Multiple myeloma: family history and mortality in second primary cancers

Since cancer survival rates in general are increasing, second primary cancers (SPCs) account for an increasing proportion of the overall cancer burden. In some cancer registries they account for more than 20% of new diagnoses1. Contributing factors for SPCs may be multiple, including iatrogenic adverse effects of chemotherapy or radiation, increased surveillance and the same causes that influenced patients’ first cancers, including family history and environmental causes2,3,4. Chemotherapy and radiation induce DNA damage which increases the risk of SPCs, and therapy-associated immunosuppression could also play a role. Treatment for multiple myeloma (MM) involves intense chemotherapy and concerns about SPCs have been raised, particularly relating to the possible effects of lenalidomide and melphalan5. The impact of family history was recently shown in survivors of Hodgkin lymphoma with an excess of lung, colorectal, and breast cancers in survivors with a family history of these cancers6. The potential importance of family history is emphasized by the fact that about 50% of patients with first primary cancer have a first-degree relative diagnosed with some cancer7. This proportion was also high among patients diagnosed with MM, 61%7. The other cancers in family members were diverse; including chronic lymphocytic leukemia and colorectal and prostate cancers8,9.

In the present study we use the Swedish Family-Cancer Database, with two goals, first to assess the influence of family history on the risk of SPC, and second to estimate the influence of SPC on mortality in MM in family members7. A family history implies that the type of SPC (e.g., lung cancer) was the same cancer that was diagnosed in a parent or sibling (e.g. lung cancer).

Methods

In the Swedish Family-Cancer Database the second generation ‘offspring’ was defined as individuals born after 1931 and their patents were defined as the parental generation. Another truncation of data was caused by the start of cancer registration in Sweden in 1958. The study included 25,787 MM diagnosed from 1958 to 2015; of these 5205 were diagnosed in the offspring generation with a median age at diagnosis of 62 years. Among MM patients 360 (6.9%) were diagnosed with SPC after a median follow-up time of 4 years. Among these 360, 246 (68.3%) had a first-degree family history of any cancer.

Relative risks (RRs) were assessed with incidence rate ratios, estimated with RRs regressed over a fixed effects generalized Poisson model. RRs for SPC were obtained by comparing incidence rates for SPC X in MM patients with rates for first cancer X in the background population of the database. Family history was defined among parents and siblings. Familial RRs were estimated by comparing incidence rates between MM patients diagnosed with cancer X as SPC and having a family history of cancer X against those diagnosed with first cancer X in the population; the reference rate was the same as above. Sex, age group, calendar-period, socio-economic status, and residential areas were treated as potential confounders and were adjusted for in the regression model. Follow-up commenced from diagnosis of MM and was terminated on SPC diagnosis, emigration, death, or end of follow-up period, i.e. 2015, whichever occurred first. Confidence intervals were calculated for 5%, 1% and 0.1% level of significance10. All cancer-related deaths were stratified into MM, SPC, and other causes, including cancers defined in death certificates and non-neoplastic causes of death. Additive and multiplicative interactions of family history and risk of SPC were tested as described11.

The study was approved by the Ethical Committee of Lund University. Analyses are performed in SAS v9.4; please contact the authors for codes.

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