Looking Beyond the Lab: Risk Factors, Survival, and Comorbidity among Individuals with Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance

Abstract

Abstract

Introduction and aims: Multiple myeloma (MM) is a haematological malignancy caused by abnormal plasma cell proliferation in the bone marrow. All MM cases are preceded by a precursor condition, monoclonal gammopathy of undetermined significance (MGUS), which does not require any treatment. Risk factors for MGUS are sex, age, pesticide exposure, and ethnicity, and studies have indicated an increased risk of MGUS in individuals with autoimmune disorders. MGUS has been associated with worse survival compared to the general population. Survival of MM has increased recently, mainly due to advances in treatment. However, MM patients typically suffer from comorbidities, which may influence survival. Parental longevity generally increases survival, but studies regarding longevity in specific diagnoses have yielded conflicting results. The impact of parental longevity on MGUS and MM remains unclear. Using population-based data, the first part (study I) investigated if parental longevity affected survival among MGUS and MM patients. The second part (study II) aimed to study the prevalence and impact of comorbidities on the survival of MM patients using the same data as in study I. The third part (study III) investigated if autoimmune diseases were associated with a diagnosis of MGUS in a screened population. Methods: In study I, we analysed parental longevity and survival in individuals with MGUS, MM, and their respective controls in Sweden, 1988-2013. All individuals diagnosed with MM in the Swedish Cancer Registry and those with MGUS in a nationwide MGUS cohort were included with four population-based controls. All individuals had a registered parent in the Swedish Multigenerational Registry. The Cox proportional hazard model evaluated the effect of parental longevity on survival, with longevity defined as exceeding 90 years of age. In study II, we investigated comorbidity and survival. All individuals registered with MM in the Swedish Cancer Registry 1990-2013 were included. Cause and date of death were identified from the Cause of Death Registry, and information on comorbidities was retrieved from the Swedish Patient Registry. A Cox model was used to analyse survival in relation to comorbidities. Study III was a cross-sectional study within the Iceland Screens Treats or Prevents Multiple Myeloma study, iStopMM, where 75,422 individuals over 40 years were screened for MGUS. Information on autoimmune disorders was gathered from the Icelandic Patient Registry. Poisson regression was used to calculate prevalence ratios (PRs) of MGUS in individuals with or without an autoimmune disease. Results: In study I, 6,812 individuals with MGUS and 19,110 controls, as well as 4,675 MM patients with 13,398 controls, were included. Parental longevity was associated with a decreased risk of death in MM and MGUS (hazard ratio (HR) 0.92; 95%

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confidence interval (CI): 0.84-0.99 and HR 0·87; 95%CI: 0.78-0.96, respectively). In study II, 13,656 patients with MM were analysed, with 54% having at least one comorbidity at diagnosis. Comorbidity increased the risk of death compared to previously healthy MM patients (HR 1.19; 95% CI: 1.14-1.25). The survival decreased with the increasing number of comorbid conditions at diagnosis, with HR 1.38 (95% CI: 1.30-1.47) for 2 comorbidities and HR 1.72 (95% CI: 1.62-1.83) for three or more comorbidities. The Charlson Comorbidity Index, CCI, had low c-statistic and area under the curve (AUC) or poor survival prediction in relation to comorbidities. In study III, 75,422 individuals were screened for MGUS, where 10,818 participants had an autoimmune disorder, of whom 599 had MGUS, with 61 a prior clinical diagnosis of MGUS. Autoimmune disorder was not associated with MGUS (PR 1.05; 95%CI: 0.97- 1.15). However, autoimmune diseases were associated with a prior clinical diagnosis of MGUS (PR 2.11; 95% CI: 1.64-2.70). Conclusions: Our findings demonstrate that host characteristics influence survival in patients with MM and MGUS. We found that a longer parental lifespan reduced the risk of death in both groups. This suggests that parental longevity, influenced by genetic and environmental factors, can have a survival advantage even in a malignant condition such as MM. In study II, we found that comorbidities are common in MM, with an increased risk of mortality with an increasing number of comorbidities. This underscores the vulnerability of MM patients at diagnosis and highlights the necessity of considering comorbidities when selecting treatment to avoid under- or over-treatment, which can negatively impact survival. In study III, we did not observe a correlation between autoimmune diseases and MGUS in a screened population. However, a clear association was found between a prior clinical diagnosis of MGUS and autoimmune disorders. This finding indicates that previous studies, not based on screened populations, were subject to ascertainment bias. Therefore, we do not recommend screening for MGUS in patients with an autoimmune disorder.

Mergæxli er illkynja blóðsjúkdómur sem orsakast af stjórnlausri fjölgun einstofna plasmafrumna í beinmerg. Forveri mergæxlis er góðkynja einstofna mótefnahækkun (monoclonal gammopathy of undetermined significance, MGUS) sem er einkennalaust ástand og þarfnast ekki meðferðar. Orsakir MGUS eru óþekktar en nokkrir áhættuþættir eru til staðar, s.s. aldur, kyn, skordýraeitur, eða kynþáttur. Fyrri rannsóknir hafa gefið til kynna aukna áhættu í tengslum við sjálfsofnæmissjúkdóma. Einstaklingar með MGUS lifa skemur en almennt þýði en lifun einstaklinga með mergæxli hefur batnað umtalsvert síðastliðin ár, þökk sé bættri meðferð. Sjúklingar með mergæxli eru hins vegar eldri og þjást af fylgisjúkdómum sem gætu haft áhrif á lifun. Langlífir foreldrar auka lífslíkur afkomenda. Rannsóknir sem skoða ákveðna sjúkdóma hafa á hinn bóginn ekki gefið einhlíta niðurstöðu og áhrif langlífra foreldra á lifun einstaklinga með mergæxli og MGUS eru óljós. Verkefninu var skipt í þrjá hluta. Markmið fyrsta hluta þess var að skoða hvort langlífi foreldra hefði áhrif á lifun einstaklinga með mergæxli og MGUS í lýðgrunduðu sænsku þýði. Í öðrum hluta verkefnisins voru áhrif fylgisjúkdóma á lifun skoðuð hjá einstaklingum með mergæxli og sömu gögn og í fyrsta hluta notuð. Í lokahluta verkefnisins voru tengsl sjálfsofnæmissjúkdóma og MGUS rannsökuð og notuð gögn úr skimunarrannsókninni, Blóðskimun til bjargar.