Multiple myeloma

Because many organs can be affected by myeloma, the symptoms and signs vary greatly. Fatigue and bone pain are the most common symptoms at presentation. The CRAB criteria were formerly the benchmark used to establish the presence of active multiple myeloma (as opposed to an earlier, generally asymptomatic, "smoldering" form of the disease). The CRAB criteria are:{{cite journal | vauthors = ((International Myeloma Working Group)) | title = Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group | journal = British Journal of Haematology | volume = 121 | issue = 5 | pages = 749–757 | date = June 2003 | pmid = 12780789 | doi = 10.1046/j.1365-2141.2003.04355.x | s2cid = 3195084 | doi-access = free | title-link = doi }}{{Cite book | vauthors = Rajkumar SV |title=ASCO-SEP : Medical Oncology Self-Evaluation Program |publisher=American Society of Clinical Oncology |year=2018 |isbn=978-0-9983747-4-1 | veditors = Hensley ML, Milowsky MI, Rajkumar SV, Schuetze SM |edition=7th |location=Alexandria, VA |chapter=Multiple Myeloma |oclc=1080368315 }}{{Cite web |title=International Myeloma Working Group (IMWG) criteria for the diagnosis of multiple myeloma |url=https://www.myeloma.org/international-myeloma-working-group-imwg-criteria-diagnosis-multiple-myeloma |url-status=live |access-date=11 June 2023 |website=International Myeloma Foundation |date= 26 October 2014|archive-date=7 December 2022 |archive-url=https://web.archive.org/web/20221207171830/https://www.myeloma.org/international-myeloma-working-group-imwg-criteria-diagnosis-multiple-myeloma }}

• Calcium: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
• Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >1.77 mol/L (>2 mg/dL)
• Anemia: hemoglobin value of >2g/dL below the lowest limit of normal, or a hemoglobin value <10g/dL
• Bone lesions: osteolytic lesions on skeletal radiography, CT, or PET/CT

{{as of|2014}} the diagnostic criteria were expanded and updated by the IMWG (International Myeloma Working Group) to add three myeloma-defining events, any one of which indicates the presence of active multiple myeloma. Each of these three events may occur before any of the CRAB criteria appears, thereby making more people eligible for treatment with myeloma drugs earlier.

File:Blausen 0656 MultipleMyeloma.png

Bone pain affects almost 70% of people with multiple myeloma and is one of the most common symptoms.{{Rp|653}}{{cite book | vauthors = Longo D |title=Harrison's Principles of Internal Medicine 18th Edition |year=2012 |publisher=Mc Graw Hill Medical |isbn=978-0-07-174889-6 |pages=938}} Myeloma bone pain usually involves the spine and ribs and worsens with activity. Persistent, localized pain may indicate a pathological bone fracture. Involvement of the vertebrae may lead to spinal cord compression or kyphosis. Myeloma bone disease is due to the overexpression of receptor activator for nuclear factor κ B ligand (RANKL) by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. The resultant bone lesions are lytic (cause breakdown) in nature, and are best seen in plain radiographs, which may show "punched-out" resorptive lesions (including the "raindrop" appearance of the skull on radiography). The breakdown of bone also leads to the release of calcium ions into the blood, leading to hypercalcemia and its associated symptoms.{{cite web|url= https://www.lecturio.com/concepts/hypercalcemia/|title= Hypercalcemia|website= The Lecturio Medical Concept Library|access-date= 11 August 2021|archive-date= 25 July 2021|archive-url= https://web.archive.org/web/20210725153306/https://www.lecturio.com/concepts/hypercalcemia/|url-status= live}}

The anemia found in myeloma is usually normocytic and normochromic. It results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines.{{cite journal | vauthors = Bruns I, Cadeddu RP, Brueckmann I, Fröbel J, Geyh S, Büst S, Fischer JC, Roels F, Wilk CM, Schildberg FA, Hünerlitürkoglu AN, Zilkens C, Jäger M, Steidl U, Zohren F, Fenk R, Kobbe G, Brors B, Czibere A, Schroeder T, Trumpp A, Haas R | display-authors = 6 | title = Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells | journal = Blood | volume = 120 | issue = 13 | pages = 2620–2630 | date = September 2012 | pmid = 22517906 | pmc = 3460684 | doi = 10.1182/blood-2011-04-347484 }}

Impaired kidney function may develop, either acutely or chronically, and with any degree of severity.{{cite journal | vauthors = Bladé J, Fernández-Llama P, Bosch F, Montolíu J, Lens XM, Montoto S, Cases A, Darnell A, Rozman C, Montserrat E | display-authors = 6 | title = Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution | journal = Archives of Internal Medicine | volume = 158 | issue = 17 | pages = 1889–1893 | date = September 1998 | pmid = 9759684 | doi = 10.1001/archinte.158.17.1889 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Knudsen LM, Hippe E, Hjorth M, Holmberg E, Westin J | title = Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group | journal = European Journal of Haematology | volume = 53 | issue = 4 | pages = 207–212 | date = October 1994 | pmid = 7957804 | doi = 10.1111/j.1600-0609.1994.tb00190.x | s2cid = 2861880 }}

The most common cause of kidney failure in multiple myeloma is due to proteins secreted by the malignant cells. Myeloma cells produce monoclonal proteins of varying types, most commonly immunoglobulins (antibodies) and free light chains, resulting in abnormally high levels of these proteins in the blood. Depending on the size of these proteins, they may be excreted through the kidneys. Kidneys can be damaged by the effects of proteins or light chains. Increased bone resorption leads to hypercalcemia and causes nephrocalcinosis, thereby contributing to kidney failure. Amyloidosis is a distant third in the causation. People with amyloidosis have high levels of amyloid protein that can be excreted through the kidneys and cause damage to the kidneys and other organs.{{cite journal | vauthors = Nasr SH, Said SM, Valeri AM, Sethi S, Fidler ME, Cornell LD, Gertz MA, Dispenzieri A, Buadi FK, Vrana JA, Theis JD, Dogan A, Leung N | display-authors = 6 | title = The diagnosis and characteristics of renal heavy-chain and heavy/light-chain amyloidosis and their comparison with renal light-chain amyloidosis | journal = Kidney International | volume = 83 | issue = 3 | pages = 463–470 | date = March 2013 | pmid = 23302715 | doi = 10.1038/ki.2012.414 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Castillo JJ | title = Plasma Cell Disorders | journal = Primary Care | volume = 43 | issue = 4 | pages = 677–691 | date = December 2016 | pmid = 27866585 | doi = 10.1016/j.pop.2016.07.002 }}

Light chains produce myriad effects that can manifest as the Fanconi syndrome (type II kidney tubular acidosis).

Collateral infections are common with multiple myeloma since the disease impairs the functioning of blood components that normally resist pathogens. The most common infections are pneumonia, urinary tract infections, and sepsis.{{Cite journal |last=Blimark |first=Cecilie |date=January 2015 |title=Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients |journal=Haematologica |volume=100 |issue=1 |pages=107–113 |doi=10.3324/haematol.2014.107714 |pmid=25344526 |pmc=4281323 }} The greatest risk period for the occurrence of infection is in the initial few months after the start of new drug therapy, since many drug therapies further suppress the normal immune response.{{cite journal | vauthors = Chapel HM, Lee M | title = The use of intravenous immune globulin in multiple myeloma | journal = Clinical and Experimental Immunology | volume = 97 | issue = Suppl 1 | pages = 21–24 | date = July 1994 | pmid = 8033429 | pmc = 1550368 }}

Infections (and "adverse events" for all diseases) are graded by a standardized scale.{{Cite web |date=27 November 2017 |title=Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0 |url=https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_8.5x11.pdf |url-status=live |access-date=12 June 2023 |website=U.S. Dept. of Health and Human Services |archive-date=19 May 2023 |archive-url=https://web.archive.org/web/20230519163350/https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Reference_8.5x11.pdf }} With some myeloma drug therapies, over 30% of people experience a "Grade 3" or higher infection (many people experience multiple such infections), calling for intervention at least by antibiotics. Of people who die within 6 months of their myeloma diagnosis, between 20% and 50% die from collateral infections.

Clinical evaluation of a person's immune response is typically performed by a lab test that measures the levels of different immunoglobulins in the blood. There are five varieties of immunoglobulins, indicated by the suffices -A, -D, -E, -G and -M.{{Cite web |title=Diagnosis of multiple myeloma |url=https://cancer.ca/en/cancer-information/cancer-types/multiple-myeloma/diagnosis |url-status=live |access-date=11 June 2023 |website=Canadian Cancer Society |archive-date=11 June 2023 |archive-url=https://web.archive.org/web/20230611214500/https://cancer.ca/en/cancer-information/cancer-types/multiple-myeloma/diagnosis }} In the aggregate, the immunoglobulin level may be elevated with the disease, but the majority of such increased antibodies are of a monoclonal variety due to the clonal plasma cell and are thus ineffective. Such ineffective antibodies are common of the immunoglobulin -A and -G varieties. When the measure of effective antibodies drops below a threshold (a condition termed hypogammaglobulinemia),{{cite journal |display-authors=6 |vauthors=Hargreaves RM, Lea JR, Griffiths H, Faux JA, Holt JM, Reid C, Bunch C, Lee M, Chapel HM |date=March 1995 |title=Immunological factors and risk of infection in plateau phase myeloma |journal=Journal of Clinical Pathology |volume=48 |issue=3 |pages=260–266 |doi=10.1136/jcp.48.3.260 |pmc=502468 |pmid=7730490}} supplemental immunoglobulins may be provided by periodic infusions to reduce the risk of collateral infections.{{Cite web |last=Lancman |first=Guido |date=15 November 2022 |title=Infections and Severe Hypogammaglobulinemia in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies |url=https://ashpublications.org/blood/article/140/Supplement%201/10073/489149/Infections-and-Severe-Hypogammaglobulinemia-in |url-status=live |access-date=11 June 2023 |archive-date=11 June 2023 |archive-url=https://web.archive.org/web/20230611214506/https://ashpublications.org/blood/article/140/Supplement%201/10073/489149/Infections-and-Severe-Hypogammaglobulinemia-in }}

Some symptoms (e.g., weakness, confusion, and fatigue) may be due to anemia or hypercalcemia. Headache, visual changes, and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome, and other neuropathies (due to infiltration of peripheral nerves by amyloid) may occur. It may give rise to paraplegia in late-presenting cases.{{Citation needed|date=August 2024}}

When the disease is well-controlled, neurological symptoms may result from current treatments, some of which may cause peripheral neuropathy, manifesting itself as numbness or pain in the hands, feet, and lower legs.{{Citation needed|date=August 2020}}

The initial symptoms may involve pain, numbness, swelling, expansion of the jaw, tooth mobility, and radiolucency.{{Cite book | veditors = Glick M |title=Burket's oral medicine |isbn=978-1-60795-188-9 |oclc=888026338 |date=January 2015|last1=Glick |first1=Michael |publisher=PMPH USA }} Multiple myeloma in the mouth can mimic common tooth problems such as periapical abscess or periodontal abscess, gingivitis, periodontitis, or other gingival enlargement or masses.{{cite journal | vauthors = Shah A, Ali A, Latoo S, Ahmad I | title = Multiple Myeloma presenting as Gingival mass | journal = Journal of Maxillofacial and Oral Surgery | volume = 9 | issue = 2 | pages = 209–212 | date = June 2010 | pmid = 22190790 | pmc = 3244103 | doi = 10.1007/s12663-010-0050-7 }}

The cause of multiple myeloma is generally unknown.

• Monoclonal gammopathy of undetermined significance (MGUS) increases the risk of developing multiple myeloma. MGUS transforms to multiple myeloma at the rate of 1% to 2% per year, and almost all cases of multiple myeloma are preceded by MGUS.{{cite journal | vauthors = Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV | display-authors = 6 | title = Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study | journal = Blood | volume = 113 | issue = 22 | pages = 5412–5417 | date = May 2009 | pmid = 19179464 | pmc = 2689042 | doi = 10.1182/blood-2008-12-194241 }}
• Smoldering multiple myeloma increases the risk of developing multiple myeloma. Individuals diagnosed with this premalignant disorder develop multiple myeloma at a rate of 10% per year for the first 5 years, 3% per year for the next 5 years, and then 1% per year.{{cite journal | vauthors = Dutta AK, Hewett DR, Fink JL, Grady JP, Zannettino AC | title = Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma | journal = British Journal of Haematology | volume = 178 | issue = 2 | pages = 196–208 | date = July 2017 | pmid = 28466550 | doi = 10.1111/bjh.14649 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Willrich MA, Murray DL, Kyle RA | title = Laboratory testing for monoclonal gammopathies: Focus on monoclonal gammopathy of undetermined significance and smoldering multiple myeloma | journal = Clinical Biochemistry | volume = 51 | pages = 38–47 | date = January 2018 | pmid = 28479151 | doi = 10.1016/j.clinbiochem.2017.05.001 }}
• Obesity is related to multiple myeloma with each increase of body mass index by five increasing the relative risk by 11%. In addition, studies have shown a positive correlation between BMI and adhesion of multiple myeloma cells.{{cite journal | vauthors = Roberts DL, Dive C, Renehan AG | title = Biological mechanisms linking obesity and cancer risk: new perspectives | journal = Annual Review of Medicine | volume = 61 | pages = 301–316 | date = 2010 | pmid = 19824817 | doi = 10.1146/annurev.med.080708.082713 }}

Studies have reported a familial predisposition to myeloma.{{cite journal | vauthors = Koura DT, Langston AA | title = Inherited predisposition to multiple myeloma | journal = Therapeutic Advances in Hematology | volume = 4 | issue = 4 | pages = 291–297 | date = August 2013 | pmid = 23926460 | pmc = 3734900 | doi = 10.1177/2040620713485375 }}{{cite journal | vauthors = Schinasi LH, Brown EE, Camp NJ, Wang SS, Hofmann JN, Chiu BC, Miligi L, Beane Freeman LE, de Sanjose S, Bernstein L, Monnereau A, Clavel J, Tricot GJ, Atanackovic D, Cocco P, Orsi L, Dosman JA, McLaughlin JR, Purdue MP, Cozen W, Spinelli JJ, de Roos AJ | display-authors = 6 | title = Multiple myeloma and family history of lymphohaematopoietic cancers: Results from the International Multiple Myeloma Consortium | journal = British Journal of Haematology | volume = 175 | issue = 1 | pages = 87–101 | date = October 2016 | pmid = 27330041 | pmc = 5035512 | doi = 10.1111/bjh.14199 }} Hyperphosphorylation of several proteins—the paratarg proteins—a tendency that is inherited in an autosomal dominant manner, appears a common mechanism in these families. This tendency is more common in African-Americans with myeloma and may contribute to the higher rates of myeloma in this group.

In a study to investigate the association between occupational exposure to aromatic hydrocarbon solvents (Benzene and its many derivatives), evidence has shown that these solvents have a role in causation of multiple myeloma. The occurrence of multiple myeloma may occur more in certain occupations. The risk of multiple myeloma occurring is greater in occupations as a firefighter, as a hairdresser, and in agricultural and industrial occupations.{{cite journal | vauthors = Sergentanis TN, Zagouri F, Tsilimidos G, Tsagianni A, Tseliou M, Dimopoulos MA, Psaltopoulou T | title = Risk Factors for Multiple Myeloma: A Systematic Review of Meta-Analyses | journal = Clinical Lymphoma, Myeloma & Leukemia | volume = 15 | issue = 10 | pages = 563–577.e3 | date = October 2015 | pmid = 26294217 | doi = 10.1016/j.clml.2015.06.003 }} The risk in certain occupations is due to exposure to different chemicals. Repeated exposure to chemicals increases the risk of multiple myeloma. The use of pesticides and hazardous chemicals in occupations, like firefighting and agriculture has been seen to cause an increase in risk for multiple myeloma. Other occupations, such as industrial occupations, are also at increased risk for multiple myeloma. Industrial workers are exposed to chemicals that have aromatic hydrocarbon solvents in them.

Exposure to aromatic hydrocarbon solvents, benzene, toluene, and xylene, can increase risk of multiple myeloma. Increased duration, high intensity of exposure, or repeated exposure was associated with an increased risk of multiple myeloma by up to 63%. The time from exposure to diagnosis was studied, and diagnosis after exposure lagged at least 20 years. When exposure to one chemical was identified, there was usually exposure to another hydrocarbon solvent identified. Multiple myeloma affects more men, older adults, and African Americans. These populations also have higher exposure frequencies than their female counterparts.

Rarely, Epstein–Barr virus (EBV) is associated with multiple myeloma, particularly in individuals who have an immunodeficiency due to e.g. HIV/AIDS, organ transplantation, or a chronic inflammatory condition such as rheumatoid arthritis.{{cite journal | vauthors = Sekiguchi Y, Shimada A, Ichikawa K, Wakabayashi M, Sugimoto K, Ikeda K, Sekikawa I, Tomita S, Izumi H, Nakamura N, Sawada T, Ohta Y, Komatsu N, Noguchi M | display-authors = 6 | title = Epstein-Barr virus-positive multiple myeloma developing after immunosuppressant therapy for rheumatoid arthritis: a case report and review of literature | journal = International Journal of Clinical and Experimental Pathology | volume = 8 | issue = 2 | pages = 2090–2102 | date = 2015 | pmid = 25973110 | pmc = 4396324 }} EBV-positive multiple myeloma is classified by the World Health Organization (2016) as one form of the Epstein–Barr virus-associated lymphoproliferative diseases and termed Epstein–Barr virus-associated plasma cell myeloma. EBV-positive disease is more common in the plasmacytoma rather than multiple myeloma form of plasma cell cancer. Tissues involved in EBV+ disease typically show foci of EBV+ cells with the appearance of rapidly proliferating immature or poorly differentiated plasma cells.{{cite journal | vauthors = Rezk SA, Zhao X, Weiss LM | title = Epstein-Barr virus (EBV)-associated lymphoid proliferations, a 2018 update | journal = Human Pathology | volume = 79 | pages = 18–41 | date = September 2018 | pmid = 29885408 | doi = 10.1016/j.humpath.2018.05.020 | s2cid = 47010934 }} The cells express products of EBV genes such as EBER1 and EBER2.{{cite journal | vauthors = Yan J, Wang J, Zhang W, Chen M, Chen J, Liu W | title = Solitary plasmacytoma associated with Epstein-Barr virus: a clinicopathologic, cytogenetic study and literature review | journal = Annals of Diagnostic Pathology | volume = 27 | pages = 1–6 | date = April 2017 | pmid = 28325354 | doi = 10.1016/j.anndiagpath.2016.09.002 }} While the EBV contributes to the development and/or progression of most Epstein–Barr virus-associated lymphoproliferative diseases, its role in multiple myeloma is not known.{{cite journal | vauthors = Dojcinov SD, Fend F, Quintanilla-Martinez L | title = EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts | journal = Pathogens | volume = 7 | issue = 1 | pages = 28 | date = March 2018 | pmid = 29518976 | pmc = 5874754 | doi = 10.3390/pathogens7010028 | doi-access = free | title-link = doi }} However, people who are EBV-positive with localized plasmacytoma(s) are more likely to progress to multiple myeloma compared to people with EBV-negative plasmacytoma(s). This suggest that EBV may have a role in the progression of plasmacytomas to systemic multiple myeloma.

File:Plasmablast, Wright stain.png, in a case of multiple myeloma of plasmablastic type.]]

B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surfaces (cell surface antigens). When they are activated to secrete antibodies, they are known as plasma cells.{{Cite book |last1=Muthusamy |first1=Natarajan |title=Williams Hematology |last2=Caligiuri |first2=Michael A. |publisher=McGraw-Hill Education |year=2021 |edition=10th |language=English |chapter=Chapter 73: The Structure of Lymphocytes and Plasma Cells}}

Multiple myeloma develops in B lymphocytes after they have left the part of the lymph node known as the germinal center. The normal cell type most closely associated with MM cells is generally taken to be either an activated memory B cell or the precursor to plasma cells, the plasmablast.{{cite book |author1=Federico Caligaris-Cappio |author2=Manlio Ferrarini |title=Human B Cell Populations |series=Chemical Immunology |volume=67 |publisher=S. Karger AG |location=Switzerland |year=1997 |page=105 |isbn=978-3-8055-6460-1 |url=https://books.google.com/books?id=1Oj7GLSeDpYC&pg=PA104 |url-status=live |archive-url=https://web.archive.org/web/20160527025435/https://books.google.com/books?id=1Oj7GLSeDpYC&pg=PA104 |archive-date=27 May 2016}}

The immune system keeps the proliferation of B cells and the secretion of antibodies under tight control. When chromosomes and genes are damaged, often through rearrangement, this control is lost. Often, a promoter gene moves (or translocates) to a chromosome, where it stimulates an antibody gene to overproduction.{{citation needed|date=February 2023}}

A chromosomal translocation between the immunoglobulin heavy chain gene (on chromosome 14, locus q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11{{cite journal | vauthors = Kyle RA, Rajkumar SV | title = Multiple myeloma | journal = The New England Journal of Medicine | volume = 351 | issue = 18 | pages = 1860–1873 | date = October 2004 | pmid = 15509819 | pmc = 2265446 | doi = 10.1056/NEJMra041875 }}) is frequently observed in people with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma.{{cite journal | vauthors = Spielmann M, Lupiáñez DG, Mundlos S | title = Structural variation in the 3D genome | journal = Nature Reviews. Genetics | volume = 19 | issue = 7 | pages = 453–467 | date = July 2018 | pmid = 29692413 | doi = 10.1038/s41576-018-0007-0 | s2cid = 22325904 | hdl = 21.11116/0000-0003-610A-5 | hdl-access = free }} The result is a proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) chromosome 13 is also observed in about 50% of cases.

Production of cytokines{{cite journal | vauthors = Tricot G | title = New insights into role of microenvironment in multiple myeloma | journal = Lancet | volume = 355 | issue = 9200 | pages = 248–250 | date = January 2000 | pmid = 10675068 | doi = 10.1016/S0140-6736(00)00019-2 | s2cid = 41876106 }} (especially IL-6) by the plasma cells causes much of their localized damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the generation of new blood vessels) is increased.{{citation needed|date=February 2023}}

The produced antibodies are deposited in various organs, leading to kidney failure, polyneuropathy, and various other myeloma-associated symptoms.

Epigenetic modifications, as DNA methylation or histone modifications, are key for the disease establishment and progression.{{Cite journal |last1=Kalushkova |first1=Antonia |last2=Nylund |first2=Patrick |last3=Párraga |first3=Alba Atienza |last4=Lennartsson |first4=Andreas |last5=Jernberg-Wiklund |first5=Helena |date=8 October 2021 |title=One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies |journal=Epigenomes |volume=5 |issue=4 |pages=22 |doi=10.3390/epigenomes5040022 |doi-access=free |issn=2075-4655 |pmc=8715477 |pmid=34968247}} In a study that investigated the DNA methylation profile of multiple myeloma cells and normal plasma cells, a gradual demethylation from stem cells to plasma cells was observed, with site-specific gain of methylation.{{Cite journal |last1=Yang |first1=Ting |last2=Liu |first2=Xiaobo |last3=Kumar |first3=Shaji K. |last4=Jin |first4=Fengyan |last5=Dai |first5=Yun |date=January 2022 |title=Decoding DNA methylation in epigenetics of multiple myeloma |url=https://linkinghub.elsevier.com/retrieve/pii/S0268960X21000783 |journal=Blood Reviews |language=en |volume=51 |pages=100872 |doi=10.1016/j.blre.2021.100872|pmid=34384602 |url-access=subscription }} Loss of methylation is associated with gene activation and gain of methylation is correlated with gene silencing. The dysregulated methylation pattern in multiple myeloma results in the activation of specific oncogenes and repression of specific tumor suppressor genes. The observed methylation pattern of CpG within intronic regions with enhancer-related chromatin marks in multiple myeloma is similar to undifferentiated precursor and stem cells. These results may represent a de novo epigenetic reprogramming in multiple myeloma, leading to the acquisition of a methylation pattern related to stemness.{{cite journal | vauthors = Agirre X, Castellano G, Pascual M, Heath S, Kulis M, Segura V, Bergmann A, Esteve A, Merkel A, Raineri E, Agueda L, Blanc J, Richardson D, Clarke L, Datta A, Russiñol N, Queirós AC, Beekman R, Rodríguez-Madoz JR, San José-Enériz E, Fang F, Gutiérrez NC, García-Verdugo JM, Robson MI, Schirmer EC, Guruceaga E, Martens JH, Gut M, Calasanz MJ, Flicek P, Siebert R, Campo E, Miguel JF, Melnick A, Stunnenberg HG, Gut IG, Prosper F, Martín-Subero JI | display-authors = 6 | title = Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers | journal = Genome Research | volume = 25 | issue = 4 | pages = 478–487 | date = April 2015 | pmid = 25644835 | pmc = 4381520 | doi = 10.1101/gr.180240.114 }}

Other studies have identified a multiple myeloma specific gene silencing pattern associated with abnormal histone modifications caused by dysregulation of the polycomb repressive complex 2 (PRC2).{{cite journal | vauthors = Kalushkova A, Fryknäs M, Lemaire M, Fristedt C, Agarwal P, Eriksson M, Deleu S, Atadja P, Osterborg A, Nilsson K, Vanderkerken K, Oberg F, Jernberg-Wiklund H | display-authors = 6 | title = Polycomb target genes are silenced in multiple myeloma | journal = PLOS ONE | volume = 5 | issue = 7 | pages = e11483 | date = July 2010 | pmid = 20634887 | pmc = 2901331 | doi = 10.1371/journal.pone.0011483 | doi-access = free | bibcode = 2010PLoSO...511483K }}{{cite journal | vauthors = Agarwal P, Alzrigat M, Párraga AA, Enroth S, Singh U, Ungerstedt J, Österborg A, Brown PJ, Ma A, Jin J, Nilsson K, Öberg F, Kalushkova A, Jernberg-Wiklund H | display-authors = 6 | title = Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target | journal = Oncotarget | volume = 7 | issue = 6 | pages = 6809–6823 | date = February 2016 | pmid = 26755663 | pmc = 4872750 | doi = 10.18632/oncotarget.6843 }} Increased expression of the PRC2 subunit, EZH2 have been described to be a common feature in multiple myeloma, resulting in an accumulation and redistribution of histone H3 lysine 27 trimethylation which advances with disease severity.{{cite journal | vauthors = Croonquist PA, Van Ness B | title = The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype | journal = Oncogene | volume = 24 | issue = 41 | pages = 6269–6280 | date = September 2005 | pmid = 16007202 | doi = 10.1038/sj.onc.1208771 | s2cid = 24588617 | doi-access = free | title-link = doi }}

Genetic abnormalities in multiple myeloma divide the disease into two main groups, hyperdiploid multiple myeloma and non-hyperdiploid multiple myeloma. Hyperdiploid MM is associated with a good prognosis and includes trisomies of odd-numbered chromosomes. Non-hyperdiploid MM has a worse outcome and is characterized by translocations on chromosome 14, which leads to the expression of oncogenes. These translocations can be t(11;14), t(6;14), t(4;14), t(14;16), t(14;20).{{Cite journal |last1=Prideaux |first1=Steven M. |last2=Conway O'Brien |first2=Emma |last3=Chevassut |first3=Timothy J. |date=2014 |title=The Genetic Architecture of Multiple Myeloma |journal=Advances in Hematology |language=en |volume=2014 |pages=1–16 |doi=10.1155/2014/864058 |doi-access=free |pmid=24803933 |pmc=3996928 |issn=1687-9104}} Other genetic alterations are 1q amplification, deletion 1p, deletion 17, deletion 13, MYC overexpression, and point mutations in key pathways.

Associated genetic mutations include ATM, BRAF, CCND1, DIS3, FAM46C, KRAS, NRAS and TP53.{{cite journal | vauthors = Weaver CJ, Tariman JD | title = Multiple Myeloma Genomics: A Systematic Review | journal = Seminars in Oncology Nursing | volume = 33 | issue = 3 | pages = 237–253 | date = August 2017 | pmid = 28729121 | doi = 10.1016/j.soncn.2017.05.001 | s2cid = 20956622 | url = https://works.bepress.com/jdtariman/44 | access-date = 13 July 2019 | archive-date = 18 July 2020 | archive-url = https://web.archive.org/web/20200718204811/https://works.bepress.com/jdtariman/44/ | url-status = live }}

{{Technical|date=July 2024|section|small=left}}

The genetic and epigenetic changes occur progressively. The initial change, often involving one chromosome 14 translocation, establishes a clone of bone marrow plasma cells that causes the asymptomatic disorder MGUS, which is a premalignant disorder characterized by increased numbers of plasma cells in the bone marrow or the circulation of a myeloma protein immunoglobulin. Further genetic or epigenetic changes produce a new clone of bone marrow plasma cells, usually descendant from the original clone, that causes the more serious, but still asymptomatic premalignant disorder smoldering multiple myeloma. This myeloma is characterized by a rise in the number of bone marrow plasma cells or levels of the circulating myeloma protein above that seen in MGUS.{{Cite journal |last1=Brigle |first1=Kevin |last2=Rogers |first2=Barbara |date=August 2017 |title=Pathobiology and Diagnosis of Multiple Myeloma |url=https://linkinghub.elsevier.com/retrieve/pii/S0749208117300475 |journal=Seminars in Oncology Nursing |language=en |volume=33 |issue=3 |pages=225–236 |doi=10.1016/j.soncn.2017.05.012|pmid=28688533 |url-access=subscription }}

Subsequent genetic and epigenetic changes lead to a new, more aggressive clone of plasma cells, which causes further rises in the level of the circulating myeloma protein, further rises in the number of bone marrow plasma cells, or the development of one or more of a specific set of "CRAB" symptoms, which are the basis for diagnosing malignant multiple myeloma and treating the disease.{{Cite journal |last=Rajkumar |first=S. Vincent |date=August 2022 |title=Multiple Myeloma: 2022 update on Diagnosis, Risk-stratification and Management |journal=American Journal of Hematology |volume=97 |issue=8 |pages=1086–1107 |doi=10.1002/ajh.26590 |pmc=9387011 |pmid=35560063}}
{{cite journal |vauthors=Rajkumar SV |title=Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management |journal=Am J Hematol |volume=99 |issue=9 |pages=1802–24 |date=September 2024 |pmid=38943315 |doi=10.1002/ajh.27422 |pmc=3629949 }}

In a small percentage of multiple myeloma cases, further genetic and epigenetic changes lead to the development of a plasma cell clone that moves from the bone marrow into the circulatory system, invades distant tissues, and thereby causes the most malignant of all plasma cell dyscrasias, plasma cell leukemia.{{cite journal | vauthors = Fernández de Larrea C, Kyle RA, Durie BG, Ludwig H, Usmani S, Vesole DH, Hajek R, San Miguel JF, Sezer O, Sonneveld P, Kumar SK, Mahindra A, Comenzo R, Palumbo A, Mazumber A, Anderson KC, Richardson PG, Badros AZ, Caers J, Cavo M, LeLeu X, Dimopoulos MA, Chim CS, Schots R, Noeul A, Fantl D, Mellqvist UH, Landgren O, Chanan-Khan A, Moreau P, Fonseca R, Merlini G, Lahuerta JJ, Bladé J, Orlowski RZ, Shah JJ | display-authors = 6 | title = Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group | journal = Leukemia | volume = 27 | issue = 4 | pages = 780–791 | date = April 2013 | pmid = 23288300 | pmc = 4112539 | doi = 10.1038/leu.2012.336 }}{{cite journal | vauthors = Simeon V, Todoerti K, La Rocca F, Caivano A, Trino S, Lionetti M, Agnelli L, De Luca L, Laurenzana I, Neri A, Musto P | display-authors = 6 | title = Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine | journal = International Journal of Molecular Sciences | volume = 16 | issue = 8 | pages = 17514–17534 | date = July 2015 | pmid = 26263974 | pmc = 4581206 | doi = 10.3390/ijms160817514 | doi-access = free | title-link = doi }} Thus, a fundamental genetic instability in plasma cells or their precursors leads to the progression:

Monoclonal gammopathy of undetermined significance → smoldering multiple myeloma → multiple myeloma → plasma cell leukemia

Being asymptomatic, monoclonal gammopathy of undetermined significance and smoldering multiple myeloma are typically diagnosed fortuitously by detecting a myeloma protein on serum protein electrophoresis tests done for other purposes. MGUS is a relatively stable condition afflicting 3% of people aged 50 and 5% of people aged 70; it progresses to multiple myeloma at a rate of 0.5–1% cases per year; smoldering multiple myeloma does so at a rate of 10% per year for the first 5 years, but then falls off sharply to 3% per year for the next 5 years and thereafter to 1% per year.

Overall, some 2–4% of multiple myeloma cases eventually progress to plasma cell leukemia.

File:Monoclonal gammopathy Multiple Myeloma.png showing a paraprotein (peak in the gamma zone) in a person with multiple myeloma]]

The globulin level may be normal in established disease. A doctor may request protein electrophoresis of the blood and urine, which might show the presence of a paraprotein (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the Bence Jones protein, which is a urinary paraprotein composed of free light chains. Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is a specific immunoglobulin (or fragment of immunoglobulin) originally produced by the mutated plasma cell which began to multiply and is now produced by the entire line of malignant cells.{{Cite journal |last1=Lyubimova |first1=N. V. |last2=Timofeev |first2=Yu S. |last3=Abaev |first3=V. M. |last4=Votyakova |first4=O. M. |last5=Kushlinskii |first5=N. E. |date=May 2018 |title=Immunochemical Diagnosis of Multiple Myeloma |url=https://pubmed.ncbi.nlm.nih.gov/29797132 |journal=Bulletin of Experimental Biology and Medicine |volume=165 |issue=1 |pages=84–87 |doi=10.1007/s10517-018-4105-y |issn=1573-8221 |pmid=29797132}}

In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of the five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains). People without evidence of a monoclonal protein may have "nonsecretory" myeloma (not producing immunoglobulins); this represents about 3% of all people with multiple myeloma.{{cite journal | vauthors = Lonial S, Kaufman JL | title = Non-secretory myeloma: a clinician's guide | journal = Oncology | volume = 27 | issue = 9 | pages = 924–8, 930 | date = September 2013 | pmid = 24282993 | url = http://www.cancernetwork.com/multiple-myeloma/non-secretory-myeloma-clinicians-guide | archive-url = https://web.archive.org/web/20180112121913/http://www.cancernetwork.com/multiple-myeloma/non-secretory-myeloma-clinicians-guide | archive-date = 12 January 2018 }}

Additional findings may include a raised calcium level (when osteoclasts are breaking down bone, releasing it into the bloodstream), raised serum creatinine level due to reduced kidney function, which is mainly due to casts of paraprotein deposition in the kidney, although the cast may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin.{{cite book |chapter=Multiple myeloma |author1=Mitchell, Richard Sheppard |author2=Kumar, Vinay |author3=Abbas, Abul K. |author4=Fausto, Nelson |title=Robbins Basic Pathology |publisher=Saunders |location=Philadelphia |isbn=978-1-4160-2973-1 |edition=8th |page=455 |year=2007}}

Other useful laboratory tests include quantitative measurement of IgA, IgG, and IgM to look for immune paresis, and beta-2 microglobulin, which provides prognostic information. On peripheral blood smear, the rouleaux formation of red blood cells is commonly seen, though this is not specific.

The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of the risk of progression from MGUS to multiple myeloma.{{cite journal | vauthors = Rajkumar SV | title = MGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and management | journal = Hematology. American Society of Hematology. Education Program | volume = 2005 | issue = 1 | pages = 340–345 | date = 1 January 2005 | pmid = 16304401 | doi = 10.1182/asheducation-2005.1.340 | doi-access = free | title-link = doi }}

This assay, the serum free light chain assay, has recently been recommended by the International Myeloma Working Group for the screening, diagnosis, prognosis, and monitoring of plasma cell dyscrasias.

File:Multiple myeloma (2) HE stain.jpg|Bone marrow aspirate showing the histologic correlate of multiple myeloma under the microscope, H&E stain

File:Plasmacytoma1.jpg|Plasmacytoma, H&E stain

File:Cast nephropathy - 2 cropped - very high mag.jpg| Micrograph showing myeloma cast nephropathy in a kidney biopsy: Hyaline casts are PAS positive (dark pink/red – right of image). Myelomatous casts are PAS negative (pale pink – left of image), PAS stain.

File:Dutcher and Russell bodies.jpg|Atypical plasma cell infiltrate with both Russell (cytoplasmic) and Dutcher (nuclear) bodies (H&E, 50x)

File:Plasmacytoma_ultramini1.jpg|Micrograph of a plasmacytoma, H&E stain

A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in the diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells that express immunoglobulin in the cytoplasm and occasionally on the cell surface; myeloma cells are often CD56, CD38, CD138, and CD319 positive and CD19, CD20, and CD45 negative. Flow cytometry is often used to establish the clonal nature of the plasma cells, which will generally express only kappa or lambda light chain. Cytogenetics may also be performed in myeloma for prognostic purposes, including a myeloma-specific fluorescent in situ hybridization and virtual karyotype.{{citation needed|date=February 2023}}

The plasma cells seen in multiple myeloma have several possible morphologies. First, they could have the appearance of a normal plasma cell, a large cell two or three times the size of a peripheral lymphocyte. Because they are actively producing antibodies, the Golgi apparatus typically produces a light-colored area adjacent to the nucleus, called a perinuclear halo. The single nucleus (with inside a single nucleolus with vesicular nuclear chromatin) is eccentric, displaced by an abundant cytoplasm.

Other common morphologies seen, but which are not usual in normal plasma cells, include:

• Bizarre cells, which are multinucleated
• Mott cells, containing multiple clustered cytoplasmic droplets or other inclusions (sometimes confused with Auer rods, commonly seen in myeloid blasts)
• Flame cells, having a fiery red cytoplasm{{Cite web|url=http://www.us.elsevierhealth.com/robbins-cotran-pathologic-basis-of-disease-9781455726134.html|title=Robbins & Cotran Pathologic Basis of Disease – 9781455726134 {{!}} US Elsevier Health Bookshop|website=www.us.elsevierhealth.com|access-date=26 October 2016|archive-date=27 April 2021|archive-url=https://web.archive.org/web/20210427165613/https://www.us.elsevierhealth.com/robbins-cotran-pathologic-basis-of-disease-9781455726134.html|url-status=live}}{{Cite book |url=https://play.google.com/store/books/details?id=N4rXh_w482MC |title=Robbins and Cotran Atlas of Pathology | vauthors = Klatt EC |date=8 September 2011 |publisher=Elsevier Health Sciences |isbn=978-1-4557-2683-7 |url-status=live |archive-url=https://web.archive.org/web/20170910182841/https://play.google.com/store/books/details?id=N4rXh_w482MC |archive-date=10 September 2017}}

Historically, the CD138 has been used to isolate myeloma cells for diagnostic purposes. However, this antigen disappears rapidly ex vivo. Recently, however, the surface antigen CD319 (SLAMF7) was discovered to be considerably more stable and allows robust isolation of malignant plasma cells from delayed or even cryopreserved samples.{{cite journal | vauthors = Frigyesi I, Adolfsson J, Ali M, Christophersen MK, Johnsson E, Turesson I, Gullberg U, Hansson M, Nilsson B | display-authors = 6 | title = Robust isolation of malignant plasma cells in multiple myeloma | journal = Blood | volume = 123 | issue = 9 | pages = 1336–1340 | date = February 2014 | pmid = 24385542 | doi = 10.1182/blood-2013-09-529800 | doi-access = free | title-link = doi }}

The prognosis varies widely depending on various risk factors. The Mayo Clinic has developed a risk-stratification model termed Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART), which divides people into high-risk and standard-risk categories.{{cite web |title=Mayo Stratification for Myeloma And Risk-adapted Therapy |url=https://nebula.wsimg.com/e1520dd2009dae7c8ea5ca513775b8fa?AccessKeyId=A0994494BBBCBE4A0363&disposition=0&alloworigin=1 |website=nebula.wsimg.com |access-date=29 September 2017 |archive-date=28 August 2021 |archive-url=https://web.archive.org/web/20210828175914/https://nebula.wsimg.com/e1520dd2009dae7c8ea5ca513775b8fa?AccessKeyId=A0994494BBBCBE4A0363&disposition=0&alloworigin=1 |url-status=live }} People with deletion of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), t(14;20) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or more) are considered to have high-risk myeloma.{{cite journal | vauthors = Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, Chng WJ, Moreau P, Attal M, Kyle RA, Caers J, Hillengass J, San Miguel J, van de Donk NW, Einsele H, Bladé J, Durie BG, Goldschmidt H, Mateos MV, Palumbo A, Orlowski R | display-authors = 6 | title = Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group | journal = Blood | volume = 127 | issue = 24 | pages = 2955–2962 | date = June 2016 | pmid = 27002115 | pmc = 4920674 | doi = 10.1182/blood-2016-01-631200 }}

The diagnostic examination of a person with suspected multiple myeloma typically includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton, and proximal long bones. Myeloma activity sometimes appears as "lytic lesions" (with local disappearance of normal bone due to resorption) or as "punched-out lesions" on the skull X-ray ("raindrop skull"). Lesions may also be sclerotic, which is seen as radiodense.{{cite journal | vauthors = Angtuaco EJ, Fassas AB, Walker R, Sethi R, Barlogie B | title = Multiple myeloma: clinical review and diagnostic imaging | journal = Radiology | volume = 231 | issue = 1 | pages = 11–23 | date = April 2004 | pmid = 14990813 | doi = 10.1148/radiol.2311020452 }} Overall, the radiodensity of myeloma is between −30 and 120 Hounsfield units (HU).{{cite journal | vauthors = Nishida Y, Kimura S, Mizobe H, Yamamichi J, Kojima K, Kawaguchi A, Fujisawa M, Matsue K | display-authors = 6 | title = Automatic digital quantification of bone marrow myeloma volume in appendicular skeletons - clinical implications and prognostic significance | journal = Scientific Reports | volume = 7 | issue = 1 | pages = 12885 | date = October 2017 | pmid = 29018236 | pmc = 5635114 | doi = 10.1038/s41598-017-13255-w | bibcode = 2017NatSR...712885N }} Magnetic resonance imaging is more sensitive than simple X-rays in the detection of lytic lesions, and may supersede a skeletal survey, especially when vertebral disease is suspected. Occasionally, a CT scan is performed to measure the size of soft-tissue plasmacytomas. Nuclear Medicine Bone scans are typically not of any additional value in the workup of people with myeloma (no new bone formation; lytic lesions not well visualized on nuclear bone scan).

File:Plasmozytom multiple Osteolysen Unterarm.png|X-ray of the forearm, with lytic lesions

File:MMPlainSkull.png|Skull X-ray showing multiple lucencies due to multiple myeloma

File:Emmentalersign .jpg|Multiple myeloma in the upper arm

File:PathFracMMPlainMark.png|Pathological fracture of the lumbar spine due to multiple myeloma

File:Multiple myeloma skull CT arrows.PNG|A CT of the brain revealed a lytic lesion in the left temporal bone (right side of image), and petrous temporal bones involving the mastoid segment of the facial nerve canal. Red arrows: lesion; green arrow: normal contralateral facial nerve canal. The lesions are consistent with a myeloma deposit.

File:CT of osteoblastic lesions of multiple myeloma.jpg|CT scan of the lower vertebral column in a man with multiple myeloma, showing multiple osteoblastic lesions: These are more radiodense (brighter in this image) than the surrounding cancellous bone, in contrast to osteolytic lesions, which are less radiodense.

Left femur with myeloma.jpg|Femur with multiple myeloma lesions

Left femur before myeloma.jpg|Same femur before myeloma lesions for comparison

Left humerus with myeloma.jpg|Humerus with multiple myeloma lesions

Left humerus with subtle signs of myeloma.jpg|Same humerus before, with just subtle lesions

In 2003, the IMWG agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma, and MGUS, which was subsequently updated in 2009:{{cite journal | vauthors = Kyle RA, Rajkumar SV | title = Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma | journal = Leukemia | volume = 23 | issue = 1 | pages = 3–9 | date = January 2009 | pmid = 18971951 | pmc = 2627786 | doi = 10.1038/leu.2008.291 }}

• Symptomatic myeloma (all three criteria must be met):
• # Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
• # A monoclonal protein (myeloma protein) in either serum or urine and it has to be more than 3g/dL (except in cases of true nonsecretory myeloma)
• # Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, CRAB):
• #* HyperCalcemia (corrected calcium >2.75 mmol/L, >11 mg/dL)
• #* Renal failure (kidney insufficiency) attributable to myeloma
• #* Anemia (hemoglobin <10 g/dL)
• #* Bone lesions (lytic lesions or osteoporosis with compression fractures)

Note: Recurrent infections alone in a person who has none of the CRAB features is not sufficient to make the diagnosis of myeloma. People who lack CRAB features, but have evidence of amyloidosis, should be considered as amyloidosis and not myeloma. CRAB-like abnormalities are common with numerous diseases, and these abnormalities must be felt to be directly attributable to the related plasma cell disorder and every attempt made to rule out other underlying causes of anemia, kidney failure, etc.

In 2014, the IMWG updated its criteria further to include biomarkers of malignancy.{{cite journal | vauthors = Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosinol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJ, Johnsen HE, Beksac M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG, Miguel JF | display-authors = 6 | title = International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma | journal = The Lancet. Oncology | volume = 15 | issue = 12 | pages = e538–e548 | date = November 2014 | pmid = 25439696 | doi = 10.1016/s1470-2045(14)70442-5 | s2cid = 36384542 | hdl = 2268/174646 | hdl-access = free }}{{Cite news |url=http://imwg.myeloma.org/international-myeloma-working-group-imwg-criteria-for-the-diagnosis-of-multiple-myeloma/ |title=International Myeloma Working Group (IMWG) Criteria for the Diagnosis of Multiple Myeloma |date=29 October 2015 |work=International Myeloma Working Group |access-date=5 August 2018 |archive-url=https://web.archive.org/web/20171107014456/http://imwg.myeloma.org/international-myeloma-working-group-imwg-criteria-for-the-diagnosis-of-multiple-myeloma/ |archive-date=7 November 2017 |url-status=dead}} These biomarkers are >60% clonal plasma cells, a serum involved / uninvolved free light chain ratio ≥ 100 (the concentration of the involved free light chain must be ≥ 100 mg/L) and more than one focal lesion ≥ 5 mm by MRI. Together, these biomarkers and the CRAB criteria are known as myeloma-defining events (MDEs). A person must have >10 % clonal plasma cells and any MDE to be diagnosed with myeloma. The biomarker criteria were added so that smouldering people with multiple myeloma at high risk of developing multiple myeloma could be diagnosed before organ damage occurred, so they would therefore have a better prognosis.

• Asymptomatic/smoldering myeloma:
• # Serum M protein >30 g/L (3 g/dL) or
• # Clonal plasma cells >10% on bone marrow biopsy and
• # No myeloma-related organ or tissue impairment
• Monoclonal gammopathy of undetermined significance (MGUS):
• # Serum paraprotein <30 g/L (3 g/dL) and
• # Clonal plasma cells <10% on bone marrow biopsy and
• # No myeloma-related organ or tissue impairment or a related B-cell lymphoproliferative disorder

Related conditions include solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (where only the antibodies produce symptoms, e.g., AL amyloidosis), and peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes.

In multiple myeloma, staging helps with prognostication but does not guide treatment decisions. The Durie-Salmon staging system was used historically and was replaced by the International Staging System (ISS), published by the International Myeloma Working Group in 2005.{{cite journal | vauthors = Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, Lahuerta JJ, Ludwig H, Morgan G, Powles R, Shimizu K, Shustik C, Sonneveld P, Tosi P, Turesson I, Westin J | display-authors = 6 | title = International staging system for multiple myeloma | journal = Journal of Clinical Oncology | volume = 23 | issue = 15 | pages = 3412–3420 | date = May 2005 | pmid = 15809451 | doi = 10.1200/JCO.2005.04.242 | doi-access = free | title-link = doi }} The revised ISS (R-ISS) was published in 2015 and incorporates cytogenetics and lactate dehydrogenase (LDH).{{cite journal |vauthors=Costa LJ, Usmani SZ |date=December 2020 |title=Defining and Managing High-Risk Multiple Myeloma: Current Concepts |journal=Journal of the National Comprehensive Cancer Network |volume=18 |issue=12 |pages=1730–1737 |doi=10.6004/jnccn.2020.7673 |pmid=33285523 |doi-access=free |title-link=doi}}{{Rp|1730–1}}{{cite journal | vauthors = Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar SV, Moreau P | display-authors = 6 | title = Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group | journal = Journal of Clinical Oncology | volume = 33 | issue = 26 | pages = 2863–2869 | date = September 2015 | pmid = 26240224 | pmc = 4846284 | doi = 10.1200/JCO.2015.61.2267 }}{{Cite book| vauthors = Liedtke M, Fonseca R |title=American Society of Hematology Self-Assessment Program | edition = Seventh |publisher=American Society of Hematology|year=2019|isbn=978-0-9789212-4-8| veditors = Cuker A, Altman J, Gerds A, Wun T |pages=722–69|chapter=Chapter 25: Plasma cell disorders}}{{Rp|732–3}}

• Stage I: β₂ microglobulin (β2M) < 3.5 mg/L, albumin ≥ 3.5 g/dL, normal cytogenetics, no elevated LDH
• Stage II: Not classified under Stage I or Stage III
• Stage III: β2M ≥ 5.5 mg/L and either elevated LDH or high-risk cytogenetics [t(4,14), t(14,16), and/or del(17p)]

The risk of multiple myeloma can be reduced slightly by maintaining a normal body weight.{{cite journal | vauthors = Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K | title = Body Fatness and Cancer--Viewpoint of the IARC Working Group | journal = The New England Journal of Medicine | volume = 375 | issue = 8 | pages = 794–798 | date = August 2016 | pmid = 27557308 | pmc = 6754861 | doi = 10.1056/NEJMsr1606602 }}

Most drug therapies employ multiple agents, e.g., so-called "triplet" or "quadruplet" therapies. Many such groupings include one or more of a monoclonal antibody (e.g., isatuximab or daratumumab), an immunomodulatory agent (e.g., lenalidomide or pomalidomide), and a proteasome inhibitor (e.g., or bortezomib, carfilzomib or ixazomib), in combination with a steroid (e.g., dexamethasone).{{Cite journal |last=Rajkumar |first=S. Vincent |date=8 December 2012 |title=Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma? |journal=Hematology. American Society of Hematology. Education Program |volume=2012 |pages=354–361 |doi=10.1182/asheducation.V2012.1.354.3798330 |pmid=23233604 |url=https://ashpublications.org/hematology/article/2012/1/354/83842/Doublets-triplets-or-quadruplets-of-novel-agents |url-status=live |access-date=10 June 2023 |doi-access=free |archive-date=11 June 2023 |archive-url=https://web.archive.org/web/20230611010004/https://ashpublications.org/hematology/article/2012/1/354/83842/Doublets-triplets-or-quadruplets-of-novel-agents }}

While triplet therapies were the standard of care for many years, current practice more commonly applies quadruplets of drugs. Such combination therapies are commonly referenced by initials, employing upper-case letters for drug brand names and lower-case letters for generic drug names, e.g., VRd for Velcade (brand name for bortezomib), Revlimid (brand name for lenalidomide) and dexamethasone. Similarly with DKRd, with the D representing Darzalex (brand name for daratumumab), and K representing Kyprolis (brand name for carfilzomib).{{Cite journal |last=Rubinstein |first=Samuel M. |date=28 January 2020 |title=Standardizing Chemotherapy Regimen Nomenclature: A Proposal and Evaluation of the HemOnc and National Cancer Institute Thesaurus Regimen Content |journal=JCO Clinical Cancer Informatics |volume=4 |issue=4 |pages=60–70 |doi=10.1200/CCI.19.00122 |pmid=31990580 |pmc=7000232 }} (Emerging practice is not to call such drugs "chemotherapy" because they are not the traditional non-specific intracellular poisons that operate in the classic "chemo" fashion of inhibiting mitosis or inducing DNA damage.{{Cite web |title=Drug Therapy for Multiple Myeloma |url=https://www.cancer.org/cancer/types/multiple-myeloma/treating/chemotherapy.html |url-status=live |archive-date=11 June 2023 |access-date=10 June 2023 |website=American Cancer Society |archive-url=https://web.archive.org/web/20230611011506/https://www.cancer.org/cancer/types/multiple-myeloma/treating/chemotherapy.html }}{{Cite web |title=What Is DARZALEX®? |date=9 April 2021 |url=https://www.darzalex.com/iv/about-darzalex/what-is-darzalex |url-status=live |access-date=10 June 2023 |archive-date=11 June 2023 |archive-url=https://web.archive.org/web/20230611010009/https://www.darzalex.com/iv/about-darzalex/what-is-darzalex }})

Commonly, the efficacy of each drug diminishes over time, as the cancer develops drug resistance mechanisms, such as by clonal evolution or genetic mutations. In part for this reason, multiple myeloma has not historically been treated when in its "smoldering" stage, since the drug(s) utilized may then be of diminished efficacy if the disease progresses to a symptomatic stage. Thus, the standard of care was "watchful waiting" while the disease smoldered.{{Cite web |title=Watchful waiting for multiple myeloma |url=https://cancer.ca/en/cancer-information/cancer-types/multiple-myeloma/treatment/watchful-waiting |url-status=live |access-date=10 June 2023 |website=Canadian Cancer Society |archive-date=11 June 2023 |archive-url=https://web.archive.org/web/20230611012406/https://cancer.ca/en/cancer-information/cancer-types/multiple-myeloma/treatment/watchful-waiting }} Increasingly, however, efforts are underway to study whether drug therapies applied during the smoldering stage might prevent the disease from ever advancing to the active stage. Exemplary are the GEM-CESAR,{{Cite web |date=10 March 2023 |title=Triplet and Quadruplet Regimens in Smoldering Multiple Myeloma |url=https://ascopost.com/issues/march-10-2023/triplet-and-quadruplet-regimens-in-smoldering-multiple-myeloma/ |url-status=live |access-date=10 June 2023 |archive-date=11 June 2023 |archive-url=https://web.archive.org/web/20230611010004/https://ascopost.com/issues/march-10-2023/triplet-and-quadruplet-regimens-in-smoldering-multiple-myeloma/?utm_source=TAP-EN-022323-Trending_MM&utm_medium=email&utm_term=764068138dfbcaf983542454ee1a5294 }} ASCENT{{Cite web |title=Aggressive Smoldering Curative Approach Evaluating Novel Therapies and Transplant (ASCENT) |url=https://clinicaltrials.gov/ct2/show/NCT03289299?term=ascent&cond=Multiple+Myeloma&cntry=US&draw=2&rank=1 |access-date=3 June 2023 |archive-date=3 June 2023 |archive-url=https://web.archive.org/web/20230603222152/https://clinicaltrials.gov/ct2/show/NCT03289299?term=ascent&cond=Multiple+Myeloma&cntry=US&draw=2&rank=1 |url-status=live }} and Immuno-PRISM{{Cite web |title=Immuno-PRISM (PRecision Intervention Smoldering Myeloma) |url=https://clinicaltrials.gov/ct2/show/NCT05469893 |access-date=3 June 2023 |archive-date=3 June 2023 |archive-url=https://web.archive.org/web/20230603222152/https://clinicaltrials.gov/ct2/show/NCT05469893 |url-status=live }} clinical trials.

After drug therapy has reduced a patient's cancer burden, some patients undergo a bone marrow transplant (more properly termed a autologous hematopoietic stem cell transplant, or ASCT) to further suppress the disease. However, this procedure is not available for frail patients,{{Cite web |title=Getting a Stem Cell or Bone Marrow Transplant |url=https://www.cancer.org/cancer/managing-cancer/treatment-types/stem-cell-transplant/process.html |url-status=live |access-date=10 June 2023 |website=American Cancer Society |archive-date=10 June 2023 |archive-url=https://web.archive.org/web/20230610213002/https://www.cancer.org/cancer/managing-cancer/treatment-types/stem-cell-transplant/process.html }} as it essentially resets aspects of the immune system and requires redevelopment of natural defenses, such as by administering childhood vaccines.{{Cite journal |last=Kamboj |first=Mini |date=1 June 2020 |title=Vaccination of the Stem Cell Transplant (SCT) recipient and the Hematologic Malignancy patient |journal=Infectious Disease Clinics of North America |volume=33 |issue=2 |pages=593–609 |doi=10.1016/j.idc.2019.02.007 |pmid=31005140 |pmc=6814287 }}

Increasingly, precision medicine therapies are being explored, with research indicating that certain variants and genetic sub-types of the disease respond more favorably to some drug therapies than others.{{Cite journal |last=Pan |first=Darren |date=20 January 2022 |title=Where We Stand With Precision Therapeutics in Myeloma: Prosperity, Promises, and Pipedreams |journal=Frontiers in Oncology |volume=11 |page=819127 |doi=10.3389/fonc.2021.819127 |pmid=35127532 |pmc=8811139 |doi-access=free }} For example, some research indicates that patients with the t(11,14) genetic translocation (present in about 15-20% of multiple myeloma patients) may particularly benefit from Venetoclax therapy (which is FDA approved for other blood cancers but not yet available for multiple myeloma patients except through clinical trials).{{Cite journal |last=Kumar |first=Shaji |date=2020 |title=Updated results from BELLINI, a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. |journal=Journal of Clinical Oncology |volume=38 |issue=15_suppl |page=8509 |doi=10.1200/JCO.2020.38.15_suppl.8509 |s2cid=219779811 |url=https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.8509 |access-date=3 June 2023 |archive-date=18 August 2023 |archive-url=https://web.archive.org/web/20230818051541/https://ascopubs.org/doi/10.1200/JCO.2020.38.15_suppl.8509 |url-status=live |url-access=subscription }}

While drug therapies commonly entail months or years of treatment, CAR-T therapy offers the alternative of a single treatment (albeit involving a prolonged hospital stay). Moreover, CAR-T treatment seems to provide a deeper, longer-lasting disease remission than existing drugs.{{Cite web |date=14 April 2021 |title=FDA Approves BCMA-Targeted CAR T-Cell Therapy for Multiple Myeloma |url=https://www.cancer.gov/news-events/cancer-currents-blog/2021/fda-ide-cel-car-t-multiple-myeloma |url-status=live |access-date=10 June 2023 |website=National Cancer Institute |archive-date=11 June 2023 |archive-url=https://web.archive.org/web/20230611012411/https://www.cancer.gov/news-events/cancer-currents-blog/2021/fda-ide-cel-car-t-multiple-myeloma }} The FDA originally approved CAR T-Cell therapy only for myeloma patients in later stages of the disease,{{Cite web |date=30 March 2022 |title=Carvykti Approval Marks Second CAR T-Cell Therapy for Multiple Myeloma |url=https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-carvykti-multiple-myeloma |url-status=live |access-date=10 June 2023 |website=National Cancer Institute |archive-date=10 June 2023 |archive-url=https://web.archive.org/web/20230610120643/https://www.cancer.gov/news-events/cancer-currents-blog/2022/fda-carvykti-multiple-myeloma }} but in 2024 expanded approval to include patients who have relapsed after only a single line of treatment.{{Cite web|date=9 April 2024|title=FDA Expands CAR T Approvals for Patients With Multiple Myeloma|url=https://www.aabb.org/news-resources/news/article/2024/04/09/fda-expands-car-t-approvals-in-multiple-myeloma|access-date=28 March 2025|website=Association for the Advancement of Blood & Biotherapies}}

A therapy that also leverages T-cell immune response is the class of drugs termed bispecific T-cell engagers (BITE), or sometimes simply bispecific antibodies. The first drug in this class approved for multiple myeloma is teclistamab, but its use is reserved for people in the later stages of the disease.{{Cite web |date=25 October 2022 |title=FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma |url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma |url-status=dead |access-date=10 June 2023 |website=U.S. Food and Drug Administration |archive-date=27 October 2022 |archive-url=https://web.archive.org/web/20221027170902/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-teclistamab-cqyv-relapsed-or-refractory-multiple-myeloma }} Another BITE drug,talquetamab is under study.{{Cite journal |last=Chari |first=Ajai |date=15 December 2022 |title=Talquetamab, a T-Cell–Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma |journal=New England Journal of Medicine |volume=387 |issue=24 |pages=2232–2244 |doi=10.1056/NEJMoa2204591 |pmid=36507686 |s2cid=254560960 |doi-access=free }}

Treatment is indicated in myeloma with symptoms. If there are no symptoms, but a paraprotein typical of myeloma and diagnostic bone marrow is present without end-organ damage, treatment is usually deferred or restricted to clinical trials.{{cite journal | vauthors = Korde N, Kristinsson SY, Landgren O | title = Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies | journal = Blood | volume = 117 | issue = 21 | pages = 5573–5581 | date = May 2011 | pmid = 21441462 | pmc = 3316455 | doi = 10.1182/blood-2011-01-270140 }} Treatment for multiple myeloma is focused on decreasing the clonal plasma cell population and consequently decrease the symptoms of disease.

The preferred treatment for those under the age of 65 is high-dose chemotherapy, commonly with bortezomib-based regimens, and lenalidomide–dexamethasone,{{cite journal | vauthors = Kyle RA, Rajkumar SV | title = Multiple myeloma | journal = Blood | volume = 111 | issue = 6 | pages = 2962–2972 | date = March 2008 | pmid = 18332230 | pmc = 2265446 | doi = 10.1182/blood-2007-10-078022 }} to be followed by a stem cell transplant. A 2016 study concluded that stem cell transplant is the preferred treatment for multiple myeloma.{{cite journal | vauthors = Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, Rojas M, Lafyatis R | display-authors = 6 | title = Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension | journal = Pulmonary Circulation | volume = 10 | issue = 1 | pages = 2937 | date = 20 September 2016 | pmid = 32166015 | doi = 10.1002/cncr.30334 | pmc = 7052475 | s2cid = 78285186 }} There are two types of stem cell transplants to treat multiple myeloma.{{Cite web |url=https://www.cancer.org/cancer/multiple-myeloma/treating/stem-cell-transplant.html |title=Stem Cell Transplant for Multiple Myeloma |website=www.cancer.org |access-date=13 October 2019 |archive-date=13 October 2019 |archive-url=https://web.archive.org/web/20191013212433/https://www.cancer.org/cancer/multiple-myeloma/treating/stem-cell-transplant.html |url-status=live }} In autologous hematopoietic stem-cell transplantation (ASCT) – the patient's stem cells are collected from the patient's blood. The patient is given high-dose chemotherapy, and the patient's stem cells are then transplanted back into the patient. The process is not curative but does prolong overall survival and complete remission. In allogeneic stem-cell transplantation, a healthy donor's stem cells are transplanted into the affected person. Allogenic stem-cell transplantation has the potential for a cure, but is used in a very small percentage of people (and in the relapsed setting, not as part of initial treatment). Furthermore, a 5–10% treatment-associated mortality rate is associated with allogeneic stem-cell transplant.

People over age 65 and people with significant concurrent illnesses often cannot tolerate stem-cell transplantation. For these people, the standard of care has been chemotherapy with melphalan and prednisone. Recent studies among this population suggest improved outcomes with new chemotherapy regimens, e.g., with bortezomib.{{cite journal | vauthors = San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, Spicka I, Petrucci MT, Palumbo A, Samoilova OS, Dmoszynska A, Abdulkadyrov KM, Schots R, Jiang B, Mateos MV, Anderson KC, Esseltine DL, Liu K, Cakana A, van de Velde H, Richardson PG | display-authors = 6 | title = Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma | journal = The New England Journal of Medicine | volume = 359 | issue = 9 | pages = 906–917 | date = August 2008 | pmid = 18753647 | doi = 10.1056/NEJMoa0801479 | hdl-access = free | hdl = 10261/59573 }}{{cite journal | vauthors = Curran MP, McKeage K | title = Bortezomib: a review of its use in patients with multiple myeloma | journal = Drugs | volume = 69 | issue = 7 | pages = 859–888 | date = May 2009 | pmid = 19441872 | doi = 10.2165/00003495-200969070-00006 }} Treatment with bortezomib, melphalan, and prednisone had an estimated overall survival of 83% at 30 months, lenalidomide plus low-dose dexamethasone an 82% survival at 2 years, and melphalan, prednisone, and lenalidomide had a 90% survival at 2 years. Head-to-head studies comparing these regimens have not been performed {{as of|2008|lc=y}}.{{cite journal | vauthors = Durie BG | title = Treatment of myeloma--are we making progress? | journal = The New England Journal of Medicine | volume = 359 | issue = 9 | pages = 964–966 | date = August 2008 | pmid = 18753654 | doi = 10.1056/NEJMe0805176 }}

There is support for continuous therapies with multiple drug combinations of antimyeloma drugs bortezomib, lenalidomide, and thalidomide as initial treatment for transplant-ineligible multiple myeloma. Further clinical studies are required to determine the potential harms of these drugs and their effect on the person's quality of life.{{cite journal | vauthors = Piechotta V, Jakob T, Langer P, Monsef I, Scheid C, Estcourt LJ, Ocheni S, Theurich S, Kuhr K, Scheckel B, Adams A, Skoetz N | display-authors = 6 | title = Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 11 | date = November 2019 | pmid = 31765002 | pmc = 6876545 | doi = 10.1002/14651858.CD013487 | collaboration = Cochrane Haematology Group }} A 2009 review noted, "Deep venous thrombosis and pulmonary embolism are the major side effects of

thalidomide and lenalidomide. Lenalidomide causes more myelosuppression, and thalidomide causes more sedation. Chemotherapy-induced peripheral neuropathy and thrombocytopenia are major side effects of bortezomib."{{cite journal | vauthors = Abraham J |title=Advances in multiple myeloma treatment: lenalidomide and bortezomib |journal=Community Oncology |date=February 2009 |volume=6 |issue=2 |pages=53–55 |doi=10.1016/S1548-5315(11)70208-X }} The addition of subcutaneous daratumumab to induction and consolidation therapy with bortezomib, lenalidomide, and dexamethasone, and to lenalidomide maintenance therapy, conferred improved progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma.{{Cite journal |last1=Sonneveld |first1=Pieter |last2=Dimopoulos |first2=Meletios A. |last3=Boccadoro |first3=Mario |last4=Quach |first4=Hang |last5=Ho |first5=P. Joy |last6=Beksac |first6=Meral |last7=Hulin |first7=Cyrille |last8=Antonioli |first8=Elisabetta |last9=Leleu |first9=Xavier |last10=Mangiacavalli |first10=Silvia |last11=Perrot |first11=Aurore |last12=Cavo |first12=Michele |last13=Belotti |first13=Angelo |last14=Broijl |first14=Annemiek |last15=Gay |first15=Francesca |date=12 December 2023 |title=Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma |url=http://www.nejm.org/doi/10.1056/NEJMoa2312054 |journal=New England Journal of Medicine |volume=390 |issue=4 |pages=301–313 |language=en |doi=10.1056/NEJMoa2312054 |pmid=38084760 |s2cid=266217426 |issn=0028-4793|hdl=11585/969802 |hdl-access=free }}

Treatment of related hyperviscosity syndrome may be required to prevent neurologic symptoms or kidney failure.{{cite journal | vauthors = Johnson WJ, Kyle RA, Pineda AA, O'Brien PC, Holley KE | title = Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis, and chemotherapy | journal = Archives of Internal Medicine | volume = 150 | issue = 4 | pages = 863–869 | date = April 1990 | pmid = 2183734 | doi = 10.1001/archinte.1990.00390160111022 }}{{cite journal | vauthors = Paul M, Walker F, Bear RA | title = Plasmapheresis therapy in a patient with multiple myeloma | journal = Canadian Medical Association Journal | volume = 127 | issue = 10 | pages = 956 | date = November 1982 | pmid = 7139441 | pmc = 1862296 }}

Most people, including those treated with ASCT, relapse after initial treatment. Maintenance therapy using a prolonged course of low-toxicity medications is often used to prevent relapse. A 2017 meta-analysis showed that post-ASCT maintenance therapy with lenalidomide improved progression-free survival and overall survival in people at standard risk.{{cite journal | vauthors = McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, Bringhen S, Musto P, Anderson KC, Caillot D, Gay F, Moreau P, Marit G, Jung SH, Yu Z, Winograd B, Knight RD, Palumbo A, Attal M | display-authors = 6 | title = Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis | journal = Journal of Clinical Oncology | volume = 35 | issue = 29 | pages = 3279–3289 | date = October 2017 | pmid = 28742454 | pmc = 5652871 | doi = 10.1200/JCO.2017.72.6679 }} A 2012 clinical trial showed that people with intermediate- and high-risk disease benefit from a bortezomib-based maintenance regimen.{{cite journal | vauthors = Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, Zweegman S, Vellenga E, Broyl A, Blau IW, Weisel KC, Wittebol S, Bos GM, Stevens-Kroef M, Scheid C, Pfreundschuh M, Hose D, Jauch A, van der Velde H, Raymakers R, Schaafsma MR, Kersten MJ, van Marwijk-Kooy M, Duehrsen U, Lindemann W, Wijermans PW, Lokhorst HM, Goldschmidt HM | display-authors = 6 | title = Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial | journal = Journal of Clinical Oncology | volume = 30 | issue = 24 | pages = 2946–2955 | date = August 2012 | pmid = 22802322 | doi = 10.1200/JCO.2011.39.6820 | hdl-access = free | hdl = 1765/73197 | url = https://pure.eur.nl/en/publications/6b7360da-51fa-4f88-afba-b518553bd7ed | access-date = 23 December 2022 | archive-date = 18 August 2023 | archive-url = https://web.archive.org/web/20230818051449/https://pure.eur.nl/en/publications/bortezomib-induction-and-maintenance-treatment-in-patients-with-n | url-status = live }}

Reasons for relapse include disease evolution, either from the selective pressure applied by treatment or by de novo mutations and/or if the disease was inadequately represented in the initial biopsy. Relapse within the first 18 months of diagnosis is considered as functional high-risk multiple myeloma. Depending on the person's condition, the prior treatment modalities used, and the duration of remission, options for relapsed disease include retreatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide, or dexamethasone, alone or in combination), and a second ASCT.

Later in the course of the disease, it becomes refractory (resistant) to formerly effective treatment. This stage is referred to as relapsed/refractory multiple myeloma (RRMM). Treatment modalities that are commonly used to treat RRMM include dexamethasone, proteasome inhibitors (e.g. bortezomib and carfilzomib), immunomodulatory imide drugs (e.g. thalidomide, lenalidomide, and pomalidomide), and certain monoclonal antibodies (e.g. isatuximab against CD38 or antibodies targeting CD319). Survival expectancy has risen in recent years,{{cite journal | vauthors = Rajkumar SV | title = Multiple myeloma: Every year a new standard? | journal = Hematological Oncology | volume = 37 | issue = Suppl 1 | pages = 62–65 | date = June 2019 | pmid = 31187526 | pmc = 6570407 | doi = 10.1002/hon.2586 }} and new treatments are under development.{{medical citation needed|date=May 2015}}

Kidney failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute kidney failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic kidney failure is dependent on the type of kidney failure and may involve dialysis.

Several newer options are approved for the management of advanced disease:

• belantamab mafodotin: a monoclonal antibody against B-cell maturation antigen (BCMA), also known as CD269, indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.{{cite web |title=FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma |publisher=U.S. Food and Drug Administration (FDA) |date=5 August 2020 |url=https://www.fda.gov/drugs/drug-approvals-and-databases/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma |access-date=6 August 2020 |archive-date=6 August 2020 |archive-url=https://web.archive.org/web/20200806201200/https://www.fda.gov/drugs/drug-approvals-and-databases/fda-granted-accelerated-approval-belantamab-mafodotin-blmf-multiple-myeloma |url-status=dead }} {{PD-notice}}{{cite press release |title=FDA Approves GSK's BLENREP (belantamab mafodotin-blmf) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma |publisher=GlaxoSmithKline |via=Business Wire |date=6 August 2020 |url=https://www.businesswire.com/news/home/20200805006105/en/ |access-date=6 August 2020}}
• carfilzomib: a proteasome inhibitor that is indicated:
• as a single agent in people who have received one or more lines of therapy
• in combination with dexamethasone or with lenalidomide and dexamethasone in people who have received one to three lines of therapy{{cite web |title=Kyprolis (carfilzomib) for Injection, for Intravenous Use. Full Prescribing Information |url=http://pi.amgen.com/united_states/kyprolis/kyprolis_pi.pdf |publisher=Onyx Pharmaceuticals |location=Thousand Oaks, CA |access-date=20 August 2016 |archive-url=https://web.archive.org/web/20161023013741/http://pi.amgen.com/united_states/kyprolis/kyprolis_pi.pdf |archive-date=23 October 2016}}
• daratumumab: a monoclonal antibody against CD38 indicated in people who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent{{cite web |title=Darzalex (daratumumab) Injection, for Intravenous Use. Full Prescribing Information |url=https://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf |publisher=Janssen Biotech |location=Horsham, PA |access-date=18 August 2016 |archive-url=https://web.archive.org/web/20160818145748/http://www.darzalex.com/shared/product/darzalex/darzalex-prescribing-information.pdf |archive-date=18 August 2016}}
• elotuzumab: an immunostimulatory humanized monoclonal antibody against SLAMF7 (also known as CD319) indicated in combination with lenalidomide and dexamethasone in people who have received one to three prior therapies{{cite web |title=Empliciti (elotuzumab) for Injection, for Intravenous Use. Full Prescribing Information |url=http://packageinserts.bms.com/pi/pi_empliciti.pdf |publisher=Bristol-Myers Squibb Company |location=Princeton, NJ |access-date=18 August 2016 |archive-url=https://web.archive.org/web/20151208064304/http://packageinserts.bms.com/pi/pi_empliciti.pdf |archive-date=8 December 2015}}
• isatuximab: a monoclonal antibody against CD38 indicated in combination with pomalidomide and dexamethasone for the treatment of adults with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.{{cite web |title=FDA approves isatuximab-irfc for multiple myeloma |publisher=U.S. Food and Drug Administration (FDA) |date=2 March 2020 |url=https://www.fda.gov/drugs/development-approval-process-drugs/fda-approves-isatuximab-irfc-multiple-myeloma |access-date=2 March 2020 |archive-date=5 March 2020 |archive-url=https://web.archive.org/web/20200305044904/https://www.fda.gov/drugs/development-approval-process-drugs/fda-approves-isatuximab-irfc-multiple-myeloma |url-status=dead }}{{cite journal | vauthors = Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, Solanki M, Meng R, Lee H, Wiederschain D, Zhu C, Rak A, Anderson KC | display-authors = 6 | title = Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab | journal = Cells | volume = 8 | issue = 12 | pages = 1522 | date = November 2019 | pmid = 31779273 | pmc = 6953105 | doi = 10.3390/cells8121522 | doi-access = free | title-link = doi }}
• ixazomib: an orally available proteasome inhibitor indicated in combination with lenalidomide and dexamethasone in people who have received at least one prior therapy{{cite web |title=Ninlaro (ixazomib) Capsules, for Oral Use. Full Prescribing Information |url=https://www.ninlaro.com/prescribing-information.pdf |publisher=Millennium Pharmaceuticals, Inc. |access-date=18 August 2016 |archive-url=https://web.archive.org/web/20160819051227/https://www.ninlaro.com/prescribing-information.pdf |archive-date=19 August 2016}}
• panobinostat: an orally available histone deacetylase inhibitor used in combination with bortezomib and dexamethasone in people who have received at least two prior chemotherapy regimens, including bortezomib and an immunomodulatory agent{{cite web |title=Farydak (panobinostat) Capsules, for Oral Use. Full Prescribing Information |url=https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/farydak.pdf |publisher=Novartis Pharmaceuticals Corporation |location=East Hanover, New Jersey |access-date=18 August 2016 |archive-url=https://web.archive.org/web/20161022203313/https://www.pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/farydak.pdf |archive-date=22 October 2016}}
• selinexor: an orally available selective inhibitor of nuclear export indicated in combination with dexamethasone in people who have received at least four prior therapies and whose disease does not respond to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody{{cite web |title=Xpovio (selinexor) Tablets, for Oral Use. Full Prescribing Information |url=https://www.xpovio.com/hcp/wp-content/uploads/sites/3/2019/07/full-us-prescribing-information.pdf |publisher=Karyopharm Therapeutics |location=Newton, MA |access-date=3 August 2019 |archive-url=https://web.archive.org/web/20190803150026/https://www.xpovio.com/hcp/wp-content/uploads/sites/3/2019/07/full-us-prescribing-information.pdf |archive-date=3 August 2019}}
• idecabtagene vicleucel: first cell-based gene therapy was approved by FDA in 2021 for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies{{cite press release|url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-multiple-myeloma|archive-url=https://web.archive.org/web/20210327135132/https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-multiple-myeloma|url-status=dead|archive-date=27 March 2021|title=FDA Approves First Cell-Based Gene Therapy for Adult Patients with Multiple Myeloma|date=27 March 2021|publisher=US Food and Drug Administration; FDA }}

Talquetamab (Talvey) and elranatamab (Elrexfio) were approved for medical use in the United States in August 2023.{{cite web | title=FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma | website=U.S. Food and Drug Administration (FDA) | date=9 August 2023 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma | access-date=10 August 2023 | archive-date=11 August 2023 | archive-url=https://web.archive.org/web/20230811072719/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-talquetamab-tgvs-relapsed-or-refractory-multiple-myeloma | url-status=dead }}{{cite press release | title=U.S. FDA Approves Talvey (talquetamab-tgvs), a First-in-Class Bispecific Therapy for the Treatment of Patients with Heavily Pretreated Multiple Myeloma | publisher=Janssen | via=PR Newswire | date=10 August 2023 | url=https://www.prnewswire.com/news-releases/us-fda-approves-talvey-talquetamab-tgvs-a-first-in-class-bispecific-therapy-for-the-treatment-of-patients-with-heavily-pretreated-multiple-myeloma-301897786.html | access-date=17 August 2023}}{{cite press release | title=FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma | website=U.S. Food and Drug Administration (FDA) | date=14 August 2023 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-elranatamab-bcmm-multiple-myeloma | archive-url=https://web.archive.org/web/20230815075256/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-elranatamab-bcmm-multiple-myeloma | url-status=dead | archive-date=15 August 2023 | access-date=14 August 2023}}{{cite press release | title=Pfizer's Elrexfio Receives U.S. FDA Accelerated Approval for Relapsed or Refractory Multiple Myeloma | publisher=Pfizer | via=Business Wire | date=14 August 2023 | url=https://www.businesswire.com/news/home/20230809028227/en/Pfizer%E2%80%99s-ELREXFIO%E2%84%A2-Receives-U.S.-FDA-Accelerated-Approval-for-Relapsed-or-Refractory-Multiple-Myeloma | access-date=17 August 2023}}

Stem cell transplant can be used to treat multiple myeloma. Stem cell transplants come with a risk of a graft-versus-host-disease. Mesenchymal stromal cells may reduce all-cause mortality if they are used for a therapeutic reason and the therapeutic use of MSCs may increase the complete response of acute and chronic GvHD, but the evidence is very uncertain. The evidence suggests that MSCs for prophylactic reason result in little to no difference in all-cause mortality, in the relapse of malignant diseases, and in the incidence of acute GvHD. The evidence suggests that MSCs for prophylactic reason reduce the incidence of chronic GvHD.{{cite journal | vauthors = Fisher SA, Cutler A, Doree C, Brunskill SJ, Stanworth SJ, Navarrete C, Girdlestone J | title = Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD009768 | date = January 2019 | pmid = 30697701 | pmc = 6353308 | doi = 10.1002/14651858.CD009768.pub2 | collaboration = Cochrane Haematological Malignancies Group }}

Plerixafor (Mozobil) was approved for medical use in the United States in 2008.{{cite web | title=Mozobil- plerixafor injection, solution | website=DailyMed | date=26 June 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=0ed08d2b-5051-46b2-aa37-1d6275bf9003 | access-date=13 September 2023}}

Motixafortide (Aphexda) was approved for medical use in the United States in September 2023.{{cite press release | title=BioLineRx Announces FDA Approval of Aphexda (motixafortide) in Combination with Filgrastim (G-CSF) to Mobilize Hematopoietic Stem Cells for Collection and Subsequent Autologous Transplantation in Patients with Multiple Myeloma | publisher=BioLineRx Ltd. | via=PR Newswire | date=11 September 2023 | url=https://www.prnewswire.com/news-releases/biolinerx-announces-fda-approval-of-aphexda-motixafortide-in-combination-with-filgrastim-g-csf-to-mobilize-hematopoietic-stem-cells-for-collection-and-subsequent-autologous-transplantation-in-patients-with-multiple-myeloma-301923206.html | access-date=13 September 2023}}

• Idecabtagene vicleucel (Abecma) – first cell-based gene therapy was approved by FDA in 2021 for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies
• Ciltacabtagene autoleucel (Carvykti) was approved for medical use in the United States in February 2022.{{cite web | title=FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma | website=U.S. Food and Drug Administration (FDA) | date=7 March 2022 | url=https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma | access-date=16 March 2022 | archive-date=17 March 2022 | archive-url=https://web.archive.org/web/20220317045650/https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-ciltacabtagene-autoleucel-relapsed-or-refractory-multiple-myeloma | url-status=dead }} {{PD-notice}} Ciltacabtagene autoleucel is indicated for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g., pamidronate or zoledronic acid) are routinely administered to prevent fractures; they have also been observed to have a direct antitumor effect even in people without known skeletal disease.{{citation needed|date=January 2017}} If needed, red blood cell transfusions or erythropoietin can be used for management of anemia.

Chemotherapies and stem cell transplants can cause unwanted bleeding and may require platelet transfusions. It was seen that platelet transfusions for people undergoing chemotherapy or stem cell transplantation for the prevention of bleeding events had different effects on the number of participants with a bleeding event, the number of days on which bleeding occurred, the mortality secondary to bleeding and the number of platelet transfusions depending on the way they were used (therapeutic, depending on a threshold, different dose schedules or prophylactic).{{cite journal | vauthors = Estcourt L, Stanworth S, Doree C, Hopewell S, Murphy MF, Tinmouth A, Heddle N | title = Prophylactic platelet transfusion for prevention of bleeding in patients with haematological disorders after chemotherapy and stem cell transplantation | journal = The Cochrane Database of Systematic Reviews | issue = 5 | pages = CD004269 | date = May 2012 | pmid = 22592695 | doi = 10.1002/14651858.CD004269.pub3 | collaboration = Cochrane Haematological Malignancies Group }}{{cite journal | vauthors = Estcourt LJ, Stanworth SJ, Doree C, Hopewell S, Trivella M, Murphy MF | title = Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation | journal = The Cochrane Database of Systematic Reviews | volume = 2015 | issue = 11 | pages = CD010983 | date = November 2015 | pmid = 26576687 | pmc = 4717525 | doi = 10.1002/14651858.CD010983.pub2 | collaboration = Cochrane Haematological Malignancies Group }}

Adding physical exercises to the standard treatment for adult patients with haematological malignancies like multiple myeloma may result in little to no difference in mortality, in the quality of life, and in the physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect and serious adverse events{{cite journal | vauthors = Knips L, Bergenthal N, Streckmann F, Monsef I, Elter T, Skoetz N | title = Aerobic physical exercise for adult patients with haematological malignancies | journal = The Cochrane Database of Systematic Reviews | volume = 1 | issue = 1 | pages = CD009075 | date = January 2019 | pmid = 30702150 | pmc = 6354325 | doi = 10.1002/14651858.CD009075.pub3 | collaboration = Cochrane Haematological Malignancies Group }}

Multiple national cancer treatment guidelines recommend early palliative care for people with advanced multiple myeloma at the time of diagnosis and for anyone who has significant symptoms.The American Society of Clinical Oncology has made this recommendation based on various cancers. See {{Citation |author1 = American Society of Clinical Oncology |author1-link = American Society of Clinical Oncology |title = Five Things Physicians and Patients Should Question |publisher = American Society of Clinical Oncology |work = Choosing Wisely: an initiative of the ABIM Foundation |url = http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf |access-date = 14 August 2012 |url-status=dead |archive-url = https://web.archive.org/web/20120731073425/http://choosingwisely.org/wp-content/uploads/2012/04/5things_12_factsheet_Amer_Soc_Clin_Onc.pdf |archive-date = 31 July 2012}}{{cite web |vauthors=Snowden JA, Ahmedzai S, Ashcroft J, etal |title=Guidelines for Supportive Care in Myeloma |url=http://www.bcshguidelines.com/documents/BCSH_MM_Supportive_Care_Guidelines__Sept_2010.pdf |date=2010 |publisher=British Committee for Standards in Haematology |url-status=dead |archive-url=https://web.archive.org/web/20150923182906/http://www.bcshguidelines.com/documents/BCSH_MM_Supportive_Care_Guidelines__Sept_2010.pdf |archive-date=23 September 2015 |access-date=21 August 2014 }}

Palliative care is appropriate at any stage of multiple myeloma and can be provided alongside curative treatment. In addition to addressing symptoms of cancer, palliative care helps manage unwanted side effects, such as pain and nausea related to treatments.{{cite journal | vauthors = Higginson IJ, Evans CJ | title = What is the evidence that palliative care teams improve outcomes for cancer patients and their families? | journal = Cancer Journal | volume = 16 | issue = 5 | pages = 423–435 | year = 2010 | pmid = 20890138 | doi = 10.1097/PPO.0b013e3181f684e5 | s2cid = 39881122 | doi-access = free | title-link = doi }}{{cite journal | vauthors = Lorenz KA, Lynn J, Dy SM, Shugarman LR, Wilkinson A, Mularski RA, Morton SC, Hughes RG, Hilton LK, Maglione M, Rhodes SL, Rolon C, Sun VC, Shekelle PG | display-authors = 6 | title = Evidence for improving palliative care at the end of life: a systematic review | journal = Annals of Internal Medicine | volume = 148 | issue = 2 | pages = 147–159 | date = January 2008 | pmid = 18195339 | doi = 10.7326/0003-4819-148-2-200801150-00010 | doi-access = free | title-link = doi }}

Oral prophylaxis, hygiene instruction, and elimination of sources of infection within the mouth before beginning cancer treatment can reduce the risk of infectious complications. Before starting bisphosphonate therapy, the person's dental health should be evaluated to assess the risk factors to prevent the development of medication-related osteonecrosis of the jaw (MRONJ). If there are any symptoms or radiographic appearance of MRONJ, such as jaw pain, loose tooth, or mucosal swelling, early referral to an oral surgeon is recommended. Dental extractions should be avoided during the active period of treatment, and the affected tooth should be treated with nonsurgical root canal therapies instead.{{cite journal | vauthors = Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, Rojas M, Lafyatis R | display-authors = 6 | title = Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension | journal = Pulmonary Circulation | volume = 10 | issue = 1 | pages = 383–399 | date = 2 May 2018 | pmid = 32166015 | doi = 10.12968/denu.2018.45.5.383 | pmc = 7052475 }}

Overall the 5-year survival rate is around 54% in the United States.{{cite web |title=Myeloma—Cancer Stat Facts |url=https://seer.cancer.gov/statfacts/html/mulmy.html |website=SEER |access-date=17 April 2020 |archive-date=7 May 2020 |archive-url=https://web.archive.org/web/20200507162617/https://seer.cancer.gov/statfacts/html/mulmy.html |url-status=live }} With high-dose therapy followed by ASCT, the median survival has been estimated in 2003 to be about 4.5 years, compared to a median around 3.5 years with "standard" therapy.{{cite journal | vauthors = Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ | display-authors = 6 | title = High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma | journal = The New England Journal of Medicine | volume = 348 | issue = 19 | pages = 1875–1883 | date = May 2003 | pmid = 12736280 | doi = 10.1056/NEJMoa022340 | s2cid = 41048909 | doi-access = free | title-link = doi }}

The international staging system can help to predict survival, with a median survival (in 2005) of 62 months for stage-1 disease, 45 months for stage-2 disease, and 29 months for stage-3 disease. The median age at diagnosis is 69 years.

SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel.{{cite journal | vauthors = Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau JL, Attal M, Marit G, Mathiot C, Facon T, Moreau P, Anderson KC, Campion L, Munshi NC, Minvielle S | display-authors = 6 | title = Prognostic significance of copy-number alterations in multiple myeloma | journal = Journal of Clinical Oncology | volume = 27 | issue = 27 | pages = 4585–4590 | date = September 2009 | pmid = 19687334 | pmc = 2754906 | doi = 10.1200/JCO.2008.20.6136 }}

The following table outlines the prognostic effect of various genetic findings in multiple myeloma, with chromosomal translocations designated t, followed by standard nomenclature thereof:{{cite journal | vauthors = Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, Rojas M, Lafyatis R | display-authors = 6 | title = Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension | journal = Pulmonary Circulation | volume = 10 | issue = 1 | pages = 361–370 | year = 2021 | pmid = 32166015 | doi = 10.1177/2045894020908782 |pmc= 7052475 }}

[[File:Lymphomas, multiple myeloma world map-Deaths per million persons-WHO2012.svg|thumb|upright=1.3|Deaths from lymphomas and multiple myeloma per million persons in 2012

{{Div col|small=yes|colwidth=10em}}{{legend|#ffff20|0–13}}{{legend|#ffe820|14–18}}{{legend|#ffd820|19–22}}{{legend|#ffc020|23–28}}{{legend|#ffa020|29–34}}{{legend|#ff9a20|35–42}}{{legend|#f08015|43–57}}{{legend|#e06815|58–88}}{{legend|#d85010|89–121}}{{legend|#d02010|122–184}}{{div col end}}

]]

File:Lymphomas, multiple myeloma world map - Death - WHO2004.svg death from lymphomas and multiple myeloma per 100,000 inhabitants in 2004.{{cite web |url=https://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |title=WHO Disease and injury country estimates |year=2009 |work=World Health Organization |access-date=11 November 2009 |url-status=live |archive-url=https://web.archive.org/web/20091111101009/http://www.who.int/healthinfo/global_burden_disease/estimates_country/en/index.html |archive-date=11 November 2009}}{{Div col|small=yes|colwidth=10em}}

{{legend|#b3b3b3|no data}}

{{legend|#ffff65|less than 1.8}}

{{legend|#fff200|1.8–3.6}}

{{legend|#ffdc00|3.6–5.4}}

{{legend|#ffc600|5.4–7.2}}

{{legend|#ffb000|7.2–9}}

{{legend|#ff9a00|9–10.8}}

{{legend|#ff8400|10.8–12.6}}

{{legend|#ff6e00|12.6–14.4}}

{{legend|#ff5800|14.4–16.2}}

{{legend|#ff4200|16.2–18}}

{{legend|#ff2c00|18–19.8}}

{{legend|#cb0000|more than 19.8}}

{{div col end}}]]

Globally, multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015.{{cite journal |last1=Vos |first1=Theo |last2=Allen |first2=Christine |last3=Arora |first3=Megha |last4=Barber |first4=Ryan M. |last5=Bhutta |first5=Zulfiqar A. |last6=Brown |first6=Alexandria |last7=Carter |first7=Austin |last8=Casey |first8=Daniel C. |last9=Charlson |first9=Fiona J. |last10=Chen |first10=Alan Z. |last11=Coggeshall |first11=Megan |last12=Cornaby |first12=Leslie |last13=Dandona |first13=Lalit |last14=Dicker |first14=Daniel J. |last15=Dilegge |first15=Tina |display-authors=1 |date=October 2016 |title=Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015 |journal=Lancet |volume=388 |issue=10053 |pages=1545–1602 |doi=10.1016/S0140-6736(16)31678-6 |pmc=5055577 |pmid=27733282 |last16=Erskine |first16=Holly E. |last17=Ferrari |first17=Alize J. |last18=Fitzmaurice |first18=Christina |last19=Fleming |first19=Tom |last20=Forouzanfar |first20=Mohammad H. |last21=Fullman |first21=Nancy |last22=Gething |first22=Peter W. |last23=Goldberg |first23=Ellen M. |last24=Graetz |first24=Nicholas |last25=Haagsma |first25=Juanita A. |last26=Hay |first26=Simon I. |last27=Johnson |first27=Catherine O. |last28=Kassebaum |first28=Nicholas J. |last29=Kawashima |first29=Toana |last30=Kemmer |first30=Laura}}{{cite journal |last1=Wang |first1=Haidong |last2=Naghavi |first2=Mohsen |last3=Allen |first3=Christine |last4=Barber |first4=Ryan M. |last5=Bhutta |first5=Zulfiqar A. |last6=Carter |first6=Austin |last7=Casey |first7=Daniel C. |last8=Charlson |first8=Fiona J. |last9=Chen |first9=Alan Zian |last10=Coates |first10=Matthew M. |last11=Coggeshall |first11=Megan |last12=Dandona |first12=Lalit |last13=Dicker |first13=Daniel J. |last14=Erskine |first14=Holly E. |last15=Ferrari |first15=Alize J. |display-authors=1 |date=October 2016 |title=Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015 |journal=Lancet |volume=388 |issue=10053 |pages=1459–1544 |doi=10.1016/s0140-6736(16)31012-1 |pmc=5388903 |pmid=27733281 |last16=Fitzmaurice |first16=Christina |last17=Foreman |first17=Kyle |last18=Forouzanfar |first18=Mohammad H. |last19=Fraser |first19=Maya S. |last20=Fullman |first20=Nancy |last21=Gething |first21=Peter W. |last22=Goldberg |first22=Ellen M. |last23=Graetz |first23=Nicholas |last24=Haagsma |first24=Juanita A. |last25=Hay |first25=Simon I. |last26=Huynh |first26=Chantal |last27=Johnson |first27=Catherine O. |last28=Kassebaum |first28=Nicholas J. |last29=Kinfu |first29=Yohannes |last30=Kulikoff |first30=Xie Rachel}} This is up from 49,000 in 1990.{{cite journal | title = Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013 | journal = Lancet | volume = 385 | issue = 9963 | pages = 117–171 | date = January 2015 | pmid = 25530442 | pmc = 4340604 | doi = 10.1016/s0140-6736(14)61682-2 | author1 = GBD 2013 Mortality and Causes of Death Collaborators }}

Myeloma is the 17th-most common cancer in the UK: around 4,800 people were diagnosed with the disease in 2011. It is the 16th-most common cause of cancer death: around 2,700 people died of it in 2012.{{cite web |title=Myeloma statistics |url=http://www.cancerresearchuk.org/cancer-info/cancerstats/types/Myeloma/ |website=Cancer Research UK |access-date=28 October 2014 |url-status=live |archive-url=https://web.archive.org/web/20141028121047/http://www.cancerresearchuk.org/cancer-info/cancerstats/types/Myeloma/ |archive-date=28 October 2014}}

In the United States in 2016, an estimated 30,330 new cases and 12,650 deaths were reported.{{cite web |title=SEER Stat Fact Sheets: Myeloma |url=http://seer.cancer.gov/statfacts/html/mulmy.html |url-status=dead |archive-url=https://web.archive.org/web/20160727230344/http://seer.cancer.gov/statfacts/html/mulmy.html |archive-date=27 July 2016 |access-date=8 August 2016 |website=NCI Surveillance, Epidemiology, and End Results Program}} These numbers are based on assumptions made using data from 2011, which estimated the number of people affected as 83,367 people, the number of new cases as 6.1 per 100,000 people per year, and the mortality as 3.4 per 100,000 people per year.

Multiple myeloma is the second-most prevalent blood cancer (10%) after non-Hodgkin's lymphoma.{{cite journal | vauthors = Collins CD | title = Problems monitoring response in multiple myeloma | journal = Cancer Imaging | volume = 5 Spec No A | issue = Spec No A | pages = S119–S126 | date = November 2005 | pmid = 16361127 | pmc = 1665317 | doi = 10.1102/1470-7330.2005.0033 }} It represents about 1.8% of all new cancers and 2.1% of all cancer deaths.

Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported number of new cases of this disease in the United States and Asians have the lowest. Results of one study found the number of new cases of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans.{{cite journal | vauthors = Brown LM, Linet MS, Greenberg RS, Silverman DT, Hayes RB, Swanson GM, Schwartz AG, Schoenberg JB, Pottern LM, Fraumeni JF | display-authors = 6 | title = Multiple myeloma and family history of cancer among blacks and whites in the U.S | journal = Cancer | volume = 85 | issue = 11 | pages = 2385–2390 | date = June 1999 | pmid = 10357409 | doi = 10.1002/(sici)1097-0142(19990601)85:11<2385::aid-cncr13>3.0.co;2-a | publisher = Wiley | s2cid = 41616510 | doi-access = free | title-link = doi }} Among African Americans, myeloma is one of the top-10 causes of cancer death.{{cite journal | vauthors = Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, Rojas M, Lafyatis R | display-authors = 6 | title = Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension | journal = Pulmonary Circulation | volume = 10 | issue = 1 | pages = 1292 | date = 6 December 2014 | pmid = 32166015 | doi = 10.1182/blood.v124.21.1292.1292 | publisher = American Society of Hematology | pmc = 7052475 }}

Multiple myeloma has been diagnosed in dogs,{{cite book | vauthors = Ettinger SJ, Feldman EC |title=Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat |date=1 June 2000 |publisher=W.B. Saunders |volume=1 |isbn=978-0-7216-7257-1 |pages=516–9}} cats, and horses.{{cite journal | vauthors = MacAllister C, Qualls C, Tyler R, Root CR | title = Multiple myeloma in a horse | journal = Journal of the American Veterinary Medical Association | volume = 191 | issue = 3 | pages = 337–339 | date = August 1987 | pmid = 3654300 }}

In dogs, multiple myeloma accounts for around 8% of all haemopoietic tumors. Multiple myeloma occurs in older dogs and is not particularly associated with either males or females. No breeds appear overrepresented in case reviews that have been conducted.{{cite journal | vauthors = Matus RE, Leifer CE, MacEwen EG, Hurvitz AI | title = Prognostic factors for multiple myeloma in the dog | journal = Journal of the American Veterinary Medical Association | volume = 188 | issue = 11 | pages = 1288–1292 | date = June 1986 | pmid = 3721983 }} Diagnosis in dogs is usually delayed due to the initial nonspecificity and range of clinical signs possible. Diagnosis usually involves bone marrow studies, X-rays, and plasma-protein studies. In dogs, protein studies usually reveal the monoclonal gammaglobulin elevation to be IgA or IgG in an equal number of cases. In rare cases the globulin elevation is IgM, which is referred to as Waldenström's macroglobulinemia.{{cite journal | vauthors = MacEwen EG, Hurvitz AI | title = Diagnosis and management of monoclonal gammopathies | journal = The Veterinary Clinics of North America | volume = 7 | issue = 1 | pages = 119–132 | date = February 1977 | pmid = 403649 | doi = 10.1016/S0091-0279(77)50010-X }} The prognosis for initial control and return to good quality of life in dogs is good; 43% of dogs started on a combination chemotherapeutic protocol achieved complete remission. Long-term survival is normal, with a median of 540 days reported. The disease eventually recurs, becoming resistant to available therapies.{{medical citation needed|date=August 2023}} The complications of kidney failure, sepsis, or pain can lead to an animal's death, frequently by euthanasia.{{medical citation needed|date=August 2023}}

• Development of analogs of thalidomide

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{{sister project links}}

{{Medical condition classification and resources

| DiseasesDB = 8628

| ICD10 = {{ICD10|C|90|0|c|81}}

| ICD9 = {{ICD9|203.0}}

| ICDO = {{ICDO|9732|3}}

| OMIM = 254500

| MedlinePlus = 000583

| eMedicineSubj = med

| eMedicineTopic = 1521

| MeshID = D009101

}}

{{Immunoproliferative immunoglobulin disorders}}

{{Chromosomal abnormalities}}

{{Authority control}}

Category:Epstein–Barr virus–associated diseases

Category:Medical mnemonics

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