820–34. doi:10.3904/kjim.2015.408. PMC 5016289. PMID 27604794.

[pmid6028709-44] Hoogstraten B, Sheehe PR, Cuttner J, Cooper T, Kyle RA, Oberfield RA, Townsend SR, Harley JB, Hayes DM, Costa G, Holland JF (July 1967). "Melphalan in multiple myeloma". Blood. 30 (1): 74–83. PMID 6028709.

[pmid9850028-45] "Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group". J. Clin. Oncol. 16 (12): 3832–42. December 1998. doi:10.1200/JCO.1998.16.12.3832. PMID 9850028.

[pmid4812771-46] Lee BJ, Sahakian G, Clarkson BD, Krakoff IH (February 1974). "Proceedings: Combination chemotherapy of multiple myeloma with alkeran, cytoxan, vincristine, prednisone, and BCNU". Cancer. 33 (2): 533–8. PMID 4812771.

[pmid3593657-47] Selby PJ, McElwain TJ, Nandi AC, Perren TJ, Powles RL, Tillyer CR, Osborne RJ, Slevin ML, Malpas JS (May 1987). "Multiple myeloma treated with high dose intravenous melphalan". Br. J. Haematol. 66 (1): 55–62. PMID 3593657.

[pmid13464965-48] THOMAS ED, LOCHTE HL, LU WC, FERREBEE JW (September 1957). "Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy". N. Engl. J. Med. 257 (11): 491–6. doi:10.1056/NEJM195709122571102. PMID 13464965.

[pmid6215815-49] Osserman EF, DiRe LB, DiRe J, Sherman WH, Hersman JA, Storb R (1982). "Identical twin marrow transplantation in multiple myeloma". Acta Haematol. 68 (3): 215–23. doi:10.1159/000206984. PMID 6215815.

[pmid3520068-50] Fefer A, Cheever MA, Greenberg PD (June 1986). "Identical-twin (syngeneic) marrow transplantation for hematologic cancers". J. Natl. Cancer Inst. 76 (6): 1269–73. PMID 3520068.

[pmid3548846-51] Gahrton G, Tura S, Flesch M, Gratwohl A, Gravett P, Lucarelli G, Michallet M, Reiffers J, Ringdén O, van Lint MT (April 1987). "Bone marrow transplantation in multiple myeloma: report from the European Cooperative Group for Bone Marrow Transplantation". Blood. 69 (4): 1262–4. PMID 3548846.

[pmid3304465-52] Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G, Jagannath S, Horwitz L (September 1987). "High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma". Blood. 70 (3): 869–72. PMID 3304465.

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@@ Line 1: / Line 1: @@
 __NOTOC__
 {{Multiple myeloma}}
-{{CMG}} {{AE}}{{HL}} {{shyam}} {{SN}}
+{{CMG}} {{AE}} {{HMHJ}}; {{HL}}; {{shyam}}; {{SN}}
 ==Overview==
-Multiple myeloma was first discovered by Dr. Samuel Solly, a surgeon working in St.Thomas hospital in London in 1844.<ref>Moehler T, Goldschmidt H. Multiple Myeloma. Springer Science & Business Media; 2011. https://books.google.com/books?isbn=3540857729 </ref>The Bence Jones protein was first discovered by  Dr. Henry Bence Jones and found to be associated with multiple myeloma in 1850; And  the  term  “Bence  Jones  protein”  was  first  used  by Fleischer in 1880.<ref name="pmid29194778">{{cite journal |vauthors=Ribatti D |title=A historical perspective on milestones in multiple myeloma research |journal=Eur. J. Haematol. |volume=100 |issue=3 |pages=221–228 |date=March 2018 |pmid=29194778 |doi=10.1111/ejh.13003 |url=}}</ref>
+Multiple myeloma was first reported by Dr. Samuel Solly in the mid-19th century. The [[Bence Jones protein]] was first discovered by Dr. Henry Bence Jones around that time and was found to be associated with multiple myeloma. In the mid-20th century, [[chemotherapy]] was first used to treat multiple myeloma. Over the ensuing years, various agents were approved by the [[Food and Drug Administration|U.S Food and Drug administration]]. In the late 20th century, it was shown that high-dose therapy and [[Autologous bone marrow transplantation|autologous stem cell transplantation]] could improve survival. The International Myeloma Working Group recently revised the criteria for a diagnosis of multiple myeloma in 2014 to better define the disease.
 ==Historical Perspective==
-*In '''1844''', Dr. Samuel Solly reported the first case of multiple myeloma. He was a surgeon working in St. Thomas Hospital at London.<ref>Moehler T, Goldschmidt H. Multiple Myeloma. Springer Science & Business Media; 2011. https://books.google.com/books?isbn=3540857729 </ref><ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref> Dr. Solly treated patients with rhubard and orange peel.
+===Discovery===
-*In '''1845''', abnormal urinary proteins were found to be associated with multiple myeloma. These were eventually coined as Bence Jones proteins. Dr. T. Watson treated patients with steel and quinine.
+*In '''1844''', Dr. Samuel Solly reported the first case of [[multiple myeloma]]. He was a [[surgeon]] working in St. Thomas Hospital at London. <ref>Moehler T, Goldschmidt H. Multiple Myeloma. Springer Science & Business Media; 2011. https://books.google.com/books?isbn=3540857729 </ref><ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
-*In '''1856''', Dr. Heller described precipitation of urinary protein above a temperature of 50 degrees Celcius. This was eventually found to be the Bence Jones protein.
+*In '''1845''', William MacIntyre observed abnormal urinary [[proteins]] to be associated with multiple myeloma. These were eventually coined as [[Bence Jones protein|Bence Jones proteins]].<ref name="pmid3304718">{{cite journal |vauthors=Rosenfeld L |title=Henry Bence Jones (1813-1873): the best "chemical doctor" in London |journal=Clin. Chem. |volume=33 |issue=9 |pages=1687–92 |date=September 1987 |pmid=3304718 |doi= |url=}}</ref>
-*In '''1850''', Dr. Henry Bence Jones first described the [[Bence Jones protein]] and found it to be associated with multiple myeloma.<ref name="pmid21509678">{{cite journal| author=Kyle RA, Steensma DP| title=History of multiple myeloma. | journal=Recent Results Cancer Res | year= 2011 | volume= 183 | issue=  | pages= 3-23 | pmid=21509678 | doi=10.1007/978-3-540-85772-3_1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21509678  }} </ref>
+*In '''1848''', Dr. Henry Bence Jones first described the [[Bence Jones protein]] and found it to be associated with [[multiple myeloma]].<ref name="pmid21509678">{{cite journal| author=Kyle RA, Steensma DP| title=History of multiple myeloma. | journal=Recent Results Cancer Res | year= 2011 | volume= 183 | issue=  | pages= 3-23 | pmid=21509678 | doi=10.1007/978-3-540-85772-3_1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21509678  }} </ref>
-*In '''1895''', [[plasma cells]] were first described. It was later found that [[plasma cell]] proliferation was the cellular basis for multiple myeloma.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1850''', William MacIntyre published the features of the first case of [[multiple myeloma]].
-*In '''1928''', Copeland and Geschickter reported the first large case series of multiple myeloma patients. They described 412 patients from 1848 to 1928 and noted that these patients had pathologic fractures, Bence Jones protein in the urine, renal dysfunction, and anemia.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref><ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1856''', Dr. Heller described [[precipitation]] of urinary [[protein]] above a temperature of 50 degrees Celsius. This was eventually found to be the [[Bence Jones protein]].<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref>
-*In '''1939''', the [[monoclonal protein]] spike (M-spike) was described on [[protein electrophoresis]]. The M-spike was noted to be the gamma-globulin region.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1875''', Waldeyer used the term "[[plasma cell]]" for the first time.<ref name="pmid19254626">{{cite journal |vauthors=Rajkumar SV |title=Multiple myeloma |journal=Curr Probl Cancer |volume=33 |issue=1 |pages=7–64 |date=2009 |pmid=19254626 |pmc=2743983 |doi=10.1016/j.currproblcancer.2009.01.001 |url=}}</ref>
-*In '''1947''', Dr. N. Alwall treated multiple myeloma patients with [[urethane]].
+*In '''1880''', Fleischer used the term [[Bence Jones protein]] for the first time.<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref>
-*In '''1956''', light chains were recognized to be a component of multiple myeloma.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1895''', [[plasma cells]] were first described. It was later found that [[plasma cell]] proliferation was the cellular basis for [[multiple myeloma]].<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
-*In the '''1960s''', the chemotherapy agent [[melphalan]] was shown to improve overall survival in multiple myeloma.<ref name="pmid27604794">{{cite journal| author=Hong J, Lee JH| title=Recent advances in multiple myeloma: a Korean perspective. | journal=Korean J Intern Med | year= 2016 | volume= 31 | issue= 5 | pages= 820-34 | pmid=27604794 | doi=10.3904/kjim.2015.408 | pmc=5016289 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27604794  }} </ref>
+*In '''1900''', Wright stated that the [[tumor]] cells in [[myeloma]] were either [[plasma cells]] or their descendants.<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid19254626">{{cite journal |vauthors=Rajkumar SV |title=Multiple myeloma |journal=Curr Probl Cancer |volume=33 |issue=1 |pages=7–64 |date=2009 |pmid=19254626 |pmc=2743983 |doi=10.1016/j.currproblcancer.2009.01.001 |url=}}</ref>
-*In '''1958''', Dr. N. Blokhin first used [[melphalan]] as a [[chemotherapy]] agent to treat multiple myeloma.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1922''', Bayne-Jones and Wilson reported 2 groups of [[Bence Jones protein]].<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref>
-*In '''1961''', the use of thalidomide was prohibited since it was found to be associated with birth defects.<ref name="pmid27604794">{{cite journal| author=Hong J, Lee JH| title=Recent advances in multiple myeloma: a Korean perspective. | journal=Korean J Intern Med | year= 2016 | volume= 31 | issue= 5 | pages= 820-34 | pmid=27604794 | doi=10.3904/kjim.2015.408 | pmc=5016289 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27604794  }} </ref>
+*In '''1928''', Perlzweig first described the presence of [[hyperproteinemia]] in [[multiple myeloma]] [[patients]].<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid14873923">{{cite journal |vauthors=KUNKEL HG, TISELIUS A |title=Electrophoresis of proteins on filter paper |journal=J. Gen. Physiol. |volume=35 |issue=1 |pages=89–118 |date=September 1951 |pmid=14873923 |pmc=2147300 |doi= |url=}}</ref>
-*In '''1962''', Gally and Edelman recognized that Bence Jones urinary protein and the serum immunoglobulin light chain had the same amino acid composition. In the same year, R.E. Maas demonstrated that [[corticosteroids]] could be used to treat multiple myeloma.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1928''', Copeland and Geschickter reported the first large case series of [[multiple myeloma]] [[patients]]. They described 412 [[patients]] from 1848 to 1928 and noted that [[these patients]] had [[Bone fracture|pathologic fractures]], [[Bence Jones protein]] in the urine, [[renal dysfunction]], and [[anemia]].<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref><ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
-*In '''1975''', the Durie-Salmon staging system was developed.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1929''', Arinkin introduced [[bone marrow aspiration]] for the [[diagnosis]] of [[multiple myeloma]] that led to significantly increase in diagnosed cases.<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref>
-*In '''1983''', T.J. McElwain and R.L. Powles showed that [[autologous stem cell transplant]] could be used to treat multiple myeloma.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1939''', the monoclonal protein spike (M-spike) was described on [[protein electrophoresis]]. The [[M-spike]] was noted to be the [[Gamma globulin|gamma-globulin]] region.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
-*In the '''1990s''', it was shown that high-dose therapy with [[autologous stem cell]] rescue led to improved patient outcomes.<ref name="pmid27604794">{{cite journal| author=Hong J, Lee JH| title=Recent advances in multiple myeloma: a Korean perspective. | journal=Korean J Intern Med | year= 2016 | volume= 31 | issue= 5 | pages= 820-34 | pmid=27604794 | doi=10.3904/kjim.2015.408 | pmc=5016289 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27604794  }} </ref>
+*In '''1956''', [[Light chain|light chains]] were recognized to be a component of [[multiple myeloma]].<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
-*In '''1999''', Singhal and colleagues showed that [[thalidomide]] had a 32% response rate in a phase II clinical trial of relapsed/refractory multiple myeloma.
+*In '''1956''', Korngold and Lipari described different classes of [[Bence Jones protein]] that were later named as kappa and lambda in their honor.<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid13304841">{{cite journal |vauthors=KORNGOLD L, LIPARI R |title=Multiple-myeloma proteins.  III.  The antigenic relationship of Bence Jones proteins to normal gammaglobulin and multiple-myeloma serum proteins |journal=Cancer |volume=9 |issue=2 |pages=262–72 |date=1956 |pmid=13304841 |doi= |url=}}</ref>
-*In '''2003''', the [[proteasome inhibitor]] [[bortezomib]] was approved by the U.S. Food and Drug Administration for the treatment of multiple myeloma.
+*In '''1961''', Jan Waldenström described the concept of [[monoclonal]] and [[polyclonal]] [[Gammopathy|gammopathies]].<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid14004528">{{cite journal |vauthors=WALDENSTROM J |title=Studies on conditions associated with disturbed gamma globulin formation (gammopathies) |journal=Harvey Lect. |volume=56 |issue= |pages=211–31 |date=1960 |pmid=14004528 |doi= |url=}}</ref>
-*In '''2005''', the International Staging System (ISS) was developed and cytogenetic classification was described.
+*In '''1962''', Gally and Edelman recognized that [[Bence Jones protein]] and the serum [[immunoglobulin]] light chain had the same [[amino acid]] composition.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref><ref name="pmid13889153">{{cite journal |vauthors=EDELMAN GM, GALLY JA |title=The nature of Bence-Jones proteins. Chemical similarities to polypetide chains of myeloma globulins and normal gamma-globulins |journal=J. Exp. Med. |volume=116 |issue= |pages=207–27 |date=August 1962 |pmid=13889153 |pmc=2137388 |doi= |url=}}</ref>
-*In '''2014''', the International Myeloma Working Group (IMWG) revised the diagnostic criteria for active multiple myeloma to include bone marrow [[plasma cell burden of 60% or greater, serum free light chain ratio of involved-to-uninvolved light chain of 100 or greater, and greater than 1 bony lesion on MRI measuring at least 5mm. The advent of the 2014 diagnostic criteria increased the proportion of patients diagnosed with active multiple myeloma.
+*In '''2005''', the International Staging System (ISS) was developed and [[cytogenetic]] classification was described.
+*In '''2014''', the International Myeloma Working Group (IMWG) revised the diagnostic criteria for active [[multiple myeloma]] to include [[bone marrow]] [[plasma cell]] burden of 60% or greater, serum free light chain ratio of involved-to-uninvolved light chain of 100 or greater, and greater than 1 bony lesion on MRI measuring at least 5 mm. The advent of the 2014 diagnostic criteria increased the proportion of patients diagnosed with active multiple myeloma.
+*In '''2015''', In June 2015, the International Myeloma Working Group (IMWG) released the Revised International Staging System for [[multiple myeloma]].
-== References ==
+===Development of Treatment Strategies===
-{{reflist|2}}
+*In '''1844''', Dr. Solly treated patients with [[rhubarb]] [[pill]] and orange peel.<ref name="pmid21509678">{{cite journal| author=Kyle RA, Steensma DP| title=History of multiple myeloma. | journal=Recent Results Cancer Res | year= 2011 | volume= 183 | issue=  | pages= 3-23 | pmid=21509678 | doi=10.1007/978-3-540-85772-3_1 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21509678  }} </ref><ref name="pmid20895811">{{cite journal |vauthors=Solly S |title=Remarks on the pathology of mollities ossium; with cases |journal=Med Chir Trans |volume=27 |issue= |pages=435–498.8 |date=1844 |pmid=20895811 |pmc=2116942 |doi= |url=}}</ref>
+*In '''1845''', [[phlebotomy]], [[leeches]], steel and [[quinine]] were attempted to treat Thomas Alexander McBean.<ref name="pmid20895811">{{cite journal |vauthors=Solly S |title=Remarks on the pathology of mollities ossium; with cases |journal=Med Chir Trans |volume=27 |issue= |pages=435–498.8 |date=1844 |pmid=20895811 |pmc=2116942 |doi= |url=}}</ref><ref name="pmid11167737">{{cite journal |vauthors=Kyle RA |title=Multiple myeloma: an odyssey of discovery |journal=Br. J. Haematol. |volume=111 |issue=4 |pages=1035–44 |date=December 2000 |pmid=11167737 |doi= |url=}}</ref>
+*In '''1947''', Dr. N. Alwall treated [[multiple myeloma]] [[patients]] with [[urethane]].<ref name="pmid20263550">{{cite journal |vauthors=ALWALL N |title=Urethane and stilbamidine in multiple myeloma report on two cases |journal=Lancet |volume=2 |issue=6472 |pages=388 |date=September 1947 |pmid=20263550 |doi= |url=}}</ref>
+*In '''1958''', Dr. N. Blokhin first used [[melphalan]] as a [[chemotherapy]] agent to treat [[multiple myeloma]].<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1961''', the use of [[thalidomide]] was prohibited since it was found to be associated with [[birth defects]].<ref name="pmid27604794">{{cite journal| author=Hong J, Lee JH| title=Recent advances in multiple myeloma: a Korean perspective. | journal=Korean J Intern Med | year= 2016 | volume= 31 | issue= 5 | pages= 820-34 | pmid=27604794 | doi=10.3904/kjim.2015.408 | pmc=5016289 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27604794  }} </ref>
+*In '''1962''', the [[chemotherapy]] agent [[melphalan]] was shown to improve overall [[survival]] in [[multiple myeloma]].<ref name="pmid27604794">{{cite journal| author=Hong J, Lee JH| title=Recent advances in multiple myeloma: a Korean perspective. | journal=Korean J Intern Med | year= 2016 | volume= 31 | issue= 5 | pages= 820-34 | pmid=27604794 | doi=10.3904/kjim.2015.408 | pmc=5016289 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27604794  }} </ref><ref name="pmid6028709">{{cite journal |vauthors=Hoogstraten B, Sheehe PR, Cuttner J, Cooper T, Kyle RA, Oberfield RA, Townsend SR, Harley JB, Hayes DM, Costa G, Holland JF |title=Melphalan in multiple myeloma |journal=Blood |volume=30 |issue=1 |pages=74–83 |date=July 1967 |pmid=6028709 |doi= |url=}}</ref>
+*In '''1967''', Maas reported improvement in 8 patients treated with [[prednisone]].<ref name="pmid19254626">{{cite journal |vauthors=Rajkumar SV |title=Multiple myeloma |journal=Curr Probl Cancer |volume=33 |issue=1 |pages=7–64 |date=2009 |pmid=19254626 |pmc=2743983 |doi=10.1016/j.currproblcancer.2009.01.001 |url=}}</ref>
+*In '''1969''', Alexanian conducted a [[randomized trial]] that showed improved [[survival]] with combination of [[prednisone]] and [[melphalan]] than [[melphalan]] alone.<ref name="pmid19254626">{{cite journal |vauthors=Rajkumar SV |title=Multiple myeloma |journal=Curr Probl Cancer |volume=33 |issue=1 |pages=7–64 |date=2009 |pmid=19254626 |pmc=2743983 |doi=10.1016/j.currproblcancer.2009.01.001 |url=}}</ref><ref name="pmid9850028">{{cite journal |vauthors= |title=Combination chemotherapy versus melphalan plus prednisone as treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. Myeloma Trialists' Collaborative Group |journal=J. Clin. Oncol. |volume=16 |issue=12 |pages=3832–42 |date=December 1998 |pmid=9850028 |doi=10.1200/JCO.1998.16.12.3832 |url=}}</ref>
+*In '''1975''', Krall, Uthoff, and Harley used a combination of [[steroids]] and [[Alkylation|alkylating agents]] such as [[carmustine]], [[melphalan]], [[cyclophosphamide]].<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid4812771">{{cite journal |vauthors=Lee BJ, Sahakian G, Clarkson BD, Krakoff IH |title=Proceedings: Combination chemotherapy of multiple myeloma with alkeran, cytoxan, vincristine, prednisone, and BCNU |journal=Cancer |volume=33 |issue=2 |pages=533–8 |date=February 1974 |pmid=4812771 |doi= |url=}}</ref>
+*In '''1987''', Selby reported complete [[remission]] in 11/41 [[myeloma]] patients treated with single high dose of intravenous [[melphalan]] but majority of those 11 patients relapsed.<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid3593657">{{cite journal |vauthors=Selby PJ, McElwain TJ, Nandi AC, Perren TJ, Powles RL, Tillyer CR, Osborne RJ, Slevin ML, Malpas JS |title=Multiple myeloma treated with high dose intravenous melphalan |journal=Br. J. Haematol. |volume=66 |issue=1 |pages=55–62 |date=May 1987 |pmid=3593657 |doi= |url=}}</ref>
+*In '''1999''', Singhal and colleagues showed that [[thalidomide]] had a 32% response rate in a phase II clinical trial of relapsed/refractory [[multiple myeloma]].
+*In '''2003''', the [[proteasome inhibitor]] [[bortezomib]] was approved by the [[U.S. Food and Drug Administration]] for the treatment of [[multiple myeloma]].
+====History of stem-cell transplantation====
+*In '''1957''', Thomas treated 6 human [[patients]] with [[intravenous]] infusion of [[bone marrow]] cells after [[total body irradiation]] or [[chemotherapy]], of these 6 patients 1 patient had [[multiple myeloma]].<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid19254626">{{cite journal |vauthors=Rajkumar SV |title=Multiple myeloma |journal=Curr Probl Cancer |volume=33 |issue=1 |pages=7–64 |date=2009 |pmid=19254626 |pmc=2743983 |doi=10.1016/j.currproblcancer.2009.01.001 |url=}}</ref><ref name="pmid13464965">{{cite journal |vauthors=THOMAS ED, LOCHTE HL, LU WC, FERREBEE JW |title=Intravenous infusion of bone marrow in patients receiving radiation and chemotherapy |journal=N. Engl. J. Med. |volume=257 |issue=11 |pages=491–6 |date=September 1957 |pmid=13464965 |doi=10.1056/NEJM195709122571102 |url=}}</ref>
+*In '''1975''', the Durie-Salmon staging system was developed to help guide the treatment.<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1982''', a physician were reported to be the recipient of the first successful syngeneic [[Hematopoietic stem cell transplantation|bone marrow transplant]] for myeloma. The donor was his identical twin brother.<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid6215815">{{cite journal |vauthors=Osserman EF, DiRe LB, DiRe J, Sherman WH, Hersman JA, Storb R |title=Identical twin marrow transplantation in multiple myeloma |journal=Acta Haematol. |volume=68 |issue=3 |pages=215–23 |date=1982 |pmid=6215815 |doi=10.1159/000206984 |url=}}</ref>
+*In '''1983''', T.J. McElwain and R.L. Powles showed that [[Bone marrow transplantation|autologous stem cell transplant]] could be used to treat [[multiple myeloma]].<ref name="pmid18332230">{{cite journal| author=Kyle RA, Rajkumar SV| title=Multiple myeloma. | journal=Blood | year= 2008 | volume= 111 | issue= 6 | pages= 2962-72 | pmid=18332230 | doi=10.1182/blood-2007-10-078022 | pmc=2265446 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18332230  }} </ref>
+*In '''1986''', Fefer reported five [[myeloma]] [[patients]] who were recipients of syngeneic [[Hematopoietic stem cell transplantation|bone marrow transplant]].<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid3520068">{{cite journal |vauthors=Fefer A, Cheever MA, Greenberg PD |title=Identical-twin (syngeneic) marrow transplantation for hematologic cancers |journal=J. Natl. Cancer Inst. |volume=76 |issue=6 |pages=1269–73 |date=June 1986 |pmid=3520068 |doi= |url=}}</ref>
+*In '''1987''', Gahrton reported median survival of 1 year in 10 [[patients]] of [[multiple myeloma]] who received allogeneic [[Hematopoietic stem cell transplantation|bone marrow transplant]].<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid3548846">{{cite journal |vauthors=Gahrton G, Tura S, Flesch M, Gratwohl A, Gravett P, Lucarelli G, Michallet M, Reiffers J, Ringdén O, van Lint MT |title=Bone marrow transplantation in multiple myeloma: report from the European Cooperative Group for Bone Marrow Transplantation |journal=Blood |volume=69 |issue=4 |pages=1262–4 |date=April 1987 |pmid=3548846 |doi= |url=}}</ref>
+*In '''1987''', Barlogie treated 7 [[patients]] of [[multiple myeloma]] refractory to [[Alkylation|alkylating agents]] with combination of high-dose [[melphalan]] with [[total body irradiation]], followed by  autologous or allogeneic [[bone marrow transplantation]]. Of these 7 patients, 6 achieved [[tumor]] mass reduction >90%. This played a critical role in developmental of future [[Organ transplant|transplantation]] strategies in myeloma patients.<ref name="pmid18332230">{{cite journal |vauthors=Kyle RA, Rajkumar SV |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |date=March 2008 |pmid=18332230 |pmc=2265446 |doi=10.1182/blood-2007-10-078022 |url=}}</ref><ref name="pmid19254626">{{cite journal |vauthors=Rajkumar SV |title=Multiple myeloma |journal=Curr Probl Cancer |volume=33 |issue=1 |pages=7–64 |date=2009 |pmid=19254626 |pmc=2743983 |doi=10.1016/j.currproblcancer.2009.01.001 |url=}}</ref><ref name="pmid3304465">{{cite journal |vauthors=Barlogie B, Alexanian R, Dicke KA, Zagars G, Spitzer G, Jagannath S, Horwitz L |title=High-dose chemoradiotherapy and autologous bone marrow transplantation for resistant multiple myeloma |journal=Blood |volume=70 |issue=3 |pages=869–72 |date=September 1987 |pmid=3304465 |doi= |url=}}</ref>
+*In the '''1990s''', it was shown that high-dose therapy with [[Bone marrow transplantation|autologous stem cell]] rescue led to [[improved patient]] outcomes.<ref name="pmid27604794">{{cite journal| author=Hong J, Lee JH| title=Recent advances in multiple myeloma: a Korean perspective. | journal=Korean J Intern Med | year= 2016 | volume= 31 | issue= 5 | pages= 820-34 | pmid=27604794 | doi=10.3904/kjim.2015.408 | pmc=5016289 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=27604794  }} </ref>
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+==References==
-[[Category:Types of cancer]]
+{{Reflist|2}}
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+[[Category:Up-To-Date]]
+[[Category:Surgery]]

Multiple myeloma historical perspective: Difference between revisions

Latest revision as of 22:47, 29 July 2020

Overview

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Laboratory findings

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