Incidence Of Second Primary Malignancies Research Articles

Exploring the risk of second primary malignancies in laryngeal cancer survivors: insights from the SEER database.

We intended to investigate the risk for second primary malignancy (SPM) development in Laryngeal Cancer (LC) survivors. We conducted a population-based analysis of SPM risk using the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database. Data of selected LC survivors from the SEER database between 2000 and 2020 were examined. Standardized Incidence ratios (SIRs) for SPM development were calculated, followed by detailed stratification according to anatomical site and different latency periods. A total of 8413 SPMs were observed in our extracted cohort. The collective standardized incidence of SPMs was 2.12 (95% CI 2.07-2.17) compared to the US population, with an absolute excess risk (AER) of 201.73 per 10,000 individuals. The highest SPM risks were observed in patients with young age at diagnosis, females, and American Indians/Alaska natives. Increased SPM risks were reported in patients receiving all modalities of treatment including surgery, chemotherapy, and radiotherapy. Most SPMs were detected in solid organs such asthe lungs and bronchus, oral cavity and pharynx, and prostate. The highest increased risks of developing SPMs were observed in Trachea, larynx, oral cavity and pharynx, lung and bronchus, and esophagus. The risk of SPMs in LC survivors was significantly increased compared to the general US population. Accordingly, a more impactful cancer surveillance strategy for LC patients should be implemented.

Association between postoperative radiotherapy for young-onset non-small cell lung cancer and risk of second primary malignancies ----Comparative study.

The most common form of therapy for non-small cell lung cancer (NSCLC) in early stage is surgery-based combination therapy, including radiotherapy and immunotherapy. However, postoperative radiotherapy (PORT) of cancer is correlated with increasing risk of second primary malignancy (SPM), especially young-onset cancer cases. We aimed to quantify the risks of SPM associated with PORT treatment for young‑onset NSCLC in early stage. We screened for SPM that developed over 5 years since the diagnosis of NSCLC. Using the data from the Surveillance, Epidemiology and End Results database, PORT-correlated risks were estimated with multivariate Logistic regression analysis. Moreover, Fine-Gray's competing risk regression analysis was used to calculate the cumulative incidence of SPMs. Among the 30308 young-onset NSCLC patients in early stage undergoing surgery, a total of 3728 patients have received PORT. Logistic regression analyses showed that PORT showed substantial correlation with elevated risks of second solid malignancies (RR = 1.31; 95% CI: 1.17-1.46), lung cancer (RR=1.23; 95% CI: 1.07-1.42), breast cancer (RR=1.74; 95% CI: 1.16-2.74) and colon and rectum cancers (RR=1.37; 95% CI: 1.07-2.06) as well as a negligible risk of second hematologic malignancies (RR = 1.15; 95% CI: 0.82-1.67). The cumulative incidence of SPMs revealed similar findings. Higher RR was obtained in NSCLC patients aged 60 to 69 years (RR = 1.33), in white race (RR = 1.36), diagnosed in 1975-2000 (RR = 1.23) and 2001-2015 (RR = 1.40), or diagnosed with lung adenocarcinoma (RR = 1.55). PORT for young-onset NSCLC in early stage was correlated with elevated risks of SPMs (lung cancer, breast cancer as well as colon and rectum cancers), supporting the need for long-term surveillance of these patients.

Incidence, risk and prognosis of second primary malignancy of patients with gastric adenocarcinoma

Due to the long-term low survival rates of gastric adenocarcinoma (GAC) patients, the occurrence and prognosis of second primary malignancies (SPMs) are often underreported and overlooked as a significant concern.To date, only a few studies have addressed this issue in the context of GAC. These studies, however, are limited by their small patient cohorts and lack of substantial, meaningful findings. Our study aims to fill this gap by investigating the incidence, risk factors, and prognostic significance of SPMs among GAC survivors. Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we analysed data from patients diagnosed with GAC between 2000 and 2020. The study employs the standardized incidence ratio (SIR) to assess the relative risk of SPMs, competing risk regression to identify risk factors for SPM development after GAC, and Kaplan-Meier and COX regression analyses for survival outcomes. Out of 44,041 GAC patients analyzed, 2,032 (4.3%) developed SPMs, with a median latency period of 36 months. The incidence of SPMs was significantly higher in GAC patients (SIR 1.36, 95% CI 1.32-1.4, EAR 53.57) compared to the general population. Key factors including older age, sex, tumor grade, summary stage, and history of surgical and radiation therapy were related to the higher risk of developing SPMs following GAC. Interestingly, GAC patients without SPMs exhibited poorer overall survival compared to those with SPMs. Age, summary stage, and surgical history were identified as independent prognostic factors for GAC patients with SPMs. This comprehensive analysis underscores the necessity of vigilant monitoring and tailored follow-up for SPMs in GAC survivors, highlighting the study's contribution to enhancing GAC survivors care strategies.

Secondary primary malignancies among patients with GU cancer.

98 Background: The risk of secondary primary malignancies (SPM) among the survivors of GU cancer is not well-established. In this study, we attempt to describe the patterns of SPMs in patients diagnosed with GU cancers. Methods: The Surveillance, Epidemiology, and End Results (SEER) database (SEER*Stat 8.4.2) was searched to obtain data on the incidence of SPM in adult patients (age >18 years) diagnosed with GU cancers, including prostate, renal, and bladder cancer. Standardized incidence ratios (SIRs) with a 95% confidence interval (CI) were calculated. SIR was defined as the observed SPMS from each category divided by the expected number of SPMs in the age-matched US population for the same period. The data was further stratified by age (<50y, 50-70y, >70y), race (White, Black, Asian/Pacific Islander), ethnicity (Hispanic, non-Hispanic), chemotherapy, and radiotherapy exposure. Results: A total of 1,041,217 patients were included in this analysis. In patients diagnosed with GU cancer, the incidence of overall SPM was 11%. Particularly, patients with GU cancers were observed to have a high incidence of Endocrine system SPM (1.52; 1.45-1.59), and urinary system SPM (1.51; 1.49-1.53) These results were consistent by different sociodemographic groups. In patients diagnosed with prostate cancer, the incidence of thyroid SPM was increased (1.31; 1.23-1.39). Particularly, prostate cancer patients treated with radiation therapy had increased incidence rates of SPM in the peritoneum, omentum and mesentery (1.57; 0.79-2.81) and urinary bladder (1.36;1.32-1.40) was higher as compared to those with no exposure to radiation therapy (1.11;1.08-1.13 and 1.03;1-1.06 respectively). Bladder cancer patients had an overall increased incidence of SPM in the esophagus (1.21; 1.08-1.35), lung, bronchus, trachea, and other respiratory organs (1.97;1.92-2.01), prostate (3.50;3.4-3.6) and kidney (1.86;1.76-1.97). A higher incidence of renal pelvis, ureter and other urinary organ SPM (11.08;10.48-11.07) was also notable in this population. Similarly, kidney cancer patients had a higher incidence of the endocrine system (3.00;2.74-3.27), prostate (1.24;1.2-1.29) and bladder 1.78;1.68-1.79 SPMs. Conclusions: This population-based study shows an increased risk of SPM development in GU cancer survivors compared to the general population. Clinicians should keep a high index of suspicion for SPMs and initiate appropriate workups at early warning signs.

Assessment of second primary malignancies among treated and untreated patients with chronic lymphocytic leukemia using real-world data from the USA.

Aim: Improved management of chronic lymphocytic leukemia (CLL) has resulted in a growing population of CLL survivors; these patients have a higher risk of developing second primary malignancies (SPMs) versus the general population. This retrospective cohort study aims to assess the timing, frequency, incidence and types of SPMs in treated and untreated patients with CLL in the USA, using the Surveillance, Epidemiology, and End Results (SEER) Medicare database, which links a nationally representative cancer registry with Medicare claims data. Patients & methods: Patients aged ≥66years with newly diagnosed CLL between 1January2010 and 31December2016, who were enrolled in Parts A and B of Medicare for ≥12months pre-diagnosis of CLL were selected from the database. Patients were assessed for ≥36months until the end of continuous enrollment in Medicare Parts A, B and D, a switch to a health maintenance organization, death, or end of the study period (December2019). Results: Of 3053 patients included in the analyses, 620 (20.3%) were treated and 2433 (79.7%) were untreated within 36months of diagnosis. Overall, 638 (20.9%) patients developed a SPM, 26.8% of patients in the treated cohort and 19.4% of patients in the untreated cohort. The most common SPMs for both cohorts were squamous cell carcinoma and acute myeloid leukemia. Among the 166 treated patients who developed a SPM, a greater proportion developed their first SPM after treatment initiation versus those who developed their first SPM prior to treatment initiation (p<0.001). A significantly lower percentage of patients who received targeted therapy developed a SPM (p<0.05) versus patients treated with anti-CD20+ chemotherapy. Conclusion: Findings indicate that treatment type and timing can affect SPM development in patients with CLL. Combined with previous findings, this can help inform best practices in monitoring for SPM in patients with CLL.

Lifetime risks of second primary malignancies after pediatric Hodgkin lymphoma and non-Hodgkin lymphoma

ObjectivesSurvivors after pediatric Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) are with lifetime risk for second primary malignancy (SPM). This necessitates a thorough analysis to better understand the potential long-term health implications for these individuals.MethodsWe used a US-wide population-based cancer registry data to quantify the SPM risk and identify its incidence patterns among pediatric lymphoma patients.ResultsWe observed 4.74-fold (95% CI 4.27–5.25) and 3.40-fold (95% CI 2.78–4.10) increased risks of SPM in survivors after pediatric HL and NHL, respectively. Through over 40 years’ follow-up, the cumulative incidence of SPM for pediatric lymphoma was persistently increasing, and here we firstly report the high 40-year cumulative incidence rates of SPM, 22.2% for HL and 12.6% for NHL, suggesting that SPM accounts for a great proportion of deaths among survivors. Of 6805 pediatric lymphomas, 462 (6.36%) developed a SPM, especially second breast and thyroid cancer, followed by hematologic neoplasms including leukemia and NHL. The competing risk analysis demonstrated gender, lymphoma subtype and radiotherapy were significantly associated with SPM. Different risk patterns of SPM were identified between pediatric HL and NHL. Chemotherapy accelerated SPM development but did not increase its incidence risk.ConclusionOverall, patients after pediatric lymphoma can be with high lifetime risk of SPM, and more attention should be paid to SPM-related signs for early detection and intervention.

Survival benefit of surgery for second primary esophageal cancer following gastrointestinal cancer: a population-based study

BackgroundThe incidence of second primary malignancy is increasing. However, although there is some information on second primary esophageal cancer (SPEC) itself, there is no study or guideline on the use of surgery for SPEC after gastrointestinal cancer (SPEC-GC). Thus, this study aimed to gather evidence for the benefits of surgery by analyzing a national cohort and determining the prognostic factors and clinical treatment decisions for SPEC-GC. MethodsData for patients with SPEC-GC were obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2019. The prognostic factors of SPEC-GC were investigated by stepwise Cox proportional hazards regression and Kaplan-Meier analyses for overall survival and cancer-specific survival. ResultsA total of 8308 patients with SPEC were selected, including 582 patients with SPEC-GC. Multivariate analysis revealed that surgery, year of diagnosis, scope of regional lymph node surgery, tumor differentiation grade, SEER historic stage, and triple therapy were significant predictors of survival outcomes (P < .05). Surgery seemed to improve the prognosis of patients with SPEC-GC significantly compared with no surgery and chemoradiotherapy (P < .001). ConclusionsSurgery should be considered as the main treatment for SPEC-GC. Surgery, year of diagnosis, scope of regional lymph node surgery, tumor differentiation grade, SEER historic stage, and triple therapy were found to be independent prognostic factors for these patients. These factors should be considered in the clinical diagnosis and treatment of SPEC-GC.

Once in a Blue Moon: Second Primary P16-Negative Tonsillar Carcinoma after Temporal Bone Squamous Cell Carcinoma

Second primary malignancy (SPM) is a well-known long-term cause of mortality in head and neck squamous cell carcinoma (HNSCC). The high incidence of head and neck SPM after HNSCC is related to field cancerisation, tobacco and alcohol exposure. Early detection of head and neck SPM is paramount to allow appropriate treatment and have better functional and survival outcomes. Further genomic study is warranted for better understanding about the risk, outcome and to improve survival of SPM. We reported the first case of second primary tonsillar carcinoma that was presented sixteen years after diagnosis of temporal bone squamous cell carcinoma (SCC) in a non-smoker patient. We highlighted the importance of having a long-term surveillance follow up in HNSCC, not only to look for locoregional recurrence and metastases but also to asses for SPM.

Incidence of Second Primary Malignancies in Medicare-Insured Patients in the US with Triple-Class Exposed Relapsed/Refractory Multiple Myeloma

Background As therapeutic advances have increased life expectancy for patients (pts) with relapsed/refractory (RR) multiple myeloma (MM), second primary malignancies (SPMs) have become an increasingly important safety consideration. Prior studies have demonstrated that treatment with alkylators, autologous stem cell transplantation, and immunomodulatory drugs (IMiDs), specifically lenalidomide, are associated with increased risk of SPM. Pts who are triple-class exposed (TCE), defined as prior exposure to an IMiD, a proteasome inhibitor (PI), and an anti-CD38 monoclonal antibody (mAb), represent an increasingly large subgroup of RRMM pts. The objective of this study was to describe the incidence and characteristics of SPMs in Medicare-insured pts with TCE RRMM initiating a new line of therapy (LOT). Methods Adult pts with an incident diagnosis (Dx) of MM (≥2 outpatient Dx 30-365 days apart OR ≥1 inpatient Dx AND 6 months of continuous eligibility prior to initial Dx) during the study period (Nov 14, 2006-Dec 31, 2020) who were TCE (≥1 claim each for an IMiD, a PI, and an anti-CD38 mAb) were selected from the Center for Medicare and Medicaid Services Chronic Conditions Data Warehouse (TCE pts were assumed to have RRMM based on exposure). The first LOT after TCE was defined as the index LOT and the associated date of initiation was defined as the index date. Pts with SPMs prior to the index date were excluded. SPMs were identified based on having ≥2 outpatient Dx of SPM (of the same cancer type) 30-365 days apart OR ≥1 inpatient Dx of SPM. Dx of SPM included Dx of invasive malignancies or myelodysplastic syndromes (MDS), excluding MM, Waldenström macroglobulinemia, plasma cell leukemia, non-melanoma skin cancers, or primary bone malignancies that were preceded by a Dx of bone metastases. The incidence of SPM was calculated per 100 person years (PY) of follow-up, considering only the first SPM for each pt. Cumulative incidence of SPM (with death as a competing risk) was also calculated. For pts who experienced SPM, overall survival (OS) and measures of healthcare resource utilization (HRU) and costs (in 2021 USD, on a per patient per month [PPPM] basis) were calculated. Results A total of 3,088 TCE RRMM pts were identified, of whom 989 had no evidence of SPM prior to the index date (Table). These 989 pts had a mean age of 75.2 years, a mean of 2.9 prior LOTs and a mean of 3.1 years since MM Dx. Over a median follow-up of 7.1 months, 166 pts (19.3 per 100 PY) experienced an SPM, including 93 (10.8 per 100 PY) with a solid tumor and 73 (8.5 per 100 PY) with a hematologic malignancy. The latter included 27 (3.1 per 100 PY) with acute myeloid leukemia (AML) and 18 (2.1 per 100 PY) with MDS. The cumulative incidence of SPM (95% confidence interval [CI]) at 12, 24, and 36 months was 15.2% (12.8-17.9%), 19.7% (16.8-22.8%), and 23.8% (20.2-27.6%), respectively (Figure). Median (95% CI) OS from SPM Dx was 7.9 months (5.4-10.9). Kaplan-Meier estimated probability of survival (95% CI) at 12, 24, and 36 months following SPM Dx was 40.3% (31.6-48.9%), 27.6% (18.6-37.4%), and 9.5% (2.1-23.8%), respectively. Mean (95% CI) total costs after SPM were $22,514 ($19,105-$26,404) PPPM. Conclusions The incidence of SPM in Medicare-insured TCE RRMM pts is high. Many SPMs in these pts, such as AML, are life-threatening and may interfere with or prevent MM treatment. Pts with SPMs have poor survival and high HRU and costs. With increasing OS for RRMM pts due to therapeutic advancements, there is a need for effective treatments that are not associated with increased risk of SPMs.

Incidence of Secondary Primary Malignancies after Long-Term Follow up of Multiple Myeloma Patients Treated with Autologous Stem Cell Transplantation - Report from Croatian Cooperative Group for Hematologic Malignancies (KroHem)

Background: Autologous stem cell transplantation (ASCT) after induction treatment is standard of care for multiple myeloma (MM) for the last 30 years. Two transplantations up-front (so-called tandem transplant) were standard of care for all MM patients. With the use of new antimyeloma agents (such as proteasome inhibitors, immunomodulators and especially monoclonal antibodies) this approach has changed and tandem transplant is now reserved mainly for patients with high-risk disease, defined by revised international staging system (R-ISS). There have been reports which cast further doubts on the value of the more aggressive tandem ASCT approach, as well as reports suggesting higher incidence of secondary primary malignancies (SPM) after high dose therapy and ASCT. Aims: To describe long-term outcomes of MM patients treated with ASCT (single, delayed, and tandem) and the rate of secondary primary malignancies. Methods: a retrospective analysis of outcomes of 577 MM patients who underwent 865 ASCT procedures between 1993 and 2017 was performed. Data were collected from 3 transplant centres and 9 other haematological centres in which MM patients were treated pre- and post-transplant. During that period treatment strategies changed significantly from single to tandem to salvage second ASCT. Results: there were 577 patients included. Median age at first transplant was 58 years (range 22 - 74). There were 295 female and 282 male patients. 346 patients received VAD (vincristine, doxorubicin, dexamethasone) and 231 received bortezomib and/or thalidomide (PI/IMiD) based regiments as induction therapy. All patients received high dose melphalan for pretransplant conditioning, 32 in combination with total body irradiation. Tandem ASCT (defined as second transplantation performed within 6 months after the first) was performed in 226 patients, single ASCT in 262 and salvage second (after relapse and/or progression) in 89 patients. Median overall survival (OS) for the entire group is 81.9 months and median progression free survival (PFS) 38.9 months. Tandem ASCT in comparison to single and second salvage transplantation resulted in statistically significant better OS (115 vs. 83 vs. 67 months respectively, p &amp;lt; 0.0001) and PFS (48 vs. 32. vs. 28 months respectively, p &amp;lt; 0.0001). There was no difference in outcomes regarding type of induction therapy, VAD vs. PI/IMiD based: median OS was 83 vs. 80 months, respectively (p=0.39) and median PFS was 39 vs. 38 months, respectively (p=0.15). 17.6% percent of patients who were treated with tandem ASCT are progression-free more than 10 years after the procedure while 10-year OS is 31.9%. 51 patients (8.8%) developed secondary malignancies (SPM). Most common SPM were lung carcinoma (10 patients), colorectal carcinoma (7 patients), myelodysplastic syndrome/acute myeloid leukaemia (6 patients), breast carcinoma (4 patients) and melanoma (4 patients). Of those 19 died due to SPM (3% of the entire patient group). There was no correlation between number of ASCT and SPM (p=0.87). Conclusion: in our group of patients tandem ASCT resulted in superior OS and PFS in comparison to single and/or salvage ASCT. Interestingly, we did not observe benefit of new drugs (PI/IMiD) in induction therapy regarding outcomes. This peculiar result might be due to rather late availability of these drugs in front line settings (bortezomib and thalidomide since 2015) and time period taken for analysis (up to 2018). SPM rate was similar to other reports and did not show significant correlation with number of ASCT. More than 15% of patients treated with tandem ASCT experienced very prolonged PFS and almost 32% had OS longer than 10 years.

Longitudinal Screening of Mutant Hematopoietic Progenitor Cells (HPC) in Multiple Myeloma (MM) and Its Association with Secondary Primary Malignancies (SPM)

Background: The incidence of SPM in transplant eligible MM patients (pts) receiving lenalidomide maintenance is ≥ 12% and is associated with inferior overall survival (OS). Recent evidence suggests that while clonal hematopoiesis does not increase the risk of SPM, specific TP53 mutant HPC may expand under lenalidomide treatment and give rise to therapy related myeloid neoplasms and acute lymphoblastic leukemia. Genetic screening may facilitate personalized treatment to minimize the risk of SPM. However, there are no longitudinal studies in purified HPC to inform on the evolution of specific gene mutations and its association with clinical outcomes. Aim: Analyze the mutational landscape of HPC at diagnosis and throughout lenalidomide based regimens. Methods: This study included 335 pts: 43 with high risk smoldering MM, 223 transplant eligible and 69 ineligible active MM respectively enrolled in the CESAR, GEM2012MENOS/GEM2014MAIN and CLARIDEX clinical trials. Of the 335 pts analyzed at diagnosis, 60 were further investigated after induction, 30 at day 100 after autologous transplant (ASCT) and 47 during maintenance. Two or more studies were available throughout treatment in 36 pts. Fluorescence activated cell sorting of CD34+ HPC was performed in a total of 500 bone marrow aspirates. DNA was analyzed with a panel of 55 genes recurrently mutated in myeloid neoplasms. Sequencing depth was &amp;gt;1000x in 95% of nucleotides. Criteria to filter out included synonymous, intronic, invalid-transcript, 5'UTR, panel error and single nucleotide polymorphisms. The criteria to filter in was a AMP/ACMG classification of uncertain significance, likely pathogenic or pathogenic. Only the latter two were included in downstream analysis. Results: HPC from 184 of the 335 (55%) pts were mutated. The frequency in high-risk smoldering MM, transplant eligible and ineligible active MM was 46%, 26% and 35%, respectively. The genes more frequently mutated were DNMT3A (n=94, 52%), TP53 (n=29, 16%) and TET2 (n=28, 15%). The median variant allele frequency was 4.9, 7.5 and 7.0, respectively. In a pt-paired analysis between diagnosis and induction, 8 mutations were present in both time points, 25 became undetectable and 22 were acquired during treatment. The latter (eg, PPM1D and SF3B1) were observed in 14 of the 60 (23%) pts. In the 30 pts with paired samples at diagnosis and at day 100 after ASCT, 4 mutations were present in both time points, 48 became undetectable and only 3 were acquired during treatment ( ATRX, MPL and SAMDL9). Thus, the frequency of mutant HPC was higher at diagnosis vs ASCT (23% vs 5%, P &amp;lt;.001). In a pt-paired analysis between diagnosis and maintenance, 13 mutations were present in both time points, 12 became undetectable and 30 were acquired during treatment. The latter (eg, PPM1D and SF3B1) were observed in 24 of the 47 (51%) pts screened at both time points, and after a median of 5 years since diagnosis. With a median follow-up of 6 years, 17 of the 335 (5%) pts developed SPM. Mutant HPC were detected in 13 of the 17 pts. Accordingly, presence of mutant HPC was associated with a 2-fold increased risk of SPM (OR: 2.3; P = .03). Of the 13 pts, 3 showed mutations at diagnosis and in 8 these emerged during maintenance. The only case developing a myeloid neoplasm had a TP53 mutation present during maintenance that was undetectable at diagnosis. Pts with mutant vs non-mutated HPC at diagnosis showed similar OS (6y rates of 86% and 81%, respectively; P =.46). Similarly, there were no differences in OS of pts with emerging mutations vs those without mutant HPC after treatment (6y rates of 85% and 83%, respectively; P =.65). Specific mutations in DNMT3A, TP53 and TET2 and were not associated with inferior OS. Conclusions: To our knowledge this is the first study analyzing the mutational landscape of purified HPC throughout lenalidomide based regimens in high risk smoldering MM as well as transplant eligible and ineligible active MM. Deep sequencing of CD34+ HPC uncovered that the frequency of mutations is similar between precursor and malignant disease, and that TP53 is amongst the top mutated genes. There was considerable volatility with presence of both transient and emerging mutations throughout treatment. Importantly, the detection of mutant HPC was associated with increased risk of SPM without differences in survival. Thus, this study supports the longitudinal screening of HPC for the identification of patients at risk of developing SPM.

Incidence of Second Primary Malignancies in Patients with AL Amyloidosis and the Impact of Disease Stage and Therapies

AL amyloidosis is a clonal disease, characterized by the production of light chains from a usually small or modest in size plasma or B-cell clone. Early mortality due to severe organ involvement is the most ominous complication, long term sequalae, associated with organ involvement resulting in end stage dysfunction occurs but other long-term complications due to therapy or immunosuppression are often neglected. The treatment of AL amyloidosis is based on the elimination of the clone with the use of chemotherapy (including high dose melphalan) or immunochemotherapy. Among patients (pts) with myeloma or other B-cell malignancies the development of 2 nd primary cancers is a well described complication, associated with longer survival, exposure to multiple drugs and long-standing immunosuppression. However, data on the incidence and risk factors for second malignancies are not available for pts with AL amyloidosis. Thus, the aim of our study was to describe the incidence and risk factors for the development of 2nd malignancies among consecutive pts with AL amyloidosis. The analysis included 417 consecutive pts, treated and followed in the Department of Clinical Therapeutics, Athens. The analysis accounted for death due to AL amyloidosis and diagnosis of 2 nd malignancy as competing events (competing risks analysis). The median age of the cohort was 65 years, 56% were females; heart, renal and liver involvement were present in 76%, 65% and 19% respectively. Per Mayo staging, 16%, 44% and 40 were stage -1, -2 and -3. Treatment, across all lines, included alkylators in 75% (mostly cyclophosphamide, melphalan was given in 21%, of which 5% as high dose), lenalidomide in 36% and daratumumab 31% while 95% had received bortezomib. The median follow up of the cohort was 56 months and the estimated median overall survival of all pts was 57 months. A second primary malignancy, after the diagnosis of AL amyloidosis, was diagnosed in 26 (6.2%) pts; these included breast (4 pts), renal (4 pts), colon (3 pts), lung (3 pts), gastric (2 pts), MDS (2 pts) and one case each from AML, ovarian, pancreatic, urothelial, sarcoma, head&amp; neck cancers while two pts had multiple 2 nd cancers. The median age of the affected pts was 66 years and 13 (50%) were males; 29% had Mayo stage-1 disease, 52% had stage -2 and 19% stage 3 disease at initial diagnosis of AL amyloidosis. Accounting for death due to amyloidosis as a competing event, the cumulative incidence of 2nd primary malignancy was 0.7% at 2 years, 2% at 3 years, 4.5% at 4 years, 5.4% at 5 years, 7% at 6 years, 8.7% at 7 years and 10.25% at 10 years (figure 1). We then performed competing event univariate analysis to evaluate the potential association of several clinical, laboratory and treatment characteristics with the probability of developing a 2 nd malignancy. Notably, there was no increased risk of a 2 nd malignancy associated with the use of alkylators (either cyclophosphamide or melphalan), or melphalan (standard or high dose), lenalidomide or daratumumab. Since 95% of ptshad been exposed to bortezomib we could not make a meaningful analysis for this drug. Among baseline clinical characteristics, the presence of purpura or liver involvement (and with a trend for heart involvement) was associated with lower probability of diagnosis of a 2 nd malignancy, in the competing risk analysis. However, when analyzing the cumulative incidence of a 2 nd malignancy in ptswith different stages per Mayo system (1 vs 2 vs 3), the 5-year cumulative probability of death among pts with stage 1 disease per Mayo 2004, was 10.5% and the 5-year cumulative probability of 2 nd malignancy was 8.9% (the respective 5-year probabilities for Mayo stage 2 were 50.2% and 5.4% and for Mayo stage 3 were 69.7% and 3.7%). Thus, 2 nd cancers seem to affect mainly those with Mayo stage 1 discase, which also have the highest probability of long term survival. The 2 nd cancer was the cause of death in 10/26 (38%) of the affected pts. In conclusion, second primary malignancies occur in 6% of pts with AL amyloidosis, affecting mostly pts without or with early cardiac involvement who have also the longest survival probability, with a 5-year cumulative risk of 9%. Second hematologic malignancies are uncommon (0.7%). We did not find a significant correlation with the use of alkylators of other specific agents. This data emphasizes the need for screening for the most common malignancies among pts with AL amyloidosis as new therapies improve the long-term survival.

Incidence and mortality of second primary malignancies after lymphoma: a population-based analysis

Background: Second primary malignancies (SPMs) account for an increasing proportion of human malignancies. We estimated the incidence, risk factors and outcomes in lymphoma survivors with SPMs. Methods: Patients diagnosed with SPMs after primary lymphoma from 2010 to 2021 were included in this study. The incidence, mortality and clinical characteristics of SPMs in our center and Surveillance, Epidemiology, and End Results database were delineated and analyzed. Standardized incidence ratio quantified second cancer risk. Results: A total of 2912 patients of lymphoma were included, 63 cases of SPM met the inclusion criteria, with the prevalence of SPMs after lymphoma was 2.16%. The male-to-female ratio of 2.32:1. The majority of these patients were older (≥60 years old, 61.90%) and previously treated with chemotherapy (68.25%). The common types among SPMs were digestive system tumors (42.86%), respiratory system tumors (20.63%) and urinary system tumors (12.70%). Additionally, cancer risks were significantly elevated after specific lymphoma though calculating the expected incidence. In terms of mortality, the diagnosis of SPMs was significantly associated with an increased risk of death over time. Moreover, although the outcome was favorable in some SPM subtypes (thyroid and breast cancer), other SPMs such as stomach and lung tumors had a dismal prognosis. Conclusion: With the improvement of medical standards, the survival of lymphoma patients has been prolonged. However, the incidence of SPM is increasing, particularly among men and older lymphoma survivors. Therefore, more attention should be invested in the SPM to further improve the prognosis of these patients.

Second primary malignancies in patients with lymphoma in Denmark after high-dose chemotherapy and autologous haematopoietic stem-cell transplantation: a population-based, retrospective cohort study

Second primary malignancies (SPMs) are known complications after chemotherapy, but the risk is not well characterised for patients with lymphoma treated with high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the rate of SPMs in this population relative to matched control individuals from the general population. In this retrospective, population-based cohort study, patients aged 18 years or older with an aggressive lymphoma who received high-dose chemotherapy and autologous HSCT in Denmark between Jan 1, 2001, and Dec 31, 2017, were included from the Danish Lymphoma Registry and matched (1:5) to control individuals from the general population on birth year and sex via the Danish Civil Registration System. Patients were eligible if they had a registered date of autologous HSCT and patients with primary CNS lymphoma were excluded. Exclusion criteria for both patients and matched control individuals were HIV infection, organ transplantation, or other malignancies before inclusion. The key endpoint was the incidence of SPMs assessed in all study participants. The effect of treatment on SPMs was also investigated in patients who were followed up from first lymphoma diagnosis, with high-dose chemotherapy and autologous HSCT as a time-dependent exposure. Of 910 patients with lymphoma assessed, 803 were included (537 [67%] were male and 266 [33%] were female); 4015 matched control individuals were included (2685 [67%] were male and 1330 [33%] were female). Ethnicity data were not available. Median follow-up was 7·76 years (IQR 4·77-11·73). The SPM rate was higher among patients receiving high-dose chemotherapy and autologous HSCT than matched control individuals (adjusted hazard ratio [HR] 2·35, 95% CI 1·93-2·87, p<0·0001). Patients receiving high-dose chemotherapy and autologous HSCT had a higher rate of non-melanoma skin cancer (2·94, 2·10-4·11, p<0·0001) and of myelodysplastic syndrome or acute myeloid leukaemia (AML; 41·13, 15·77-107·30, p<0·0001) than matched control individuals, but there was no significant difference in the rate of solid tumours (1·21, 0·89-1·64, p=0·24). The cumulative risk of SPMs at 10 years was 20% (95% CI 17-23) in patients compared with 14% (13-15) in matched control individuals. High-dose chemotherapy and autologous HSCT was associated with an increased risk of SPMs when analysed as a time-dependent exposure from first lymphoma diagnosis (adjusted HR 1·58, 95% CI 1·14-2·17, p=0·0054). High-dose chemotherapy and autologous HSCT was associated with an increased risk of non-melanoma skin cancer and myelodysplastic syndrome or AML but not with increased risk of solid tumours in patients treated for lymphoma. These findings are relevant for future individualised risk-benefit assessments when choosing between high-dose chemotherapy and autologous HSCT and chimeric antigen receptor T-cell therapy in this setting. Danish Cancer Society.

Maintenance lenalidomide in newly diagnosed transplant eligible and non-eligible myeloma patients; profiling second primary malignancies in 4358 patients treated in the Myeloma XI Trial

Early trials of long-term lenalidomide use reported an increased incidence of second primary malignancy (SPM), including acute myeloid leukaemia and myelodysplastic syndrome. Later, meta-analysis suggested the link to be secondary to lenalidomide in combination with melphalan. Myeloma XI is a large, phase III randomised trial in-which lenalidomide was used at induction and maintenance, in transplant eligible (TE) and non-eligible (TNE) newly diagnosed patients (NCT01554852). Here we present an analysis of SPM incidence and profile the SPM type to determine the impact of autologous stem cell transplantation (ASCT) and lenalidomide exposure in 4358 patients treated on study. Data collection took place from the start of the trial in May 2010, to May 2019, as per the protocol timeline. The Median follow-up following maintenance randomisation was 54.5 and 46.1 months for TE and TNE patients, respectively. In the TE pathway, the overall SPM incidence was 7.7% in lenalidomide maintenance patients compared to 3.2% in those being observed (p=0.006). Although the TNE lenalidomide maintenance patients had the greatest SPM incidence (15.4%), this was not statistically significant when compared to the observed patients (10%, p=0.10).The SPM incidence was higher in patients who received lenalidomide at induction and maintenance (double exposure), when compared to those treated with lenalidomide at one time point (single exposure). Again, this was most marked in TNE patients where the overall SPM incidence was 16.9% in double exposed patients, compared to 11.7% in single exposed patients, and 11.2% in patients who did not receive lenalidomide (p=0.04). This is likely an effect of treatment duration, with the median number of cycles being 27 in the TNE double exposed patients, vs 6 in the single exposure patients.Haematological SPMs were uncommon, diagnosed in 50 patients (incidence 1.1%). The majority of cases were diagnosed in TE patients treated with lenalidomide maintenance (n=25, incidence 2.8%), suggesting a possible link with melphalan. Non-melanoma skin cancer incidence was highest in patients receiving lenalidomide maintenance, particularly in TNE patients, where squamous cell carcinoma and basal cell carcinoma were diagnosed in 5.5% and 2.6% of patients, respectively. The incidence of most solid tumour types was higher in lenalidomide maintenance patients.Mortality due to progressive myeloma was reduced in patients receiving lenalidomide maintenance, noted to be 16.6% compared 22.6% in those observed in TE patients and 32.7% compared to 41.5% in TNE patients. SPM related mortality was low, 1.8% and 6.1% in TE and TNE lenalidomide maintenance patients, respectively, compared to 0.4% and 2.8% in those being observed. This provides reassurance that long-term lenalidomide treatment is safe and associated with improved outcomes in TE and TNE populations, although monitoring for SPM development should be incorporated into clinic review processes. Primary financial support was from Cancer Research UK [C1298/A10410].

Changing trends in the risk factors for second primary malignancies after autologous stem cell transplantation for multiple myeloma before and after the introduction of proteasome inhibitors and immunomodulatory drugs.

The incidence of second primary malignancies (SPM) in long-term survivors of multiple myeloma (MM) is increasing because of increased life expectancy. We retrospectively analyzed the risk factors for SPM in patients with MM after autologous stem cell transplantation (ASCT) before and after the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs). In total, 2,340 patients newly diagnosed with MM who underwent ASCT between 1995 and 2016 were enrolled in this study. Forty-three patients developed SPM (29 solid, 12 hematological, and 2 unknown tumors), with cumulative incidence rates of 0.8% and 2.5% at 24 and 60 months, respectively. The cumulative incidence rates of hematological and solid SPM at 60 months were 0.8% and 1.8%, respectively. The overall survival (OS) rate at 60 months after ASCT was 62.9% and the OS rates after the diagnosis of SPM at 24 months were 72.2% for hematological SPM and 70.9% for solid SPM. Multivariate analysis revealed that the use of IMiDs (P=0.024) and radiation (P=0.002) were significant independent risk factors for SPM. The probabilities of developing SPM and death due to other causes (mainly MM) at 60 months were 2.5% and 36.5%, respectively, indicating that the risk of SPM was lower than that of death from MM. Furthermore, SPM between the pre-novel and novel agent eras (ASCT between 2007 and 2016) groups significantly increased (1.9% vs. 4.3% at 60 months; P=0.022). The early occurrence of SPM after ASCT should be monitored cautiously.

Incidence of second primary malignancies (SPMs) in patients with multiple myeloma (MM) receiving anti-CD38 monoclonal antibodies (mAbs): A systematic review and meta-analysis.

e24078 Background: The addition of anti-CD38 mAbs, daratumumab and isatuximab, to standard anti-myeloma regimens have drawn scrutiny towards long-term safety concerns, including the risk of SPMs. ICARIA-MM study reported SPMs in 3.9% patients (pts.) in the Isatuximab, pomalidomide and dexamethasone (Isa-Pd) arm compared to 0.7% in the Pd arm. We hypothesized that exposure to anti-CD38 mAbs could potentially increase risk of SPMs due to prolonged immunosuppression. An assessment of this association is warranted, given the improved life expectancy and growing prevalence of pts. with MM. Methods: We performed a meta-analysis on data obtained from RCTs published between January 2005 and April 2022 that compared anti-CD38 mAb-based regimens to other standard anti-myeloma regimens (control) in pts. with newly diagnosed or relapsed/refractory (r/r) MM. Total number of SPMs (including categories) were extracted for pts. in both groups. Malignant melanomas were included under solid SPM category. Binary outcome data were analyzed using fixed-effect Peto method. Treatment effect estimates were expressed as odds ratio (OR) and 95% confidence interval (CI). I2 &gt; 50% indicated substantial heterogeneity. Results: 10 RCTs involving 4980 pts. were included, with 2824 (57%) and 2156 (43%) pts. randomized to the anti-CD38 mAb and control arms, respectively (Table). Overall, 191 and 112 SPMs were reported in the anti-CD38 mAb and control arms, respectively. At a median follow-up of 35.3 months, anti-CD38 mAb exposure was associated with an increased risk of developing SPMs compared to control (6.8% vs. 5.2%; OR: 1.53 [95% CI: 1.20-1.95]; I2= 0%). Non-melanoma cutaneous cancers were the most common, and higher in the anti-CD38 mAb vs. control arms (92 versus 47; OR: 1.77 [95% CI: 1.25-2.51]; I2= 0%). The increase in solid cancers (including melanoma) (OR: 1.28 [95% CI: 0.85-1.95]) and hematologic SPMs (OR: 1.86; [95% CI: 0.81-4.27] was not significant. On sensitivity analysis, the total number of SPMs were higher in the anti-CD38 mAb arm vs. control arm, regardless of the presence of immunomodulatory drugs in combination regimen. Conclusions: This meta-analysis shows an increased risk of SPMs in pts. with MM exposed to daratumumab or isatuximab, particularly that of non-invasive cutaneous tumors. This association should be further investigated in real-world settings using large databases. [Table: see text]

Incidence of second primary malignancies in patients with multiple myeloma receiving anti-CD38 monoclonal antibodies: A systematic review and meta-analysis

Anti-CD38 monoclonal antibodies (mAbs) are commonly used for treating newly diagnosed and relapsed/refractory (r/r) multiple myeloma (MM). However, concerns have been raised about the occurrence of second primary malignancies (SPMs) in patients receiving anti-CD38 mAbs. Assessing the safety data for rare adverse events like SPMs is challenging because individual clinical trials are typically focused on the primary endpoint. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) published between January 2005 and April 2022, including patients with newly diagnosed or r/r MM. Our aim was to compare SPM rate with the use of anti-CD38 mAb-based regimens with other anti-myeloma regimens. After a median follow-up of 35.3 months (range: 8.2–56.2), we found that exposure to anti-CD38 mAbs was associated with an increased risk of developing SPMs compared to the control group (6.8% vs. 5.2%; Peto odds ratio [OR]: 1.53 [95% confidence interval (CI): 1.20–1.95]; I2= 0%, p-value for heterogeneity= 0.44). This increased risk was primarily driven by non-melanoma cutaneous cancers (92 vs. 47; Peto OR: 1.77 [95% CI: 1.25–2.51]; I2 = 0%, p-value for heterogeneity = 0.54). However, there was no significant difference in the incidence of solid tumors (including malignant melanoma) (OR: 1.28 [95% CI: 0.85–1.95]) or hematologic SPMs (OR: 1.86; [95% CI: 0.81–4.27]). In conclusion, the use of anti-CD38 mAb-based combination regimens is associated with a higher risk of non-invasive cutaneous SPMs, but not solid tumors or hematologic SPMs. The increased occurrence of non-invasive cutaneous SPMs may be due to enhanced monitoring resulting from longer treatment duration with anti-CD38 mAbs.

Correlation between lymphoma and second primary malignant tumor.

Although studies have investigated the risk of second primary malignancies (SPMs) associated with lymphoma of various sites, limited studies have investigated risk of lymphoma with different SPMs and risk factors related to different SPMs. We conducted a retrospective cohort study to evaluate the cumulative incidence and risk factors of different secondary SPMs in patients previously diagnosed as lymphoma, and to compare the survival rates of SPMs and primary malignant tumors. Retrospective analysis was performed on data obtained from Surveillance, Epidemiology, and End Results database. Patients with an initial primary malignancy diagnosis of lymphoma between 2000 and 2019 were included in the study. The statistical analysis was conducted from March 2022 to January 2023. The development of an SPM defined as any type of malignant tumor 292,210 patients remained in final cohort, including 35,220 patients with secondary primary malignant tumor. The cumulative incidence of SPMs during 20 years of follow-up is 1.95% in combined respiratory system, 0.14% in central nervous system, is 0.82% hepatobiliary pancreatic system, is 1.31% in urinary system, is 1.92% digestive tract. Multivariate competitive risk model analysis showed that Different characteristics of lymphoma patients were associated with secondary different types of SPMS. The risk of secondary SPMs in lymphoma patients after radiotherapy and chemotherapy varies with the change of diagnosis time, diagnosis age and incubation period. Propensity score matching and Kaplan-Meier analysis showed that the survival rate of secondary tumor was significantly lower than that of matched primary malignant tumor. This study reminds us to consider the possibility of SPMs in the initial treatment of lymphoma patients, and develop a follow-up plan according to the characteristics of patients to reduce the risk of SPMs. Occurring more than 6 months after the diagnosis of lymphoma. The cumulative incidence of SPMs was estimated by Fine-Gray competing risk regression. Poisson regression was used to evaluate the therapeutic factors associated risk for SPMs in patients undergoing radiotherapy or chemotherapy. The Kaplan-Meier method was used to assess the survival outcomes of patients with SPMs.

Risk of second primary malignancies in survivors of pancreatic neuroendocrine neoplasms from 2000 to 2018.

As a result of improved survival, cancer survivors continue to remain at risk of developing second primary malignancies (SPMs). However, the association between first primary pancreatic neuroendocrine neoplasms (PanNENs) and SPMs has not been thoroughly investigated. Using the Surveillance, Epidemiology, and End Results-18 database, patients histologically diagnosed with PanNENs as their first malignancy between 2000 and 2018 were identified. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) and excess absolute risks per 10000 person-years of SPMs were calculated to estimate the risk of being diagnosed with subsequent cancers compared with the general population. A total of 489 (5.7%) PanNENs survivors developed an SPM during the follow up, with a median latency between first and second cancer diagnoses of 32.0months. The overall SIR of SPMs was 1.30 (95% CI: 1.19, 1.42) and the excess absolute risk was 35.67 cases per 10000 person-years in comparison with the general population. Age 25-64years at PanNENs diagnosis was associated with statistically higher risks for SPMs of all cancers combined. Latency stratification was significant for elevated SPMs risk between 2-23 and 84+months after diagnosis. White patients were found to have a significantly increased incidence of SPMs (SIR: 1.23, 95% CI: 1.11, 1.35), mainly owing to the higher risk of stomach, small intestine, pancreas, kidney and renal pelvis, and thyroid cancers. Pancreatic neuroendocrine neoplasms survivors experience a significant increase in the burden of SPMs compared with the reference population. The heightened relative risk calls for careful long-term scrutiny as part of survivorship care plans.