The Impact of Prior Malignancies on Second Malignancies and Survival in MM Patients: A Population-Based Study
Authors: Jonsdottir Gudbjorg , Lund Sigrún H. , Björkholm Magnus , Turesson Ingemar , Wahlin Anders , Hultcrantz Malin , Porwit Anna , Landgren Ola , Kristinsson Sigurdur Y 
Published: October 2019

Abstract
Background
Awareness of second malignancies in patients with multiple myeloma (MM) has been increasing during recent years. We have previously shown that second malignancies are associated with a decreased life expectancy in MM patients. Information regarding prior and second malignancies in MM is limited as these patients are often excluded from clinical trials and previously published results from other groups have been conflicting. In the present study we aimed to evaluate two hypotheses. Firstly we hypothesize that prior malignancy is a proxy for genetic instability that could be a risk factor for subsequent malignancy development in MM patients. There is limited data regarding this association in the literature and in two recent registry studies the results were inconclusive. Secondly, to further assess the clinical implication of prior malignancies in MM patients we assessed survival in these patients compared to MM patients without a history of prior malignancy.
Patients and Methods
All patients diagnosed with MM from January 1, 1973 to December 31, 2013 were identified from the Swedish Cancer Register. All prior and subsequent malignant diagnoses were identified through cross-linkage within the registry. A Cox regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) where prior malignancy was compared in MM patients who developed a subsequent malignancy and MM patients who did not. In another Cox regression model, survival was compared in MM patients with and without a prior malignancy. The same method was used to estimate if there was a dose-dependent relationship, i.e. if an increasing number of prior malignancies was associated with a poorer outcome.
Results
A total of 22,359 patients were diagnosed with MM during the study period. Of these, 2,620 (12%) patients had one or more prior malignancy diagnosis at the time of MM diagnosis and 1,243 (6%) patients developed subsequent malignancies. Among the MM patients who developed a subsequent malignancy, 148 (12%) had a prior malignancy diagnosis. Hematological malignancies were 7% of prior malignancies and 17% of subsequent malignancies. MM patients with a prior malignancy diagnosis did not have increased risk of developing a subsequent malignancy compared to MM patients without a prior malignancy (HR 1.0, 95% CI 0.9-1.2). MM patients with a prior malignancy diagnosis had a statistically significant 10% increased risk of death (HR=1.1, 95% CI 1.1-1.2, p<0.001) compared to MM patients without a prior malignancy diagnosis. MM patients with 2 or more prior malignancy diagnoses had a 20% increased risk of death (HR=1.2, 95% CI 1.1-1.4, p=0.002) compared to MM patients without a prior malignancy diagnosis (Figure).
Summary and Conclusions
In our large population-based study we found that prior malignancy negatively impacts survival in MM patients and that more than one prior malignancy decreases survival even further. Interestingly, a prior malignancy did not increase the risk of developing a subsequent malignancy in MM patients. We confirmed prior reports of solid tumors being more common than hematological malignancies, both prior and subsequent to the MM diagnosis. A prior malignancy was associated with a reduced survival in MM patients without being a risk factor for subsequent malignancies. The underlying explanation for this is probably multifactorial, and could include reduced dose intensity of chemotherapy, complications from treatment, or that MM that develops after another malignancy might be biologically different. Given the increase of cancer survivors in general, our findings are of importance both for the individual patients and their families as well as for the treating physician.
Figure Survival in MM patients without a prior cancer diagnosis compared to MM patients with one and two or more prior cancer diagnoses Figure. Survival in MM patients without a prior cancer diagnosis compared to MM patients with one and two or more prior cancer diagnoses

Disclosures
Landgren: Takeda: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Medscape: Employment, Other: Chairman for Medscape Myeloma Program; Amgen: Speakers Bureau; Celgene: Speakers Bureau; BMS: Speakers Bureau.