Second Primary Malignancies In Patients Research Articles

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.

IMiD/CELMoD-induced growth suppression of adult T-cell leukemia/lymphoma cells via cereblon through downregulation of target proteins and their downstream effectors.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive T-cell neoplasia associated with human T-cell leukemia virus type 1 (HTLV-1) infection and has an extremely poor prognosis. Lenalidomide (LEN; a second-generation immunomodulatory drug [IMiD]) has been employed as an additional therapeutic option for ATL since 2017, but its mechanism of action has not been fully proven, and recent studies reported emerging concerns about the development of second primary malignancies in patients treated with long-term IMiD therapy. Our purpose in this study was to elucidate the IMiD-mediated anti-ATL mechanisms. Thirteen ATL-related cell lines were divided into LEN-sensitive or LEN-resistant groups. CRBN knockdown (KD) led to a loss of LEN efficacy and IKZF2-KD-induced LEN efficacy in resistant cells. DNA microarray analysis demonstrated distinct transcriptional alteration after LEN treatment between LEN-sensitive and LEN-resistant ATL cell lines. Oral treatment of LEN for ATL cell-transplanted severe combined immunodeficiency (SCID) mice also indicated clear suppressive effects on tumor growth. Finally, a novel cereblon modulator (CELMoD), iberdomide (IBE), exhibited a broader and deeper spectrum of growth suppression to ATL cells with efficient IKZF2 degradation, which was not observed in other IMiD treatments. Based on these findings, our study strongly supports the novel therapeutic advantages of IBE against aggressive and relapsed ATL.

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.

Risk prediction of second primary malignancies in patients after rectal cancer: analysis based on SEER Program

BackgroundThis study will focus on exploring the clinical characteristics of rectal cancer (RC) patients with Second Primary Malignancies (SPMs) and constructing a prognostic nomogram to provide clinical treatment decisions.MethodsWe determined the association between risk factors and overall survival (OS) while establishing a nomogram to forecast the further OS status of these patients via Cox regression analysis. Finally, we evaluated the performance of the prognostic nomogram to predict further OS status.ResultsNine parameters were identified to establish the prognostic nomogram in this study, and, the C-index of the training set and validation set was 0.691 (95%CI, 0.662–0.720) and 0.731 (95%CI, 0.676–0.786), respectively. The calibration curve showed a high agreement between the predicted and actual results, and the receiver operating characteristic (ROC) curves verified the superiority of our model for clinical usefulness. In addition, the nomogram classification could more precisely differentiate risk subgroups and improved the discrimination of SPMs’ prognosis.ConclusionsWe systematically explored the clinical characteristics of SPMs after RC and constructed a satisfactory nomogram.

Beyond remission: secondary primary malignancies in patients with lymphoma after autologous haematopoietic stem-cell transplantation

Beyond remission: secondary primary malignancies in patients with lymphoma after autologous haematopoietic stem-cell transplantation

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.

Incidental discovery of second primary malignancies in patients diagnosed with breast cancer: An institutional case series.

e12552 Background: National guidelines recommend tissue biopsy of suspected recurrent breast cancer, to confirm diagnosis and to characterize disease phenotype, receptor status, and molecular markers. Despite this, clinicians frequently rely on imaging alone to diagnose recurrent breast cancer; indeed, our group recently published data revealing that only half of patients in Washington state diagnosed with metastatic breast cancer between 2008 and 2017 underwent confirmatory biopsies for suspected metastatic disease on imaging. Here we present evidence of how this failure to fully evaluate suspected breast cancer recurrence could potentially lead to misdiagnosis. Methods: We surveyed our breast medical oncology faculty to identify patients treated at Fred Hutchinson Cancer Center (FHCC) from 2018 to 2022 in which a second primary carcinoma (not including non-melanoma skin cancers) was discovered as part of breast cancer workup and treatment. Results: We identified 10 cases of second primary diagnoses. Of these, the majority (7/10) were lung cancer; other diagnoses included neuroendocrine tumors (1), chronic lymphocytic leukemia (1), and thyroid cancer (1). In the case of lung cancers, patients were typically diagnosed during staging or CT evaluation for radiation or reconstruction, in which a pulmonary nodule raised suspicion for malignancy. In five cases, patients were treated with curative intent for both of their early-stage primary malignancies, and remain disease-free on endocrine therapy alone. In two cases, patients with biopsy-proven metastatic breast cancer were found to have new suspicious lung lesions, which on biopsy were found to represent lung adenocarcinoma; these patients were treated surgically for their lung cancer and continued long-term therapy for metastatic breast cancer. Conclusions: While imaging can raise strong suspicion for metastatic recurrence of breast cancer, the assumption that an apparently metastatic lesion 1) indeed represents metastasis and 2) represents metastatic spread of the known primary rather than another malignancy, risks treating both the primary tumor and the newly detected condition inappropriately. Biopsy is critical for confirmation of metastatic disease vs second primary or other etiology. As patients with metastatic breast cancer are surviving longer as our cancer-directed therapies improve, appropriate diagnostic measures for a suspicious non-breast malignancy are recommended for optimal care. Novel imaging modalities such as 18F-fluoroestradiol (FES) PET and others could be explored in discriminating between metastatic lesions and unrelated conditions.

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.

Age-specific characteristics of head and neck second primary malignancies in patients treated for nasopharyngeal carcinoma: a retrospective study

This study was performed to analyse the age-specific characteristics of head and neck second primary malignancies (SPMs) in patients treated for nasopharyngeal carcinoma (NPC). The medical records of 56 NPC patients diagnosed with head and neck SPMs were reviewed retrospectively. Patients < 45 years old at NPC diagnosis were assigned to the younger group and those ≥ 45 years of age were assigned to the older group. The treatment of the index NPC, latency period, pathological TNM stage, survival status, and SPM subsite were analysed. Patients in the older group were found to have a shorter median latency period than those in the younger group: 8.5 years (range 3–20 years) versus 11 years (range 1–30 years) (P = 0.015). The proportion of SPMs in the jaw was significantly higher in the younger group (P = 0.002). Patients in the younger group receiving radiotherapy with chemotherapy had a shorter latency period (P = 0.003) and higher risk of developing SPMs in the jaw (P = 0.036) than those receiving radiotherapy alone. A long-term and age-dependent regular customised follow-up strategy for NPC is necessary for the prevention and early detection of head and neck second primary malignancies.

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 patients with chronic lymphocytic leukemia: a population-based study in the Netherlands, 1989-2019

The longevity of patients with chronic lymphocytic leukemia (CLL) has improved progressively over the past decades, making it essential to understand long-term health outcomes, such as second primary malignancies (SPMs). Therefore, this nationwide, population-based study assessed the risk of SPM development in CLL patients diagnosed during 1989-2019 in the Netherlands compared to the expected number of malignancies in an age-, sex-, and period-matched group from the general Dutch population. In 24,815 CLL patients followed for 162,698.49 person-years, 4369 SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.63 (95% confidence interval [CI] 1.59–1.68). This elevated risk was observed for solid (SIR, 1.67; 95% CI, 1.65–1.75) and hematological SPMs (SIR 1.42; 95% CI, 1.24–1.62). The highest risk for SPMs was noted beyond five years post-diagnosis (SIR, 1.70; 95% CI, 1.62–1.77), for male individuals (SIR, 1.70; 95% CI, 1.64–1.77), and patients aged 18–69 years (SIR, 1.92; 95% CI, 1.79–2.05). The risk of SPMs was higher in CLL patients who received anti-neoplastic therapy (SIR, 2.12; 95% CI, 1.96–2.28), as compared with those who did not (SIR, 1.58; 95% CI, 1.53–1.63). Routine surveillance activities and tailored interventions to counteract the increased morbidity and excess mortality associated with SPMs are essential for improving long-term outcomes in CLL patients.

Association between radiotherapy and risk of second primary malignancies in patients with resectable lung cancer: a population-based study

BackgroundThe most common form of treatment for non-metastatic lung cancer is surgery-based combination therapy, which may also include adjuvant radiotherapy or chemotherapy. Second primary malignancies (SPMs) are uncommon but significant radiation side effects in patients with resectable lung cancer, and SPMs have not been adequately investigated. Our study aims to assess the correlations of radiotherapy with the development of SPMs in patients with resectable lung cancer.MethodsWe screened for any primary malignancy that occurred more than five years after the diagnosis of resectable lung cancer. Based on the large cohort of the Surveillance, Epidemiology and End Results database, radiotherapy-correlated risks were estimated using the Poisson regression analysis and the cumulative incidence of SPMs was calculated using Fine-Gray competing risk regression analysis.ResultsAmong the 62,435 patients with non-metastatic lung cancer undergoing surgery, a total of 11,341 (18.16%) patients have received radiotherapy. Our findings indicated that radiotherapy was substantially related to a high risk of main second solid malignancies (RR = 1.21; 95%CI, 1.08 to 1.35) and a negligible risk of main second hematologic malignancies (RR = 1.08; 95%CI, 0.84 to 1.37). With the greatest number of patients, the risk of acquiring a second primary gastrointestinal cancer was the highest overall (RR = 1.77; 95 percent CI, 1.44 to 2.15). The cumulative incidence and standardized incidence ratios of SPMs revealed similar findings. Furthermore, the young and the elderly may be more vulnerable, and the highest risk of acquiring most SPMs was seen more than ten years after lung cancer diagnosis. Additionally, more attention should be paid to the second primary gastrointestinal cancer in young individuals with resectable lung cancer.ConclusionAfter receiving radiotherapy, an increased risk of developing second primary solid and gastrointestinal cancers was observed for patients with resectable lung cancer. The prevention of SPMs associated with radiotherapy requires further attention.

Risk and outcome of second primary malignancy in patients with classical Hodgkin lymphoma

Hodgkin lymphoma survivors demonstrated increased risk of secondary primary malignancies (SPMs), but comprehensive analysis of the risk and outcome of SPMs in classical Hodgkin lymphoma (cHL) patients has not yet been reported. Patients with cHL from 1975 to 2017 were identified from the Surveillance, Epidemiology and End Results (SEER) database. Standardized incidence ratios were calculated for the risk of solid and hematologic SPMs in cHL patients compared to the general population. The outcome of cHL patients developing SPMs were assessed by performing survival, competing risks regression, and cox proportional regression analyses. In a follow-up of 26,493 cHL survivors for 365,156 person years, 3866 (14.59%) secondary cancers were identified, with an standardized incidence ratio of 2.09 (95% CI: 2.02-2.15). The increased risk was still notable after follow-up of 10 years or more, and the risk is more pronounced for patients with female gender, younger age, advanced stage, chemotherapy, and radiation therapy. The overall survival is worse for cHL patients with SPMs after 11 years of follow-up (P < .0001). The main cause of death for cHL patients with SPMs is not cHL but other causes including SPMs. Multivariate Cox regression analysis confirmed SPMs as an independently adverse prognostic factor for cHL survivors (hazard ratio, 1.13; 95% CI, 1.05-1.21, P = .001). There is a significantly increased risk of developing SPMs for cHL survivors. The overall survival is worse for cHL patients and SPMs is an independent prognostic factor for cHL.

Incidence of Second Primary Malignancies (SPMs) in Patients in the US with Triple-Class-Exposed (TCE) Relapsed or Refractory Multiple Myeloma (RRMM)

Background Therapeutic advances have increased life expectancy for patients with RRMM. As survival has improved, SPMs have become an increasingly important safety consideration for RRMM patients. Prior studies have demonstrated that treatment with alkylators, autologous stem cell transplantation (ASCT), and immunomodulatory drugs (IMiDs), specifically lenalidomide, are associated with increased SPM risk. Patients who are TCE (exposure to ≥1 IMiD, ≥1 proteasome inhibitor [PI], and ≥1 anti-CD38 monoclonal antibody [mAb]) represent an increasingly large subgroup of RRMM patients. The objective of this study was to describe the incidence of SPMs in patients with TCE RRMM. These data may inform development and selection of novel treatments for these patients. Methods Data were from two large US health-insurance claims databases: the Optum Clinformatics® Data Mart and the IQVIA PharMetrics® Plus Health Insurance Claims database. TCE RRMM patients were selected if they had ≥1 confirmed diagnosis of multiple myeloma (MM) on or after December 1, 2015 (date of approval by the US Food and Drug Administration of 1st anti-CD38 mAb for RRMM) and evidence of being TCE. The first line of therapy (LOT) after becoming TCE was identified ("index LOT") and the date of initiation of this LOT was defined as the "index date". Patients who experienced SPMs prior to the index date were excluded. SPMs were identified based on having at least one inpatient or two outpatient diagnoses (of the same cancer type) of invasive malignancies or myelodysplastic syndromes (MDS) other than MM, Waldenstrom macroglobulinemia, plasma cell leukemia, non-melanoma skin cancers, or primary bone malignancies that were preceded by a diagnosis of bone metastases. The incidence of SPM was calculated per 100 person years (PY) of follow-up, considering only the first SPM for each patient. Cumulative incidence of SPM with death as competing risk was calculated for patients in Optum database (data on mortality was unavailable in the PharMetrics database). Results A total of 1,110 TCE RRMM patients were identified in the two databases, of whom 726 had no evidence of SPM prior the index date (Table). These 726 patients had a mean age of 66.6 y; 45% were female, with a mean of 3 prior LOTs and 3.2 years since diagnosis. Over a mean (SD) follow-up of 11.7 (10.4) months, 96 patients (14.8 per 100 PY) experienced a new SPM, including 47 (7.2 per 100 PY) with solid tumor and 51 (7.9 per 100 PY) with a hematologic malignancy. The latter included 22 (3.4 per 100 PY) with acute myeloid leukemia (AML) and 17 (2.6 per 100 PY) with myelodysplastic syndrome. Among patients in the Optum database (N=416), the cumulative incidence of SPM (95%CI) was estimated to be 10.3% (7.4% , 13.7%), 14.9% (10.8% , 19.6%), and 20.1% (13.9% , 27.2%) at 12, 24, and 36 months, respectively (Figure). Conclusions The incidence of SPM in TCE RRMM patients is clinically significant. Many SPMs in these patients are potentially serious malignancies, including AML and MDS. There is a need for effective treatments for TCE RRMM that are not associated with increased risks of SPMs. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Second primary malignancies in patients with haematological cancers treated with lenalidomide: a systematic review and meta-analysis

Lenalidomide has been standard therapy for multiple myeloma and other haematological malignancies for more than a decade. Previous meta-analyses identified an association between lenalidomide and second primary malignancies (SPM) in patients with multiple myeloma. However, newer randomised controlled trials using lenalidomide for other indications have not reported an increased incidence of SPM. The aim of this study was to investigate the risk of developing SPM with lenalidomide use in all disease settings. We did a systematic review of randomised controlled trials that reported SPM in patients treated with lenalidomide. PubMed, Embase, CENTRAL, Europe PubMed Central, and ClinicalTrials.gov were searched from Jan 1, 2004, to March 18, 2022. Randomised controlled trials with at least one lenalidomide group and one non-lenalidomide group were selected, regardless of the disease setting. Studies with a median follow-up of less than 12 months were excluded. Summary data were extracted by two reviewers (KS and KL) independently and verified by a third reviewer (JF). We then conducted a meta-analysis to assess the risk ratio (RR) of SPM with lenalidomide use across various disease subtypes using a random-effects model. We chose random effects for the primary analysis because of anticipated heterogeneity between different diseases, but we used fixed effects for stratified meta-analysis of multiple myeloma studies. Risk of bias was assessed with the PROTECT tool. The study was registered with PROSPERO, CRD42021257508. Our search yielded 9078 studies, and 38 trials that included 14 058 patients were eligible for meta-analysis after screening, 18 of which were in multiple myeloma. The RR across all malignancies was 1·16 (95% CI 0·96-1·39). However, there was heterogeneity across indications (p=0·020). The RR when lenalidomide was used for multiple myeloma was 1·42 (1·09-1·84). There was no increase in SPM in lymphoma or chronic lymphocytic leukaemia (0·90 [0·76-1·08]) and myelodysplastic syndrome (0·96 [0·23-3·97]) trials. In the setting of multiple myeloma, lenalidomide increased both solid and haematological SPM, both in the no-transplantation and post-transplantation settings. From the 38 trials, 21 (55%) had low risk of bias, 12 (32%) had unclear risk of bias, and five (13%) had high risk of bias. Based on the current data, lenalidomide-induced SPM seem to occur exclusively in patients with multiple myeloma. Thus, lenalidomide can be used for other indications without the major concern of a therapy-related neoplasm. In the multiple myeloma setting, lenalidomide is an effective drug, but patients should be monitored both for haematological and solid tumour SPM. This monitoring includes patients that have not received autologous haematopoietic stem-cell transplantation. Further investigations are needed to improve understanding on why lenalidomide only promotes SPM in patients with multiple myeloma. None.

Analysis and prediction of second primary malignancy in patients with breast cancer.

Second primary malignancy (SPM) is common in breast cancer (BC). The present study aimed to profile the characteristics of BC with SPM and to identify patients at high risk of SPM. Clinical and outcome data of BC cases were retrieved from the SEER database. Principal component analysis and a random forest model were utilized to create a model for predicting the occurrence of SPMs. Of the 286,047 BC cases analyzed, 9.32% developed SPMs. Approximately 70% of BCs that developed SPMs were ductal carcinoma and 71% of BCs that developed SPMs were human epidermal growth factor receptor 2 (HER2)-/hormone receptor (HR)+. The overall survival (OS) of the SPM cohort was significantly worse (hazard ratio: 1.49; 95% CI: 1.44-1.53; log-rank P<0.001). After adjusting for metastasis status, SPM was still a poor prognostic factor (hazard ratio: 1.71; 95% CI: 1.70-1.82; log-rank P<0.001). Of note, 50.5% of the SPMs occurred in the breast and the OS of the breast SPM group was significantly better than that of the other single-organ SPM group (hazard ratio: 0.46; 95% CI: 0.45-0.49; log-rank P<0.001) and the multiple-organ SPM group (hazard ratio: 0.44; 95% CI: 0.39-0.50; log-rank P<0.001). A random forest model created from clinical features predicted SPM with a positive predictive value of 32.3% and negative predictive value of 90.7% in the testing set. Thus, SPM occurs in nearly 1/10 of BC survivors and its existence and occurrence site significantly influence OS. SPM may be partly predicted from clinical features. In addition, it was indicated that postmenopausal elderly patients with a HER2-/HR+ molecular subtype should be more watchful and undergo screenings for SPMs.

Risk of second primary malignancy in patients with primary myelofibrosis: a SEER database study

Prior studies report a greater incidence of second primary malignancy (SPM) among patients with myeloproliferative neoplasms, although the true risk in primary myelofibrosis (PMF) has not been elucidated. We utilized the Surveillance, Epidemiology, and End Results database to evaluate the risk of SPM in PMF patients and analyzed the effects of sociodemographic factors on the risk of SPM. Out of 5273 patients, 385 patients (7.30%) developed SPM. SPM occurred at SIR of 1.95 (95% CI 1.76–2.15) and AER of 149.01 per 10,000 population. A significantly higher incidence of melanoma (SIR 1.76, 95% CI 1.01–2.86), lymphoma (SIR 3.38, 95% CI 2.28–4.83), and leukemia (SIR 27.19, 95% CI 23.09-31.81) was observed. The risk was significantly higher in patients ≤60 years, males, chemotherapy recipients, within 5 years of PMF diagnosis, and for PMF diagnosed after 2009.

P1225: SECONDARY PRIMARY MALIGNANCIES (SPM) AFTER HIGH-DOSE CHEMOTHERAPY (HDT) WITH AUTOLOGOUS STEM CELL TRANSPLANT (ASCT) FOR LYMPHOMA: A DANISH NATIONWIDE COHORT STUDY

Background: High-dose chemotherapy (HDT) with autologous stem cell transplant (ASCT) have resulted in more long-term lymphoma survivors. However, HDT-ASCT is potentially associated with an increased risk of secondary primary malignancies (SPM) leading to loss of lifetime for these patients. Aims: To investigate the risk and types of SPM in lymphoma patients treated with HDT-ASCT compared to the risk of malignancies in a matched background population and to explore risk factors for SPM in HDT-ASCT treated lymphoma patients. Methods: In a nationwide matched cohort study, The Danish Lymphoma Register was used to identify all adult patients treated with HDT-ASCT in Denmark between 2001-2017 for diffuse large B-cell lymphoma, Hodgkin lymphoma, peripheral T-cell lymphoma, or mantle cell lymphoma, excluding patients with other prior cancers. Patients were matched in a ratio of 1:5 to cancer-free comparators from the Danish background population. Malignancies were identified in the Danish National Patient Register using ICD-10 codes and compared between the two groups using the Aalen-Johansen estimator, Cox regression, and incidence rate ratios (IRRs). Results: A total of 856 HDT-ASCT treated lymphoma patients and 4,280 matched comparators were followed for a median of 8 years. The cumulative risk of SPM with death as competing risk was higher for patients compared to comparators with risks at 5, 10, and 15 years of 8.9% [95% confidence interval 6.9;11.0], 16.3% [13.3;19.3], and 20.1% [16.1;24.2] for patients compared to 4.8% [4.1;5.5], 10.5% [9.3;11.7], and 16.6% [14.6;18.5] for comparators (Fig. 1a). The crude hazard ratio (HR) of SPM among patients vs comparators was 2.26 [1.83;2.79]. After adjusting for sex, educational level (low/high), chronic obstructive pulmonary disease (COPD), and alcohol-related diseases (neurological, mental, cardiovascular, or chronic use), the HR was 2.50 [2.02;3.10]. Compared to comparators, patients had increased rates of non-melanoma skin cancer (IRR 3.47 [2.18;5.38]) and myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) (IRR 35.32 [15.73; 94.26]) (Table 1). Rates of other malignancies (oral, gastrointestinal, respiratory, breast, female- or male genital, urinary, soft tissue, and melanoma) were similar between the two groups. The 15-year cumulative risk of MDS/AML was 4.6% [2.8;6.3] for patients (Fig. 1c) and the median overall survival following secondary MDS/AML was only 7 months. In comparison, median overall survival was 40 months in a sex- and age matched background population with newly diagnosed MDS/AML (Fig. 1d). Risk factors for SPM in lymphoma patients were older age (HR 1.06 [1.04;1.08] per year) and COPD (HR 3.15 [1.16;8.57]). Prior therapy (number of lines, intensive chemotherapy, radiotherapy), time since diagnosis, Ann Arbor stage, performance status, alcohol-related disease, and education were not associated with SPM. Table 1. - Rates of SPM per 1,000 person-years in lymphoma patients and matched comparators Comparators Patients SPM type Rate Rate IRR IRR 95% CI Overall 11.35 24.77 2.18 1.76; 2.18 Hematological 0.45 7.74 17.05 9.5; 32.16 MDS/AML 0.18 6.41 35.32 15.73; 94.26 MDS 0.12 3.98 32.89 12.27; 113.84 AML 0.06 2.43 40.19 10.79; 259.78 Non-melanoma skin cancer 1.79 6.19 3.47 2.18; 5.38 Image:Summary/Conclusion: Lymphoma patients treated with HDT-ASCT have an increased risk of SPM compared to a matched background population, especially for non-melanoma skin cancer and MDS/AML. Risk factors for SPM in patients were older age and COPD. These findings are important in the light of new potential treatment alternatives, such as CAR-T.

Risk of second primary malignancy in patients with primary myelofibrosis: A SEER database study.

e19079 Background: Primary myelofibrosis (PMF) carries a poorer prognosis compared to other BCR-ABL-negative myeloproliferative diseases (MPD), and there is increased risk of early mortality due to blast transformation, thrombosis, bleeding complications, and progression of disease. Prior studies report greater incidence of second primary malignancy (SPM) among MPD patients, although the true risk in PMF has not been elucidated. We performed a large database study to evaluate the risk of SPM in PMF patients and analyzed the effects of sociodemographic factors on the risk of SPM. Methods: We used the Surveillance, Epidemiology, and End Results (SEER) database to identify all patients with a histologic diagnosis of PMF from 2009 to 2018. SPM was defined as any subsequent malignancy that developed at least 1 year after the diagnosis of PMF. Using multiple primary standardized incidence ratio (SIR) session of the SEER*Stat software (version 8.3.9), we calculated SIR and absolute excess risk (AER) of SPM for the entire cohort of PMF and also stratified based on age, sex, race, marital status, receipt of chemotherapy, follow-up duration, and year of diagnosis. We generated the 95% confidence intervals (CI) and p-values assuming Poisson distribution of the observed incidences of SPM. Results: A total of 5,273 patients with PMF were included in the analysis, of which 342 patients (6.4%) developed SPM. SPM occurred at SIR of 1.97 (95% CI 1.77-2.18, p&lt;0.05) and AER of 151.87 per 10,000 population. A significantly higher incidence of melanoma (SIR 1.96, 95% CI 1.14-3.14, p&lt;0.05), lymphoma (SIR 3.45, 95% CI 2.31-4.96, p&lt;0.05), and leukemia (SIR 26.87, 95% CI 22.69-31.59, p&lt;0.05) was observed. There was no statistically significant difference in SIR based on sex, race, marital status, follow-up duration, and receipt of chemotherapy. The risk was significantly higher in patients ≤60 years vs patients &gt;60 years (SIR 2.34, 95% CI 1.89-2.86 vs SIR 1.86, 95% CI 1.65-2.10, p 0.01) and for PMF diagnosed after 2009 vs ≤2009 (SIR 2.64, 95% CI 2.26-3.07 vs SIR 1.61, 95% CI 1.40-1.85, p&lt;0.001). Conclusions: Patients with PMF are at a high risk of developing SPM, especially leukemia and lymphoma. Data suggests higher incidence of SPM in patients aged ≤60 years and in the decade after 2009. The impact of ruxolitinib, which was approved in 2011, on the incidence of SPM deserves further study. [Table: see text]