DEFINITION
 

Multiple myeloma is a cancer that typically involves multiple bones. It arises in the bone marrow from plasma cells, which are cells that normally produce antibodies. Tumor cells are post-germinal centre cells, which express immunoglobulin heavy chain (IgH) postswitch isotypes.

Patients with myeloma have an elevated amount of an antibody which can be measured in the blood and/or urine. The abnormal antibody is called “M component”, and “M” stands for “monoclonal”, which means tumoral.

The M component belongs to one of several classes of antibodies:
  - IgG
  - IgA
  - IgM
  - IgD
  - IgE
In 20% of myeloma patients, only a small portion of the antibody called “light chain” is produced. Light-chain myeloma may be either of two types:
  - Kappa
  - Lambda
Myeloma can rarely be “non-secretory”.

The term "multiple myeloma" was introduced in 1873 by von Rusitzky.

The first documented case of multiple myeloma was described in 1844 by Solly.

The term "plasma cell" was introduced in 1875 by Waldeyer. The morphologic characteristics of plasma cells (eccentric position of the nucleus, the perinuclear pale area, and others) have been described in 1895 by Marschalko.

The terms "kappa" and "lambda" for the immunoglobulin light chains have been introduced in 1956, in honor of Korngold and Lipari, his technician.

 

Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group.
Br J Haematol. 2003 Jun;121(5):749-57
International Myeloma Working Group.
The IMWG has reviewed the criteria for diagnosis and classification of plasma cell dyscrasias, including:
 - MGUS, with M protein <3 g/dL and bone marrow clonal cells <10%
 - Smoldering myeloma, with M protein >3 g/dL and/or bone marrow clonal cells >10% but no clinical manifestations of CRAB
 - Symptomatic myeloma, with CRAB symptoms (hyperCalcemia, Renal insufficiency, Anemia, and Bone lesions)
 - Extramedullary plasmacytoma
 - Solitary plasmacytomas

Multiple myeloma.
Blood. 2008 Mar 15;111(6):2962-72.
Kyle RA, Rajkumar SV.
[Review]

Guidelines for the diagnosis and management of multiple myeloma 2011.
Br J Haematol. 2011 Jul;154(1):32-75.
Bird JM, Owen RG, D'Sa S, Snowden JA, Pratt G, Ashcroft J, Yong K, Cook G, Feyler S, Davies F, Morgan G, Cavenagh J, Low E, Behrens J; Haemato-oncology Task Force of British Committee for Standards in Haematology (BCSH) and UK Myeloma Forum.
[Review]

 

 

 

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)

Every case of myeloma is preceded by MGUS, a premalignant condition characterized by the presence of monoclonal proteins in the blood and/or urine. Most individuals with MGUS remain asymptomatic and do not develop multiple myeloma.

The term MGUS was coined by Dr. Kyle in 1978.

 

INCIDENCE
About 3% of persons older than 50 years of age.

TYPES
  - Non-IgM MGUS
  - IgM MGUS
  - Light-chain MGUS

DIAGNOSIS
The diagnosis of MGUS is based on the following criteria:
  - Monoclonal proteins, usually <3 g/dL
  - <10% plasma cells in the bone marrow
  - No clinical manifestations related to myeloma (e.g., hypercalcemia, renal insufficiency, anemia, and bone lesions)

CLINICAL MANIFESTATIONS
The vast majority of patients are healthy.
Patients with MGUS  are predisposed to develop:
  - Multiple myeloma (or other lymphoproliferative disorders)
  - Peripheral neuropathy
  - Osteopenia and osteoporosis
  - Venous thromboembolism

TREATMENT
It is not necessary.

PROGNOSIS
MGUS evolves to cancer, usually multiple myeloma, at a rate of 1% per year.
Ig-M MGUS usually evolves to lymphoplasmacytic lymphoma or other lymphomas (about 15%)
Risk factors for progression:
  - Non-IgG paraprotein
  - M component >1.5 g/dL
  - Very high serum free kappa or lambda
  - Abnormal plasma cells/normal plasma cells ratio >95% at flow cytometry of bone marrow

 

Monoclonal gammopathy of undetermined significance. Natural history in 241 cases.
Am J Med. 1978 May;64(5):814-26.
Kyle RA.

Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study.
Blood. 2009 May 28;113(22):5412-7.
Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, Dispenzieri A, Kumar S, Clark RJ, Baris D, Hoover R, Rajkumar SV.

Monoclonal Gammopathy in HIV-1-Infected Patients: Factors Associated With Disappearance Under Long-Term Antiretroviral Therapy.
J Acquir Immune Defic Syndr. 2015 Nov 1;70(3):250-5.
Casanova ML, Makinson A, Eymard-Duvernay S, Ouedraogo DE, Badiou S, Reynes J, Tuaillon E.

In this study, 77 patients with HIV and MGUS were followed over time. After a median follow-up of 6.8 years, the MGUS disappeared in 66% of patients, and the disappearance was associated with HIV virologic control with antiretroviral therapy, and with the absence of chronic HCV infection. Only 1 patient developed multiple myeloma, 3 years after the diagnosis of MGUS.

Donor Monoclonal Gammopathy May Cause Lymphoproliferative Disorders in Solid Organ Transplant Recipients.
Am J Transplant. 2016 Sep;16(9):2676-83.
Felldin M, Ekberg J, Polanska-Tamborek D, Hansson U, Sender M, Rizell M, Svanvik J, Mölne J.
This is an interesting study, which showed that individuals with MGUS who are donors for solid organ transplant recipients may cause donor-transmitted lymphoproliferative diseases in the recipients. A donor had an IgM-kappa paraprotein (3.7 g/dL), and this caused a lymphoplasmacytic lymphoma in 2 kidney recipients, and an MGUS in a liver recipient. A second donor had an IgG-lambda paraprotein (0.8 g/dL), and this caused a myeloma in 2 kidney and 1 liver recipient, and an MGUS in a heart recipient (for a total of 7 organ recipients from 2 different donors). The authors state that this donor-transmitted neoplasms develop via passenger lymphoplasmacytic cells/plasma cells in solid organ recipient.

Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study.
Chang SH, Luo S, Thomas TS, O'Brian KK, Colditz GA, Carlsson NP, Carson KR.
J Natl Cancer Inst. 2016 Dec 31;109(5).
These authors studied the outcomes of 7878 patients with MGUS after a median follow-up of about 5 years and a half. They concluded that obesity is a risk factor for progression to multiple myeloma. However, the difference was not high, because myeloma developed in 72 (3.5%) normal-weight patients, and in 113 (4.3%) obese patients. Black race was another risk factor to progression to multiple myeloma.

 

BGUS

Clinical characteristics and outcomes in biclonal gammopathies.
Am J Hematol. 2016 May;91(5):473-5.
Mullikin TC, Rajkumar SV, Dispenzieri A, Buadi FK, Lacy MQ, Lin Y, Dingli D, Go RS, Hayman SR, Zeldenrust SR, Russell SJ, Lust JA, Leung N, Kapoor P, Kyle RA, Gertz MA, Kumar SK.
These authors identified 539 patients with biclonal gammopathies. Of these, 393 had BGUS (biclonal gammopathy of undertermined significance), and 22 of this subset of patients progressed to a hematologic malignancy: symptomatic myeloma (11), smoldering myeloma (6), primary amyloidosis (3), or lymphoplasmacytic lymphoma (2). The rate of progression to hematologic malignancy was approximately 1% per year, which is similar to the rate of progression with MGUS. According to this study, the overall clinical significance of a BGUS is very similar to that of MGUS. 

 

 


 

INCIDENCE

 

Multiple myeloma is rare, because it develops in approximately 1 case in 20,000 people every year.

Multiple myeloma accounts for 1% of malignancies, and 10% of all hematologic malignancies.

It does not occur in the pediatric population: most patients are >40 year. The median age at diagnosis is 70 years.

Americans of African descent have a higher incidence of myeloma.

 

 


 

RISK FACTORS

 

The cause is unknown in most patients. For undetermined reasons, normal B lymphocytes acquire an injury in their DNA and become malignant plasma cells, which proliferate and accumulate in the bone marrow.

Myeloma is a multifactorial disease, with a wide variety of risk factors:
  - Genetic factors
  - Lifestyle factors: excess body weight
  - Environmental/occupational factors: exposure to radiation, pesticides, petroleum products, use of hair dye for >20 years
  - Presence of other diseases: rheumatoid arthritis

A familial predisposition is found in a few patients, but the vast majority cases are not related to familial inheritance.

The association between myeloma and obesity is clear. Obesity is the only modifiable risk factor for the development of myeloma.

Although tobacco is one of the most common causes of cancer in general, cigarette smoking does not seem to promote the development of multiple myeloma.

 

No association between cigarette smoking and incidence of plasma cell myeloma: A meta-analysis of 17 observational studies.
Am J Hematol. 2012 Jul;87(7):729-31.
Castillo JJ, Dhami PK, Curry S, Brennan K.

A pooled analysis of cigarette smoking and risk of multiple myeloma from the international multiple myeloma consortium.
Cancer Epidemiol Biomarkers Prev. 2015 Mar;24(3):631-4.
Andreotti G, Birmann BM, Cozen W, De Roos AJ, Chiu BC, Costas L, de Sanjosé S, Moysich K, Camp NJ, Spinelli JJ, Pahwa P, Dosman JA, McLaughlin JR, Boffetta P, Staines A, Weisenburger D, Benhaim-Luzon V, Brennan P, Costantini AS, Miligi L, Campagna M, Nieters A, Becker N, Maynadié M, Foretová L, Zheng T, Tricot G, Milliken K, Krzystan J, Steplowski E, Baris D, Purdue MP.
This epidemiologic study confirmed that smoking is not a risk factor for multiple myeloma.

 

 

GENETIC / FAMILIAL RISK

Hereditary predisposition to MM is seen in a very small fraction of cases.

Familiality of benign and malignant paraproteinemias. A population-based cancer-registry study of multiple myeloma families.
Haematologica. 2005 Jan;90(1):66-71.
Ogmundsdóttir HM, Haraldsdóttirm V, Jóhannesson GM, Olafsdóttir G, Bjarnadóttir K, Sigvaldason H, Tulinius H.
Although inheritance does not seem to be a major risk factor for the development of paraproteinemias, the occurrence of multiple cases of benign and malignant paraproteinemias in a few families does suggest a hereditary contribution. This survey investigated the familiality of MM, using a family registry of 218 MM cases and the records of the Icelandic Cancer Registry. First-degree relatives of MM patients did not have an increased relative risk of developing MGUS, but they had a significantly increased risk of developing MM (RR = 2.33, CI 1.12-4.26), especially for female relatives. In 3 families, both myeloid and lymphoid malignancies occurred.

Familial risk for non-Hodgkin lymphoma and other lymphoproliferative malignancies by histopathologic subtype: the Swedish Family-Cancer Database.
Blood. 2005 Jul 15;106(2):668-72.
Altieri A, Bermejo JL, Hemminki K.
Authors used the Swedish Family-Cancer Database to calculate standardized incidence ratios (SIRs) for NHL and MM in 4455 offspring whose parents or siblings were affected with different types of lymphoproliferative malignancies. For a parental history of MM, the risk for MM was significantly increased (SIR = 2.5).

Incidence of monoclonal B-cell disease in siblings of patients with multiple myeloma.
Haematologica. 2006 Feb;91(2):274-6.
Engelhardt M, Ihorst G, Behringer D, Finke J, Roth B.
Authors observed clustering of monoclonal B-cell disease in siblings screened as donors for MM patients who needed an allogeneic stem cell transplantation (SCT). Of 134 donors, the incidence of monoclonal B-cell disease was 8/84 in siblings and 1/50 in matched unrelated donors. In 5 MM families scheduled for allogeneic SCT, monoclonal B-cell disease was detected in 8 of 27 siblings.

Familial myeloma.
N Engl J Med. 2008 Jul 10;359(2):152-7.
Lynch HT, Ferrara K, Barlogie B, Coleman EA, Lynch JF, Weisenburger D, Sanger W, Watson P, Nipper H, Witt V, Thomé S.
Authors describe a family with 5 cases of multiple myeloma, 3 cases of MGUS, and 5 cases of prostate cancer in two generations.

Increased risk of monoclonal gammopathy in first-degree relatives of patients with multiple myeloma or monoclonal gammopathy of undetermined significance.
Blood. 2009 Jul 23;114(4):785-90.
Vachon CM, Kyle RA, Therneau TM, Foreman BJ, Larson DR, Colby CL, Phelps TK, Dispenzieri A, Kumar SK, Katzmann JA, Rajkumar SV.
This study examined whether MGUS is increased in first-degree relatives of patients with MM or MGUS. The authors collected serum samples from 911 first-degree relatives of 232 patients with MM and 97 patients with MGUS. MGUS was detected in 8.1% (95% CI, 6.3-9.8) of first-degree relatives, a higher rate than in the control population. The prevalence of MGUS in relatives increased with age. These findings support the role for genetic susceptibility, shared environmental influences, or an interaction between both.

Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden.
Blood. 2009 Jul 23;114(4):791-5.
Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C, Mellqvist UH, Wahlin A, Bjorkholm M, Turesson I.
This study examined whether MGUS is increased in first-degree relatives of patients with MGUS. The authors evaluated 4,458 patients with MGUS, 17,505 normal controls, 14,621 first-degree relatives of patients, and 58,387 first-degree relatives of normal controls (n = 58387). The relatives of patients with MGUS had an increased risk of MGUS (relative risk = 2.8), multiple myeloma (RR = 2.9), lymphoplasmacytic lymphoma (RR = 4.0), and chronic lymphocytic leukemia (RR = 2.0). These findings support the role for genetic susceptibility, shared environmental influences, or an interaction between both.

Patterns of hematologic malignancies and solid tumors among 37,838 first-degree relatives of 13,896 patients with multiple myeloma in Sweden.
Kristinsson SY, Björkholm M, Goldin LR, Blimark C, Mellqvist UH, Wahlin A, Turesson I, Landgren O.
Int J Cancer. 2009 Nov 1;125(9):2147-50.
In order to elucidate the impact of genetic factors in the pathogenesis of multiple myeloma, these authors assessed the risk for hematologic malignancies and solid tumors among first-degree relatives of myeloma patients. The analysis included:
  - 13,896 patients with MM
  - 54,365 matched controls
  - 37,838 first-degree relatives of patients with MM
  - 151,068 first-degree relatives of matched controls
When compared with first-degree relatives of matched controls, first-degree relatives of patients with MM had an increased risk of developing multtiple myeloma (RR 2.1), MGUS (RR 2.1), acute lymphoblastic leukemia (RR 2.1), and bladder cancer (RR 1.3). These findings support a role for a shared susceptibility that predisposes to MM, MGUS, acute lymphoblastic leukemia, and bladder cancer. It cannot be established whether the shared susceptibility involves only genetic factors, shared environmental factors, or both.

Lower incidence of plasma cell neoplasm is maintained in migrant Chinese to British Columbia: findings from a 30-year survey.
Leuk Lymphoma. 2011 Dec;52(12):2316-20.
Chan V, Song K, Mang O, Ip DK, Au WY.
In order to determine the importance of genetic vs environmental factors in the development of multiple myeloma, these authors reviewed the incidence of myeloma in patients of Chinese ethnicity who lived in British Columbia. They found these patients had the same incidence of myeloma of the Chinese population living in Hong Kong (1.6-1.8/100,000), but lower than the non-Chinese population of British Columbia. These findings suggest that genetic factors are more important than environmental factors in the development of multiple myeloma.

The CCND1 c.870G>A polymorphism is a risk factor for t(11;14)(q13;q32) multiple myeloma.
Nat Genet. 2013 Apr 26;45(5):522-5.
Weinhold N, Johnson DC, Chubb D, Chen B, Försti A, Hosking FJ, Broderick P, Ma YP, Dobbins SE, Hose D, Walker BA, Davies FE, Kaiser MF, Li NL, Gregory WA, Jackson GH, Witzens-Harig M, Neben K, Hoffmann P, Nöthen MM, Mühleisen TW, Eisele L, Ross FM, Jauch A, Goldschmidt H, Houlston RS, Morgan GJ, Hemminki K.
This study indicates that genetic factors confer a risk of a specific chromosomal translocation.

Israeli-born offspring of Jewish immigrants of Middle Eastern origin have a lower incidence of multiple myeloma than those of European origin: a cohort study of 746 200 Israeli men followed from late adolescence.
Leuk Lymphoma. 2014 Oct;55(10):2290-5.
Leiba M, Afek A, Derazne E, Keinan-Boker L, Leiba A, Nagler A, Shamiss A, Kark JD.
This study supports the existence of a genetic component in the pathogenesis of multiple myeloma. Data from the Israeli National Cancer Registry showed that second generation man of Middle Eastern origin had a lower risk of developing myeloma compared to those of European origin.

 

 

EXPOSURE TO RADIATION

Monoclonal gammopathy of undetermined significance in atomic bomb survivors: incidence and transformation to multiple myeloma.
Br J Haematol. 2003 May;121(3):405-10.
Neriishi K, Nakashima E, Suzuki G.
Among 6737 atomic bomb survivors, 112 developed MGUS, and 16 died with multiple myeloma. The authors found that the transformation from MGUS to MM was faster in exposed persons than in the control group, but the difference was not statistically significant.

Incidence of haematopoietic malignancies in US radiologic technologists.
Occup Environ Med. 2005 Dec;62(12):861-7.
Linet MS, Freedman DM, Mohan AK, Doody MM, Ron E, Mabuchi K, Alexander BH, Sigurdson A, Hauptmann M.
The investigators followed 71,894 US radiology technologists, collecting data on risks of hematopoietic malignancies associated with protracted exposure to radiation. Only 28 cases of MM developed, and authors concluded that working as a radiology technologist did not increase the risk of multiple myeloma. Risk was increased for non-CLL leukaemias.

The 15-Country Collaborative Study of Cancer Risk among Radiation Workers in the Nuclear Industry: estimates of radiation-related cancer risks.
Radiat Res. 2007 Apr;167(4):396-416.
Cardis E, Vrijheid M, Blettner M, Gilbert E, Hakama M, Hill C, Howe G, Kaldor J, Muirhead CR, Schubauer-Berigan M, Yoshimura T, Bermann F, Cowper G, Fix J, Hacker C, Heinmiller B, Marshall M, Thierry-Chef I, Utterback D, Ahn YO, Amoros E, Ashmore P, Auvinen A, Bae JM, Bernar J, Biau A, Combalot E, Deboodt P, Diez Sacristan A, Eklöf M, Engels H, Engholm G, Gulis G, Habib RR, Holan K, Hyvonen H, Kerekes A, Kurtinaitis J, Malker H, Martuzzi M, Mastauskas A, Monnet A, Moser M, Pearce MS, Richardson DB, Rodriguez-Artalejo F, Rogel A, Tardy H, Telle-Lamberton M, Turai I, Usel M, Veress K.
This 15-Country collaborative study analysed outcomes in 407,391 nuclear industry workers to estimate cancer risk following protracted low doses of ionizing radiation. A significant association was seen between radiation dose and increase in cancer mortality (5233 deaths). Among 31 specific types of cancer studied, they found a significant association for lung cancer and a borderline significant association for multiple myeloma (83 deaths, p=0.06).

Relationship between monoclonal gammopathy of undetermined significance and radiation exposure in Nagasaki atomic bomb survivors.
Blood. 2009 Feb 19;113(8):1639-50.
Iwanaga M, Tagawa M, Tsukasaki K, Matsuo T, Yokota K, Miyazaki Y, Fukushima T, Hata T, Imaizumi Y, Imanishi D, Taguchi J, Momita S, Kamihira S, Tomonaga M.
These authors investigated the possible relationship between radiation exposure and MGUS prevalence in Nagasaki atomic bomb survivors between 1988 and 2004. 1082 cases of MGUS were identified from 52,525 study participants. MGUS prevalence correlated with dose of radiation, and the correlation was observed in persons exposed at age 20 years or younger, but not in those exposed at age 20 years or older. Although people exposed at younger age had a significantly high risk of MGUS when exposed to a high radiation dose, no clear association was found between radiation exposure and progression of MGUS to multiple myeloma.

Pelvic radiotherapy and the risk of secondary leukemia and multiple myeloma.
Cancer. 2010 May 15;116(10):2486-92.
Wright JD, St Clair CM, Deutsch I, Burke WM, Gorrochurn P, Sun X, Herzog TJ.
This study analyzed the risk of leukemia and myeloma among 66,896 patients who received pelvic radiotherapy, compared with 132,372 individuals not treated with radiation. The authors found that pelvic radiation was associated with an increased risk of secondary leukemia, but not an increase the risk of multiple myeloma.

 

 


Giampaolo Talamo, M.D.