Impact of Achieving an Early Complete Response in Multiple Myeloma and Predictors of Subsequent Outcome

Background: Achievement of a complete response (CR) to therapy in multiple myeloma (MM) early in disease course correlates with improvement in clinical outcomes, reflective of therapeutically sensitive disease biology. While depth of response is known to impact overall survival (OS) and progression-free survival (PFS), the effect of known prognostic variables at baseline including FISH risk and International Staging System (ISS) score outside of clinical trial settings is not well described. We sought to determine the impact of known prognostic variables in MM including FISH and ISS risk in the context of NDMM patients achieving a CR to therapy and to also examine additional predictors of outcome among this cohort. Methods: A retrospective study was conducted on 1869 NDMM patients who had ≥ 2 consecutive monoclonal protein immunofixation (IFE) studies in the serum and urine available within 24 months from diagnosis. We identified the number of patients who had ≥ 2 negative serum and urine IFE as a surrogate for achieving CR (N=461), since a bone marrow biopsy is not routinely performed to confirm CR in the non-trial setting. A Kaplan-Meier model was used to compare median PFS and OS between patients achieving a CR vs. non-CR and a multivariate analysis was performed to adjust for known prognostic variables. A cox proportional hazards model was used to determine the prognostic impact of baseline FISH (high risk vs. standard risk) and ISS scores (3 vs.1 and 2) on PFS and OS, among patients achieving a CR vs. non-CR, and identify additional prognostically significant variables within the CR cohort. Results: The median length of follow-up for the entire cohort (n=1869) was 64 months (range: 1-199). The median time from diagnosis to achievement of CR among the CR cohort was 9.8 months (0.20-23.8 months). The median PFS for CR (n=461) vs. non-CR (n=1408) patients was 42.0 vs. 29.3 months (p<.0001) and median OS was 124.4 vs. 85.6 months (p<.0001), respectively (Figure 1). The impact of achieving a CR on outcomes was retained after adjusting for FISH, ISS, age, sex, autologous stem cell transplant, and involved heavy chain as follows: PFS HR 0.57 (0.43-0.76; p=0.0001); OS HR 0.56 (0.43-0.74; p<0.0001). The baseline FISH and ISS risk on PFS and OS comparing CR vs. non-CR patients are shown in Table 1, with both variables having statistically insignificant impact on PFS and OS among the CR cohort. We examined several variables present at baseline and at the time of CR to determine their impact on PFS and OS, including age, sex, and non-IgG involved heavy chain (baseline), and thrombocytopenia (<150,000), hypoalbuminemia (<3.5 g/dL), and immunoparesis (at time of CR). The following variables were found as inferior predictors on PFS within the CR cohort with hazard ratios as follows: male gender, HR 1.36 (1.05-1.75; p=0.02) and non-IgG involved heavy chain, HR 2.2 (1.55-3.2).The following variables were found as predictors for inferior outcomes on OS within the CR cohort with hazard ratios as follows: Age> 75 years, HR 2.7 (1.54-4.8; p=.0005); male gender, HR 1.5 (1.1-2.02; p=.008); serum albumin <3.5, HR 1.54 (1.1-2.08; p=.004); and non-IgG involved heavy chain, HR 1.75 (1.23-2.47; p=.002). On multivariate analysis, age, hypoalbuminemia, and non-IgG involved heavy chain retained prognostic significance for OS. Conclusion: Attainment of an early CR in NDMM confers improvement in PFS and OS. Our study confirms these findings and suggests that achievement of CR neutralizes the impact of baseline FISH and ISS risk on PFS and OS. Among the CR cohort, age> 75 years, male sex, non-IgG involved heavy chain, and hypoalbuminemia at the time of CR predict for inferior overall survival. Figure 1 Figure 1. Disclosures Dingli: Sanofi: Consultancy; Alexion: Consultancy; Novartis: Research Funding; GSK: Consultancy; Apellis: Consultancy; Janssen: Consultancy. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy. Dispenzieri: Alnylam: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Sorrento Therapeutics: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy, Research Funding. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Lin: Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Juno: Consultancy; Merck: Research Funding; Sorrento: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Novartis: Consultancy; Takeda: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Legend: Consultancy. Kumar: Merck: Research Funding; Antengene: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding.

Preoperative Tumor Abnormal Protein as a Promising Biomarker to Predict Oncological Outcome of Hepatocellular Carcinoma After Curative Resection

Background: TAP (tumor abnormal protein) has been used as an important indicator in the early diagnosis of cancers, and some literatures showed that TAP can act as a prognostic factor in different kinds of cancer. The objective of this study was to explore the potential relationship between TAP and the prognosis of HCC after radical hepatectomy, and attempted to construct a robustly predictive nomogram on the strength of TAP and other prognostic variables of HCC patients.Methods: This retrospective study included 168 HCC patients (tumor recurrence occurred in 78 patients) who had undergone curative resection during January 2018 to June 2020 at the Department of Hepatopancreatobiliary Surgery of Liaoning Cancer Hospital & Institute. Serum TAP was detected by Abnormal Sugar Chain Structure of Glycoproteins, and according to the area of condensation particle, the whole population was categorized into the TAP high group (TAP≥225μm2) and TAP low group (TAP<225μm2).Results: There was no correlation between maximum tumor size and TAP. In the whole population or subgroups stratified by maximum tumor size, the recurrence-free survival (RFS) rate of the TAP low group was distinctly higher than TAP high group (P<0.05 for all). The multivariate analysis revealed that TAP (hazard ratio [HR], 3.47; 95% CI, 2.18-5.51; P<0.001), large tumor size (HR, 2.18; 95% CI, 1.36-3.49; P<0.001), poor tumor differentiation (HR, 0.53; 95% CI, 0.33-0.84; P=0.007) and presence of microvascular invasion (MVI) (HR, 2.03; 95% CI, 1.28-3.22; P=0.003) were independently associated with RFS. The prognostic implication of nomogram incorporating TAP, maximun tumor diameter, tumor differentiation and MVI was stronger than the model that integrated maximun tumor diameter, degree of tumor differentiation and MVI only.Conclusion: The present study suggested that higher preoperative TAP was correlated with undesirable prognosis in HCC patients who had undergone radical hepatectomy,and on the strength of prognostic variables identified by multivariate analysis, we constructed a robust nomogram for RFS of postoperative HCC patients.

Salvage surgery for patients with residual/persistent diseases after improper or insufficient treatment of oral squamous cell carcinoma: can we rectify these mistakes?

Background Patterns of failure after treatment of oral and squamous cell carcinomas (OSCC) are diversified, with recurrences being one of the common causes. A special group of patients are sometimes encountered in the outpatient clinic for improper or insufficient initial treatment with reports of positive margins, implying residual/persistent diseases. The question of whether these patients can be surgically salvaged remain unanswered. Methods A retrospective study was performed between January 2013 and December 2017 for patients with residual or rapid recurrent (within 3 months) OSCCs, who received salvage surgeries in our institution. The patients with residual/persistent OSCCs were those with microscopic or macroscopic positive surgical margins, while those with rapid recurrent OSCCs were those with close or negative margins, but unabated painful symptoms right after treatment. Both clinicopathological and prognostic variables were analyzed. The focus was also directed towards lessons for possible initial mistakes, resulting in these residual/persistent diseases. Results Of 103 patients, 68 (66%) were men, with mean age of 56.3 years. The overall survival reached 60.2%. Regarding the primary OSCC status, most of our patients (n = 75, 72.8%) were diagnosed with ycT2–3 stages. Besides, most patients were found with macroscopic residual diseases (52.4%) before our salvage surgery. The sizes of the residual/persistent OSCCs were generally under 4 cm (87.3%) with minimally residual in 21 (20.4%). Among all the variables, primary T stage (p = 0.003), and residual lesion size (p < 0.001) were significantly associated with the prognosis in multivariate analysis. Though the causes for the initial surgical failure were multifactorial, most were stemmed from poor planning and unstandardized execution. Conclusions Cases with residual/persistent OSCCs were mostly due to mistakes which could have been avoided under well-round treatment plans and careful surgical practice. Salvage surgery for cases with smaller residual/persistent OSCCs is still feasible with acceptable outcomes.

Novel Insights for Patients with Multiple Basal Cell Carcinomas and Tumors at High-Risk for Recurrence: Risk Factors, Clinical Morphology, and Dermatoscopy

Introduction: Basal cell carcinoma (BCC) quite frequently presents as multiple tumors in individual patients. Neoplasm’s risk factors for local recurrence have a critical impact on therapeutic management. Objective: To detect risk factors for multiple BCCs (mBCC) in individual patients and to describe clinical and dermatoscopic features of low- and high-risk tumors. Materials & Methods: Our study included 225 patients with 304 surgically excised primary BCCs. All patients’ medical history and demographics were recorded. Clinical and dermatoscopic images of BCCs were evaluated for predefined criteria and statistical analyses were performed. Results: Grade II-III sunburns before adulthood (OR 2.146, p = 0.031) and a personal history of BCC (OR 3.403, p < 0.001) were the major predisposing factors for mBCC. Clinically obvious white color (OR 3.168, p < 0.001) and dermatoscopic detection of white shiny lines (OR 2.085, p = 0.025) represented strongly prognostic variables of high-risk BCC. Similarly, extensive clinico-dermatoscopic ulceration (up to 9.2-fold) and nodular morphology (3.6-fold) raise the possibility for high-risk BCC. On the contrary, dermatoscopic evidence of blue-black coloration had a negative prognostic value for high-risk neoplasms (light OR 0.269, p < 0.001/partial OR 0.198, p = 0.001). Conclusions: Profiling of mBCC patients and a thorough knowledge of high-risk tumors’ clinico-dermatoscopic morphology could provide physicians with important information towards prevention of this neoplasm.

Prognostic Factors for Wilms Tumor Recurrence: A Review of the Literature

In high-income countries, the overall survival of children with Wilms tumors (WT) is ~90%. However, overall, 15% of patients experience tumor recurrence. The adverse prognostic factors currently used for risk stratification (advanced stage, high risk histology, and combined loss of heterozygosity at 1p and 16q in chemotherapy-naïve WTs) are present in only one third of these cases, and the significance of these factors is prone to change with advancing knowledge and improved treatment regimens. Therefore, we present a comprehensive, updated overview of the published prognostic variables for WT recurrence, ranging from patient-, tumor- and treatment-related characteristics to geographic and socioeconomic factors. Improved first-line treatment regimens based on clinicopathological characteristics and advancing knowledge on copy number variations unveil the importance of further investigating the significance of biological markers for WT recurrence in international collaborations.

Construction and validation of prognostic nomogram for metaplastic breast cancer

In this study we aimed to develop nomogram models for predicting the overall survival (OS) and cancer-specific survival (CSS) of patients with metaplastic breast cancer (MBC). Data of patients diagnosed with MBC from 1973 to 2015 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate Cox analyses were performed to identify independent prognostic factors for OS and CSS of MBC patients. The obtained prognostic variables were combined to construct nomogram models for predicting OS and CSS in patients with MBC. Model performance was evaluated using concordance index (C-index) and calibration plots. Data from 1125 patients were collected and divided into a training (750) and a validation (375) cohort. The multivariate Cox model identified age, TNM stage, tumor size, and radiotherapy as independent covariates associated with OS and CSS. The nomogram constructed based on these covariates demonstrated excellent accuracy in estimating 3-, and 5-year OS and CSS, with a C-index of 0.769 (95% CI, 0.731-0.808) for OS and 0.761 (95% CI, 0.713-0.809) for CSS in the training cohort. In the validation cohort, the nomogram-predicted C-index was 0.738 (95%CI, 0.676-0.800) for OS and 0.747 (95%CI, 0.667-0.827) for CSS. All calibration curves exhibited good consistency between predicted and actual survival. The nomogram models established in this study may enhance the accuracy of prognosis prediction and therefore may improve individualized assessment of survival risks and enable constructive therapeutic suggestions.

Validation of a Prototype Global 4D-Var Data Assimilation System for the MPAS-Atmosphere Model

A four-dimensional variational (4D-Var) data assimilation (DA) system is developed for the global nonhydrostatic atmospheric dynamical core of the Model for Prediction Across Scales (MPAS). The nonlinear forward and adjoint models of the MPAS-Atmosphere dynamic core are included in a Python-driven structure to formulate a continuous 4D-Var DA system, shown to effectively minimize the cost function that measures the distances between the nonlinear model simulations and observations. In this study, three idealized experiments with a six-hour assimilation window are conducted to validate and demonstrate the numerical feasibilities of the 4D-Var DA system for both uniform- and variable-resolution meshes. In the first experiment, only a single point observation is assimilated. The resulting solution shows that the analysis increments have highly flow-dependent features. The observations in the second experiment are all model prognostic variables that span the entire global domain, the purpose of which is to check how well the initial conditions six hours prior to the observations can be reversely inferred. The differences between the analysis and the referenced "truth" are significantly smaller than those calculated with the first guess. The third experiment assimilates the mass field only, i.e., potential temperatures in the case of MPAS-Atmosphere, and examines the impacts on the wind field and the mass field under initial conditions. Both the wind vectors and potential temperatures in the analysis agree more with the referenced "truth" than the first guess because the adjustments made to the initial conditions are dynamically consistent in the 4D-Var system.

COVID-19 related outcomes for hospitalized patients (pts) with solid malignancies (SM).

e18626 Background: Pts with malignancies are at risk for developing severe complications of COVID-19 with high mortality rate. We retrospectively analyzed COVID-19 related outcomes for hospitalized pts with SMs. Methods: We collected data on hospitalized pts with SMs and COVID-19 from 3/1/20 to Jan 1/1/21. Diagnosis COVID-19 was confirmed by RT-PCR of nasopharyngeal swabs. We assessed the association between the 30-day mortality and potential prognostic variables such as tumor types, cancer status, timing of treatment, types of anticancer therapy using logistic regression analyses. Results: A total of 246 hospitalized pts with SMs had COVID-19. Median age was 70 years, 87 (35%) were ≥75 years, 151 (61%) were female. The most common SMs were breast (56 [23%]), non-small cell lung (44 [18%]) and colon (31 [13%]). 154 (63%) pts were on active anticancer therapies. Of those 88 (35.5%) received treatment within 2 weeks, 16 (16.5%) within 4-12 weeks, 99 (39.9%) >3 months prior to COVID-19 diagnosis. 101 (65%) pts received cytotoxic chemotherapies, 26 (16.8%) received immune check point inhibitors (ICIs), 17 (11%) received targeted agents such as anti-EGFR therapy and 11 (7.1%) received monoclonal antibodies. Overall 30-day mortality was 42%, however, all pts with melanoma (7/7) died. The 30-day mortalities for pts who received anticancer treatments within 4 weeks, 4-12 weeks and >12 weeks of COVID-19 diagnosis were 47%, 50%, and 37%. For pts who never received treatment, 30-day mortality was 31%. For pts were in remission, stable disease and progressive disease, the 30-day mortalities were 32%, 35% and 62%. The 30-day mortalities for pts who received cytotoxic therapy, monoclonal antibodies, targeted therapies and ICIs, were 38%, 46%, 41% and 69%. Logistic regression analysis showed that pts who were >80 years of age (OR 3.6, 95% CI 1.6-8.1), had progressive disease (OR 3.4, 95% CI 1.8-6.5) or treated with ICIs (OR 3.6, 95% CI 1.5-8.7) were associated with higher 30-day mortality. Conclusions: COVID-19 associated 30-day mortality is high for hospitalized pts with SMs. Early surveillance of clinical deterioration could be helpful for hospitalized SMs pts with risk factors identified here. Further studies are needed to discern the observed association between ICIs use and worse COVID-19 outcome.[Table: see text]