Open access Original research BMJ Open: first published as 10.1136/bmjopen-2020-041296 on 22 February 2021. Downloaded from Health impact of monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B- cell lymphocytosis (MBL): findings from a UK population-based cohort Maxine JE Lamb ,1 Alexandra Smith ,1 Daniel Painter ,1 Eleanor Kane ,1 Timothy Bagguley ,1 Robert Newton ,1,2 Debra Howell ,1 Gordon Cook,3 Ruth de Tute,4 Andrew Rawstron,4 Russell Patmore,5 Eve Roman 1 To cite: Lamb MJE, Smith A, ABSTRACT Strengths and limitations of this study Painter D, et al. Health impact Objective To examine mortality and morbidity patterns of monoclonal gammopathy before and after premalignancy diagnosis in individuals of undetermined significance ► Data are from an established population- based co- with monoclonal gammopathy of undetermined (MGUS) and monoclonal B- hort within which all haematological malignancies significance (MGUS) and monoclonal B-cell lymphocytosis cell lymphocytosis (MBL): and related clonal disorders are diagnosed, moni- findings from a UK population- (MBL) and compare their secondary healthcare activity to tored and coded at a single laboratory. that of the general population. based cohort. BMJ Open ► Providing nationally generalisable data, all diagnoses 2021;11:e041296. doi:10.1136/ Design Population- based patient cohort, within which are included, and complete follow- up is achieved via bmjopen-2020-041296 each patient is matched at diagnosis to 10 age- matched linkage to nationwide administrative datasets. and sex- matched individuals from the general population. ► Prepublication history for ► The age- matched and sex-ma tched general popula- this paper is available online. Both cohorts are linked to nationwide information tion cohort enables baseline activity and rate ratios To view these files, please visit on deaths, cancer registrations and Hospital Episode to be calculated, both before and after premalignan- the journal online (http:// dx. doi. Statistics. cy detection. org/ 10. 1136/ bmjopen- 2020- Setting The UK’s Haematological Malignancy Research ► Analyses are constrained by the fact that hospital 041296). Network, which has a catchment population of around 4 episodes statistics are primarily collected for admin- http://bmjopen.bmj.com/ million served by 14 hospitals and a central diagnostic Received 04 June 2020 istrative and clinical purposes and not for research. laboratory. Revised 20 January 2021 Accepted 22 January 2021 Participants All patients newly diagnosed during 2009– 2015 with MGUS (n=2193) or MBL (n=561) and their age and sex-ma tched comparators (n=27 538). systemic disease resulting in wide- ranging organ/tissue Main outcome measures Mortality and hospital inpatient damage and excess mortality. and outpatient activity in the 5 years before and 3 years after diagnosis. Results Individuals with MGUS experienced excess BACKGROUND on September 24, 2021 by guest. Protected copyright. morbidity in the 5 years before diagnosis and excess Monoclonal gammopathy of undetermined mortality and morbidity in the 3 years after diagnosis. significance (MGUS) and monoclonal B-cell Increased rate ratios (RRs) were evident for nearly all lymphocytosis (MBL) are premalignant clinical specialties, the largest, both before and after monoclonal B- cell disorders, the former diagnosis, being for nephrology (before RR=4.29, 95% progressing to myeloma at a rate of around CI 3.90 to 4.71; after RR=13.8, 95% CI 12.8 to 15.0) and 1% per year1 2 and the latter to chronic rheumatology (before RR=3.40, 95% CI 3.18 to 3.63; after lymphocytic leukaemia (CLL) at around RR=5.44, 95% CI 5.08 to 5.83). Strong effects were also 2% per year.3 4 Diagnosed more frequently evident for endocrinology, neurology, dermatology and in men than women and people over 60 © Author(s) (or their respiratory medicine. Conversely, only marginal increases 5 6 employer(s)) 2021. Re- use in mortality and morbidity were evident for MBL. years of age, overt symptoms of haemato- permitted under CC BY. Conclusions MGUS and MBL are generally considered logical malignancy are, by definition, absent Published by BMJ. 7 to be relatively benign, since most individuals with in both MBL and MGUS. Accordingly, For numbered affiliations see monoclonal immunoglobulins never develop a B-cell although some premalignant disorders are end of article. malignancy or any other monoclonal protein-rela ted found coincidentally during routine health Correspondence to organ/tissue-rela ted disorder. Nonetheless, our findings checks, others are identified during diag- Professor Eve Roman; offer strong support for the view that in some individuals, nostic work- up investigations; MGUS during eve. roman@ york. ac. uk monoclonal gammopathy has the potential to cause the course of tests applied to detect a range Lamb MJE, et al. BMJ Open 2021;11:e041296. doi:10.1136/bmjopen-2020-041296 1 Open access BMJ Open: first published as 10.1136/bmjopen-2020-041296 on 22 February 2021. Downloaded from of potential conditions and illnesses8 9 and MBL during made during 2009–2015, MBL was defined by a periph- episodes of unexplained lymphocytosis.4 10 eral blood monoclonal B- cell count <5×109/L in individ- In addition to the association with haematological uals with no other features of a B-cell lymphoproliferative malignancy, individuals with MGUS or MBL sometimes disorder, in MGUS by a serum paraprotein less than 30 experience higher than expected levels of mortality and g/L and in those where a bone marrow examination was morbidity that are independent of cancer.4 8 11–16 Indeed, considered necessary following clinical examination, a although most individuals with these disorders suffer clonal bone marrow plasma cells/lymphoplasmacytic no obvious ill effects, interest in their relationship with infiltration of less than 10%. Hence, within the HMRN other comorbidities has increased markedly in recent region, as in other diagnostic settings,21 22 invasive bone years, MBL largely in relation to its potential to impact on marrow examinations in patients with MGUS are gener- the immune response17 and MGUS due to the systemic ally only carried when laboratory or clinical features organ and tissue damage that can be caused by mono- are indicative of an underlying plasma cell neoplasm, clonal immunoglobulins secreted by the abnormal B- cell lymphoproliferative disorder, monoclonal immunoglob- clone.18 Hitherto, however, most information about these ulin deposition disease (eg, amyloidosis) or conditions associations has been derived either from case–control like polyneuropathy, organomegaly, endocrinopathy, studies established to look at risk factors for disease devel- monoclonal gammopathy and skin changes (POEMS) opment (eg, family history of disease) and additional syndrome.7 tests applied to specific patient groups (eg, patients with To facilitate comparisons with unaffected individuals, kidney disease) or cohort studies that track individuals HMRN also has a general population cohort. To create with either MGUS or MBL forwards in time from their this ‘control’ cohort, all patients diagnosed during 2009– diagnosis.5 13 18 However, despite the undoubted interest 2015 with a haematological malignancy or related clonal in the sequence of health events, as far as we are aware, no disorder (n=18 127) were individually matched on sex systematic population- based investigations of the comor- and age at the point of diagnosis to 10 randomly selected bidity patterns that precede and succeed a diagnosis of individuals from the same catchment population. All either MGUS or MBL have been undertaken in the same controls were assigned a serial number that linked them cohort. to their matched case and a ‘pseudodiagnosis’ date that With a view to shedding light on the health events corresponded to their matched case’s diagnosis date. occurring before and after the diagnosis of MGUS and Individuals in the patient cohort and the comparison MBL, the present report uses data from an established UK cohort are linked to the same nationwide information on population- based patient cohort of haematological malig- deaths, cancer registrations and Hospital Episode Statis- nancies and related disorders to examine the comorbidity tics (HES). At the point of selection and matching, all patterns of individuals with these premalignancy clonal controls were resident in the HMRN region and none disorders (MGUS=2193, MBL=561). To enable effect had a previous cancer registration for a haematological http://bmjopen.bmj.com/ size quantification, these patterns are compared with the malignancy.23 24 Hence, for the control cohort (in contrast baseline activity of an individually age- matched and sex- to the patient cohort) no additional health information matched (10 per patient) general population comparison outside that contained within national administrative cohort. datasets was available. Using similar methods to those previously described,23–25 associations with hospital inpatient activity (HES admitted METHODS patient care) and outpatient activity (HES outpatient Cases are from the Haematological Malignancy Research (HES- OP)) in the 5 years prior to diagnosis/pseudodiag- on September 24, 2021 by guest. Protected copyright. Network (HMRN; www. HMRN. org), a specialist UK nosis through to the 3 years after diagnosis were investi- registry established in 2004 to provide robust generalis- gated. HES inpatient data contain ICD-10 codes derived able data to inform contemporary clinical practice