EXPOSURE TO CHEMICALS

A cohort mortality study of chemical laboratory workers at Department of Energy Nuclear Plants.
Am J Ind Med. 2008 Sep;51(9):656-67.
Kubale T, Hiratzka S, Henn S, Markey A, Daniels R, Utterback D, Waters K, Silver S, Robinson C, Macievic G, Lodwick J.
This study evaluates the mortality experience of 6,157 chemical laboratory workers employed at the US Department of Energy facilities, to assess the relation between chemical exposure and mortality risk due to cancer. There was a statistically higher occurrence of deaths due to MM among females (number of observed deaths: 7), lung cancer, and leukemia among workers employed 20+ years (possibly due to radiation and benzene exposure).

Pesticide exposure and risk of monoclonal gammopathy of undetermined significance in the Agricultural Health Study.
Blood. 2009 Jun 18;113(25):6386-91.
Landgren O, Kyle RA, Hoppin JA, Beane Freeman LE, Cerhan JR, Katzmann JA, Rajkumar SV, Alavanja MC.
This study evaluates 678 men with a clear exposure to pesticides (restricted-use pesticide applicators)  to compared the risk of MGUS with that of 9,469 controls. Among 555 male pesticide applicators older than 50 years, 38 (6.8%) were found to have MGUS, a rate 1.9-fold higher than controls. Risk was higher among users of the chlorinated insecticide dieldrin, the fumigant mixture carbon-tetrachloride/carbon disulfide, and the fungicide chlorothalonil. Since the prevalence of MGUS among pesticide applicators was twice that in controls, the data support the hypothesis that specific pesticides can promote the development of multiple myeloma.

Multiple pesticide exposures and the risk of multiple myeloma in Canadian men.
Int J Cancer. 2013 Oct 15;133(8):1846-58.
Kachuri L, Demers PA, Blair A, Spinelli JJ, Pahwa M, McLaughlin JR, Pahwa P, Dosman JA, Harris SA.
This is a case-control study with 342 cases of multiple myeloma and 1,357 controls. It reported significant associations for some pesticides, suggesting that some chemicals (carbamate pesticides, phenoxy herbicides, organochlorines, carbaryl, captan, and mecoprop) may be risk factors for multiple myeloma.

Evaluation of mortality among marines and navy personnel exposed to contaminated drinking water at USMC base Camp Lejeune: a retrospective cohort study.
Environ Health. 2014 Feb 19;13(1):10.
Bove FJ, Ruckart PZ, Maslia M, Larson TC.
Two drinking water systems at U.S. Marine Corps Base Camp Lejeunem (North Carolina) were contaminated with solvents during the years 1950s-1985. Among 154,932 cases exposed to drinking the contaminated water, the mortality hazard ratio for multiple myeloma was elevated (1.68, 95% CI: 0.76-3.72).

Mortality study of civilian employees exposed to contaminated drinking water at USMC Base Camp Lejeune: a retrospective cohort study.
Environ Health. 2014 Aug 13;13:68.
Bove FJ, Ruckart PZ, Maslia M, Larson TC.
Two drinking water systems at U.S. Marine Corps Base Camp Lejeunem (North Carolina) were contaminated with solvents during the years 1950s-1985. Among 4,647 civilian, full-time workers exposed to drinking contaminated waters in 1973-1985, the mortality hazard ratio for multiple myeloma was elevated (1.84, 95% CI: 0.45-7.58).

 

 

VIRUSES - INFECTIONS

HCV

Hepatitis C virus, human herpesvirus 8, and the development of plasma-cell leukemia.
N Engl J Med. 2003 Jan 9;348(2):178-9.
Hermouet S, Corre I, Gassin M, Bigot-Corbel E, Sutton CA, Casey JW.
This study presents a case of plasma cell leukemia in which the monoclonal IgG-kappa antibody was directed against the HCV core protein. This was demonstrated by immunoblotting. Immunofluorescence studies showed that the malignant plasma cells were infected by HCV and produced HCV core protein.

Non-Hodgkin's lymphoma and other nonhepatic malignancies in Swedish patients with hepatitis C virus infection.
Hepatology. 2005 Mar;41(3):652-9.
Duberg AS, Nordström M, Törner A, Reichard O, Strauss R, Janzon R, Bäck E, Ekdahl K.
These authors evaluated the association between hepatitis C virus (HCV) infection and several hematologic malignancies, including MM, HL, NHL, CLL, and ALL in a Swedish cohort of 27,150 HCV+ persons. The relative risk of malignancy was expressed as a standardized incidence ratio (SIR)-the observed number compared to the expected number. During 1990-2000 there were 15 cases of MM. It was found that the risk of MM was significantly increased in persons with more than 15 years of infection, with a relative risk of 2.54 (95% CI, 1.11-5.69).

Hepatitis C virus (HCV) infection, monoclonal immunoglobulin specific for HCV core protein, and plasma-cell malignancy.
Blood. 2008 Nov 15;112(10):4357-8.
Bigot-Corbel E, Gassin M, Corre I, Le Carrer D, Delaroche O, Hermouet S.
Among 700 patients with monoclonal immunoglobulins, 10 (1.4%) were found to be HCV+. The monoclonal component was purified in 7 cases. The monoclonal Ig reacted against:
  - The C22-3 fragment of the HCV-core protein (4 cases: 2 IgG, 1 IgA, and 1 IgM)
  - The NS-4 of HCV (2 cases: 2 IgG)
  - Did not recognize HCV (1 case)
Interestingly, 1 of 4 patients with monoclonal antibodies against the HCV-core protein developed multiple myeloma.

EBV

Development of monoclonal gammopathy precedes the development of Epstein-Barr virus-induced posttransplant lymphoproliferative disorder.
Liver Transpl Surg. 1996 Sep;2(5):375-82.
Badley AD, Portela DF, Patel R, Kyle RA, Habermann TM, Strickler JG, Ilstrup DM, Wiesner RH, de Groen P, Walker RC, Paya CV.

CMV

Transient monoclonal gammopathy associated with cytomegalovirus infection.
Blood. 1974 Aug;44(2):189-95.
Vodopick H, Chaskes SJ, Solomon A, Stewart JA.

High rate of monoclonal gammopathy among immunocompetent subjects with primary cytomegalovirus infection.
Clin Infect Dis. 2002 Dec 1;35(11):1430-3.
Bühler S, Laitinen K, Holthöfer H, Järvinen A, Schauman KO, Hedman K.

Accurate identification of paraprotein antigen targets by epitope reconstruction.
Blood. 2008 Jan 1;111(1):302-8.
Sompuram SR, Bastas G, Vani K, Bogen SA.
Authors applied a technology called "epitope-mediated antigen prediction" (E-MAP) to try to systematically identify the protein targets of paraproteins. They first reconstructed the paraproteins' epitope by analyzing the peptides binding to them, then they interrogated the protein database, searching for a match. E-MAP analysis of 2 MM paraproteins identified human cytomegalovirus (CMV) as a target in both, one binding to the AD-2S1 epitope of CMV glycoprotein B, and the other one binding to the amino terminus of the CMV UL-48 protein.

HHV-8

Absence of biologically important Kaposi sarcoma-associated herpesvirus gene products and virus-specific cellular immune responses in multiple myeloma.
Blood. 2002 Jul 15;100(2):698-700.
Brander C, Raje N, O'Connor PG, Davies F, Davis J, Chauhan D, Hideshima T, Martin J, Osmond D, Kedes DH, Walker BD, Scadden DT, Anderson KC.

The association between Kaposi sarcoma-associated herpesvirus (KSHV) and MM was controversial. This study assessed the presence of viral RNA transcripts as well as KSHV-specific cellular immune responses in MM patients, using highly sensitive reverse transcription-PCR for detection of viral transcripts of KSHV open reading frame (ORF) 26, ORF72, and ORF74. No viral gene transcripts in long-term cultures of bone marrow stromal cells from 23 patients with MM were detected. Assays for KSHV-specific cytotoxic T-lymphocyte (CTL) activity did not show any specific responses in 16 patients with MM. This study failed to show an important association between KSHV infection and MM.

H. PYLORI

Role of Helicobacter pylori infection in the incidence and clinical course of monoclonal gammopathy of undetermined significance.
Am J Gastroenterol. 2002 Jun;97(6):1371-4.
Malik AA, Ganti AK, Potti A, Levitt R, Hanley JF.
57 patients with MGUS 57 underwent evaluation for H. pylori infection and 39 of them (68%) were found to have the infection. Interestingly, the eradication of H. pylori with combination therapy led to the disappearance of the MGUS in 11 of these 39 patients (28%).

Helicobacter pylori infection and monoclonal gammopathy of undetermined significance.
Br J Haematol. 2002 Dec;119(3):706-8.
Rajkumar SV, Kyle RA, Plevak MF, Murray JA, Therneau TM.
This study did not confirm the previous findings of Malik et al. regarding the disappearance of MGUS after therapy of H. Pylory infection. The seroprevalence of H. Pylori infection was found to be similar in 93 MGUS patients (30%) and 98 control subjects (32%), and H. pylori therapy did not lead to resolution of MGUS.

 

 

AUTOIMMUNE DISEASES

Familial characteristics of autoimmune and hematologic disorders in 8,406 multiple myeloma patients: a population-based case-control study.
Int J Cancer. 2006 Jun 15;118(12):3095-8.
Landgren O, Linet MS, McMaster ML, Gridley G, Hemminki K, Goldin LR.
Authors conducted a population-based case-control study to evaluate risk of MM associated with personal history of autoimmune diseases and occurrence of autoimmune and several hematologic disorders in first-degree relatives. Data were obtained for 8,406 MM cases diagnosed in Sweden in 1958-1998, compared with 16,543 matched controls, 22,490 first-degree relatives of cases, and 44,436 first-degree relatives of controls. The risk for MM was significantly increased among subjects with a personal history of pernicious anemia (OR = 3.27; 2.22-4.83) and family history of SLE (OR = 2.66; 1.12-6.32). Compared with controls, relative risk of MM was significantly increased (RR = 1.67; 1.02-2.73) in relatives of cases. MM cases had more cases of MGUS among their relatives than controls. Risk of MM was not increased in persons whose relatives had hematologic malignancies other than MM. Authors found no significant association between personal/familial autoimmune diseases and MM.

Systemic lupus erythematosus and multiple myeloma: an uncommon association. Two cases and literature review.
Clin Exp Rheumatol. 2008 Jul-Aug;26(4):667-70.
Maamar M, Tazi Mezalek Z, Harmouche H, Adnaoui M, Aouni M, Maaouni A.
The coexistence of systemic lupus erythematosus and multiple myeloma is very rare. Authors report two cases of SLE and MM, and review the literature on this subject. Two female patients of 50 and 35 years old developed MM 7 and 3 years respectively after the diagnosis of SLE. In the second case, SLE was associated to monoclonal gammopathy.

Association of thyroid disease and thyroid autoimmunity with multiple myeloma risk: a case-control study.
Leuk Lymphoma. 2008 Aug;49(8):1545-52.
Dalamaga M, Karmaniolas K, Papadavid E, Pelecanos N, Migdalis I.
This study explored whether thyroid disease and autoimmune thyroid disease (ATD) are associated with MM risk. 73 patients with MM and 73 controls were studied between 2001 and 2007. The prevalence of clinical thyroid disease in MM patients was significantly higher than in controls, and ATD was associated with increased risk of MM. A person with any thyroid disease >10 years has about 2.41 times higher risk to develop MM than an individual without any thyroid disease (95% CI: 1.35-4.29). A familial history of thyroid disease was associated with increased risk of MM (OR = 3.23, 95% CI: 1.25-8.31).

Personal and family history of immune-related conditions increase the risk of plasma cell disorders: a population-based study.
Blood. 2011 Dec 8;118(24):6284-91.
Lindqvist EK, Goldin LR, Landgren O, Blimark C, Mellqvist UH, Turesson I, Wahlin A, Björkholm M, Kristinsson SY.

Prevalence of monoclonal gammopathy among patients with psoriatic arthritis.
J Rheumatol. 2012 Mar;39(3):564-7.
Eder L, Thavaneswaran A, Pereira D, Sussman G, Gladman DD.
Among 361 patients with psoriatic arthritis, 35 (10%) were found to have MGUS. Therefore, in these patients, MGUS was more common than in the general population. One patient had multiple myeloma.

 

 

EXCESS BODY WEIGHT

Obesity is a risk factor for multiple myeloma.

Anthropometric characteristics and risk of multiple myeloma.
Epidemiology. 2005 Sep;16(5):691-4.
Blair CK, Cerhan JR, Folsom AR, Ross JA.
Obesity could influence carcinogenesis of MM. Authors prospectively studied the association between anthropometric characteristics and incidence of MM in a sample of 37,083 postmenopausal women. During 16 years of follow up, 95 cases of MM were identified. Women with greater adiposity had an increased risk of MM.

Body mass index and risk of multiple myeloma: A meta-analysis of prospective studies.
Eur J Cancer. 2011 Jul;47(11):1606-15.
Wallin A, Larsson SC.
This meta-analysis of 15 cohort studies on myeloma incidence and 5 studies on myeloma mortality concluded that excess body weight is a risk factor for multiple myeloma.

Body Mass Index and Physical Activity at Different Ages and Risk of Multiple Myeloma in the NIH-AARP Diet and Health Study.
Am J Epidemiol. 2013 Apr 15;177(8):776-86.
Hofmann JN, Moore SC, Lim U, Park Y, Baris D, Hollenbeck AR, Matthews CE, Gibson TM, Hartge P, Purdue MP.
This epidemiological study supports the hypothesis that obesity is a risk factor for multiple myeloma.

 

 

OTHER

Extramedullary plasmacytoma. A form of marginal zone cell lymphoma?
Am J Clin Pathol. 1999 Jan;111(1):111-6.
Hussong JW, Perkins SL, Schnitzer B, Hargreaves H, Frizzera G.
Extramedullary plasmacytoma (EMP) shares similar histologic and clinical features with marginal zone B-cell lymphomas (MZL) with plasmacytic differentiation, suggesting a possible histogenetic relationship. Authors reviewed 5 cases of EMPs and suggest that EMPs may represent MZL that have undergone an extensive degree of plasmacytic differentiation.

A common clonal origin of nodal marginal zone B-cell lymphoma and plasma cell myeloma demonstrating different immunophenotypes: a case report of composite lymphoma.
Diagn Mol Pathol. 2004 Jun;13(2):75-80.
Saito H, Oka K, Nakamura N, Nagayama R, Hakozaki H, Mori N.
This is a case report of an 83-year-old male with MM and nodal marginal zone lymphoma in a cervical lymph node. Bone marrow biopsy showed MM, with plasma cells positive for IgA-kappa, while cervical LN biopsy revealed nodal marginal zone B-cell lymphoma, with lymphoma cells positive for IgG-lambda. Interestingly, Southern blot of the IgH gene showed same clonal rearrangement in both LN and bone marrow, and sequence analyses of the IgH gene showed an identical sequence of CDR3 in both samples. Thus, authors demonstrated a common clonal origin of the nodal MZL and MM.

Multiple myeloma of the thoracic spine developed at the previous trauma site: case report.
Eur Spine J. 2005 Sep;14(7):698-701.
Erdogan B, Sener L, Kilic D, Bolat F, Altinors N.
This is a case report of a 62-year-old man who initially had a traumatic T7 compression fracture and developed a multiple myeloma two years later at that site. Authors speculate that a preceding trauma may be a causative factor in plasma cell dyscrasias.

Risk of multiple myeloma and monoclonal gammopathy of undetermined significance among white and black male United States veterans with prior autoimmune, infectious, inflammatory, and allergic disorders.
Blood. 2008 Apr 1;111(7):3388-94.
Brown LM, Gridley G, Check D, Landgren O.
This is a retrospective study of more than 4 million male US veterans, exploring the role of prior autoimmune, infectious, inflammatory, and allergic disorders in the etiology of MM and MGUS. The analysis included 4641 patients with MM, and 2046 patients with MGUS. Significantly elevated risks of MM were associated with autoimmune (RR, 1.15), infectious (RR, 1.29), and inflammatory disorders (RR, 1.18).
 - Specific prior autoimmune diseases: polymyositis/dermatomyositis, systemic sclerosis, autoimmune hemolytic anemia, pernicious anemia, and ankylosing spondylitis.
 - Specific prior infectious diseases: pneumonia, hepatitis, meningitis, septicemia, herpes zoster, and poliomyelitis.
 - Specific prior inflammatory diseases: glomerulonephritis, nephrotic syndrome, and osteoarthritis.
Risks for MGUS were of similar magnitude. Authors conclude that various types of immune-mediated conditions might act as triggers for MM/MGUS development.

Plasma cell neoplasms in US solid organ transplant recipients.
Am J Transplant. 2013 Jun;13(6):1523-32.
Engels EA, Clarke CA, Pfeiffer RM, Lynch CF, Weisenburger DD, Gibson TM, Landgren O, Morton LM.
Among 202,600 solid organ transplant recipients, 140 patients developed plasma cell neoplasms (102 cases of myeloma and 38 cases of plasmacytomas). Although the risk was 1.8-fold increased relative to the general population (95% CI 1.5-2.1), I am not particularly impressed by the frequency: only 1 case of myeloma in 1986 transplanted patients.

Survival Analyses and Prognosis of Plasma-Cell Myeloma and Plasmacytoma-Like Posttransplantation Lymphoproliferative Disorders.
Clin Lymphoma Myeloma Leuk. 2016 Dec;16(12):684-692.e3.
Rosenberg AS, Ruthazer R, Paulus JK, Kent DM, Evens AM, Klein AK.
These authors report 212 cases of "Myeloma/plasmacytoma-like post-transplantation lymphoproliferative disorder" (PTLD-MM), after solid organ transplantation. Extramedullary disease was present in 58% of cases. Median OS of the entire group was only 2.4 years (but many patients were treated with old chemotherapy regimens). Median OS of patients more recently diagnosed (2006-2010) was 44 months.

 

 

IDENTIFICATION OF ANTIGENIC TARGETS

Antigenic targets in MM are identified only rarely, therefore the role of an antigenic stimulus in the pathogenesis of MM is unlikely. The malignant transformation seems to be a random event in the plasma cells, independent from their antigenic specificity. This hypothesis is also supported by the lack of preferential use of V genes in MGUS and MM.

Identification of antigenic targets of paraproteins by expression cloning does not support a causal role of chronic antigenic stimulation in the pathogenesis of multiple myeloma and MGUS.
Int J Cancer. 2007 Jul 15;121(2):459-61.
Preuss KD, Held G, Kubuschok B, Hung CZ, Malatsidze N, Wagner M, Pfreundschuh M.
Antigenic targets of paraproteins in both MGUS and MM could have a role as growth stimulators in the pathogenesis of these neoplasms. These authors tried to identify such targets, and they screened cDNA libraries from several tissues, for reactivity with paraproteins in the sera from 115 patients with MGUS and MM. Since these authors did not find a consistent reactivity to auto-, allo- and heteroantigens, they concluded that a causal role of the antigenic stimulus in the pathogenesis of MGUS and MM is unlikely.

A frequent target of paraproteins in the sera of patients with multiple myeloma and MGUS.
Int J Cancer. 2009 Aug 1;125(3):656-61.
Preuss KD, Pfreundschuh M, Ahlgrimm M, Fadle N, Regitz E, Murawski N, Grass S.
The authors screened a human fetal brain-derived macroarray with Ig from 192 patients with MGUS or MM. 29 (15.1%) paraproteins reacted with paratarg-7, a protein of unknown function (as of 2009), expressed in all human tissues.

Multiple myeloma shows no intra-disease clustering of immunoglobulin heavy chain genes.
Haematologica. 2012 Jun;97(6):849-53.
Ferrero S, Capello D, Svaldi M, Boi M, Gatti D, Drandi D, Rossi D, Barbiero S, Mantoan B, Mantella E, Zanni M, Ghione P, Larocca A, Passera R, Bertoni F, Gattei V, Forconi F, Laurenti L, Del Poeta G, Marasca R, Cortelazzo S, Gaidano G, Palumbo A, Boccadoro M, Ladetto M.
This study analyzed 345 immunoglobulin sequences of multiple myeloma and investigated for stereotyped receptor clusters. The findings did not support a pathogenetic role for antigen selection in multiple myeloma.

Clonal Immunoglobulin against Lysolipids in the Origin of Myeloma.
N Engl J Med. 2016 Feb 11;374(6):555-61.
Nair S, Branagan AR, Liu J, Boddupalli CS, Mistry PK, Dhodapkar MV.
Gaucher's disease is a genetic disease characterized by the accumulation of glucocerebroside, a sphyngolipid. These patients have an increased risk of monoclonal gammopathies. In this study, the authors showed that the clonal immunoglobulin present in patients with Gaucher's disease are directed against lyso-glucosylceramide (LGL1). The same reactivity was found in about one third of patients with sporadic monoclonal gammopathies.

 

 


Giampaolo Talamo, M.D.