Second Primary Malignancies Among Patients with Multiple Myeloma

Introduction. Treatment for multiple myeloma (MM) has undergone significant transformation in the past decade with the introduction of novel therapeutic agents, including proteasome inhibitors (PI), immunomodulatory imides (IMiD) and monoclonal antibodies (mAb), leading to significant improvements in drug tolerability, treatment response and overall survival. As overall survival improves, patients with MM are at increased risk of developing second primary malignancies. Therefore, we evaluated the incidence of second primary malignancies among patients with MM. Methods. Using data from 30,630 1-year survivors of MM reported to 13 cancer registries that constitute the Surveillance, Epidemiology, and End Results (SEER) program (1992-2015; median survival time, 4.5 years), we calculated standardized incidence ratios (SIR) for all second primary malignancies, any solid and any hematologic malignancy and cancer sites among patients with MM, stratified by calendar year of first primary diagnosis consistent with advances in treatment for MM (1992-1999, 2000-2007, 2008-2015). Individual treatment data were unavailable. Excess absolute risk (excess cancer risk per 10,000 person-years) was calculated as ([observed cancers minus expected cancers]/person-years) multiplied by 10,000. Hazard ratios were calculated using Cox proportional hazards adjusted for confounders. Analyses were conducted using SAS v.9.4. Results. Overall, among 30,630 1-year survivors of first primary MM, the standardized incidence of any second primary malignancy was significantly increased (n=1,962; SIR=1.15, 95% confidence interval [CI], 1.10-1.20; P<0.0001) and SIRs were elevated in each of the three calendar periods (1992-1999, SIR=1.14; 2000-2007, SIR=1.11; 2008-2015, SIR=1.22). Of all the second primary malignancies, the incidence of any solid tumor was increased (n=1,584; SIR=1.05, 95% CI 0.99-1.10; P=0.09), albeit not significantly, with SIRs for specific solid tumor sites ranging from 0.80 to 2.23. In contrast, the incidence of any hematologic malignancy overall was significantly increased (n=317; SIR=2.28, 95% CI 2.03-2.54; P<0.0001) with the largest SIRs observed for any leukemia (SIR=5.86, 95% CI 4.91-6.94; P=<0.0001) and SIRs for leukemia subtypes ranging from 2.07 to 14.87. The SIR for any lymphoma was also increased but to a lesser extent (SIR=1.57, 95% CI 1.35-1.82; P<0.0001). Notably, SIRs for any leukemia decreased over the three time periods (1992-1999, SIR=6.40; 2000-2007, SIR=5.77; 2008-2015, SIR=5.51) whereas SIRs for any lymphoma increased (1992-1999, SIR=1.21; 2000-2007, SIR=1.60; 2008-2015, SIR=1.81) leading to an excess absolute risk of any hematologic malignancy of 1.5 per 10,000 person-years in the latest calendar period. No differences were observed by sex or ancestry. Discussion. We confirm that MM patients are at increased risk of second primary malignancies, and particularly other blood cancers. The transposition of leukemia and lymphoma incidence over time may reflect the effect of treatment changes in recent years. Additional studies, which include individual treatment data and longer follow up time from large and diverse populations, are required to further define these relationships. Disclosures No relevant conflicts of interest to declare.

Death by suicide, other externally caused injuries and cardiovascular diseases within 6 months of cancer diagnosis (J-SUPPORT 1902)

Objective To conduct the first national population-based study in Japan to characterize risks of death by suicide, other externally caused injuries and cardiovascular diseases within 6 months of cancer diagnosis. Methods Cancer patients diagnosed between 1 January and 30 June 2016 and registered in the National Cancer Registry in Japan were followed up until death or 6 months after diagnosis. We calculated standardized mortality ratios and excess absolute risks per 10 000 person-years for death by suicide, other externally caused injuries and cardiovascular diseases compared with the Japanese general population. Results Of 546 148 patients with cancer (249 116 person-years at risk), we observed 145 suicides, 298 deaths due to other externally caused injuries and 2366 cardiovascular deaths during the follow-up period. Standardized mortality ratios within 6 months were 2.68 for suicide (95% confidence interval, 2.26–3.16; excess absolute risk, 3.65), 1.49 for other externally caused injuries (95% confidence interval, 1.32–1.67; excess absolute risk, 3.92) and 1.38 for cardiovascular diseases (95% confidence interval, 1.33–1.44; excess absolute risk, 26.85). Risks were highest during the first month after cancer diagnosis (standardized mortality ratios: suicide, 4.06 [95% confidence interval, 2.90–5.53]; other externally caused injuries, 2.66 [95% confidence interval, 2.17–3.12] and cardiovascular diseases, 2.34 [95% confidence interval, 2.18–2.51]). Conclusions The first 6 months, and especially the first month, after cancer diagnosis were found to be a critical period for risks of death by suicide, other externally caused injuries and cardiovascular diseases. Our findings suggest that oncologists need to evaluate suicidal and cardiovascular risks of patients immediately after cancer diagnosis and provide preventive interventions.

Quantifying Donor Effects on Transplant Outcomes Using Kidney Pairs from Deceased Donors

Background and objectivesIn kidney transplantation, the relative contribution of donor versus other factors on clinical outcomes is unknown. We sought to quantify overall donor effects on transplant outcomes for kidney donations from deceased donors.Design, setting, participants, & measurementsFor paired donations from deceased donors resulting in transplants to different recipients, the magnitude of donor effects can be quantified by examining the excess of concordant outcomes within kidney pairs beyond chance concordance. Using data from the Organ Procurement and Transplantation Network between the years 2013 and 2017, we examined concordance measures for delayed graft function, death-censored 1-year graft failure, and death-censored 3-year graft failure. The concordance measures were excess relative risk, excess absolute risk, and the fixation index (where zero is no concordance and one is perfect concordance). We further examined concordance in strata of kidneys with similar values of the Kidney Donor Profile Index, a common metric of organ quality.ResultsIf the transplant of the kidney mate resulted in delayed graft function, risk for delayed graft function was 19% higher (95% confidence interval [95% CI], 18% to 20%), or 1.76-fold higher (95% CI, 1.73- to 1.80-fold), than baseline. If a kidney graft failed within 1 year, then the kidney mate’s risk of failure was 6% higher (95% CI, 4% to 9%), or 2.85-fold higher (95% CI, 2.25- to 3.48-fold), than baseline. For 3-year graft failure, the excess absolute risk was 7% (95% CI, 4% to 10%) but excess relative risk was smaller, 1.91-fold (95% CI, 1.56- to 2.28-fold). Fixation indices were 0.25 for delayed graft function (95% CI, 0.24 to 0.27), 0.07 for 1-year graft failure (95% CI, 0.04 to 0.09), and 0.07 for 3-year graft failure (95% CI, 0.04 to 0.10). Results were similar in strata of kidneys with a similar Kidney Donor Profile Index.ConclusionsOverall results indicated that the donor constitution has small or moderate effect on post-transplant clinical outcomes.

The Risk of Radiogenic Second Cancer Based on Differential DVH: Central Nervous System Malignant Tumor in Children

Objectives: To quantify the risk of radiogenic second cancer in pediatric patients receiving hippocampal-sparing craniospinal irradiation either with intensity-modulated radiation therapy or tomotherapy due to the development of a solid second cancer after radiotherapy using the concept of excess absolute risk. Methods: Computed tomography images of 15 pediatric patients who received craniospinal irradiation treatment were selected for this study. For each case, intensity-modulated radiation therapy and tomotherapy plans were computed. Then, the dosimetry parameters were analyzed. Differential dose–volume histograms were generated, and the excess absolute risks were calculated for each plan of each patient. Results: The tomotherapy group was superior to the intensity-modulated radiation therapy group in target area homogeneity index ( P < .001). Tomotherapy offered greater hippocampal sparing than intensity-modulated radiation therapy in terms of D 2% (15.66 vs 23.05 Gy, P < .001) and Dmean (9.79 vs 20.29 Gy, P < .001). Tomotherapy craniospinal irradiation induced a much higher risk than intensity-modulated radiation therapy craniospinal irradiation to the thyroid and lungs (excess absolute risk: thyroid 28.7 vs 26.9 per 10 000 PY, P = .010; lung 20.5 vs 18.9 per 10 000 PY, P = .003). Both techniques conferred a higher risk to the stomach, but there was little difference. In addition, the 2 plans induced less carcinogenic risk to the liver (excess absolute risk 4.2 vs 4.0 per 10 000 PY, P = .020). Conclusions: The tomotherapy plan has obvious advantages in the protection of the hippocampus for children undergoing craniospinal irradiation treatment. Tomotherapy increased the risk of radiogenic second cancer in organ at risk, and therefore, it is imperative to take the risk factor into consideration in the formulation of treatment protocols.

Second Cancer Incidence Among Chronic Lymphocytic Leukemia (CLL) Patients: A French Population-Based Study

Introduction. The risk of developing a second primary cancer (SPC) is increased in patients with CLL. The mechanisms explaining this association could be related to lifestyle, environment, host factors or interactions or other influences. We conducted an epidemiological study based on 10 French registries and evaluated the risk of developing SPC in patients with CLL. Methods. Data from French population-based registries were used to establish a cohort of all patients diagnosed with a first cancer between 1989 and 2004 and followed-up until December 31, 2007. The person-year approach was used to estimate Standardized Incidence Ratios (SIRs) and Excess Absolute Risks (EARs) of metachronous SPC. Multivariate Poisson regression modules were then used to model SIRs and EARs separately by gender, adjusting for age, year of diagnosis, follow-up and first cancer site. All patients with CLL did not have HIV/AIDS-related disease. Results. Among 288,967 patients, 21,226 patients (7.5%) developed SPC. Among 4,148 CLL patients (Male: 2,336, Female: 1,812, median age: 70 years), 479 patients (11.5%) developed SPC after a median time of 54 months (2-199). EARs of SPC are different between male and female. In male, localizations of SPC are lung, bronchus and trachea, colorectum, colon, stomach and Hodgkin's disease. Their respective EARs are shown in table 1 and no excess absolute risk was observed for 24 other localizations. In female, localizations of SPC are rectum, stomach and melanoma of skin. Their respective EARs are shown in table 2 and no excess absolute risk was observed for 21 other localizations. Table 1: Excess Absolute Risks (EARs) of second primary cancer (SPC) for male Male SIR SIR IC95% EAR EAR IC95% Lung, bronchus and trachea 2.08 1.61 2.64 26.1 14.8 39.8 Colorectum 1.54 1.15 2.03 13.2 3.7 25.1 Colon 1.63 1.11 2.3 9.3 1.6 19.2 Stomach 1.91 1.07 3.15 5.4 0.4 12.7 Hodgkin's disease 8.71 2.34 22.29 2.7 0.5 7.4 Table 2: Excess Absolute Risks (EARs) of second primary cancer (SPC) for female Female SIR SIR IC95% EAR EAR IC95% Rectum 2.17 1.19 3.64 6.7 1.1 15.2 Stomach 3.04 1.45 5.58 6 1.3 13.4 Melanoma of skin 2.59 1.04 5.34 3.8 0.1 10.4 Conclusion. The risk for developing SPC after CLL is increased for male and female, especially solid cancers. Except Hodgkin's disease for male patients, there is no increase for other malignant hematological diseases, including acute leukemia and myelodysplastic syndrome. CLL survivors face a high risk of new malignancies and the excess risk of SPC increases with follow-up. As the SPC risk is closely tied to patient's characteristics, a personalized surveillance is required to allow optimal SPC prevention and early detection strategies. Disclosures No relevant conflicts of interest to declare.

Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study

The contribution of specific cancer therapies, comorbid medical conditions, and host factors to mortality risk after pediatric Hodgkin lymphoma (HL) is unclear. We assessed leading morbidities, overall and cause-specific mortality, and mortality risks among 2742 survivors of HL in the Childhood Cancer Survivor Study, a multi-institutional retrospective cohort study of survivors diagnosed from 1970 to 1986. Excess absolute risk for leading causes of death and cumulative incidence and standardized incidence ratios of key medical morbidities were calculated. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of risks for overall and cause-specific mortality. Substantial excess absolute risk of mortality per 10 000 person-years was identified: overall 95.5; death due to HL 38.3, second malignant neoplasms 23.9, and cardiovascular disease 13.1. Risks for overall mortality included radiation dose ≥ 3000 rad ( ≥ 30 Gy; supra-diaphragm: HR, 3.8; 95% CI, 1.1-12.6; infradiaphragm + supradiaphragm: HR, 7.8; 95% CI, 2.4-25.1), exposure to anthracycline (HR, 2.6; 95% CI, 1.6-4.3) or alkylating agents (HR, 1.7; 95% CI, 1.2-2.5), non–breast second malignant neoplasm (HR, 2.6; 95% CI 1.4-5.1), or a serious cardiovascular condition (HR, 4.4; 95% CI 2.7-7.3). Excess mortality from second neoplasms and cardiovascular disease vary by sex and persist > 20 years of follow-up in childhood HL survivors.